WO2011110219A1

WO2011110219A1 - A process for making prasugrel

Info

Publication number: WO2011110219A1
Application number: PCT/EP2010/052971
Authority: WO
Inventors: Lambertus Thijs; Jie Zhu; Arjanne Overeem; Rolf Keltjens
Original assignee: Synthon Bv
Priority date: 2010-03-09
Filing date: 2010-03-09
Publication date: 2011-09-15
Also published as: EP2545059A1; CN102869668A

Abstract

The present invention relates to A compound of general Formula (A), and/or acid addition salts thereof, wherein R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group and R₁,R₂is independently a C1-C10 alkyl group, optionally having one or more carbons substituted by a hydroxy group, or R₁,R₂ together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring, to a process of making and use in making prasugrel.

Description

A PROCESS FOR MAKING PRASUGREL

BACKGROUND OF THE INVENTION

Prasugrel, chemically 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- ahydro-thieno-[3,2-c] pyridine of formula (I)

is a pharmaceutically active compound, which has been developed for the manufacture of a medicament for treatment or prophylaxis of thrombosis or embolisms. It has been disclosed in EP 54241 1 (compound 190) and in US 5,288,726.

Prasugrel has one asymmetric carbon (marked by the asterisk in the formula (I)), and is marketed in the registered medicinal products as a racemate. It may form acid addition salts, for instance prasugrel hydrochloride (see EP 2003136), which is the active ingredient in the medicinal products (sold, e.g., under brand name EFIENT or EFFIENT).

Various processes are known for making prasugrel. Any of the processes comprise, as the key step, a step of N-alkylation on a tetrahydrothienopyridine nitrogen atom, by which two basic "fragments" of the final molecule are coupled together. The nature of the fragments is schematically shown using a dotted line in the following variant of the chemical formula of prasugrel:

fragment 1

fragment 2

The first process, disclosed in EP 542411 and WO 2004/098713, starts with 2-oxo- 2,4,5, 6,7, 7a-hexahydrothieno[3,2-c]pyridine (compound (B), prepared by a multistep process according to EP 192535), which is coupled with 2-fluoro-a-cyclopropylcarbonylbenzyl bromide (CI) to yield "2-ketoprasugrel" of formula (II), the 2-keto-group of which is finally subjected to a reductive acetylation to yield prasugrel of formula (I).

It has been reported that the coupling of (B) and (CI) has a poor yield of about 35%.The next step to prasugrel proceeded with a yield of 65%, which gives an overall yield over the two steps of 23% (see Ref. Example 1 of WO'713 and Example 23 of EP '411).

The bromo functionality in (CI) may be replaced by a methane sulfonate group as taught by WO 2009/006859. No significant improvement has been obtained by this modification.

The second process, which has been disclosed in EP 785205 (WO 96/11203), improves the low yields of the preceded process, which are apparently caused by instability of the keto- group of the thiolactone compound (B) at the reaction conditions (apparently, the thiolactone structure is susceptible to an easy ring opening). The keto group of the compound (B) is protected by silylation, preferably by a tert.butyldimethylsilyl (TBDMS) group, to yield the corresponding silyl-enol ether (D). This compound then serves as reaction partner in the coupling with fragment (CI) to yield a "silyl-prasugrel" of formula (III). Replacement of the silyl, e.g. TBDMS, group by an acetate group gives prasugrel in good yield.

WO2008-108291 suggests that a chlorinated analogue of the compound (CI) may be used in this process as well.

The third process has been disclosed in Chinese patent applications CN 101245073, CN101250192 and CN 101250193. It is based on the prior protection of position 2 of the compound (B) by converting it into a methylenolether (E), which is then coupled with fragment (CI). The resulting "methoxy-prasugrel" (IV) is hydrolysed with an acid to yield "keto-prasugrel" (II). Finally the keto function is converted into an enolacetate yielding prasugrel (I).

B

(ID ω

While processes for making prasugrel are known in the art, they suffer either from low yields or from a need of a multistep protection/deprotection reaction sequence. An improvement in this respect is therefore desirable. In particular, intermediates having the thiolactone structure (B) have to be avoided due to their instability in subsequent reactions.

SUMMARY OF THE INVENTION

The present invention provides a new group of intermediates that are useful in making the compound prasugrel, processes of making them and processes for converting them into prasugrel.

In a first aspect, the present invention provides 5-R-2-(amino-substituted) -4,5,6,7- tetrahydrothieno[3,2-c]pyridine compounds of general formula (A) and/or acid addition salts thereof,

wherein R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group

and Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R₂ together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring.

Within the general formula (A), compounds wherein R is alpha-cyclopropylcarbonyl-2- fluorobenzyl group, i.e. compounds of subformula (A-1), are preferred.

In a second aspect, the invention provides processes for making compounds of the general formula (A).

The invented processes comprise reacting a compound of formula (V)

wherein L is a leaving group, for instance a halo-group, most preferably a bromo-group, and R is defined as in the formula (A)

with an amine of formula (VII) H N

\

^R2 (VII)

wherein Ri,R2 are identical with those as defined for the formula (A).

The process may be optionally followed by a step of isolation of the compound (A) from the reaction mixture and/or by converting group R into another group R within the definition above

In a third aspect, the present invention provides a process for making the compounds of formula (V) comprising the step of reacting 5-R-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (VI),

wherein R is defined as in the formula (A),

with a donor of the leaving group L,

optionally followed by isolation of the compound (V) from the reaction mixture and/or by converting group R into another group R within the definition above.

In a fourth aspect, the present invention provides a process for making prasugrel of formula (I) and/or pharmaceutically acceptable salts thereof comprising the step of converting a compound of formula (A) into the compound of formula (II)

followed by a step of converting the compound of formula (II) into prasugrel (I). In particular, the process does not employ thiolactone compounds of formula (B)

as the intermediate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel intermediates and novel processes that may be used in making prasugrel (I) and/or pharmaceutically acceptable acid addition salts thereof.

As indicated above, each of the known syntheses of prasugrel is based on coupling of two basic fragments: the "thieno-pyrimidyl" fragment properly substituted in the position 2 (the above "Fragment 2" or its precursor) and the "fluorophenyl" fragment (the above "Fragment 1" or its precursor) followed by a subsequent step of conversion of a group in the position 2 of the so-formed condensation product into the desired acetoxy-group. The choice of the group in the position 2 is apparently motivated by attempts to find a proper substituent, which would be stable enough under the reaction conditions of coupling the two basic fragments.

Each of the known "thienopyrimidyl" fragments used in the prasugrel synthesis so far - compounds (II), (III) and (IV) - can be prepared by using the starting material of formula (B).

However, this compound is quite unstable under the reaction conditions with the "fluorophenyl" fragment (e.g. compound (CI))

(CI) , which leads to very low yields of the condensation reaction and low purity of the condensation product. In particular, the thiolactone ring structure of (B) undergoes a ring opening easily. Therefore, there were reported later variations, in which the unstable thiolactone moiety was somehow modified and the modified reagent (e.g. compound (III) or (IV)) was used in the synthesis. This, in essence, required at least one extra reaction step comprising the "protection" of the keto-group in the lactone ring.

Moreover, the compound (B) can be prepared only by a multistep process.

The present inventors have found that the use of compound (B) and the associated synthetic approaches in the synthesis of prasugrel may be avoided by the processes and compounds of the present invention.

In summary, the invented processes are depicted in the scheme below (the "Prot-" is a nitrogen protecting group). The dotted line represents possible conversions, which are however not preferred within the present invention.

which are useful as intermediates in a process for making prasugrel of formula (I). In compounds of the general formula (A), R is a hydrogen atom or a nitrogen-protecting group or a alpha-cyclopropylcarbonyl-2-fluorobenzyl group

and Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R2 together with the bridging nitrogen may form a C3-C10 ring, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring.

The nitrogen protecting group R may be benzyl, trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group.

The - R1R2 moiety may advantageously comprise an optionally substituted

dialkylamino group, e.g. N-methyl-N-2-hydroxy ethyl group, or a 6 membered nitrogen- comprising ring, e.g. N- morpholinyl or N-piperazinyl group.

Within the general formula (A), compounds of sub formula (A-l) are preferred.

The compounds of formula (A) may form acid addition salts with various inorganic or organic acids; examples of these acids are, without limitation, hydrochloric, hydrobromic, sulfuric, methane sulfonic, benzene sulfonic, p-toluene sulfonic, formic, acetic, maleic, fumaric, oxalic, citric or succinic acid. The compounds of formula (A) and/or its acid addition salts are preferably useful in its isolated form, which yet preferably is a solid state form such as any crystalline or an amorphous form; the solid state forms also embrace solvates and hydrates. Due to the intended industrial application, compounds (A) with more than 95% chemical purity, and particularly with more than 99% chemical purity are preferred.

The new compounds of formula (A) may be prepared by a process, in which a compound of formula (V)

(V) reacts with an amine of formula (VII)

wherein are identical with those as defined for the formula (A) and each independently represent a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxygroup, or together with the bridging nitrogen may form a C3- C10 ring, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring. The -NR R2 moiety may advantageously comprise an optionally substituted dialkylamino group, e.g. N-methyl-N- 2 -hydroxy ethyl group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N- piperazinyl group.

The leaving group L is typically a halo-group, most preferably a bromo-group.

The nitrogen-protecting group may be a benzyl,trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group. (Compound V-2).

The product of formula (A) corresponds accordingly to the chemical formula (A-2).

The R-group may also be the l-(2-fluorophenyl)-cyclopropylcarbonylmethyl group (compound V-l),

whereby the product of the general formula (A) corresponds to the chemical formula (A-l)

Finally, the R-group in the starting compound (V) may also be hydrogen (compound

V-3),

whereby the reaction product corresponds to the formula (A-3)

The reaction between the compound of formula (V) and the amine of formula (VII) typically proceeds under general conditions of so called Ullmann condensation reaction, which is a copper-mediated nucleophilic replacement of a halide by an amine. Generally, the reaction requires a copper catalyst/mediator, a solvent, e.g. a protic solvent, a base, and an enhanced temperature. A molar excess of the amine is preferred.

Any compound of the formula (A) defined above may be isolated from the reaction mixture by conventional isolation techniques such as extraction, chromatography and/or precipitation, and purified if desired. Preferably, it is isolated in a solid state form, which is advantageous from the aspects of storage and handling. Alternately, the compound of the formula (A) defined above may be used in the process of making prasugrel without isolation, e.g. as an extract in an inert solvent.

The amines of formula (A) may also be isolated in a form of an acid addition salt, e.g. a hydrochloride.

If necessary or desired, the R-group in the compound of formula (A) may be converted into another R- group. For instance, the nitrogen-protective group in the compound of formula (A-2) may be removed and replaced by hydrogen yielding a compound of formula (A-3), and/or the hydrogen group in compound (A-3) may be replaced by the l-(2-fluorophenyl)- cyclopropylcarbonyl-methyl group yielding the compound (A-l). Known techniques or apparent analogies of these techniques may be used for such conversion. For instance, the compound of formula (A-3) may react with 2-fluoro-a-cyclopropylcarbonylbenzylhalide of formula (C),

wherein X is a halo-group, preferably with the corresponding bromide (compound CI), in an inert solvent and under presence of a base, e.g. an organic base. The desired (A-l) may be isolated from the reaction mixture by precipitation or extraction/evaporation techniques. Preferably, the -NR R2 group in the compound (A-3) is N-morpholinyl group or N-(2- hydroxyethyl)-N-methylamino group.

The compound (CI) is obtainable according to processes known in the art (e.g.

EP1298132, ref. ex. lb).

The starting compounds of formula (V) can be made by a process, which comprises a step of reacting a 5-R-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (VI),

wherein R is defined as in the formula (A), with a donor of leaving group L.

The "donor of leaving group L" is a compound, the reaction of which with the compound (VI) provides the compound of formula (V). For instance, if the leaving group L is a halo-, such as chloro- or bromo- group, then the donor of the leaving group L may be the corresponding halogen, e.g. chlorine or bromine.

The compound of formula (VI) may be used for the reaction as a free base, or in a form of a salt, e.g. a hydrochloride.

The reaction between the compound (VI) and the donor of the leaving group L proceeds in an inert solvent, generally at ambient or higher than ambient temperatures and the reaction product (V) may be isolated from the reaction mixture by conventional techniques.

Preferably, it is isolated in a solid state form, which is advantageous for aspects of storage and handling. Alternately, a compound of formula (V) defined above may be used in the next step without isolation, e.g. as an extract in such inert solvent, which is suitable for the next reaction step. The process of making the compound (V) may also comprise a step of converting a group R into another group R, whereby this converting step may precede or follow the step of reacting with the donor of leaving group L. For instance, compound (VI), in which R is hydrogen (compound VI-3)

may be converted into a compound, in which R is a nitrogen protective group (compound (VI-

2) ),

e.g. benzyl, trityl, benzyloxycarbonyl, tert-butyl, tertbutylcarbonyl, or tert.butyloxycarbonyl group. Accordingly, the compounds (VI-3) and (VI-2) may be converted into a compound of formula (VI- 1)

by a reaction with the 2-fluoro-a-cyclopropylcarbonylbenzylhalide of formula (C), preferably with the corresponding bromide (compound CI), under conditions discussed above.

As apparent from the above, the compound of formula (VI-3) is the basic starting material of the overall process of the present invention. It is commercially available.

As an example of a process, in which the R-converting step follows the step of reacting with the donor of leaving group L, one may mention a step of protecting the ring-nitrogen in (V-3) by a suitable protective agent to yield the N-protected compound (V-2), a step of deprotection of the nitrogen-protective group in the compound (V-2) to yield compound (V-3) and/or a step of condensation of the compound (V-3) with 2-fluoro-a-cyclopropyl- carbonylbenzylhalide of formula (C) yielding the compound of formula (V-l).

The deprotection agent should be selected as such to avoid the simultaneous removal of the group in the position 2, e.g., by hydrolysis. Accordingly, the deprotection reaction preferably proceeds at anhydrous conditions. A suitable deprotecting agent, particularly for removal of the trityl group, is, e.g., anhydrous HC1 or p-toluene sulfonic acid.

The compounds of formula (A) and preferably the compound (A-1) and/or any of its acid addition salts are useful as starting materials for making prasugrel (I). The process of converting a compound of formula (A) into prasugrel comprises a step of converting the -NR R2 group into the =0 group. If the starting compound of formula (A) is the compound (A-2) or (A-3), the product of the conversion is the compound (B), which has to be converted into prasugrel by a multistep procedure known in the art (see, e.g., EP 54241 1). Such procedure however exhibits only low yields and is not preferred. However, the step of making the compound (B) is not disclaimed from the present invention.

The preferred starting material for the conversion step is the compound (A-1). The product of the conversion of the amino-group into a keto-group is then compound (II),

which is the last intermediate for making prasugrel.

The conversion of the compound (A-1) to the compound (II) may be executed by the reaction of the compound (A-1) with an aqueous acid. For instance, diluted hydrochloric acid may be used as the reagent, as well as the solvent. The reaction proceeds by heating the mixture, e.g. at a temperature from between 40°C to the reflux temperature, preferably at 50- 90 °C. The course of the reaction may be monitored by a suitable analytical technique, e.g. by HPLC or TLC. After termination of the reaction, the reaction mixture is preferably neutralized and the product is isolated from the reaction mixture, e.g. by an extraction with a water immiscible organic solvent.

In the last step of the overall process, the compound (II) is converted into prasugrel by procedures known in the art (e.g. in EP 542411), i.e. by a reaction with acetic acid anhydride in a presence of a strong base, e.g. sodium hydride. Once made, prasugrel is advantageously isolated from the reaction mixture by conventional techniques such as, for example, extraction, crystallization, trituration and chromatography, and purified, if desired or necessary. It may be isolated either as a free base or in a form of an acid addition salt, for instance as prasugrel hydrochloride. The isolated forms also comprise hydrates and solvates. Prasugrel prepared according to a process of the present invention may be used as a medicinal product, i.e. it may be formulated with suitable excipients into various medicinal dosage forms, e.g. tablets, capsules, injections, implants etc, for treatment or prevention of any disease treatable by prasugrel.

The present invention will be further illustrated by way of the following examples. These examples are non-limiting and do not restrict the scope of the invention.

EXAMPLES

Example 1 2-Bromo-4,5,6J-tetrahvdro-thienor3,2-c1pyridine

To a mixture of 3.52 g of tetrahydro-thieno-pyridine.HCl (0.02 Mol) in 15 ml of dichloromethane and 30 ml of Ι¾0, with stirring at RT, was added 1.15 ml bromine (-0.022 Mol) dropwise. The addition was completed in -15 minutes. Then, 50 ml dichloromethane was added. Mixture was neutralized to pH 8.5. Separated (¾(¾ layer was dried and concentrated in vacuo to give a crude product (4.3 g).

Example 2 2-Bromo-N-tert.butvloxvcarbonvl-4,5,6,7-tetrahvdro-thienor3,2-c1pyridine

To a solution of 2-Bromo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (10 g) in 100 ml dry dichloromethane, triethylamine (12.7 ml) and di-tert-butyldicarbonate (10.8 ml) were added. The reaction mixture was stirred with cooling using an ice bath for 45 minutes. The reaction was followed by HPLC. Reaction mixture was washed with water (100 ml), 1M HC1 (50 ml), sat. NaHCC aq. (50 ml), water (100 ml). Organic solvent was dried on a2S04, filtered and removed solvent under reduced pressure. Crude product was suspended in heptane (15 ml) and diisopropylether (70 ml), and stirred with cooling (ice-bath) for 1 hour. White solid was filtered off and dried overnight at room temperature. Yield: 8.137 g of white solid. Second crop solid was obtained from filtrate, 3.95 g, white solid.

Example 3 2-(l -morpholinyl) -N-tert.butyloxycarbonyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridine

To a solution of 2-bromo-N-tert.butyloxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c] - pyridine (4.24g) in 50 ml Ν,Ν-dimethylethanolamine, copper powder (85 mg), copper iodide (253 mg), potassium phosphate tribasic (7 g) and morpholine (5.8 ml) were added. The reaction mixture was heated to 80°C, stirred for 24 hours and left at room temperature for 4 days. Water (100 ml) and dichloromethane (100 ml) were added to the reaction mixture. Separated aqueous layer was extracted once with dichloromethane (100 ml). The organic layers were combined and washed with brine (100 ml). The organic solvent was dried on Na₂S0₄, filtered and evaporated under reduced pressure. Product was purified by column chromatography, (heptane/ethyl acetate 92/8). Yield: 1.23 g, yellow solid.

Example 4 2-(l -morpholinyl) -4,5,6,7-tetrahydro-thieno[3,2-c]pyridine

To a solution of 2-Bromo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (412.5 mg) in 5 ml Ν,Ν-Dimethylethanolamine, copper powder (15 mg), copperiodide (36 mg), potassium phosphate tribasic (1 g) and morpholine (5 ml) were added. The reaction mixture was heated to 80°C for 72 hours. Water (25 ml) and DCM (50 ml) were added to the reaction mixture. Separated aqueous layer was extracted with DCM (2x25 ml). The organic layers were combined and washed with brine (30 ml). The organic solvent was dried on Na₂S0₄, filtered and evaporated under reduced pressure. Product was isolated by preperative HPLC. (No yield was determined.) Example 5 2-(l-morpholinvr) -4,5,6,7-tetrahydro-thieno[3,2-c]pyridine cK>

Through a solution containing 2-(l-morpholinyl) -N-tert.butyloxycarbonyl-4,5,6,7- tetrahydro-thieno[3,2-c]pyridine morpholine compound (655 mg) in diethyl ether (35 ml), with cooling using an ice bath, HCl gas was bubbled for total 10 minutes. The reaction was followed by HPLC. After completion, precipitated solid was filtered off. Obtained solid was dissolved in water (150 ml). 1 M NaOH (8 ml) solution was added and the water layer was extracted with dichloromethane. The organic layers were combined and dried on a₂S0₄, filtered and evaporated under reduced pressure. Isolated yield: 395 mg, off- white solid.

Example 6 2-(N-morpholinvl)-5-(alpha-cvclopropvlcarbonvl-2-fluorobenzyl)-4.5.6.7- tetrahydro-thieno-[3,2-c] pyridine

To a solution containing 2-(l-morpholinyl) -4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (606 mg) and 2-fluoro-a-cyclopropylcarbonylbenzyl bromide (697 mg) in acetonitrile (10 ml), with cooling using an ice bath, triethylamine (0.75 ml) was added dropwise. The reaction was followed by HPLC. After completion, solvent was evaporated. The rest was redissolved in ethyl acetate (50 ml). The organic layer was washed twice with water (100 ml) and dried on Na₂S0₄, filtered and evaporated under reduced pressure. Yield: 1.13 g.

Example 7 2-oxo-5-(alpha-cvclopropvlcarbonvl-2-fluorobenzyl)-2A5,6J,7a- hexahydrothieno[3,2-c]pyridine

A solution of 2-( -morpholinyl)-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)- 4,5,6,7-tetrahydro-thieno-[3,2-c] pyridine (0.95g) in 1M HCl (15 ml) was heated to 70°C for 5 hours. The reaction was followed by HPLC. After completion, the mixture was basified to pH 10 and extracted with ethyl acetate (2x50 ml). The organic layer was dried on a₂S0₄, filtered and evaporated under reduced pressure. Yield: 477 mg, orange oil.

Example 8 2-acetoxv-5-(alpha-cvclopropvlcarbonvl-2-fluorobenzyl)-4,5,6J- tetrahydro-thieno-[3,2-c] pyridine

To a solution of 2-oxo-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-2,4,5, 6,7,7a- hexahydrothieno[3,2-c]pyridine (477 mg) and acetic anhydride (1 ml) in DMF (5 ml), with cooling using an ice bath, sodium hydride (60% mineral oil) (102mg) was added in portions. The reaction was followed by HPLC. Ethyl acetate (10 ml) was added to the reaction mixture. The mixture was extracted with 1M HC1 (2x5 ml). The acid layers were combined and basified to pH 6, followed by an extraction with ethyl acetate (2x25 ml). The organic layer was washed with brine (25 ml), dried on Na₂S0₄, filtered and evaporated under reduced pressure. The obtained crude oil was purified by column chromatography. Yield: 155 mg, white solid.

Example 9 2-rMethyl-(4.5.6.7-tetrahvdro-thienor3.2-c1pvridin-2-vl)-amino1-ethanol

A mixture containing 4.3 g 2-Bromo-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine, 130 mg Cu powder, 380 mg Cul and 8.4 g K2PO4 in 20 ml 2(methylamino)ethanol was stirred at 80°C for 18 hours. After cooling to RT, 25 ml ¾0 and 25 ml dichloromethane were added. The mixture was further stirred for 25 minutes. Layers were separated. Water layer was extracted twice with CH₂CI₂. Combined CH₂CI₂ layers were washed with brine (20 ml), dried and concentrated in vacuo to give a solid product (4.3 g). The crude product was triturated with 20 ml diisopropylether for 30 minutes and filtered off. A more pure solid (3.56 g) was obtained. Example 10 1 -Cyclopropyl-2-(2-fluoro-phenyl)-2- {2-[(2-hydroxy-ethyl)-methyl- amino]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl}-ethanone

To a solution of 3.56 g of 2-[Methyl-(4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl)- amino]-ethanol in 50 ml dichloromethane was added, with stirring at ~5°C, 2-fluoro-a- cyclopropylcarbonylbenzyl bromide followed by 3 ml triethylamine. Mixture was stirred at RT for 5 hours. 50 ml H₂0 was added. The mixture was adjusted to pH 5. Separated water layer was extracted with CH2CI2 (2x50 ml). The combined CH2CI2 layers were filtered over 15 g silica gel and concentrated to give 3.32 g of the product.

Example 11 2-oxo-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-2,4,5,6,7,7a- hexahydrothieno[3,2-c]pyridine

A mixture of 2.2 g crude l-Cyclopropyl-2-(2-fluoro-phenyl)-2- {2-[(2-hydroxy-ethyl)- methyl-amino]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl}-ethanone in 30 ml 1 N HC1 was stirred at 90°C for 4 hours. After cooling to RT, the reaction mixture was basified to pH 10 and extracted with EtOAc (2x50 ml). Combined EtOAc layers were washed with brine (15 ml), dried and concentrated in vacuo to give 1.55 g of an oily product.

Example 12 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7- tetrahydro-thieno-[3,2-c] pyridine

A mixture of 1.55g crude 2-oxo-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)- 2,4,5, 6,7,7a-hexahydrothieno[3,2-c]pyridine from Example 1 1 in 8 ml DMF and 3 ml AC₂O was stirred at ~5°C. NaH (0.3 g, 60% in mineral oil) was added in portions. The mixture was stirred for 3 hours at ~5°C. Then 30 ml EtOAc was added followed by 1 ml water. The mixture was extracted with HC1 solution (1 M, 2x5 ml). Combined acidic layers were neutralized to pH 6 and extracted with EtOAc (50 ml). Separated EtOAc layer was washed with brine (10 ml), dried and concentrated in vacuo to give the desired product (900 mg).

The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

1 A compound of general formula (A) and/or acid addition salts thereof,

and Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R2 together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring.

2. The compound according to claim 1, wherein the nitrogen protecting group R is a benzyl, trityl, benzyloxycarbonyl, tert.butyl, tert.butylcarbonyl, or

tert.butyloxycarbonyl group, and/or -NR1R2 is an optionally substituted dialkylamino group, e.g. N-methyl-N-2-hydroxyethyl group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N-piperazinyl group.

3. A process for making a compound of general formula (A) and acid addition salts thereof,

comprising reacting a compound of formula (V)

with an amine of formula (VII)

(VII) wherein L is a leaving group, preferably a halo-group, most preferably a bromo-group,

R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group,

Ri,R₂ is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R₂ together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring.

The process according to claim 3, wherein the nitrogen protecting group R is a benzyl, trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group.

The process according to claims 3 or 4, wherein - R₁R₂ is an optionally substituted dialkylamino group, e.g. N-methyl-N-2-hydroxyethylamino- group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N-piperazinyl group.

The process according to claims 3-5, wherein the reaction between the compound of formula (V) and the amine of formula (VII) proceeds under conditions of Ullmann condensation reaction.

The process according to claims 3-6, wherein the compound of the formula (A) is isolated from the reaction mixture.

The process according to claims 3-7, followed by a step of converting the the R-group in the compound of formula (A) into another R-group, and preferably the hydrogen group in the compound of formula (A-3)

is replaced by (2-fluorophenyl)-cyclopropylcarbonyl-methyl group yielding the compound (A-l),

such as by reacting with 2-fluoro-a-cyclopropylcarbonylbenzylhalide of formula (C)

wherein X- is a halo-group, preferably a bromo-group or chlorogroup.

A process for making a compound of formula (V)

wherein R is is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group and

L is a leaving group, preferably a halo-group, most preferably a bromo-group or chloro-group

comprising the step of reacting 5-R-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of formula (VI), or an acid addition salt thereof,

with a donor of the leaving group L.

10. The process according to claims 9, wherein the compound (V) is isolated from the reaction mixture.

1 1. The process according to claims 9 or 10 further comprising a step of converting a group R into another group R, whereby this converting step may precede or follow the step of reacting with the donor of leaving group L.

12. A process of making a compound of formula (II)

comprising reacting the compound of formula (A-l)

wherein Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring,

with an aqueous acid, preferably with aqueous hydrochloric acid.

13. The process according to claim 12, wherein -NR R2 is an optionally substituted

dialkylamino group, e.g. N-methyl-N-2-hydroxyethylamino- group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N-piperazinyl group.

14. The process according to claims 12 or 13, wherein the compound of the formula (II) is isolated from the reaction mixture.

15. The process according to claims 12-14, further comprising a step of converting the compound of formula (II) to prasugrel of formula (I)

16, A process for making prasugrel of formula (I), compris

a) converting, in one or more steps, the compound of formula (VI-3)

into a compound of formula (V)

wherein R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group and

L is a leaving group, preferably a halo-group and most preferably a bromo- group;

b) reacting the compound of formula (V) with an amine of formula (VII) H N

\

^R2 (VII)

yielding a compound of formula (A)

wherein Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R2 together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring;

c) converting, if the group R in the compound (V) or (A) is not a alpha- cyclopropylcarbonyl-2-fluorobenzyl group, said group R into said alpha- cyclopropylcarbonyl-2-fluorobenzyl group;

d) hydro lyzing the so provided compound of formula (A-1)

into the compound of formula (II)

e) reacting the compound of formula (II) with acetic acid anhydride to form prasugrel of formula (I)

17. The process according to claim 16, wherein the nitrogen-protecting group R is benzyl, trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group and/or the -NRiR₂ is an optionally substituted dialkylamino group, e.g. N-methyl-N- 2 -hydroxy ethyl group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N-piperazinyl group.

18. Use of the compound of formula (A)

wherein R is a hydrogen atom or a nitrogen-protecting group or an alpha- cyclopropylcarbonyl-2-fluorobenzyl group,

and Ri,R2 is independently a CI -CIO alkyl group, optionally having one or more carbons substituted by a hydroxy group, or Ri,R₂ together with the bridging nitrogen may form a ring comprising from 3 to 10 carbon atoms, optionally also comprising another nitrogen, oxygen or sulfur atom in the ring and/or a nitrogen-, oxygen-, or sulfur-comprising substituent on the ring,

in a process of making prasugrel of the formula (I).

The use according to claim 18, wherein the nitrogen-protecting group R is benzyl, trityl, benzyloxycarbonyl, tert-butyl, tert.butylcarbonyl, or tert.butyloxycarbonyl group and/or the -NR1R2 group is an optionally substituted dialkylamino group, e.g. N- methyl-N-2-hydroxyethyl group, or a 6 membered nitrogen-comprising ring, e.g. N- morpholinyl or N-piperazinyl group.