WO2002018357A1 - A ONE-POT PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF 4, 5, 6, 7 - TETRAHYDROTHIENO (3,2-c) PYRIDINE DERIVATIVES HAVING ANTITHROMBOTIC ACTIVITY - Google Patents
A ONE-POT PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF 4, 5, 6, 7 - TETRAHYDROTHIENO (3,2-c) PYRIDINE DERIVATIVES HAVING ANTITHROMBOTIC ACTIVITY Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- R represents hydrogen atom or C0 2 R 2 group wherein R 2 is C alkyl and Ri is Cj. 4 alkyl, C ⁇ alkoxy, Cj. 4 acyloxy, hydroxy, nitro or halo.
- the pharmaceutically acceptable acid addition salts of the compounds of the formula I may also be obtained by introduction of a single carbon atom followed by insilu cychsation of N-(substituted benzyl)-2-(2-thienyl)ethyl a ine salt of the formula VA:
- Formula VA wherein R and Ri are each as defined above and X is chloro group. This is done by reaction of the compound of the formula VA with a cyclic dioxy compound such as 1,3-dioxolane, 4- methyl- 1,3-dioxane, 1,3-dioxane or 1,4-dioxane or a cyclic dithio compound such as 4-methyl-l,3- ithiane,
- a cyclic dioxy compound such as 1,3-dioxolane, 4- methyl- 1,3-dioxane, 1,3-dioxane or 1,4-dioxane or a cyclic dithio compound such as 4-methyl-l,3- ithiane,
- 1,3-dJtthiane 1,4-dithiane or 1,3-dithiolane in the presence of an acid catalyst such as hydrochloric acid, optionally in a solvent such as methanol, ethanol or iso-propanol, at 60 - 100°C
- an acid catalyst such as hydrochloric acid
- a solvent such as methanol, ethanol or iso-propanol, at 60 - 100°C
- Reagents such as 1,3-dioxolane or 1,3-dithiane are expensive and their use makes this process uneconomical. Also these reagents e.g.
- 1,3-dioxolane have low flash point and need special care during hmd ⁇ mg. This process is also not commercially viable.
- Formula VB wherein R and Ri are each as defined above is by reaction of the compound of the formula VB with compound such as halogenomethyl ether, halogenomethyl thioether, halogenomethyl ester or a triazine, trioxane or trithian derivative or polyoxymethylene derivative or a polytiiiomethylene derivative under anhydrous conditions using inert solvent such as dimethyl formamide, dimethyl sulfoxide, chlorinated hydrocarbon or ether at 0 - 150°C. If during the above reaction, acid is not generated, an acid such as hydrochloric acid which is anhydrous is required to be added to the reaction medium to produce the pharmaceutically acceptable acid addition salt of compound of the formula I (US Patent No 4174448).
- compound such as halogenomethyl ether, halogenomethyl thioether, halogenomethyl ester or a triazine, trioxane or trithian derivative or polyoxymethylene derivative or a polytiiiomethylene derivative under
- the pharmaceutically acceptable acid addition salt of the compound of the formula I may also be prepared by the reaction of the compound of the formula VB with aqueous formaldehyde to obtain a formol compound of the formula VI:
- Another route as per US Patent No 4127580 for the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I describes reaction of the compound of the formula VA with aqueous formaldehyde in a solvent such as water or ethanol or a mixture of both, in the presence of acid such as hydrochloric acid at ⁇ 90°C.
- the resulting compound ie the compound of the formula I is isolated and treated with dry acid such as dry hydrochloric acid to obtain the compound of the formula I in the form of its pharmaceutically acceptable acid addition salt.
- This route also comprises two steps in the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I and is lengthy and time consuming.
- the reaction medium is aqueous
- the phaimaceutically acceptable acid addition salt of the compound of the formula I does not precipitate out. Instead compound of the formula I is produced on completion of the first reaction step. Therefore, in order to achieve maximum recovery of the pharmaceutically acceptable acid addition salt of the compound of the formula I, following completion of the first reaction step, the reaction mixture has to be subjected to solvent extraction to isolate and obtain maximum yield of the compound of the formula I. Solvent extraction is cumbersome and makes the process time-consuming. Use of dry acid and that too in stoichiometric proportions increases the cost of the process and makes it uneconomical and cumbersome. The yield of the pharmaceutically acceptable acid addition salt of tlie compound of the formula I as obtained by this method is low and reported to be -64%.
- Yet another process for the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I comprises reaction of the compound of the formula VB with paraformaldehyde in the presence of an anhydrous acid such as anhydrous formic acid or anhydrous hydrochloric acid.
- the resulting compound of the formula I is isolated by solvent extraction and treated with anhydrous acid to obtain the pharmaceutically acceptable acid addition salt of the compound of the formula I (US Patent No 5204469).
- This process also involves two steps in the preparation of the acid addition salt of the compound of the formula I and is lengthy and time consuming. Isolation of the compound of the formula I employs solvent extraction which is tedious and time-consuming and lengthens the process.
- the isolated compound of the formula I additionally, is required to be made anhydrous before treatment with anhydrous acid to convert it to its pharmaceutically acceptable acid addition salt. Maintenance of anhydrous conditions is cumbersome and use of anhydrous acid and that too in high stoic ometric proportions further renders the process expensive and uneconomical.
- An object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, ⁇ , 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which is short, less time consuming and simple.
- Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which does not demand anhydrous conditions.
- Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which is economical.
- Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which results in liighly pure products in high yields.
- Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which eliminates use of hazardous reagents and is safe.
- Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which is commercially feasible. Disclosure of the invention
- Formula I having antithrombotic activity, wherein R is hydrogen atom or C0 2 R 2 group wherein R 2 is C alkyl and Ri is Ci. 4 alkyl, C alkoxy, Ci. 4 acyloxy, hydroxy, nitro or halo, or racemic or enantiomeric isomer thereof, the process comprising reacting N-(substituted benzyl)-2-(2- thienyl)ethylamine salt of the formula VA
- Formula V A wherein R and Rj are each as defined above and X is chlor r hydrogen sulfate group, or racemic or enantiomeric isomer thereof; with paraformaldehyde in C ⁇ . 6 alkanol in the presence of a mineral acid catalyst at 70 - 110 °C.
- the compounds of the formula VA or its racemic or enantiomeric isomer may be prepared in known manner (US Patents Nos 4127580 and 5204469).
- R and Ri are hydrogen atom and 2-chloro group respectively, or R and R t are CO 2 CH3 group and 2-chloro group respectively and preferably X is chloro group.
- R does not represent hydrogen atom in the compound of the formula I or VA the compound of the formula I or VA may be racemic or enantiomeric. If the compound of the formula I or VA s enantiomeric, it is preferably (+) isomer and R and Rj are C0 2 CH 3 group and 2-chloro group respectively.
- the C ⁇ personally6 alkanol may be Cj. 6 alkyl alcohol such as methanol, ethanol, iso-propanol, n-butanol, sec-butanol, iso-butanol, t-butanol, n- pentanol, n-hexanol.
- iso-propanol, t-butanol or n-butanol is used.
- the mineral acid may be hydrochloric acid, sTilfuric acid, hydrobromic acid or methane sulfonic acid.
- hydrochloric acid is used since it is inexpensive.
- Use of hydrochloric acid may also be conducive for the reaction, especially when X is chloro group in the compound of the formula VA due to the common-ion effect.
- the reaction is carried out at 75 - 80°C.
- the isolation of the product involves filtration of the resulting solid during the reaction.
- the compound of the formula VA is taken up for reaction in a relatively moisture free medium in the presence of paraformaldehyde. Therefore the sparingly water soluble pharmaceutically acceptable acid addition salts of the compounds of the formula I are directly precipitated during the reaction, which can be easily filtered. Cumbersome isolation techniques like solvent extraction are not necessary.
- the process of the invention is a one-pot reaction which is simple and is short and less time consuming.
- the compound of the formula VB its salt ie. the compound of the formula VA is taken up for reaction as per the invention. Therefore the mineral acid required for the reaction is used only in catalytic amounts. The process of the invention is therefore economical and also less tedious since it does not demand anhydrous medium/ reagents acid.
- the process of the invention is further made inexpensive since it does not use expensive reagents and solvents like 1,3-dioxolane or d ⁇ nethyl formamide. Since the reaction medium is relatively moisture free, no impurities are formed and the required pharmaceutical products are obtained in high yield (-80-90%) and high purity (-99%).
- the process of the invention does not use hazardous reagents and is safe. For the above reasons, the process of the invention is also commercially feasible.
- Example 3 Preparation of ticlopidine hvdrochloride - The procedure of Example 1 was followed using n-butanol instead of t-butanol to obtain ticlopidine hydrochloride.
- Example 1 The procedure of Example 1 was followed using iso ⁇ butanol instead of t-butanol to obtain ticlopidine hydrochloride.
- (+)-clopidogrel hydrochloride was cooled to 25 - 30°C and quenched with water (500 ml).
- Sodium bicarbonate 42g, 0.5 mole was added and the mixture was extracted with methylene chloride (IL). The organic layer was separated and evaporated to dryness.
- the residue of (+)-clopidogrel was o dissolved in acetone (IL) and to it was added conc.suliuric acid (45.7 g, 0.45 mole).
- the reaction mixture was relluxed for 2 hours and cooled to 20 - 15°C.
- the white precipitate solid was filtered and dried at 50°C to obtain (+)-clopidogrel hydrogen sulfate.
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Abstract
A one-pot process for the preparation of pharmaceutically acceptable acid addition salts of 4,5,6,7-tetrahydrothieno(3,2-c) pyridine derivatives of formula (I) having antithrombotic activity, wherein R is hydrogen atom or CO2R2 group wherein R2 is C1-4 alkyl and R1 is C1-4 alkyl, C1-4 alkoxy, C1-4 acyloxy, hydroxy, nitro or halo, or racemic or enantiomeric isomer thereof. The process comprises reaction of N-(substituted benzyl)-2-(2-thienyl)ethylamine salt of formula VA wherein R and R1 are each as defined above and X is chloro or hydrogen sulfate group or racemic or enantiomeric isomer thereof, with paraformaldehyde in C1-6 alkanol in the presence of a mineral acid catalyst at 70 - 110 °C.
Description
TITLE OF THE INVENTION
A one-pot process for the preparation of pharmaceutically acceptable acid addition salts of 4, 5, 6, 7 - tetrahydrothieno (3,2-c) pyridine derivatives having antithrombotic activity.
Technical Field
4, 5, 6, 7 - tetrahydrothieno (3,2-c) pyridine derivatives are of the formula I:
Formula 1 wherein R represents hydrogen atom or C02R2 group wherein R2 is C alkyl and Ri is Cj.4 alkyl, C^ alkoxy, Cj.4 acyloxy, hydroxy, nitro or halo.
Of particular interest, in the invention are the pharmaceutically acceptable acid addition salts of the compound of the formula 1 wherein R and Rj represent hydrogen atom and 2-chloro group respectively ie ticlopidine and the (+) enantiomer of the compound of the formula I wherein R and Ri represent C02CH3 group and 2-chloro group respectively ie (+) clopidogrel.
Ticlopidine as hydrochloride and (+) clopidogjrel as hydrogen sulfate are reported to selectively interfere with adenosine phosphate ( ADP) mediated platelet aggregation and cause an irreversible non-competitive inhibition of platelet function.
Background Art
The pharmaceutically acceptable acid addition salts of the compounds of the formula I, or racemic or enantiomeric isomer thereof may be obtained by reaction of the compound of the formula II:
Formula II l o with substituted benzyl chloride of the formula III:
Formula IV is difficult and expensive.
The pharmaceutically acceptable acid addition salts of the compounds of the formula I, may also be obtained by introduction of a single carbon atom followed by insilu cychsation of N-(substituted benzyl)-2-(2-thienyl)ethyl a ine salt of the formula VA:
Formula VA wherein R and Ri are each as defined above and X is chloro group. This is done by reaction of the compound of the formula VA with a cyclic dioxy compound such as 1,3-dioxolane, 4- methyl- 1,3-dioxane, 1,3-dioxane or 1,4-dioxane or a cyclic dithio compound such as 4-methyl-l,3- ithiane,
1,3-dJtthiane., 1,4-dithiane or 1,3-dithiolane in the presence of an acid catalyst such as hydrochloric acid, optionally in a solvent such as methanol, ethanol or iso-propanol, at 60 - 100°C (EP Patent No 829482A2). Reagents such as 1,3-dioxolane or 1,3-dithiane are expensive and their use makes this process uneconomical. Also these reagents e.g.
1,3-dioxolane have low flash point and need special care during hmdϋmg. This process is also not commercially viable.
Another process for the preparation of the pharmaceutically acceptable acid addition salts of the compounds of the formula I by introduction of a single carbon atom and cychsation of N-(substituted benzyl)-2-(2-thienyl)ethyl amine of the formula VB:
Formula VB wherein R and Ri are each as defined above, is by reaction of the compound of the formula VB with compound such as halogenomethyl ether, halogenomethyl thioether, halogenomethyl ester or a triazine, trioxane or trithian derivative or polyoxymethylene derivative or a polytiiiomethylene derivative under anhydrous conditions using inert solvent such as dimethyl formamide, dimethyl sulfoxide, chlorinated hydrocarbon or ether at 0 - 150°C. If during the above reaction, acid is not generated, an acid such as hydrochloric acid which is anhydrous is required to be added to the reaction medium to produce the pharmaceutically acceptable acid addition salt of compound of the formula I (US Patent No 4174448). Experimental example no 12, particularly, of this US patent describes a process under the above conditions, but using paraformaldehyde for introduction of a single carbon atom in the compound of the formula VB in the presence of anhydrous hydrochloric acid in dimethyl foimamide. The acid is required atleast in stoichiometric proportion to assist cychsation and further to obtain pharmaceutically acceptable acid addition salt of the compound of the formula I. Stoichiometric proportions involve large quantities of acid which is uneconomical. Also use of the compound of the formula VB for reaction, requires acid which is anhydrous so as to allow precipitation of the reaction product ie the pharmaceutically acceptable acid addition salt of the
compound of the formula I. Preparation of anhydrous acid in dimethyl formamide is cumbersome and expensive since it requires an additional step. This reaction uses solvents such as dimethyl formamide which are expensive and uneconomise the process. Maintenance of anhydrous reaction conditions as required by this process calls for strict vigilance at the time of carrying out the reaction thereby making the process tedious.
The pharmaceutically acceptable acid addition salt of the compound of the formula I may also be prepared by the reaction of the compound of the formula VB with aqueous formaldehyde to obtain a formol compound of the formula VI:
Formula VI wherein R and Rj are each as defined above. The formol compound of the formula VI is isolated and made moisture-free and is further reacted with dry acid such as dry hydrochloric acid in an aprotic polar solvent such as dimethyl acetamide, N-methyl pyrrohdone, N,N-dimethylacetamide or dimethylsulfoxide (US Patent No 4127580). This route comprises two steps in the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I and is lengthy and time consuming. Moreover, making the intermediate moisture-free and maintaining anhydrous conditions to allow the precipitation of the pharmaceutically acceptable acid addition salts of the compound of the formula I are both cumbersome and expensive and uneconomical. Use of stoichiometric
proportions of anhydrous acid makes the process further expensive and uneconomical. The yield of the pharmaceutically acceptable acid additional salt of the compound of the formula I as obtained by this route is reported to be of the order of 86%.
Another route as per US Patent No 4127580 for the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I describes reaction of the compound of the formula VA with aqueous formaldehyde in a solvent such as water or ethanol or a mixture of both, in the presence of acid such as hydrochloric acid at ~90°C. The resulting compound ie the compound of the formula I is isolated and treated with dry acid such as dry hydrochloric acid to obtain the compound of the formula I in the form of its pharmaceutically acceptable acid addition salt. This route also comprises two steps in the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I and is lengthy and time consuming. Since the reaction medium is aqueous, the phaimaceutically acceptable acid addition salt of the compound of the formula I does not precipitate out. Instead compound of the formula I is produced on completion of the first reaction step. Therefore, in order to achieve maximum recovery of the pharmaceutically acceptable acid addition salt of the compound of the formula I, following completion of the first reaction step, the reaction mixture has to be subjected to solvent extraction to isolate and obtain maximum yield of the compound of the formula I. Solvent extraction is cumbersome and makes the process time-consuming. Use of dry acid and that too in stoichiometric proportions increases the cost of the process and makes it uneconomical and cumbersome. The yield of the
pharmaceutically acceptable acid addition salt of tlie compound of the formula I as obtained by this method is low and reported to be -64%.
Yet another process for the preparation of the pharmaceutically acceptable acid addition salt of the compound of the formula I comprises reaction of the compound of the formula VB with paraformaldehyde in the presence of an anhydrous acid such as anhydrous formic acid or anhydrous hydrochloric acid. The resulting compound of the formula I is isolated by solvent extraction and treated with anhydrous acid to obtain the pharmaceutically acceptable acid addition salt of the compound of the formula I (US Patent No 5204469). This process also involves two steps in the preparation of the acid addition salt of the compound of the formula I and is lengthy and time consuming. Isolation of the compound of the formula I employs solvent extraction which is tedious and time-consuming and lengthens the process. The isolated compound of the formula I, additionally, is required to be made anhydrous before treatment with anhydrous acid to convert it to its pharmaceutically acceptable acid addition salt. Maintenance of anhydrous conditions is cumbersome and use of anhydrous acid and that too in high stoic ometric proportions further renders the process expensive and uneconomical.
OBJECTS AND SUMMARY OF THE INVENTION
An object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, δ, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which is short, less time consuming and simple.
Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which does not demand anhydrous conditions.
Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which is economical.
Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which results in liighly pure products in high yields.
Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which eliminates use of hazardous reagents and is safe.
Another object of this invention is to provide a one-pot process for the preparation of pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetrahydro thieno(3, 2-c) pyridine derivatives having antithrombotic activity, which is commercially feasible.
Disclosure of the invention
According to the invention there is provided a one-pot process for the preparation of pharmaceutically acceptable acid addition salts of 4, 5, 6, 7-tetrahydrothieno(3,2-c) pyridine derivatives of the formula I:
Formula I having antithrombotic activity, wherein R is hydrogen atom or C02R2 group wherein R2 is C alkyl and Ri is Ci. 4 alkyl, C alkoxy, Ci. 4 acyloxy, hydroxy, nitro or halo, or racemic or enantiomeric isomer thereof, the process comprising reacting N-(substituted benzyl)-2-(2- thienyl)ethylamine salt of the formula VA
Formula V A wherein R and Rj are each as defined above and X is chlor r hydrogen sulfate group, or racemic or enantiomeric isomer thereof; with paraformaldehyde in Cι.6 alkanol in the presence of a mineral acid catalyst at 70 - 110 °C.
The compounds of the formula VA or its racemic or enantiomeric isomer may be prepared in known manner (US Patents Nos 4127580 and 5204469).
In the compound of the formula I or V A preferably R and Ri are hydrogen atom and 2-chloro group respectively, or R and Rt are CO2CH3 group and 2-chloro group respectively and preferably X is chloro group.
If R does not represent hydrogen atom in the compound of the formula I or VA the compound of the formula I or VA may be racemic or enantiomeric. If the compound of the formula I or VA s enantiomeric, it is preferably (+) isomer and R and Rj are C02CH3 group and 2-chloro group respectively.
The Cι„6 alkanol may be Cj.6 alkyl alcohol such as methanol, ethanol, iso-propanol, n-butanol, sec-butanol, iso-butanol, t-butanol, n- pentanol, n-hexanol. Preferably iso-propanol, t-butanol or n-butanol, is used.
The mineral acid may be hydrochloric acid, sTilfuric acid, hydrobromic acid or methane sulfonic acid. Preferably hydrochloric acid is used since it is inexpensive. Use of hydrochloric acid may also be conducive for the reaction, especially when X is chloro group in the compound of the formula VA due to the common-ion effect.
Preferably the reaction is carried out at 75 - 80°C.
The isolation of the product involves filtration of the resulting solid during the reaction.
If the compound of the formula VA (R = C02CHs, Rj = 2- chloro group) taken up for reaction is in racemic form, then the resulting phaπnaceutically acceptable acid addition salt of the compound of the formula I may be converted to the free base and resolved to obtain the desired isomer in known manner (US Patent No 4847265). If the compound of the formula VA (R = C02CHs, Rj = 2-chloro group) is in an enantiomeric form, the corresponding enantiomeric pharmaceutically acceptable acid addition salt of the compound of the formula I is obtained and if required this salt may be further converted to the useful acid addition salt by addition of sulfuric acid.
According to the invention the compound of the formula VA is taken up for reaction in a relatively moisture free medium in the presence of paraformaldehyde. Therefore the sparingly water soluble pharmaceutically acceptable acid addition salts of the compounds of the formula I are directly precipitated during the reaction, which can be easily filtered. Cumbersome isolation techniques like solvent extraction are not necessary. The process of the invention is a one-pot reaction which is simple and is short and less time consuming. Instead of the compound of the formula VB, its salt ie. the compound of the formula VA is taken up for reaction as per the invention. Therefore the mineral acid required for the reaction is used only in catalytic amounts. The process of the invention is therefore economical and also less tedious since it does not
demand anhydrous medium/ reagents acid. The process of the invention is further made inexpensive since it does not use expensive reagents and solvents like 1,3-dioxolane or dύnethyl formamide. Since the reaction medium is relatively moisture free, no impurities are formed and the required pharmaceutical products are obtained in high yield (-80-90%) and high purity (-99%). The process of the invention does not use hazardous reagents and is safe. For the above reasons, the process of the invention is also commercially feasible.
The following experimental examples are illustrative of the invention but not limitative of the scope thereof.
Example 1 Preparation of 5-(2-chlorobenz¥ft-4.S.6.7-tetrahvdrothieno(3.2-c) pyridine as its hydrochloride (ie compound of the formula I. R = H. Ri
- 2-chloro. as its hydrochioride or ticlopidine hydrochloride) :
To a suspension of N-(2-chlorobenzyl)-2-(2- tlιienyl)ethylamhιe hydrochloride of the formula VA (R = H, R* = 2- chloro) [288 g, 1.0 mole], in t-butanol (864 ml), was added paraformaldehyde (100.8 g, 3.36 moles) and 37% aqueous hydrochloric acid (2.9 ml). The reaction mixture was refluxed for 5 hrs at 75 -80°C and then cooled to 10 - 15°C to precipitate ticlopidine hydrochloride as white crystalline solid which was filtered and dried at 80°C.
Yield = 270 g (90%) Purity = 99.6% [by High Performance Liquid
Chromatography ( HPLC)]
Example 2 Preparation of ticlopidine hydrochioride:-
The procedure of Example 1 was followed using isopropanol instead of t-butanol to obtain ticlopidine hydrochloride . Yield = 80 %
Purity = 99.6% (byHPLC)
Example 3 Preparation of ticlopidine hvdrochloride - The procedure of Example 1 was followed using n-butanol instead of t-butanol to obtain ticlopidine hydrochloride.
Yield = 85 % Purity = 993% (by HPLC)
Example 4
Preparation of ticlopidine hydrochloride: -
The procedure of Example 1 was followed using iso~butanol instead of t-butanol to obtain ticlopidine hydrochloride.
Yield = 85 % Purity = 99.1% (by HPLC)
Example 5
Preparation of S-(+V2-r2-cMorophenyi)-2-f4»5.6t7- tetrahvdrothienof3.2-clpyridin-5-vftacetic add methyl ester as its hydrogen sulfate (ie. compound of the formula 1. R = C aCHa. Rt = 2 chloro as its hydrogen sulfate or (SM+Vdopidogrel hydrogen sulfate*;-
To a suspension of (+)-methyl- -(2-tMenylethylamino)-N- (2-chlorophenyl)acetate hydrochloride (105 g , 0.305 mole) in iso-propanol (375 ml) was added paraformaldehyde (37.0 g, 1.23 mole) and 37% aqueous hydrochloric acid (1.0 ml). The reaction mixture was refluxed for s 6 hours at 75 - 80°C and then evaporated to dryness. The residue of
(+)-clopidogrel hydrochloride was cooled to 25 - 30°C and quenched with water (500 ml). Sodium bicarbonate (42g, 0.5 mole) was added and the mixture was extracted with methylene chloride (IL). The organic layer was separated and evaporated to dryness. The residue of (+)-clopidogrel was o dissolved in acetone (IL) and to it was added conc.suliuric acid (45.7 g, 0.45 mole). The reaction mixture was relluxed for 2 hours and cooled to 20 - 15°C. The white precipitate solid was filtered and dried at 50°C to obtain (+)-clopidogrel hydrogen sulfate.
Yield = 12 g (87.83%) s Purity - 99.5% (byHPLC)
Specific rotation = + 55.9° (C = 1.891 in ethanol) MP = 182 - 184°C
Example 6 0 Preparation of (AV2-(2-chlorophenyft-2-(4t5.6.7-tetrahydrothieno(3.2- c)pyridin-5-yR acetic add methyl ester as its hydrochloride (ie compound of the formula I R = CO?CHs. Rt = 2-chloro as its hydrochloride or (±) dopidogrel Iivdt ochloi ide):-
To a suspension of (±)-methyl- -(2-tMenylethylamino)-N-(2- 5 chlorophenyl)acetate hydrochloride (17 g, 0.049 mole ) in iso-propanol (50 ml), was added paraformaldehyde (5.1 g, 0.17 mole) and 37% aqueous
hydrochloric acid (0.17 ml). The reaction mixture was refluxed for 6 hours at 75 - 80°C and cooled to 10 - 15°C to precipitate the racemic clopidogrel hydrochloride as white sohd which was filtered and dried at 70°C. Yield = 14 g (79.6%)
Purity = 99.4% (byHPLC)
Example 7 Preparation of S-(÷)-2-(2-chioropheny,ft-2~(4t5.6.7- tetιahγdrothieao(3«2-c1_pyridin-5-vftacetic add methyl ester as its hydrogen sulfate (ie compound of the formula I R = CO?CH», R< = 2- chloro as its hydrogen sulfate or (+Vclopidogrel hydrogen sutfate;-
To a suspension of (+)-methyl- -(2-thienylethylamino)-N-(2- chlorophenyl)acetate hydrogen sulfate (4.0 g, 0.01 mole) in iso-propanol (12.0 πύ) was added paaraformaldehyde (1.18 g, 0.039 mole) mid 9$% sulfuric acid (0.04 ml). The suspension was slowly heated to reflux for 6 hrs at 75-77°C and cooled to 10-15°C. The wliite sohd was filtered and dried at 50°C to furnish (+)-clopidogreI hydrogen sulfate.
Yield = 3.30 g (80.5%)
Purity - 99.4% (byHPLC)
Specific rotation = + 55.6° (C = 1.891 in methanol)
Example 8
Preparation of (± -2-(2-chlorophenγlV2-(4t5^6«7-tetrahydrothienof3t2- c]pyridin-5-yftacet add methyl ester as its hydrogen sulfate (ie, compound of the formula 1« R = CQαCHa, Rt = 2-chloro as its hydrogen sulfate) or (±Vdopidogrel hydrogen sulfate:
To a suspension of (±)-methyi- -(2-tMenylethylaoπ!iino)-N- (2-cHoroph§nyl)acetate hydrogen sulfate (5.0 g, 0.012 mole) in iso- propanol (15.0 ml) was added paraformaldehyde (1.47 g, 0.049 mole) and 98% sulfuric acid (0.05 ml). The reaction mixture was refluxed for 6 hrs at 75-80°C and cooled to 10-15°C to precipitate white sohd which was filtered mid dried at 65-70°€ to obtain (±)-clopidogrel hydrogen sulfate. Yield = 4.1 g (80%)
Purity = 99.3% (byHPLC)
Claims
1?
1) A one-pot process for the preparation of pharmaceutically acceptable acid addition salts of 4, 5, 6, 7-tetrahydrothieno(3,2-c) pyridine derivatives of the formula I:
3) A process as claimed in clάm 1 or 2, wheiew. the [.$ alkanol is iso-propanol, t-butanol or n-butanol.
4) A process as claimed in any one of claims 1 to 3, wherein the mineral acid catalyst is hydrochloric acid.
5) A process as claimed m. any one of claims 1 to 4, wherein X is chloro group.
6) A process as claimed in any one of claims 1 to 5, wherein the reaction is carried out at 75 - 80°C.
7) A process as claimed in any one of claims 1 to 6, wherein R and Rj are hydrogen atom and 2-chloro group respectively.
8) A process as clame in claim 7, wherein the phaπnaceutically acceptable acid adάiύon salt of 4, 5, 6, 7- tetiahydrothieno(3,2-c) pyridine derivative is hydrochloride.
9) A process as claimed in any one of claims 1 to 6, wherein R and Ri are CO2CΗ3 group and 2-chloro group respectively.
10) A process as claimed in claim 9, wherein the pharmaceutically acceptable acid addition salt of 4, 5, 6, 7-tetxahydrothieno(3,2-c) pyridine derivative is hydrogen sulfate.
11) A process as claimed in claim 9 or 10, wherein the enantiomer is (+) isomer.
12) A process for the preparation of pharmaceutically acceptable acid addition salts of 4, 5, 6, 7-tetrahydrothiεno(3,2-c) pyridine 0 derivatives of the formula I:
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2000/000080 WO2002018357A1 (en) | 2000-08-29 | 2000-08-29 | A ONE-POT PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF 4, 5, 6, 7 - TETRAHYDROTHIENO (3,2-c) PYRIDINE DERIVATIVES HAVING ANTITHROMBOTIC ACTIVITY |
| AU2001228789A AU2001228789A1 (en) | 2000-08-29 | 2000-08-29 | A one-pot process for the preparation of pharmaceutically acceptable acid addition salts of 4, 5, 6, 7 tetrahydrothieno (3,2-c) pyridine derivatives having antithrombotic activity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2000/000080 WO2002018357A1 (en) | 2000-08-29 | 2000-08-29 | A ONE-POT PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF 4, 5, 6, 7 - TETRAHYDROTHIENO (3,2-c) PYRIDINE DERIVATIVES HAVING ANTITHROMBOTIC ACTIVITY |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002018357A1 true WO2002018357A1 (en) | 2002-03-07 |
| WO2002018357A8 WO2002018357A8 (en) | 2002-06-20 |
Family
ID=11076265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2000/000080 WO2002018357A1 (en) | 2000-08-29 | 2000-08-29 | A ONE-POT PROCESS FOR THE PREPARATION OF PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF 4, 5, 6, 7 - TETRAHYDROTHIENO (3,2-c) PYRIDINE DERIVATIVES HAVING ANTITHROMBOTIC ACTIVITY |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2001228789A1 (en) |
| WO (1) | WO2002018357A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005117866A1 (en) * | 2004-06-01 | 2005-12-15 | Ivax Pharmaceuticals S.R.O. | Amorphous clopidogrel hydrochloride and its antithrombotic use |
| EP1740593A1 (en) | 2004-04-19 | 2007-01-10 | KRKA, tovarna zdravil, d.d., Novo mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2007032023A2 (en) | 2005-07-12 | 2007-03-22 | Rpg Life Sciences Limited | A process for preparation of methyl-(+)-(s)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4h)-acetic acid methyl ester or salts thereof having higher chiral purity and products thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4127580A (en) * | 1975-02-07 | 1978-11-28 | Parcor | Process for the preparation of thieno-pyridine derivatives |
| EP0466569A1 (en) * | 1990-07-10 | 1992-01-15 | Sanofi | Process for preparation of N-phenylacetyl derivative of tetrahydrothieno[3,2-c]pyridine and intermediate of synthesis |
| WO1999018110A1 (en) * | 1997-10-06 | 1999-04-15 | Sanofi-Synthelabo | Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates |
-
2000
- 2000-08-29 WO PCT/IN2000/000080 patent/WO2002018357A1/en active Application Filing
- 2000-08-29 AU AU2001228789A patent/AU2001228789A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4127580A (en) * | 1975-02-07 | 1978-11-28 | Parcor | Process for the preparation of thieno-pyridine derivatives |
| EP0466569A1 (en) * | 1990-07-10 | 1992-01-15 | Sanofi | Process for preparation of N-phenylacetyl derivative of tetrahydrothieno[3,2-c]pyridine and intermediate of synthesis |
| WO1999018110A1 (en) * | 1997-10-06 | 1999-04-15 | Sanofi-Synthelabo | Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1740593A1 (en) | 2004-04-19 | 2007-01-10 | KRKA, tovarna zdravil, d.d., Novo mesto | Processes for the preparation of clopidogrel hydrogen sulfate polymorphic form i |
| WO2005117866A1 (en) * | 2004-06-01 | 2005-12-15 | Ivax Pharmaceuticals S.R.O. | Amorphous clopidogrel hydrochloride and its antithrombotic use |
| WO2007032023A2 (en) | 2005-07-12 | 2007-03-22 | Rpg Life Sciences Limited | A process for preparation of methyl-(+)-(s)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4h)-acetic acid methyl ester or salts thereof having higher chiral purity and products thereof |
| WO2007032023A3 (en) * | 2005-07-12 | 2007-07-12 | Rpg Life Sciences Ltd | A process for preparation of methyl-(+)-(s)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4h)-acetic acid methyl ester or salts thereof having higher chiral purity and products thereof |
| US8063217B2 (en) | 2005-07-12 | 2011-11-22 | Rpg Life Sciences Limited | Process for preparation of methyl-(+)-(S)-alpha-(2-chlorophenyl)-6, 7-dihydrothieno[3,2-C]pyridine-5(4H) -acetic acid methyl ester or salts thereof having higher chiral purity and products thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002018357A8 (en) | 2002-06-20 |
| AU2001228789A1 (en) | 2002-03-13 |
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