Specification
FORM 2
THE PATENT ACT 1970
(39ofl970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION (See section 10 and rule 13)
"A PROCESS FOR THE PREPARATION OF p^ASUGREL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"
Glenmark Generics Limited an Indian Company, registered under the Indian company s ^ct '"57 and having
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing 'A,
B.D. Sawant Marg, Chakala, Andlneri (East), Mumbai - 400 099
The following specification describes the nature of the invent,on:
Prasugrel is a P2Y12 (P2T) antagonist which has been filed for regulatory approval in the U.S. for the secondary prevention of thrombotic cardiovascular complications. Prasugrel hydrochloride is chemically described as 2-acetoxy-5-(.alpha.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydromieno[3,2-c]pyridine
hydrochloride tiiiu la icpicscincu uy siiut-iuiai luiiiiuia {i).
Prasugrel
US Patent No. 5,874,581 describes a process for the preparation of prasugrel using alkyl-sil-ylprotected tetrahydrothienopyridine intermediate, illustrated by below scheme:
OTBDMS +
HN
HN
O .TsOH
TBDMSCI
1
TEA
CI
O
^
TEA *
OTBDMS
TEA/DMAP
AC20
^^
Prasugrel
SUMMARY OF THE INVENTION
In one aspect, the present invention particularly provides a process for preparinj prasugrel of formula la or a pharmaceutical ly acceptable salt thereof
^^
la
comprising:
reacting a compound 2-(triphenylmethyl)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula II
^^
II
with an acetylating agent in the presence of a base and an organic solvent.
In a second aspect, the present invention relates to a process for preparing the
compound of formula II comprising:
with a cyclopropane carbonitrile of formula III
reacting a compound 2-(triphenylmethyl)-5-(a-bromo-2-fluorobenzyl)-4,5, 6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula IV
III in the presence of magnesium or derivative thereof and an organic solvent.
In a third aspect, the present invention relates to-a process for preparing the compound of formula IV comprising: a) reaction of the compound 5,6,7,7a-tetrahydro-4H-thieno-[3,2-c]pyridin-2-one or a salt thereof of formula IX
IX with a compound trityl halide of structural formula VIII
\ /
/~
X VIII
where X = F, CI, Br or I in the presence of a base and an organic.solvent to afford the compound 4,5,6,7-tetrahydrothieno-5-(triphenylmethyl)[3,2-c]pyridine-2(3H)-one of formula VII
Ph ph
VII
b) reaction of the compound of formula VII with a compound l-(bromomethyl)-2-fluorobenzene of formula VI
.Br
VI
in the presence of a base and an organic solvent to afford the compound 2-
(triphenylmethyl)-2-fluorobenzyl)T4.5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of
formula V
VPh
^^
V
c) reaction of the compound of formula V with bromine or its derivative in the presence of organic solvent to afford the compound of formula IV
Vph
ph ph
In a fourth aspect, the present invention provides 4, 5, 6,7-tetrahydrothieno-5-(triphenylmethyl)[3,2-c]pyridine-2(3H)-one a compound of formula VII or a salt thereof.
K™
Ph
VII
In a fifth aspect, the present invention provides 2-(triphenylmethyl)-2fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one a compound of formula V or a salt thereof.
■S
^^
VPh
V
In a sixth aspect, the present invention provides 2-(triphenylmethyl)-5-(a-bromo-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one a compound of formula IV or a salt thereof.
VPh
^^
IV
In a seventh aspect, the present invention provides 2-(triphen_ylmeth_yl)-5-(a-cyclopropylcarbonyl-2-f!uorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)oneof formula II or a salt thereof.
^
II
In an eighth aspect of the present invention provides the novel compounds of formulae II, IV, V and VII and their use as intermediates in the preparation of prasugrel or pharmaceutical acceptable salts thereof.
In a ninth aspect of the present invention provides a pharmaceutical composition comprising prasugrel or its pharmaceutically acceptable salts, obtained by the process of the present invention and at least a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWING
Fig. I: is a schematic representation of the process of the present invention.
DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment of the present invention, provides a process for preparinj prasugrel of formula la or a pharmaceutical^ acceptable salt thereof.
comprising :
reacting a compound 2-(triphenylmethyl)-5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula II
^^
II
with an acetylating agent in the presence of a base and an inert organic solvent.
The base is selected from, but is not limited to organic amines, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine and the like; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide. Of these, the alkali metal carbonates are preferred. The amount of base employed is an equimolar amount to 5 times the equimolar amount of the starting material of formula II. When excess of an organic amine is employed as the base, this may optionally serve as the solvent.
The acetylating agent is selected from, but is not limited to acetyl chloride, acetic anhydride, ethyl acetate, acetic acid and the like and mixtures thereof, preferably acetic anhydride.
The reaction is normally and preferably effected in the presence of a solvent. The solvent is selected from, aprotic polar solvents, such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethyl acetam id e (DMA), acetonitrile and the like; hydrocarbon solvents, such as n-hexane, n-heptane, cyclohexane, toluene and the like and mixtures thereof, preferably acetonitrile.
In general, the reaction temperature is from about-10°C to about 100° C,. preferably from about 0 °C to about 50 °C, although this may vary depending on the nature of the starting material of formula II and on the solvent employed.
The time required for the reaction is a period of from about 30 minutes to about 20 hours,. Preferably from 30 minutes to J 0 hours,
. In another preferred embodiment of the present invention provides a process for preparation of the compound of formula II comprising:
with a cyclopropane carbonitrile of formula 111
III
reacting a compound 2-(triphenylmethyI)-5-(a-bromo-2-fluorobenzyl)-4,5, 6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)one of formula IV
in the presence of magnesium or derivative thereof and an inert organic solvent.
The inert solvent is selected from, but not limited to ether, such as diethyl ether, tetrahydrofuran, preferably tetrahydrofuran.
The reaction temperature is from about 0°C to about 150° C,. preferably from about 25°C to about 100° C.
The time required for the reaction can be a period of from about 30 minutes to about 24 hours,, preferably from about 1 to 10 hours.
The resulting Grignard reagent complex, from the reaction of magnesium with a compound of formula IV, is then reacted with a compound of formula III to afford the compound of formula II.
Typically, the molar amount of compound of formula 111 may be 1 to 2 times the molar amount of the compound of formula IV, preferably 2 molar amounts; the molar amount of base may be 1 to 4 times the molar amount of the compound of formula IV, preferably 2 molar amounts.
In a further preferred embodiment of the present invention, the compound of formula IV is prepared by the process comprising:
a) reacting a compound 5,6,7,7a-tetrahydro-4 H-thieno-[3,2-c]pyridin-2-one or a salt thereof of formula IX
with a compound trityl halide of formula VIM
where X - F, CI, Br or I
in the presence of a base and an organic solvent to afford the compound 4,5,6,7-tetrahydthieno-5-(triphenylmethyl)[3,2-c]pyridine-2(3H)-one of formula VII
VII
b) reacting a compound of formula VII with a compound l-(bromomethyl)-2-fluorobenzene of formula VI
VI
in the presence of a base and an organic solvent to afford the compound 2-(triphenylmethyl)-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)oneof formula V.
The reaction solvent, which can be used in reaction of a compound of formula IX and a compound of formula VIII may include an ether, such as tetrahydrofuran, diethyl ether, dioxane and the like; a chlorinated solvent, such as methylene chloride, ethylene dichloride, chloroform, and the like; an aromatic hydrocarbon solvent, such as toluene, xylene and the like; a nitrile solvent, such as acetonitrile, propionitriie, benzonitrile and the like; an amide
type solvent such as dimethylformamide, dimethylacetami,^ dimethylimidazolidone, or mixtures thereof, preferably acetonitrile.
The base may be inorganic or organic, for example aika]j meta| carbonates such sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; or their aqueous or alcoholic mixtures thereof; organic bases su^h as triethylamine, diisopropyl ethy! amine, pyridine and the like, preferably triethylamine.
The reaction step of a compound of formula IX and a compound of formula VIII can be carried out optionally neat.
The reaction temperature is generally in the range of a^out _20 °c to about the boiling point of the reaction solvent, preferably at temperatures of ab^ut Q°C to about 80°C when the stabilities of the compounds to be used are taken into considera:jon
The _mnlar .ratio of .the. reaction substrates is ^ener^jK, jfop p^pihw^opyndme of formula IX: the base (for example, tertiary amine): the trityl halide of formula VIII may be about 1:0.5: 1 to about 1.0:3:2.
The isolation of the desired compound of formula VII ftom jne reaction mixture can be carried out using a single method or combination of methoc}s known in the art such as crystallization, extraction, washing, column chromatography, ttc
The substituted benzyl halide of formula VI is reacted Vyjm a condensed hydropyridyl compound of formula VII, to give the compound of formula V jnis reaction may be carried out in the presence or absence of an inert solvent (preferably irt me presence of an inert solvent) and in the presence or absence of a base (preferably ir^ tne presence of a base).
In a preferred embodiment of the present invention, tlle compounds of formulae VII and V can optionally be obtained by a one pot reaction.
There is no specific limitation on the nature of the base employed, and any base known in the art for use in similar reactions may equally be iasecj here. The base is selected from, but not limited to organic amines, such as triethy|arnjne, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, picc,|inej iutidine, colliding 1,8-diazabicyclo[5.4.0]undec-7-ene or l,5-diazabicyclo[4.3.0]non.5_ene; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium t-bu^ox|cje- alkali metal carbonates such as sodium carbonate or potassium carbonate; and alkaij metal hydroxides, such as
sodium hydroxide or potassium hydroxide. Of these, the alkali metal carbonates are preferred.
The amount of base employed is from an equimolar amount to 5 times the equimolar amount with respect to the starting material of formula VI, preferably an equimolar amount. Optionally, when an excess of an organic amine is employed as the base, this may additionally serve as the solvent.
The reaction of a compound of formula VI and a compound of formula VII is normally and preferably effected in the presence of a solvent. The solvent is preferably inert to the reaction, but allows some degree of dissolution of the reactants. The solvent is selected from, but not limited to ethers, such as diethyl ether, tetrahydrofuran or dioxane; ketones, such as acetone or methyl ethyl ketone; esters, such as ethyl acetate; alcohols, such as methanol, ethanol, propanol, isopropanol or butanol; nitriles, such as acetonitrile; amides, such as N,N-dimethylformamide, N,N-dimethyl acetamide, N-methyl-2-pyrrolidone or hexamethyl phosphoric triamide; and sulfoxides, such as dimethyl sulfoxide. Of these, the amides or the sulfoxides are preferred.
The temperature of the reaction can be from about 0°C to about 200° C, preferably from about room temperature to aboutl50°C. The time required for the reaction can be a period of from 1 to 24 hours, preferably from 2 to 15 hours.
In a preferred embodiment of the present invention, the reaction of a compound of formula VI and a compound of formula VII can be optionally accelerated in the presence of an ammonium salt, for example, a quaternary ammonium salt, like tetramethylammonium halide,tetraethylammoniumhaiide,tetrabutylammoniumhalide, trialkylmonobenzylammonium halide such as trimethylbenzylammonium chloride and/or an alkali metal halide such as potassium bromide, sodium iodide and the like, preferably a quaternary ammonium salt.
After completion of the reaction, the desired compound of formula V can be obtained from the reaction mixture by conventional means known to one of skilled in the art. Should the target compound be produced immediately in the form of crystals, these can be optionally separated by filtration. Alternatively, a suitable recovery procedure optionally comprises: adding water; neutralizing the mixture, if necessary; extracting the mixture with a water-immiscible organic solvent; drying the extract; and distilling the solvent off. The product thus obtained can be, optionally further purified by conventional means, such as recrystallization
or chromatographic separation techniques, for example preparative thin layer chromatography or column chromatography, notably column chromatography.
In a further preferred embodiment of the present invention provides a process for the preparation of a compound of formula IV,
^^
IV
comprising:
reacting a compound of formula V with bromine or its derivative in the presence of an inert organic solvent
^^
V
The bromine or bromo derivative is selected from, but not limited to bromine, hydrobromic acid (aqueous or cone), ammonium bromide, N-bromosuccinamide, N-bromosuccinamide in benzoyl peroxide and the like; in the presence of an inert solvent, preferably hydrobromic acid (aqueous or cone.)
Suitable inert solvents that can be used include but are not limited to alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutyl alcohol, tertiary butyl alcohol and the like; nitriles such acetonitrile, propionitrile and the like; halogenated hydrocarbons such as methylene chloride, chloroform, chorobenzene and the like; preferably a halogenated hydrocarbon.
The reaction temperature can be from about 0°C to about 100°C, preferably at a temperature from about 25°C to about 50°C.
The time required for the bromination reaction can be a period of from 30 minutes to 20 hours, preferably from 1 to 15 hours.
The oxopyridyl compound of formula IX, a tautomer thereof and salts thereof used as one of the starting materials, can be prepared according to the method described in Japanese Provisional Patent Publication No. 246187/1986, which is incorporated herein by reference.
In a preferred embodiment of the present invention, the process is optionally carried out in situ; or by one pot synthesis.
In a further embodiment of the present invention, the above reaction steps (i.e. the process for preparing a compound of formula IL the process for preparing a compound of formula IV, the process for preparing a compound of formula V. the process for preparing a compound of formula VII can be combined starting from intermediates of compounds of formulae IX and VIII, to obtain a continuous process for preparing a compound of formula I. The process of utilizing the combination of all of the reaction steps comprises preparing prasugrel hydrochloride of formula I.
In another embodiment of the present invention, a compound of formulae la or I is optionally purified by re-crystallization using a solvent or mixture of solvents.
In a further embodiment of the present invention, a compound of formulae la or I is optionally converted into a pharmaceutically acceptable salt
In a preferred embodiment of the present invention, the acid addition salt of a compound of formula la is prepared by addition of a compound of formula la to an acid, preferably hydrochloric acid, hydrogen chloride (gas) in the presence or absence of an inert solvent, preferably in an inert solvent, by dropwise addition or addition of an acid (preferably hydrochloric acid, hydrogen chloride (gas). Optionally, the seed crystals of said salt can be added.
The acid addition salts that may be used are selected from, but not limited to salts with mineral acids, especially hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid; salts with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids, such as
benzenesulfonic acid or p-toluenesulfonic acid; and salts witli organic carboxylic acids, such as acetic acid, propionic acid, butyric acid, fumaric acid, tartaric acid, oxalic acid, malonic acid, maleic acid, malic acid, succinic acid, benzoic acid, maridelic acid, ascorbic acid, lactic acid, gluconic acid or citric acid.
The acid moiety of acid addition salts of 2-acetoxy-5-(.alpha.-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydr othieno[3,2-c]pyridine is, for example, an inorganic acid such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid; or an organic acid such as trifluoroacetic acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, and preferably hydrochloric acid or maleic acid.
The solvent used can be any liquid which has no advise effect on the reaction and it can dissolve the starting material to some extent. The solvents, that can be used include aliphatic hydrocarbons such as hexane, cyclohexane, heptane ; aromatic hydrocarbons such as taluens.
Documents
Application Documents
| # |
Name |
Date |
| 1 |
2609-MUM-2008-CORRESPONDENCE(5-1-2010).pdf |
2018-08-09 |
| 1 |
2609-MUM-2008-FORM 5(16-12-2009).pdf |
2009-12-16 |
| 2 |
2609-MUM-2008-FORM 2(TITLE PAGE)-(16-12-2009).pdf |
2009-12-16 |
| 2 |
2609-mum-2008-correspondence.pdf |
2018-08-09 |
| 4 |
2609-MUM-2008-DRAWING(16-12-2009).pdf |
2009-12-16 |
| 4 |
2609-mum-2008-discription(provisional).pdf |
2018-08-09 |
| 5 |
2609-mum-2008-form 1.pdf |
2018-08-09 |
| 5 |
2609-MUM-2008-DESCRIPTION(COMPLETE)-(16-12-2009).pdf |
2009-12-16 |
| 6 |
2609-mum-2008-form 2(title page).pdf |
2018-08-09 |
| 6 |
2609-MUM-2008-CORRESPONDENCE(16-12-2009).pdf |
2009-12-16 |
| 7 |
2609-MUM-2008-CLAIMS(16-12-2009).pdf |
2009-12-16 |
| 8 |
2609-mum-2008-form 2.pdf |
2018-08-09 |
| 8 |
2609-MUM-2008-ABSTRACT(16-12-2009).pdf |
2009-12-16 |
| 9 |
2609-mum-2008-form 3.pdf |
2018-08-09 |
| 9 |
2609-MUM-2008-FORM 3(5-1-2010).pdf |
2018-08-09 |
| 10 |
2609-mum-2008-form 3.pdf |
2018-08-09 |
| 10 |
2609-MUM-2008-FORM 3(5-1-2010).pdf |
2018-08-09 |
| 11 |
2609-mum-2008-form 2.pdf |
2018-08-09 |
| 11 |
2609-MUM-2008-ABSTRACT(16-12-2009).pdf |
2009-12-16 |
| 12 |
2609-MUM-2008-CLAIMS(16-12-2009).pdf |
2009-12-16 |
| 13 |
2609-mum-2008-form 2(title page).pdf |
2018-08-09 |
| 13 |
2609-MUM-2008-CORRESPONDENCE(16-12-2009).pdf |
2009-12-16 |
| 14 |
2609-mum-2008-form 1.pdf |
2018-08-09 |
| 14 |
2609-MUM-2008-DESCRIPTION(COMPLETE)-(16-12-2009).pdf |
2009-12-16 |
| 15 |
2609-MUM-2008-DRAWING(16-12-2009).pdf |
2009-12-16 |
| 15 |
2609-mum-2008-discription(provisional).pdf |
2018-08-09 |
| 17 |
2609-MUM-2008-FORM 2(TITLE PAGE)-(16-12-2009).pdf |
2009-12-16 |
| 17 |
2609-mum-2008-correspondence.pdf |
2018-08-09 |
| 18 |
2609-MUM-2008-CORRESPONDENCE(5-1-2010).pdf |
2018-08-09 |
| 18 |
2609-MUM-2008-FORM 5(16-12-2009).pdf |
2009-12-16 |