FIELD OF THE INVENTION:
The present invention provides an improved process for the preparation of prasugrel and its
pharmaceutical acceptable salt. Prasugrel chemically known as 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine or 5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2,-c]pyridine-2yl acetate and having the structural formula.
(Formula Removed)
and its pharmaceutically acceptable salts.
The present invention also provides an improved process for the preparation of cyclopropyl 2-fluorobenzyl ketone, 2-Fluoro-α-cyclopropyl carbonylbenzyl bromide, 5,6,7,7a Tetrahydro-4H- theino-[3,2-c]- pyridone-2 p-toluenesulfonate or its hydrochloride salt and 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin -2-one.
BACKGROUND OF THE INVENTION:
Prasugrel has a chemical name 2-acetoxy-5(α-cyclcopropylcarbonyl-2-flurobenzyl)-4,5,6,7-tetrahydrotheino[3,2-c]pyridine, or a 5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxethl]-4,5,6,7-tetrahydrotheino[3,2,-c]pyridine-2-ylacetate, and having the structural formula
(Formula Removed)
Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticloidine and clopidogrel. These agents are believed to reduce the aggregation of platelets by irreversibly binding to P2Y12 receptors. Prasugrel is a novel platelet inhibitor that is expected to be administered as a solid oral dosage form. Prasugrel is undergoing the approval process for acute coronary syndromes planned for percutaneous coronary intervention (PCI)
US 5,288,726 discloses process for the preparation of prasugrel and its pharmaceutically acceptable salts involves the acetylation of 5-(α-cyclopropylcarbonyl-2-fluoro benzyl)-2-oxo-2,4,5,6,7,7a-hexahydrotheieno[3,2-c]pyridine in the presence of a strong base like sodium hydride. However, use of strong base like sodium hydride is not advisable when the reaction is performed at an industrial scale.
WO 2009/062044 process for preparing prasugrel or its pharmaceutically acceptable salts by condensing a compound of formula II with a compound of Formula II or its acid addition salt to obtain of formula IV
(Formula Removed)
The above process involves time consuming processes, such as, for example, column purifications or tedious separations to reduce the impurities level. It involves the use of high solvent quantities.
WO 2009/066326 discloses process for the preparation of prasugrel and its pharmaceutically acceptable salts as shown in the scheme below:
(Scheme Removed)
In the above process, ketone derivative is prepared by using 2-Fluoro benzyl bromide and cyclopropyl cyanide, followed by bromination of ketone in chloroform.
Further, 4,5,6,7,-tetrahydro thieno [3,2,-c]-pyridine hydrochloride directly reacted with trityl chloride in presence of triethylamine in dichloromethane. Product is isolated in cyclohexane.
In addition, this patent involves use of acetic anhydride for acetylation. Acetic anhydride is banned material.
In the present invention, starting materials are different and also involves use of class 3 solvent instead of class 2 solvents. Selection of solvents plays a critical role in the process since they are not completely removed by practical manufacturing techniques.
The above cited document involves use of class 2 solvents. The use of class 2 solvent should be limited in order to protect patients from potential adverse effects. In this view, present invention provides a process wherein class 3 solvents, less toxic solvents is employed.
This appropriate selection of the solvent for the synthesis of drug resulted enhancement in the yield, crystal form, purity and solubility.
For instance, acetonitrile is class 2 solvent, as used in the cited document WO2009/062044 having limit only 410 ppm while acetic acid is class 3 solvent having limit 5000ppm.
Hence, there is a need to develop a process which can be performed at an industrial scale.
The present invention overcomes the problems associated with priori art, and provides a process for the preparation of prasugrel and its pharmaceutically acceptable salts, with better yield and purity.
OBJECT OF THE INVENTION
The primary objective of the invention is to provide simple and cost effective process for the preparation of Prasugrel and its hydrochloride salt.
Another objective of the present invention is to provide process for preparing prasugrel intermediates
Yet another objective of the invention is to provide a process for the preparation of Prasugrel hydrochloride wherein the process excludes the use of chromatographic purification.
SUMMARY OF THE INVENTION
The prime aspect is to develop an improved process for the preparation of prasugrel of formula 14 and it hydrochloride addition salt of formula 15 by developing a process to obtain highly pure advanced prasugrel intermediates and prasugrel free base. Thus method embodied in this invention increases the yields, avoid the chromatographic techniques which is not commercial viable for bulk drug industries and reduces the time cycle for each batch run, reduces cost, efforts and thereby makes the process highly economical and eco-friendly.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved method for the preparation of pharmaceutically acceptable salt of prasugrel from a compound of formula (14). The process comprising the following steps that are explained in scheme 1:
(Scheme Removed)
Scheme-1: depicts a schematic diagram for the preparation of Prasugrel hydrochloride
according to the present invention.
i) Cyanation of 2-fluoro benzylchloride with sodium cyanide.
(Formula Removed)
ii) Hydrolysis of 2-fluoro benzyl cyanide in the presence of sodium hydroxide in a mixture of water.
(Formula Removed)
iii) Coupling of 2-fluoro phenyl acetic acid with Methylcyclopropane carboxylatc in presence of isopropyl magnesium bromide in tetrahydrofuran, toluene or mixture thereof.
(Formula Removed)
iv) Bromination of cyclopropyl 2-fluorobenzyl ketone in presence of N-bromo succinamide/ Hydrobromic acid in Ethyl acetate or Dichloromethane or Chloroform or carbon tetrachloride or mixture thereof.
(Formula Removed)
v) Thiophene 2-ethyl amine react with paraformaldehyde in the presence of hydrochloric acid in DMF to produce 4,5,6,7-Tetrahydro theino [3,2-c]-pyridine Double.
(Formula Removed)
vi) Protection of amino group with trityl chloride in the presence of triethyl amine in dichloromethae.
(Formula Removed)
vii) Oxidation of 5-Triphenyl methyl-tetrahydro-4,5,6,7- theino-[3,2-c]-pyridine by reacting with n-butyl lithium, trimethyl borate and followed by hydrogen peroxide in tetrahydrofuran, toluene or mixture thereof.
(Formula Removed)
viii) Deprotection of amino group by using hydrochloric acid or weak acid like p-toluene sulfonic acid monohydrate.
(Formula Removed)
ix) Coupling of 5,6,7,7a-Tetrahydro-4H-theino-[3,2-c]-pyridone-2 hydrochloride salt with 2-Fluoro-α-cyclopropylcarbonylbenzyl bromide in the presence of triethyl amine in dichloromethane.
(Formula Removed)
x) Deprotection of Alkylsilyl group by using hydrochloric acid or week acid in ethyl acetate, MDC, Toluene or mixture thereof.
(Formula Removed)
xi) Acetylation of 2-(tert-Butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluorobcnzyl)-
4,5,6,7-tetrahydrothieno[3,2-c]-pyridine or 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-
4,5,6,7-tetrahydrothieno[3,2-c]-pyridine with acetyl chloride or acetic anhydride in presence of acetic acid in toluene.
(Formula Removed)
xii) Pharmaceutical acceptable salt preparation by using Hydrochloric acid
(Formula Removed)
Accordingly, the present invention relates to an improved process of preparing prasugrel of formula 14
and its hydrochloride salt comprising of:
a. reacting a 2-Fluoro-α-cyclcopropylcarbonylbenzyl bromide of formula (5) with
(Formula Removed)
b. 2-(tert-Butyldimethylsilyloxy)-5(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-
tetrahydrothieno-[3,2,-c]-pyridine of formula (11),
(Formula Removed)
in the presence of organic base and solvent to provide a compound of formula (12),
(Formula Removed)
c. acetylating the compound of formula (12) with a acetylating agent in the presence
of an organic base and solvent to provide prasugrel compound of formula (14).
One embodiment of the present invention, wherein the process of preparing 2-Fluoro-α-cyclopropylcarbonylbenzyl bromide of formula (5), comprises of:
(Formula Removed)
a. reacting 2-Fluorophenyl acetic acid and methylcyclopropane carbxoylate or ethylcyclopropane carboxylate in the presence of isopropyl magnesium bromide and solvent to obtain a cyclopropyl 2-fluorobenzyl ketone compound of formula (4),
(Formula Removed)
b. bromination of compound of formula (4) in the presence of N-bromo succinamide and benzoyl peroxide in a organic solvent to obtain 2-Fluoro-α-cyclopropylcarbonylbenzyl bromide of formula (5).
In one another embodiment of the present invention, wherein the process of preparing 2-(tert-Butyldimethylsilyloxy)-5(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno-[3,2,-c]-pyridine of formula (11) comprises of:
a. protecting amino functional group of 4,5,6,7-tetrahydrotheno [3,2,-c]-pyridine
or its salt of formula (7),
(Formula Removed)
with a tritylchloride in the presence of base and solvent followed by crystallization to provide a compound of formula (8),
(Formula Removed)
b. oxidizing formula (8) into 2-oxo compound of formula (9) by reacting it with
n-butyl lithium, trimethyl borate and then treating with hydrogen peroxide
borate in a solvent followed by crystallization
(Formula Removed)
c. deprotecting amino group in formula (9) by treating it with hydrochloride or
weak acid in the presence of a solvent to provide formula (10)
(Formula Removed)
d. reacting compound of formula (10) with Tert-butyldimethylsilylchloride
(TBDMSC1) in the presence of base to obtain compound of formula (11)
Yet another embodiment of the present invention, wherein the process the acetylating agent is selected from acetyl chloride and solvent is acetic acid, toluene or mixture thereof.
A further embodiment of the present invention wherein organic base is selected from trimethyl amine, triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine, ammonia, ammonium bicarbonate and preferable base is triethyl amine.
Yet another embodiment of the present invention is wherein solvent is selected from a group comprising of benzene, toluene or xylene, dichloromethane, chloroform, methylene chloride, ethylene chloride, methyl isobutyl ketone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, DMF, DMSO, methanol, ethanol, IPA or t-butanol or mixture thereof.
Still another embodiment of the present invention wherein solvent in 2 step (a) is toluene, tetrahydrofuran or mixture thereof and preferable solvent is mixture of toluene and tetrahydrofuran.
Yet another embodiment of the present invention, wherein solvent in 2 step (b) is ethyl acetate, dichloromethane, chloroform, carbon tetrahydrochloride or mixture thereof and preferable solvent is a mixture of ethyl acetate and dichloromethane and most preferable solvent is ethyl acetate.
Still another embodiment of the present invention wherein base in 3 step (a) is selected from diisopropyl ethyl amine, triethyl amine or ammonia.
Yet another embodiment of the present invention, wherein solvent in claim 3 step (a), solvent is selected from hexane, diisopropyl ether, methanol or mixture thereof and preferable solvent is methanol.
Still another embodiment of the present invention wherein solvent in claim 3 step (b), is toluene, tetrahydrofuran or mixture thereof and preferable solvent for reaction is mixture of toluene and tetrahydrofuran
Yet another embodiment of the present invention, wherein solvent in claim 3 step(b) for crystallization is methanol, hexane, diisopropyl ether or mixture thereof and preferable solvent is methanol.
Still another embodiment of the present invention wherein solvent in claim 3 step (c), solvent is acetone, tetrahydrofuran, methanol or mixture thereof and preferable solvent is acetone.
Yet another embodiment of the present invention wherein weak acid in claim 3 step (c) is selected from an inorganic acid like hydrochloric acid or organic acid like benzene sulfonic acid, p-toluene sulfonic acid.
Still another embodiment of the present invention wherein base in claim 3 step (d) is selected from diisopropyl ethyl amine, triethyl amine, ammonia or ammonium bicarbonate and preferable base is triethyl amine.
ADVANTAGES OF INVENTION:
i) Chromatographic purification of prasugrel or its intermediates is not required.
ii) Highly economically and eco-friendly process.
iii) Avoid the use of class I solvents like Carbon tetrachloride.
The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and not to be construed as limitations of the present invention, as many variations are possible without departing from the spirit and scope of the invention.
Example 1
Preparation of 2-Fluorobenzyl cyanide
In a 1 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-fluorobenzyl chloride (100 g, 0.69 moles), tetrabutyl ammonium bromide (4.5 g, 0.014 moles) and dichloromethane (280 ml) is added in a clear solution of Sodium cyanide (41 g, 0.84 moles) in water (280 ml) at 25 °C (±5 °C). Stir the reaction mass for 12 to 16 hrs at 25 °C (±5 °C). Separate the organic after reaction completion. Organic layer washed with water and recover the solvent under vacuum to obtain pure 2-Fluorobenzyl cyanide (95 g, GC purity 99%).
Example 2
Preparation of 2-Fluoro phenyl acetic acid
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 20% sodium hydroxide aqueous solution (51 g, 1.275 moles) was added in 2-fluoro benzyl cyanide (100 g, 0.74 moles) at 5 °C (±5 °C). Reflux the reaction mass for 2 to 4 hrs at 95 °C (±5 °C). Cool the reaction mass after reaction completion. Reaction mass washed with toluene (1 ltr) then adjust the pH 2 to 3 with hydrochloric acid and extract the product with dichloromethane (3 x 200 ml) Recover the solvent under vacuum and product was crystallized in hexane. Filter the product and slurry wash with hexane. Dry the material at 35 to 40 C to obtain pure 2-fluoro phenyl acetic acid (95 g, HPLC purity 99%).
Example 3
Preparation of Cyclopropyl 2-fluorobenzyl ketone
Method A
In a 5 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, Isopropyl bromide (303 g, 2.06 moles) is added slowly to a suspension of magnesium (61 g, 2.51 moles) in tetrahydrofuran (1.3 ltr) at 65 °C (±2 °C). Reflux the reaction mass for 1 hr and cool to 15 °C (±2 °C). Slowly add (100g, 0.65 moles) 2-fluoro benzyl acetic acid (solution in 0.6 ltr toluene) in the reaction mass (Grignard prepared as above) at 15 °C (±2 °C). Reflux the reaction mass for 2 to 3 hrs at 65 °C (±2 °C) and cool to 5 °C (±2 °C). Slowly add Methyl cyclopropyl carboxylate (68 g, 0.68 moles) in the reaction mass 5 °C (±2 °C). Reflux the reaction mass for 2 to 3 hrs at 65 °C (±2 °C) and cool to 5 °C (±2 °C). Reaction was quench by adding water and adjusts the pH (6.5 to 7.0) by adding HC1. Organic layer separated and aqueous layer extracted with toluene. Combined organic layer washed with 10% sodium bicarbonate solution then water and dried over sodium sulfate. Recover the solvent under vacuum and product was purified by HVD to obtained pure cyclopropyl 2-fluorobenzyl ketone (85 g, HPLC purity 99%).
Method B
In a 5 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, Isopropyl bromide (303 g, 2.06 moles) is added slowly to a suspension of magnesium (61 g, 2.51 moles) in tetrahydrofuran (1.3 ltr) at 65 °C (±2 °C). Reflux the reaction mass for 1 hr and cool to 15 °C (±2 °C). Slowly add (100g, 0.65 moles) 2-fluoro benzyl acetic acid (solution in 0.6 ltr toluene) in the reaction mass (Grignard prepared as above) at 15 °C (±2 °C). Reflux the reaction mass for 2 to 3 hrs at 65 °C (±2 °C) and cool to 5 °C (±2 °C). Slowly add Ethyl cyclopropyl carboxylate (78 g, 0.68 moles) in the reaction mass 5 °C (±2 °C). Reflux the reaction mass for 2 to 3 hrs at 65 °C (±2 °C) and cool to 5 °C (±2 °C). Reaction was quench by adding water and adjusts the pH (6.5 to 7.0) by adding HC1. Organic layer separated and aqueous layer extracted with toluene. Combined organic layer washed with 10% sodium bicarbonate solution then water and dried over sodium sulfate. Recover the solvent under vacuum and product was purified by HVD to obtained pure cyclopropyl 2-fluorobenzyl ketone (85 g, HPLC purity 99%).
Example 4
Preparation of 2-Fluoro-α-cyclopropyl carbonyl- benzyl bromide
Method A
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, N-Bromo succinamide(125 g, 0.55 moles) and benzoyl peroxide (1.8 g, 0.007 moles) was added to a solution of cyclopropyl 2-fluorobenzyl ketone (100 g, 0.56 moles) in Ethyl acetate at 25 °C (±5 °C). Stir the reaction mass for 30 to 40 hrs at 60 °C (±2 °C). Cool the reaction mass and filter through hyflo. Recover the solvent under vacuum and dissolved into petroleum ether, hexane, heptanes or mixture thereof. Cool to 5 °C (±2 °C) and separate the brown colour lower layer, if any. Recover the solvent under vacuum to obtain pure 2-Fluoro-a-cyclopropylcarbonylbenzyl bromide (140 g, HPLC purity 95%) Method B
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, N-Bromo succinamide(125 g, 0.55 moles) and benzoyl peroxide (1.8 g, 0.007 moles) to a solution of cyclopropyl 2-fluorobenzyl ketone (100 g, 0.56 moles) in a mixture of Dichloromethane (700 ml) and ethyl acetate (300 ml) at 25 °C (±5 °C). Stir the reaction mass for 30 to 40 hrs at 45 °C (±2 °C). Cool the reaction mass and filter through hyflo. Recover the solvent under vacuum and dissolved into petroleum ether, hexane, heptanes or mixture thereof. Cool to 5 °C (±2 °C) and separate the brown colour lower layer, if any. Recover the solvent under
vacuum to obtain pure 2-Fluoro-a-cyclopropylcarbonylbenzyl bromide (130 g, HPLC purity 95%)
Method C
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, N-Bromo succinamide(125 g, 0.55 moles) and benzoyl peroxide (1.8 g, 0.007 moles) to a solution of cyclopropyl 2-fluorobenzyl ketone (100 g, 0.56 moles) in carbon tetrachloride at 25 °C (±5 °C). Reflux the reaction mass for 30 to 40 hrs at 70 °C (±2 °C). Cool the reaction mass and filter through hyflo. Recover the solvent under vacuum and dissolved into petroleum ether, hexane, heptanes or mixture thereof. Cool to 5 °C (±2 °C) and separate the brown colour lower layer, if any. Recover the solvent under vacuum to obtain pure 2-Fluoro-α-cyclopropylcarbonylbenzyl bromide (140 g, HPLC purity 95%)
Example 5
Preparation of 4,5,6,7-Tetrahydro theino-[3,2-c]-pyridine hydrochloride
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-thienyl ethylamine (100g, 0.79 moles) was added in dichloromethane (600 ml) at 25 °C (±5 °C) and stir for 5 to 10 minutes. Add paraformaldehyde (26.4 g, 0.88 moles) to the reaction mass and reflux azeotropiccally for 4 to 6 hrs at 40 to 45 °C. Cool the reaction to room temperature and add 7% hydrochloric acid in N,N-dimethyl formamide (200 ml) to the reaction mass at 25 °C (±5 °C). Stir the reaction mass for 4 to 6 hrs at 70 °C (±5 °C). Cool the reaction to 15 °C (+2 °C) and stir for 8 to 10 hrs for crystallisation. Filter the product and wash with chilled dichloromethane. Dry the material under vacuum at 30 to 40 °C to obtain 4,5,6,7-Tetrahydro theino-[3,2-c]-pyridine hydrochloride (120 g, 99%).
Example 6
Preparation of 5-Triphenyl methyl-tetrahydro-4,5,6,7-thieno-[3,2-c]-pyridine
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, trityl chloride (159 g, 0.57 moles) was added to a solution of 4,5,6,7-Tetrahydro thieno [3,2-c]-pyridine hydrochloride (lOOg, 0.57 moles) and triethyl amine (118 g, 1.17 moles) in dichloromethane (1 ltr) at 12 °C (±2 °C). Stir the reaction mass for 2 to 3 hrs at at 28 °C (±2 °C) and quench the reaction mass by adding water. Product extracted in dichloromethane, organic layer washed with 10% sodium chloride solution and dried over sodium sulfate. Recover the solvent under vacuum and product was crystallized in Methanol. Filter the product and slurry wash with methanol. Dry the material under vacuum at 30 to 40 °C to obtain 5-Triphenyl methyl-tetrahydro-5, 6, 7,7a 4H- thieno-[3,2-c]-pyridone-2 (180 g, 99%).
Example 7
Preparation of 5-Triphenyl methyl-tetrahydro-5, 6, 7,7a 4H- thieno-[3,2-c]-pyridone-2 Method A
In a 5 ltr 4-neckcd flask equipped with a thermometer and mechanical stirrer, (246 ml, 0.39 moles) n-butyl lithium (1.6 mole solution in hexane) was added to a solution of 5-Triphenyl methyl-tetrahydro-4,5,6,7- thieno-[3,2-c]-pyridine (100 g, 0.26 moles) was added at -5 4 5 °C in a mixture of tetrahydrofuran and toluene (700 ml; 2:5). Stir the reaction mass for 1 to 2 hrs at 10 ±2 °C. Cool the mass to -5 ±5 °C. Slowly add a solution trimethyl borate (60 g, 0.58 moles) in toluene (100 ml) to the reaction mass and stir for 1 to 2 hrs at 10 ±2 °C. Reaction mass was quenched by adding hydrogen peroxide and water. Product extract with toluene (2 x 200 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in diisopropyl ether, methanol or mixture thereof. Filter the product and slurry wash with diisopropyl ether, methanol or mixture thereof. Dry the material under vacuum at 30 to 40 °C to obtain 5-Triphenyl methyl-tetrahydro-5, 6, 7,7a 4H- thieno-[3,2-c]-pyridone-2 (80 g, 99%). Method B
In a 5 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, (246 ml, 0.39 moles) n-butyl lithium (1.6 mole solution in hexane) was added to a solution of 5-Triphenyl methyl-tetrahydro-4,5,6,7- thieno-[3,2-c]-pyridine (100 g, 0.26 moles) was added at -5 1 5 "C in tetrahydrofuran, toluene or mixture thereof (700 ml). Stir the reaction mass for 1 to 2 hrs at 10 ±2 °C. Cool the mass to -5±5 °C. Slowly add a solution of tri n-butyl borate (156 ml, 0.58 moles) in toluene (100 ml)to the reaction mass and stir for 1 to 2 hrs at 10 ±2 °C. Reaction mass was quenched by adding hydrogen peroxide and water. Product extract with toluene (2 x 200 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in diisopropyl ether, methanol or mixture thereof. Filter the product and slurry wash with diisopropyl ether, methanol or mixture thereof. Dry the material under vacuum at 30 to 40 oC to obtain 5-Triphenyl methyl-tctrahydro-5, 6, 7,7a 4H- thieno-[3,2-c]-pyridone-2 (75 g, 99%).
Example 8
Preparation of 5, 6, 7,7a -Tetrahydro-4H- theino-[3,2-c]- pyridone-2 p-toluene sulfonate
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, p-toluene sulfonic acid monohydrate (48 g, 0.25 moles) was added in solution of 5-Triphcnyl mcthyl-tetrahydro-5, 6, 7,7a 411- theino-[3,2-c]- pyridone-2 (100 g, 0.25 moles) in tetrahydrofuran
(1000 ml) at 25 ±5 °C. Stir the reaction mass for 8 to 10 hrs at 25 ±5 °C. Filter the product and wash with tetarhydrofuran. Dry the material under vacuum at 70 to 80 °C to obtain 5, 6, 7,7a -Tetrahydro-4H- theino-[3,2-c]- pyridone-2 p-toluene sulfonate (75 g, 99.4%).
Example 9
Preparation of 5, 6, 7,7a -Tetrahydro-4H- theino-[3,2-c]- pyridone-2 hydrochloride
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, hydrochloride (0.32 ml) was added in solution of 5-Triphenyl methyl-tetrahydro-5, 6, 7,7a 4H- theino-[3,2-c]- pyridone-2 (100 g, 0.25 moles) in acetone (500 ml) at 25 ±5 °C. Stir the reaction mass for 1 hr at 50 ±2 °C then cool the reaction mass to 25 ±5 °C and stir for 8 to 10 hrs at 25 ±5 °C. Filter the product and wash with acetone. Dry the material under vacuum at 60 ±2 °C to obtain 5, 6, 7,7a -Tctrahydro-4H- theino-[3,2-c]- pyridone-2 hydrochloride (42 g, 99%). Optional purification:
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 5, 6, 7,7a -Tetrahydro-4H- theino-[3,2-c]- pyridone-2 hydrochloride (100 g) was charged in methanol, acetone, tetrahydrofuran or mixture thereof (300 ml) at 25 ±5 °C and reflux the suspension for 30 minutes. Cool the mass to 10 ±5 °C and stir for 1 to 2 hrs. Filter the product and wash with methanol, acetone or mixture thereof (50 ml). Dry the material under vacuum at 60 i-2 °C to obtain pure 5, 6, 7,7a -Tctrahydro-4H- theino-[3,2-c]- pyridone-2 hydrochloride (80 g, 99.7%).
Example 10
Preparation of 2-(tert-Butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno -[3,2-c]-pyridine Method A
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, Tert.-butyldimethylsilylchloride (90 g, 0.60 moles) was added slowly in a mixture of 5,6,7,7a-Tetrahydro-4H-thieno-[3,2-c]- pyridone-2 hydrochloride (100 g, 0.52 moles) and triethyl amine (56 g 0.55 moles) in dichloromethane (300 ml) at 0 ±5 °C under nitrogen atmosphere. Stir the reaction mass for 4 to 6 hrs at 20 ±5 °C. Slowly add 2-Fluoro-α-cyclopropyl carbonylbenzyl bromide (148 g, 0.58 moles) and triethyl amine (101 g, 1.0 moles) and stir the reaction mass for 20 to 24 hrs. Reaction mass quench into water and product extract with dichloromethane. Organic layer wash with 10% sodium chloride solution then water. Organic layer dried over sodium sulafate and recover the solvent under vacuum. Product crystallized in methanol. Filter the product and slurry washed methanol, and Dry the material under
vacuum at 40-45 °C to obtain 2-(tert-Butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine (140 g, 99.5%). Method B
In a 2 ltr 4-ncckcd flask equipped with a thermometer and mechanical stirrer, Tert.-butyldimethylsilylchloride (69.2 g, 0.46 moles) was added slowly in a mixture of 5,6,7,7a-Tetrahydro-4H-thieno-[3,2-c]- pyridone-2 p-toluenesulfonate (100 g, 0.31 moles) and triethyl amine (33.84 g 0.33 moles) in dichloromethane (300 ml) at 0 ±5 oC under nitrogen atmosphere. Stir the reaction mass for 4 to 6 hrs at 20 ±5 °C. Slowly add 2-Fluoro-α-cyclopropyl carbonyl- benzyl bromide (80 g, 0.31 moles) and triethyl amine (140 g, 0.59 moles) and stir the reaction mass for 20 to 24 hrs. Reaction mass quench into water and product extract with dichloromethane. Organic layer wash with 10% sodium chloride solution then water. Organic layer dried over sodium sulfate and recover the solvent under vacuum. Product crystallized in methanol. Filter the product and slurry washed methanol, and Dry the material under vacuum at 40-45 °C to obtain 2-(tert-Butyldimethylsilyloxy)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tctrahydrothieno[3,2-c]-pyridine (100 g, 99.5%).
Example 11
Preparation of 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-
pyridin -2-one
Method A
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-(tert-
Butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno
-[3,2-c]-pyridine (100 g, 0.22 moles) was suspended in ethyl acetate (500 ml) at 20+5 OC and
stir for 10 to 20 min. Slowly add hydrochloric acid (100 ml) and stir for 30 to 45 minutes at
20 ±5 oC. Reaction mass quenched into 20% sodium bicarbonate solution after the reaction
completion. Organic layer washed with water, dried over sodium sulfate and recover the
solvent under vacuum. Product crystallized in petroleum ether or hexane. Filter the product
and slurry washed with petroleum ether or hexane. Dry the product at 40 to 50°C to obtain 5-
(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin -2-one (70 g,
99.5%).
Method B
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-Fluoro-α-
cyclopropyl carbonyl- benzyl bromide (148 g, 0.58 moles) was added slowly in a mixture of
5,6,7,7a-Tetrahydro-4H-thieno-[3,2-c]- pyridone-2 hydrochloride (100 g, 0.52 moles) and Ammonium bicarbonate (120 g 1.51 moles) in dichloromethane (500 ml) at 5 ±5 °C. Stir the reaction mass for 12 to 16 hrs at 20 ±5 °C. Reaction mass quench into water and product extract with dichloromethane. Organic layer wash 10% sodium chloride solution then water. Organic layer dried over sodium sulafate and recover the solvent under vacuum. Product crystallized in petroleum ether or hexane. Filter the product and slurry washed with petroleum ether or hexane. Dry the product at 40 to 50 °C to obtain 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin -2-one (40 g, 98%).
Example 12
Preparation of 2-(Acetoxy)-5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine (Prasugrel) Method A
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-(tert-Butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno -[3,2-c]-pyridine (100 g, 0.22 moles) was suspended in a mixture of toluene (400ml) and acetic acid (100 ml) under nitrogen atmosphere at 20 ±5 °C and stir for 10 to 20 min. Slowly add a solution of acetyl chloride (30 g, 0.38 moles) in acetic acid (140 ml) at 20 ±2 °C. Stir the reaction mass for 4 to 6 hrs at 20 ±2 °C. Slowly add acetyl chloride (180 g, 2.29 moles) in reaction mass at at 20 ±2 °C and stir for 12 to 16 hrs at 20 ±2 °C. Quench the reaction mass into 30% sodium bicarbonate solution. Product extract with ethyl acetate (2 x 500 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in methanol, ethyl acetate, hexane or mixture thereof. Filter the product and slurry wash with methanol or ethyl acetate or hexane or mixture thereof. Dry the material at atmospheric pressure at 40-45 °C to obtain prasugrel (80 g, 99%).
Method B
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 5-(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno -[3,2-c]-pyridine (100 g, 0.30 moles) was suspended in a mixture of toluene (400ml) and acetic acid (100 ml) under nitrogen atmosphere at 20 ±5 °C and stir for 10 to 20 min. Slowly add acetyl chloride (180 g, 2.29 moles) in reaction mass at 20 ±2 °C and stir for 12 to 16 hrs at 20 ±2 °C. Quench the reaction mass into 30% sodium bicarbonate solution. Product extract with ethyl acetate (2 x
500 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in methanol, ethyl acetate, hexane or mixture thereof. Filter the product and slurry wash with methanol or ethyl acetate or hexane or mixture thereof. Dry the material at atmospheric pressure at 40-45 °C to obtain prasugrel (70 g, 99%). Method C
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-(tert-Butyldimethylsilyloxy)-5-(α-cyclopropylcarbonyl-2-fluoro-benzyl)-4,5,6,7-tetrahydrothieno -[3,2-c]-pyridine (100 g, 0.22 moles) was suspended in acetic acid (800 ml) under nitrogen atmosphere at 20 ±5 °C and stir for 10 to 20 min. Slowly add acetic anhydride (180 g, 0.33 moles) solution in acetic acid (150 ml) at 20 ±2 °C. Stir the reaction mass for 12 to 16 hrs at 20 ±2 °C and quench the reaction mass into 30% sodium bicarbonate solution. Product extract with ethyl acetate (2 x 500 ml), organic layer washed with sodium chloride solution then water and dried over sodium sulfate. Recover the solvent under vacuum and crystalise the product in methanol, ethyl acetate, hexane or mixture thereof. Filter the product and slurry wash with methanol or ethyl acetate or hexane or mixture thereof. Dry the material at atmospheric pressure at 40-45 °C to obtain prasugrel (65 g, 99%).
Example 13
Preparation of 2-(Acetoxy)-5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-
tetrahydrothieno[3,2-c]-pyridine Hydrochloride (Prasugrel hydrochloride)
Method A
In a 2 ltr 4-necked flask equipped with a thermometer and mechanical stirrer, 2-(Acetoxy)-5-(α-cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine Hydrochloride (100 g, 0.27 moles) was suspended in ethyl acetate (1500 ml) under nitrogen atmosphere at 20 ±5 °C and stir for 10 to 20 min. Add active carbon in the reaction mass and stir for 5 to 10 min. Filter the reaction mass through hyflo supercell and washed with ethyl acetate. Cool the reaction at 5 ±2 °C and slowly add 15% hydrochloric acid solution in Diisopropylether at 5 ±2 °C and heat the reaction at 60 ±2 °C stir for 1 to 2 hrs. Filter the product and slurry washed with ethyl acetate Dry the material under vacuum at 40-45 °C to obtain prasugrel hydrochloride (95 g, 99%).

We Claim:
1. An improved process of preparing prasugrel of formula 14
(Formula Removed)
and its hydrochloride salt comprising of:
a. reacting a 2-Fluoro-α-cyclcopropylcarbonylbenzyl bromide of formula (5)
with
(Formula Removed)
b. 2-(tert-Butyldimethylsilyloxy)-5(α-cyclopropylcarbonyl-2-fluoro-benzyl)-
4,5,6,7-tetrahydrothieno-[3,2,-c]-pyridine of formula (11),
(Formula Removed)
in the presence of organic base and solvent to provide a compound of formula (12),
(Formula Removed)
c. acetylating the compound of formula (12) with a acetylating agent in the
presence of an organic base and solvent to provide prasugrel compound of
formula (14).
2. The process of preparing 2-Fluoro-α-cyclopropylcarbonylberrzyl bromide of formula
(5), as claimed in claim 1 comprises of:
(Formula Removed)
a. reacting 2-Fluorophenyl acetic acid and methylcyclopropane carbxoylate or
ethylcyclopropane carboxylate in the presence of isopropyl magnesium
bromide and solvent to obtain a cyclopropyl 2-fluorobenzyl ketone compound
of formula (4),
(Formula Removed)
b. bromination of compound of formula (4) in the presence of N-bromo
succinamide and benzoyl peroxide in a organic solvent to obtain 2-Fluoro-α-
cyclopropylcarbonylbenzyl bromide of formula (5).
3. The process of preparing 2-(tert-Butyldimethylsilyloxy)-5(α-cyclopropylcarbonyl-2-
fluoro-benzyl)-4,5,6,7-tetrahydrothieno-[3,2,-c]-pyridine of formula (11) as claimed in claim 1 comprises of:
a. protecting amino functional group of 4,5,6,7-tetrahydrotheno [3,2,-c]-pyridine
or its salt of formula (7),
(Formula Removed)
with a tritylchloride in the presence of base and solvent followed by crystallization to provide a compound of formula (8),
(Formula Removed)
b. oxidizing formula (8) into 2-oxo compound of formula (9) by reacting it with
n-butyl lithium, trimethyl borate and then treating with hydrogen peroxide
borate in a solvent followed by crystallization
(Formula Removed)
c. deprotecting amino group in formula (9) by treating it with hydrochloride or
weak acid in the presence of a solvent to provide formula (10)
(Formula Removed)
d. reacting compound of formula (10) with Tert-butyldimethylsilylchloride
(TBDMSC1) in the presence of base to obtain compound of formula (11)
4. The process as claimed in claim 1, wherein the acetylating agent is selected from acetyl chloride and solvent is acetic acid, toluene or mixture thereof.
5. The process as claimed in claim 1, wherein organic base is selected from trimethyl amine, triethyl amine, tributyl amine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and diisopropylethyl amine, ammonia, ammonium bicarbonate and preferable base is triethyl amine.
6. The process as claimed in claim 1, wherein solvent is selected from a group comprising of benzene, toluene or xylene, dichloromethane, chloroform, methylene chloride, ethylene chloride, methyl isobutyl ketone, acetone, ethyl methyl ketone, ethyl acetate, isopropyl acetate, DMF, DMSO, methanol, ethanol, IPA or t-butanol or mixture thereof.
7. The process as claimed in claim 2 step (a), wherein solvent is toluene, tetrahydrofuran or mixture thereof and preferable solvent is mixture of toluene and tetrahydrofuran.
8. The process as claimed in claim 2 step (b), wherein solvent is ethyl acetate, dichloromethane, chloroform, carbon tetrahydrochloride or mixture thereof and
preferable solvent is a mixture of ethyl acetate and dichloromethane and most preferable solvent is ethyl acetate.
9. The process as claimed in claim 3 step (a), wherein base is selected from diisopropyl ethyl amine, triethyl amine or ammonia.
10. The process as claimed in claim 3 step (a), wherein solvent is selected from hexane, diisopropyl ether, methanol or mixture thereof and preferable solvent is methanol.
11. The process as claimed in claim 3 step (b), wherein solvent for reaction is toluene, tetrahydrofuran or mixture thereof and preferable solvent for reaction is mixture of toluene and tetrahydrofuran
12. The process as claimed in claim 3 step(b), wherein solvent used for crystallization is methanol, hexane, diisopropyl ether or mixture thereof and preferable solvent is methanol.
13. The process as claimed in claim 3 step (c), wherein solvent is acetone, tetrahydrofuran methanol or mixture thereof and preferable solvent is acetone.
14. The process as claimed in claim 3 step (c), wherein weak acid is selected from an inorganic acid like hydrochloric acid or organic acid like benzene sulfonic acid, p-toluene sulfonic acid.
15. The process as claimed in claim 3 step (d), wherein base is selected from diisopropyl ethyl amine, triethyl amine, ammonia or ammonium bicarbonate and preferable base is triethyl amine.