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Title:
SYNTHESIS OF 2-(3,4-DIFLUOROPHENYL)CYCLOPROPANECARBOXYLIC ACID
Document Type and Number:
WIPO Patent Application WO/2013/124280
Kind Code:
A1
Abstract:
The present invention relates to the field of organic synthesis and describes the synthesis of specific intermediates suitable for the preparation of triazolopyrimidine compounds such as ticagrelor.

Inventors:
STERK, Damjan (Verovskova 57, 1526 Ljubljana, SI)
ZUPANCIC, Borut (Verovskova 57, 1526 Ljubljana, SI)
Application Number:
EP2013/053301
Publication Date:
August 29, 2013
Filing Date:
February 20, 2013
Export Citation:
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Assignee:
LEK PHARMACEUTICALS D.D. (Verovskova 57, 1526 Ljubljana, SI)
STERK, Damjan (Verovskova 57, 1526 Ljubljana, SI)
ZUPANCIC, Borut (Verovskova 57, 1526 Ljubljana, SI)
International Classes:
C07C67/327; C07C45/68; C07C51/08; C07C51/083; C07C51/09; C07C51/41; C07C67/08; C07C67/31; C07C69/732; C07C69/74; C07C253/14; C07C253/30; C07C255/16; C07C255/30; C07C255/46
Domestic Patent References:
WO2008018822A12008-02-14
WO2001092200A12001-12-06
WO2011017108A22011-02-10
WO2000034283A12000-06-15
WO2001092263A12001-12-06
WO2010030224A12010-03-18
WO2011017108A22011-02-10
WO2001092200A12001-12-06
WO2008018822A12008-02-14
WO2008018823A12008-02-14
WO2011132083A22011-10-27
WO2012001531A22012-01-05
Foreign References:
EP0577949A11994-01-12
Other References:
TSAI T Y ET AL: "Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY, PERGAMON, GB, vol. 17, no. 6, 15 March 2009 (2009-03-15), pages 2388 - 2399, XP025981936, ISSN: 0968-0896, [retrieved on 20090220], DOI: 10.1016/J.BMC.2009.02.020
SPRINGTHORPE ET AL: "From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 17, no. 21, 1 November 2007 (2007-11-01), pages 6013 - 6018, XP022267216, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2007.07.057
BIOORG. MED. CHEM. LETT., vol. 17, 2007, pages 6013 - 6018
Attorney, Agent or Firm:
KUNIC-TESOVIC, Barbara (Lek Pharmaceuticals d.d, Verovskova 57, 1526 Ljubljana, SI)
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Claims:
Claims

1 . A process for the preparation of a compound of formula VI

VI wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COOF , wherein is linear or branched C Ce alkyl,

the process comprising the steps of:

(i) providing a compound of formula V

V wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COOR^ wherein is linear or branched C^Ce alkyl,

(ii) converting the hydroxyl group of the compound of formula V to a group selected from the group consisting of unsubstituted or substituted alkanesulfonyloxy and unsubstituted or substituted arenesulfonyloxy, and

(iii) converting the obtained compound by cyclization in a presence of a base to provide a compound of formula VI.

The process according to claim 1 , wherein R is selected from a group consisting of COOMe, COO/Pr and CN.

The process according to claim 1 , wherein in step (ii) the hydroxyl group is converted to a group selected from methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy.

The process according to claim 1 , wherein in step (iii) the base is an alkali metal alkoxide or a group selected from the group consisting of lithium diisopropylamide, sodium hexamethyldisilazane, phenyllithium and sodium hydride. The process according to claim 4, wherein the alkali metal alkoxide is selected from potassium ferf-butoxide, potassium fert-pentoxide and sodium fert-butoxide.

The process according to claim 1 , wherein the compound of formula V is prepared by comprising the steps of

(i) providing a compound of formula IV

wherein R is as defined above, and

(ii) reducing the keto group of the compound of formula IV to yield the compound of formula V.

7. The process according to claim 6, wherein the compound of formula IV is prepared by comprising the steps of:

(i) providing a compound of formula I

I

(ii) reacting the compound of formula I with a compound of formula Ila or Mb

Ila wherein R2 and R3 are independently selected from a group consisting of hydroxyl, CI, Br and I,

to yield a compound of formula Ilia or 1Mb, respectively

and

(iii) converting the compound of formula Ilia or 1Mb to the compound of formula IV.

The process according to claim 1 , wherein the compound of formula VI is further converted to a compound of formula VII or a salt thereof

VII

9. The process according to claim 8, wherein the compound of formula VII or a salt thereof is further converted to a compound of formula VIII or a salt thereof

VIII 10. A compound of the following formula Va or Vb

1 1 . A compound of the following formula Vlb

Vlb

12. Use of a compound as defined in claim 10 or claim 1 1 , and their stereochemically isomeric forms, in the preparation of ticagrelor.

Description:
Synthesis of 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid

The present invention relates to the field of organic synthesis, in particular to the synthesis of specific intermediates suitable for the synthesis of triazolopyrimidine compounds.

An important triazolopyrimidine compound is ticagrelor (TCG; Brilinta ; 3-[7-[[(1 R,2S)- 2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio / )-3/-/-i,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)-(1 S,2S,3fl,5S)-1 ,2-cyclopentanediol) having the following structural formula.

Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation (WO 00/34283). The synthesis of ticagrelor (TCG) is demanding. There are five to six known synthetic variants, which are described in the basic patent application WO 00/34283, an improved one in patent application WO 01 /92263, and a further improved one in patent application WO 10/030224 respectively derived from the originator AstraZeneca, while two are published in a "deutero" patent application WO 1 1 /017108 of Auspex Pharmaceuticals. Further, there is one synthetic path published in a scientific journal (Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018).

The ticagrelor molecule consists of three main parts, an essential part being the cyclopropyl moiety. All synthetic approaches mentioned above utilize the intermediate CPA (trans-^ R,2S)- 2-(3,4-difluorophenyl)cyclopropylamine) of formula VIII as one of the key intermediates.

VIII

There are several synthetic paths for preparation of intermediate CPA known in the literature.

According to WO 01 /92200 and WO 01/92263 (Scheme 1 ) CPA is prepared as shown in Scheme 7. 3,4-Difluorobenzaldehyde is reacted with malonic acid in the presence of pyridine and piperidine to yield (£)-3-(3,4-difluorophenyl)-2-propenoic acid, which is converted to (£)-3- (3,4-difluorophenyl)-2-propenoyl chloride by using thionyl chloride in the presence of toluene and pyridine. A solution of L-menthol in toluene is added to the obtained compound in the presence of pyridine to yield (1 ft,2S,5ft)-2-isopropyl-5-methylcyclohexyl (£)-3-(3,4- difluorophenyl)-2-propenoate, which is with dimethylsulfoxonium methylide, sodium iodide and NaOH in DMSO converted to (1 ft,2S,5ft)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4- difluorophenyl)cyclopropanecarboxylate. The latter is then hydrolysed to trans-^ R,2R)-2-(3,4- difluorophenyl)cyclopropanecarboxylic acid, which is subsequently converted to trans-^ R,2R)- 2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride with thionyl chloride. In the last two steps, the obtained carbonyl chloride is first converted to the corresponding azide by addition of sodium azide and tertbutylammonium bromide, which is finally converted to CPA. Pyridine

65°C

Scheme 1 : Synthesis of CPA as described in WO 01 /92200 and WO 01/92263.

The eight steps synthesis described Scheme 1 is very long, uses toxic compounds like sodium azide and pyridine, and is not economical as expensive reagents like trimethylsulfoxonium iodide are used. Moreover, the overall yield of the reaction is low. Another process for the preparation of CPA is described in Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018. The synthesis of the trans-^ ft,2S)-phenylcyclopropylamine begins with derivatisation of substituted cinnamic acid A with Oppolzer's sultam to give B. Diastereoselective cyclopropanation then provides, after recrystallisation, cyclopropylamide C in high chiral purity which is readily saponified to acid D. A four-step Curtius rearrangement gives CPA.

1. CIC0 2 Et, Et 3 N, acetone

Scheme 2: Synthesis of CPA as described in Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018. This 8 steps long synthesis presented in Scheme 2 involves the use of hazardous and explosive materials like sodium hydride, diazomethane and sodium azide. Moreover, highly expensive chiral sultamam and palladium acetate are used. In addition, this lengthy process involves column chromatographic purifications, which are generally undesirable in view of large scale industrial applicability

According to WO 08/018822 and WO 08/018823, CPA is prepared as shown in Scheme 3. First step involves reacting 1 ,2-difluorobenzene with chloroacetyl chloride in the presence of aluminium trichloride to produce 2-chloro-1 -(3,4-difluorophenyl)ethanone. The keto group of the latter is then reduced by the use of chiral oxazaborolidine catalyst and borane dimethylsulfide complex to yield 2-chloro-1 -(3,4-difluorophenyl)ethanol, which is then reacted with triethylphosphoacetate in the presence of sodium hydride in toluene to produce trans-^ R,2R)- 2-(3,4-difluorophenyl)cyclopropyl carboxylate. In the final two steps the ester compound is first converted to amide by methyl formate in the presence of ammonia, said amide is then reacted with sodium hydroxide and sodium hypochlorite to produce CPA.

Scheme 3: Synthesis of CPA as described in WO 08/018822 and WO 08/018823.

The disadvantages of the process described in WO 08/018822 and WO 08/018823 are the use of expensive chiral oxazaborolidine catalyst and toxic borane dimethylsulfide complex as well as use of explosive materials like sodium hydride.

According to WO 1 1/017108, CPA is prepared by a process as described in Scheme 4. First, (£)-3-(3,4-difluorophenyl)acrylic acid is reacted with oxalyl dichloride in the presence of N,N- dimethylformamide and dichlorometane to produce the corresponding acryloyi chloride, which is then reacted with a mixture of (2fl)-bornane-10,2-sultam and triethylamine to yield [3aS- [1 (£),3a,6,7a]]-1 -[3-(3,4-difluorophenyl)-1 -oxo-2-propenyl]-hexahydro-8,8-dimethyl-3/-/-3a,6- methano-2,1 -benzisothiazole-2,2-dioxide. Said intermediate is then reacted with methyl-1 - nitrosourea in NaOH and ethyl ether, and with palladium acetate reagent to convert the propenyl group into cyclopropyl group. In the final two steps the obtained intermediate is first converted to (1 fl,2/7)-frans-2-(3,4-difluorophenyl)cyclopropyl carboxylic acid by lithium hydroxide in the presence of tetrahydrofuran, said acid is then reacted with diphenylphosphoryl azide and triethylamine in toluene and HCI to produce CPA.

Scheme 4: Synthesis of CPA as described in WO 1 1 /017108. The disadvantage of the process described in WO 1 1 /017108 is the use of expensive chiral sultam and palladium acetate reagent.

Another synthetic route for preparing CPA is described in WO 1 1 /132083 (Scheme 5). 1 ,2- Difluoro benzene is reacted with 3-chloropropionyl chloride to produce 3-chloro-1 -(3',4'- difluorophenyl)-propan-1 -one, which is by addition of Ν,Ν-dimethylformamide, phloroglucinol and sodium iodide in the next step converted to 1 -(3',4'-difluorophenyl)-3-nitro-propan-1 -one. The keto group of the latter intermediate is in the subsequent step stereochemically reduced to hydroxyl group by the use of chiral oxazaborolidine together with borane dimethyl sulfide or borane-N,/V,diethyl aniline complex in the presence of tetrahydrofurane. The obtained (l /^-l - (3',4'-difluorophenyl)-3-nitro-propan-1 -ol is then added to a mixture of triphenylphosphine and diethylazodicarboxylate in benzene to yield trans-^ S,2ft)-2-(3',4'-difluorophenyl)-1 - nitrocyclopropane, which is in the last step converted to CPA by reduction of the nitro group by catalytic hydrogenaiton with palladium catalyst and zink dust.

The disadvantage of the process described in WO 1 1 /132083 is the use of expensive chiral oxazaborolidine and palladium catalyst, sodium iodide, toxic borane dimethylsulfide complex, heavy metals and hazardous diethyl azodicarboxylate.

Scheme 5: Synthesis of CPA as described in WO 1 1 /132083.

WO 12/001531 describes another alternative synthetic path for preparation of CPA (Scheme 6). In this case the starting reagent 3,4-difluorobenzaldehide is reacted with a mixture of methyltriphenylphosphonium bromide, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and toluene to yield 3,4-difluorostyrene. The obtained intermediate is then added to dichloro(p- cymene)ruthenium(ll) dimer and (S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine, which is followed by addition of ethyl diazoacetate to yield ethyl trans-^ fl,2fl)-2-(3,4-difluorophenyl)-1 - cyclopropane-carboxylate, which is converted to trans-^ fl,2/7)-2-(3,4-difluorophenyl)-1 - cyclopropane-carboxylic acid by hydrolysis in the presence of sodium hydroxide and methanol. The obtained carboxylic acid is with aqueous hydroxylamine solution further converted to trans- (1 ft,2ft)-2-(3,4-difluorophenyl)-1 -cyclopropanecarboxamide, which is mixed with pyridine and acetic anhydride to yield trans- \ ft,2ft)-/V-(acetyloxy)-2-(3,4-difluorophenyl)-1 -cyclopropane carboxamide. To the obtained intermediate in the presence of tetrahydrofurane the 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU) is added, which is followed by addition of isopropyl acetate and ammonium chloride to finally yield CPA.

Scheme 6: Synthesis of CPA as described in WO 12/001531.

The disadvantage of the process described in WO 12/001531 is the use of expensive chiral ligand, dichloro(p-cymene)ruthenium(ll) dimer, and use of toxic pyridine.

A major drawback of the hitherto known synthesis schemes for the preparation of CPA is that the synthesis is long and/or expensive or environmentally unfriendly reagents are used, which makes the prior art processes unsuitable for large scale preparation of CPA of formula VIII. A need therefore remains for an alternative but commercially viable process for preparation of CPA.

Summary of the Invention

The object of the present invention was to provide an industrially applicable and economical process for obtaining 2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (VII), an important intermediate in preparation of CPA (VIII).

The present invention provides a process for the preparation of a compound of formula VI

VI wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COOF^ , wherein is linear or branched C Ce alkyl,

the process comprising the steps of:

(i) providing a compound of formula V

wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COORT , wherein is linear or branched C Ce alkyl,

(ii) converting the hydroxyl group of the compound of formula V to a better leaving group, and (iii) converting the obtained compound by cyclization in a presence of a base to provide a compound of formula VI.

The term "better leaving group" means a group selected from the group consisting of unsubstituted or substituted alkanesulfonyloxy and unsubstituted or substituted arenesulfonyloxy. Preferably, the better leaving group is unsubstituted or fluoro-substituted d- C 6 alkanesulfonyloxy or unsubstituted or substituted arenesulfonyloxy. Preferred groups are methanesulfonyloxy (mesyloxy), trifluoromethanesulfonyloxy, benzenesulfonyloxy and p- toluenesulfonyloxy. The term "base" as used herein means alkali metal alkoxide or a base stronger than alkali metal alkoxide. Preferred alkali metal alkoxide is selected from potassium tert-butoxide, potassium fert-pentoxide and sodium fert-butoxide. Preferred base stronger than alkali metal alkoxide is selected from the group consisting of lithium diisopropylamide, sodium hexamethyldisilazane, phenyllithium and sodium hydride.

The process defined above allows for preparation or synthesis of the compound of formula VII with an industrially applicable and economical process while using environmentally friendly reagents. Preferred embodiments will be described below. The present invention further provides novel compounds that are useful as intermediates in the preparation of ticagrelor (TCG). Description of the Invention and of Preferred Embodiments

Aspects and preferred embodiments of the present invention will be described in further detail below, noting however that such aspects as well as embodiments and examples are presented for illustrative purposes only and shall not limit the invention in any way.

According to a preferred embodiment, the compound of formula V is prepared by comprising the steps of

(i) providing a compound of formula IV

iv

wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COOR T , wherein is linear or branched C Ce alkyl, and

(ii) reducing the keto group of the compound of formula IV to yield the compound of formula V.

The group convertible to carboxyl group can be any group that allows the formation of carbanion on a carbon atom attached to it and can be further transformed to carboxyl group. Said group is preferably selected from the group consisting of carboxylic ester (COOR^, cyano, trihalomethyl, ethynyl group and a carboxamide group.

The R T group of the carboxylic ester COOR T can be any substituted or unsubstituted linear or branched alkyl, for example linear or branched C Ce alkyl, cyclic alkyl, for example L-menthyl, or substituted or unsubstituted aryl. Preferably is selected from the group consisting of methyl (Me), ethyl (Et), propyl (Pr), secondary such as /so-propyl (iPr) or tertiary alkyl such as fert-butyl (tBu).

Reduction of keto group of the compound of formula IV can be performed by any suitable reducing agent, for example metal borohydride, or alternatively by using heterogeneous or homogeneous catalysts usually employed for reduction of ketones and hydrogen or hydrogen donor.

In another embodiment of the present invention, the compound of formula IV is prepared from a compound of formula I with a process comprising: (i) providing a compound of formula I

I

(ii) reacting the compound of formula I with a compound of formula Ila or Mb

Ila wherein R 2 and R 3 are independently selected from a group consisting of hydroxyl, CI, Br and I,

to yield a compound of formula Ilia or Illb, respectively

Illb wherein R 3 is as defined above, and

(iii) converting the compound of formula Ilia or Illb to the compound of formula IV.

The reaction of the compound of formula I with the compound of formula Ila or Mb is performed in the presence of a Lewis acid, for example AICI 3 . This Friedel-Crafts reaction can be conducted in any solvent, preferred solvents are dichloromethane and 1 ,2-difluorobenzene. The substituents R 2 and R 3 in the compound of formula Mb is a leaving group, preferably selected from a group consisting of hydroxyl, CI, Br and I, most preferably CI.

Alternatively, the compound of formula IV can also be directly obtained by reacting a compound of formula I with the compound of formula II lc

Illc

wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COOF^ , wherein is linear or branched C Ce alkyl, and R 2 is selected from a group consisting of hydroxyl, CI, Br and I.

In another preferred embodiment, the compound of formula VI is further converted to the compound of formula VII or a salt thereof by means of basic or acidic hydrolysis, optionally in the presence of a cosolvent.

VII A suitable salt of intermediate VII is a metal salt, for example an alkali metal or earth alkali metal salt. The preferred salt of intermediate VII is lithium salt.

In another embodiment, the compound of formula VII or a salt thereof, prepared by the process of the present invention, is further converted to CPA, a compound of formula VIII, by a process known in the art. A process described in Bioorg. Med. Chem. Lett. 2007, 17, 6013-6018 (Scheme 2) or the one described in WO 1 1 /017108 (Scheme 4) can be followed.

In a particularly preferred embodiment, the compound of formula VII is synthesized as shown in Scheme 7. 1 ,2-Difluorobenzene (I) and succinic anhydride (Ma) as starting materials are reacting in the presence of a Lewis acid such as AICI 3 to give Ilia as white solid. This Friedel- Crafts reaction can be conducted in any solvent, preferably in CH 2 CI 2 or 1 ,2-difluorobenzene. Ilia is then esterified in the presence of an appropriate solvent and acid, preferably H 2 S0 4 , to afford esters IVa or IVc as white solid. In the next step, the keto group of the respective ester is reduced using reducing agent such as metal borohydride or other reducing agent. The reduction can be carried out either in stereoselective way or not. It can be reduced in the presence of heterogeneous or homogeneous catalyst usually employed for reduction of ketones and hydrogen or hydrogen donor to form Va or Vc in enantiomerically pure form or as a mixture of enantiomers. The hydrogen donor can be formic acid and its derivatives, borane and its derivatives, cyclohexene and its derivatives or other hydrogen donor used in reduction of ketones. Reduction can also be carried out following biochemical principles. Va and Vc are then cyclized to cyclopropane compounds Via or Vic. First, the hydroxyl group is converted to a better leaving group by either formation of substituted or unsubstituted arylsulfonate or substituted or unsubstituted alkylsulfonate ester, and then cyclization is performed by addition of a base, preferably potassium fert-butoxide or sodium hydride. In the last step a simple basic or acidic hydrolysis is performed to afford the compound of formula VII.

Scheme 7 showing process embodiments of the present invention. This synthetic route of Scheme 7 was found particularly advantageous for its simplicity and possibility of preparation of the compound of formula VII enriched in one enantiomer.

In another particularly preferred embodiment, the compound of formula VII is synthesized as shown in Scheme 8. 3-Chloro-1 -(3,4-difluorophenyl)propan-1 -one (1Mb') is prepared by reacting 1 ,2-dif luorobenzene (I) with 3-chloropropionyl chloride (Mb') in the presence of a Lewis acid such as AICI 3 , optionally without the use of additional solvent. Next, a solution of 3-chloro-1 - (3,4-difluorophenyl)propan-1 -one (1Mb') is reacted with a base, followed by cyanide such as sodium cyanide to form IVb. Base can also be cyanide itself. Solvent can be either protic or aprotic, preferably the solvent is selected from d-C 6 alcohols, most preferably solvent is ethanol. In the next step, IVb is reduced with reducing agent such as metal borohydride or other reducing agent or it is reduced in the presence of heterogeneous or homogeneous catalyst usually employed for reduction of ketones and hydrogen or hydrogen donor to form Vb in enantiomerically pure form or as mixture of enantiomers. The reduction can be carried out either in stereoselective way or not. The hydrogen donor can be formic acid and its derivatives, borane and its derivatives, cyclohexene and its derivatives or other hydrogen donor used in reduction of ketones. Reduction can also be carried out following biochemical principles. Next, Vb is transformed by first converting hydroxyl group to a better leaving group by either formation of substituted or unsubstituted arylsulfonate or substituted or unsubstituted alkylsulfonate ester and then to Vlb by addition of a base, preferably potassium fert-butoxide or sodium hydride. Alternatively, the base used in the reaction from Vb to VIb can also be the same base as the one used for the transformation of hydroxyl group to a better leaving group as described above. In the last step, VIb is transformed to VII by hydrolysis in basic or acidic conditions, optionally in the presence of a cosolvent.

VIb VII

Scheme 8 showing process embodiments of the present invention.

Alternatively, the compound with the activated hydroxyl group can optionally be isolated before base induced transformation to VIb.

Alternatively, the compound of formula Vb can be treated with phosphine derivatives such as trialkyl or triaryl phosphines, preferably triphenylphosphine and dialkyl diazodicarboxylate such as diethyl diazodicarboxylate (DEAD) in the presence of a base to yield the compound of formula VIb.

Further aspects of the present invention reside in the provision of valuable intermediate compounds of formula V and VI, and a salt of compound of formula VII, all useful in the synthesis of ticagrelor (TCG):

wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COOF , wherein F is linear or branched C Ce alkyl; wherein R is a group convertible to carboxyl group selected from the group consisting of CN, trihalomethyl and COORT , wherein is linear or branched C Ce alkyl;

A suitable salt of intermediate VII is a metal salt, for example an alkali metal or earth alkali metal salt. The preferred salt of intermediate VII is lithium salt.

Particular examples of such useful intermediate compounds are listed by their respective formulas below:

The following manner of presentation of structures of compounds VI and VII

means that the position of substituents is trans and may contain a mixture of both enantiomers

as a racemic mixture, a mixture enriched in one enantiomer or one particular enantiomer. The ratio of enantiomer mainly depends on enantioselectivity of reduction of the keto group in the compound of formula IV, which can be carried out by achiral reducing agents, such as borohydrides, by achiral agents such as boranes with chiral promotors such as with oxazaborolidine, by enantioselective reducing agents, by enantiomerically enriched chiral catalyst and hydrogen or hydrogen donor or by enzymatic way. Preferably the selection of reducing system should be carried out in such way that the synthesis leads to the intermediates with configuration at the position of the aryl substituent, which finally leads to cyclopropyl intermediates suitable for the synthesis of ticagrelor.

VI

The enantiomerically enriched intermediates with suitable configuration at the position of the aryl substituent can be obtained also by other processes well known in the art, such as for example chromatography on chiral column, crystallization, crystallization by formation of diastereomeric salts or kinetic resolution.

In the following the present invention will be described in further detail by illustrative, non- limiting examples. Preparation of 4-(3,4-difluorophenyl)-4-oxobutanoic acid (Ilia)

To a mixture of 1 ,2-difluorobenzene (I) (15 mL) and succinic anhydride (Ma) (4.0 g, 40.0 mmol) was slowly added AICI 3 (16.0 g, 120 mmol). The resulting reaction mixture was stirred at 40 °C for 16 h, then it was poured to the mixture of 37% HCI (20 mL) and ice (50 g). After extraction with MeTHF (3 x 20 mL), combined organic layers are dried over MgS0 4 , and then concentrated to afford crude product, which was then recrystallized from toluene to give 6.6 g (77% yield) of title compound as white powder. Melting point 80 °C; MS (ESI) mlz: 215 [MH] + .

Example 2: Preparation of methyl 4-(3,4-difluorophenyl)-4-oxobutanoate (IVc)

Ilia IVc

A mixture of Ilia (1 .5 g, 7.0 mmol) and H 2 S0 4 (96%, 0.15 g) in MeOH (20 mL) is stirred at 60 °C for 2 hours, then the resulting reaction mixture was poured in the solution of K 2 C0 3 (3 g) in water (50 mL). Ice (50 g) was added and mixture was stirred for 15 min. White solid was then filtered off, washed with water and dried to afford title compound as white powder (1 .57 g, 98% yield). Melting point 46 °C; MS (ESI) mlz: 229 [MH] + . Example 3: Preparation of isopropyl 4-(3,4-difluorophenyl)-4-oxobutanoate (IVa)

Ilia IVa

A mixture of la (1 .5 g, 7.0 mmol) and H 2 S0 4 (96%, 0.15 g) in /PrOH (20 mL) is stirred at 80 °C for 16 hours, then the resulting reaction mixture was poured in the solution of K 2 C0 3 (3 g) in water (50 mL). Ice (50 g) was added and mixture was stirred for 15 min. White solid was then filtered off, washed with water and dried to afford title compound as white powder (1 .50 g, 84% yield). Melting point 36 °C; MS (ESI) m/z: 257 [MH] + .

Example 4: Preparation of methyl 4-(3,4-difluorophenyl)-4-hydroxybutanoate (Vc)

IVc Vc

To a solution of IVc (1 .0 g, 4.38 mmol) in MeOH (7 mL) / Et 2 0 (7 mL) NaBH 4 (83 mg, 2.19 mmol) was added at 0 °C. The resulting reaction mixture was stirred at 0 °C for 15 min, then saturated solution of NaHC0 3 (30 mL) was added, and product was extracted to THF (3 x 10 mL). Combined organic layers were dried over Na 2 S0 4 , and then concentrated. Purification by chromatography (Si0 2 , hexane:EtOAc) afforded title compound as colorless oil (0.89 g, 88% yield). MS (ESI) m/z: 230 [MH] + .

Example 5: Preparation of isopropyl 4-(3,4-difluorophenyl)-4-hydroxybutanoate (Va)

IVa Va To a solution of IVa (1 .4 g, 5.46 mmol) in /PrOH (20 mL) NaBH 4 (0.10 g, 2.73 mmol) was added at 0 °C. The resulting reaction mixture is stirred at room temperature for 2 h, then AcOH (0,1 mL) and water (100 mL) were added, and product was extracted to THF (3 x 20 mL). Combined organic layers were dried over MgS0 4 , and then concentrated. Purification by chromatography (Si0 2 , hexane:EtOAc) afforded title compound as colorless oil (0.73 g, 56% yield). MS (ESI) m/z: 259 [MH] + .

Example 6: Preparation of methyl frans-2-(3,4-difluorophenyl)cyclopropanecarboxylate (Vic)

Vc Vic

To a solution of Vc (0.89 g, 3.87 mmol) and triethylamine (1 .08 mL, 7.74 mmol) in dry THF (15 mL) was added under stirring at 0 °C MsCI (0.33 mL, 4.26 mmol). Resulting reaction mixture was stirred at 0 °C for 20 min, then fBuOK (0.65 g, 5.81 mmol) was added, and reaction mixture was stirred at 0 °C for additional 20 min. Then 1 M HCI (10 mL) was added, product was extracted to MeTHF (3 x 10 mL), combined organic phases were dried over MgS0 4 , then concentrated to afford crude compound, which was then purified by chromatography (Si0 2 , hexane:EtOAc) to afford title compound as colorless oil (0.52 g, 63%). MS (ESI) m/z: 213 [MH] + . Example 7: Preparation isopropyl frans-2-(3,4-difluorophenyl)cyclopropanecarboxylate (Via)

Va Via

To a solution of Va (0.5 g, 1 .94 mmol) and triethylamine (0.54 mL, 3.87 mmol) in dry THF (10 mL) was added under stirring at 0°C MsCI (0.17 mL, 2.13 mmol). Resulting reaction mixture was stirred at 0°C for 20 min, then fBuOK (0.43 g, 3.87 mmol) was added, and reaction mixture was stirred at 0°C for additional 20 min. Then 1 M HCI (10 mL) was added, product was extracted to MeTHF (3 x 10 mL), combined organic phases were dried over MgS0 4 , then concentrated to afford crude compound, which was then purified by chromatography (Si0 2 , hexane:EtOAc) to afford title compound as colorless oil (0.37 g, 79%). MS (ESI) m/z: 241 [MH] + . Example 8: Preparation of frans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (VII)

Vic VII

To a solution of Vic (0.36 g, 1 .70 mmol) in EtOH (5 mL) was added 5 M NaOH (0.37 mL, 1.87 mmol). Resulting reaction mixture was stirred at room temperature for 16 h. 1 M HCI (20 mL) was added, product was extracted to MeTHF (3 x 10 mL), combined organic phases were dried over MgS0 4 , and concentrated to afford white solid (0.28 g, 83% yield). MS (ESI) m/z: 199 [MH] + .

Example 9: Preparation of frans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (VII)

Via VII To a solution of Via (100 mg, 0.42 mmol) in EtOH (5 mL) was added 8 M NaOH (0.1 mL). Resulting reaction mixture was stirred at room temperature for 16 h. 1 M HCI (5 mL) was added, product was extracted to MeTHF (3 x 5 mL), combined organic phases were dried over MgS0 4 , and concentrated to afford white solid (61 mg, 73% yield).

Example 10: Preparation of 3-chloro-1 -(3,4-difluorophenyl)propan-1 -one (1Mb')

A mixture of AICI 3 (160 g), 1 ,2-difluorobenzene (I) and 3-chloropropionyl chloride (Mb') (96 mL) was stirred at 45 °C for 6 hours and the resulting mixture was poured into a mixture of ice (640 g) and concentrated HCI (60 mL). Another portion of ice (300 g) was added, the phases were separated and the organic phase was washed twice with dichloromethane (2 χ 100 mL). Combined organic phases were washed twice with satureted aqueous NaHC0 3 (2 χ 500 mL), dried with magnesium sulfate, filtered and concentrated under reduced pressure to give 206 g of 3-chloro-1 -(3,4-difluorophenyl)propan-1 -one (1Mb') as an oil.

Example 11 : Preparation of 4-(3,4-dif luorophenyl)-4-oxobutanenitrile (IVb)

To a solution of 3-chloro-1 -(3,4-difluorophenyl)propan-1 -one (1Mb') (20 g, 98 mmol) in ethyl acetate (50 mL) was added potassium tert-butoxide (9.60 g, 98 mmol) at 70 °C and stirred for 15 min and then cooled to 25 °C. The resulting mixture was filtered to remove salts (salts were washed with 5 mL of ethyl acetate and 10 mL of ethanol). To thus obtained was added dropwise a solution of sodium cyanide (9.6 g, 195 mmol) in water (50 mL) during 30 minutes. After the addition was complete the mixture was stirred at 25 °C for additional 0.5 hours, ethanol was added (20 mL) and the mixture was stirred for additional 3 hours. Phases were separated and the lower water layer was extracted with ethyl acetate (25 mL). The combined organic phases were washed with brine ( 3 χ 25 mL) and concentrated under reduced pressure to give 18.5 g (97 %) 4-(3,4-difluorophenyl)-4-oxobutanenitrile (IVb) as oil that crystallized on standing. 1 H NMR (CDCI 3 , 500 MHz): 5 2.78 (t, J = 7.1 Hz, 2H), 3.34 (t, J = 7.1 Hz, 2H), 7.29 (m, 1 H), 7.74 (m, 1 H), 7.80 (m, 1 H). Example 12: Preparation of 4-(3,4-difluorophenyl)-4-hydroxybutanenitrile (Vb)

To a cold (0 °C) solution of 4-(3,4-difluorophenyl)-4-oxobutanenitrile (IVb) (10 g, 51 mmol) in methanol (100 mL) was added portion wise sodium borohydride (1 .93 g) and the mixture was stirred at 5 °C for additional 30 minutes. Acetic acid (10 mL) was added drop wise and the methanol was removed under reduced pressure. Ethyl acetate (100 mL) was added and the resulting mixture was washed with water (3 χ 30 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the remaining oil was added methyl tert-butyl ether (30 mL, MTBE), filtered through the pad of silica gel (washed with some additional MTBE) and concentrated under reduced pressure. To the remaining oil was added toluene (20 mL) and again concentrated under reduced pressure to give 8.8 g (87 %) of 4-(3,4-difluorophenyl)-4- hydroxybutanenitrile (Vb) as an oil. 1 H NMR (CDCI 3 , 500 MHz): δ 1.96 (m, 2H), 2.38 (m, 1 H), 2.53 (m, 1 H), 4.75 (m, 1 H), 7.04 (m, 1 H), 7.15 (m, 2H). Example 13: Preparation of (S)-4-(3,4-difluorophenyl)-4-hydroxybutanenitrile (Vb')

Vb"

Mixture of 4-(3,4-difluorophenyl)-4-oxobutanenitrile (IVb) (1 .95 g, 10.0 mmol), ( ,/ )-TsDPEN- Ru(mesitylene)CI (30 mg, 0.05 mmol) and HC0 2 H : Et 3 N = 5 : 2 (4.4 g) in EtOAc (40 mL) was stirred at 20 °C for 16 h. Organic layer was washed with 1 M HCI (2 x 20 mL) and water (2 x 20 mL). Organic layer was then dried over MgS0 4 and concentrated. Crude product was purified by chromatography (silica gel; hexane/ethyl acetate) to afford 1 .87 g (95 %) of (S)-4-(3,4- difluorophenyl)-4-hydroxybutanenitrile (Vb'). 1 H NMR (CDCI 3 , 500 MHz): δ 1.96 (m, 2H), 2.38 (m, 1 H), 2.53 (m, 1 H), 4.75 (m, 1 H), 7.04 (m, 1 H), 7.15 (m, 2H); 91 % ee. Example 14: Preparation of frans-2-(3,4-difluorophenyl)cyclopropanecarbonitrile (VIb)

To a cold (0 °C) solution of 4-(3,4-difluorophenyl)-4-hydroxybutanenitrile (Vb) (5.7 g, 29 mmol) and triethylamine (8.0 mL, 57 mmol) in dry tetrahydrofurane (100 mL) was added methanesulfonyl chloride (2.5 mL, 32 mmol) and stirred at 0 °C for another 20 min. Potassium tert-butoxide (6.4 g, 57 mmol) was added and stirred at 0 °C for another 20 min. 1 M aqueous solution of HCI (57 mL) was added and the resulting solution was extracted with diethyl ether (3 x 70 mL). Combined ethereal layers were washed with brine (50 mL) and concentrated under reduced pressure. Crude product was purified by chromatography (silica gel; hexane/ethyl acetate 9 : 1 7 : 3) to give 2.84 g (55 %) of frans-2-(3,4-difluorophenyl)- cyclopropanecarbonitrile (VIb) as an oil. 1 H NMR (CDCI 3 , 500 MHz) : δ 1 .41 (m, 1 H), 1 .53 (m, 1 H), 1 .64 (m, 1 H), 2.60 (m, 1 H), 6.87 (m, 1 H), 6.92 (m, 1 H), 7.10 (m, 1 H).

Example 15: Preparation of (1 fl,2fl)-2-(3,4-difluorophenyl)cyclopropanecarbonitrile (VIb')

IVb' VIb'

To a cold (0 °C) solution of (S)-4-(3,4-difluorophenyl)-4-hydroxybutanenitrile (Vb') (1 1 .5 g, 58.5 mmol) and triethylamine (16.3 mL, 1 17 mmol) in dry tetrahydrofurane (200 mL) was added in 30 min methanesulfonyl chloride (5.4 mL, 70.2 mmol) and stirred at 25 °C for 1 h. Potassium tert- butoxide (6.4 g, 57 mmol) was then added at 0 °C, and stirred at 25 °C for 1 h. 2 M aqueous solution of HCI (50 mL) was added and the resulting solution was extracted with diisopropyl ether (3 χ 30 mL). Combined ethereal layers were washed with brine (100 mL), dried over MgS0 4 , and concentrated under reduced pressure. Crude product was purified by chromatography (silica gel; hexane/ethyl acetate) to give 4.17 g (40 %) of VIb' as an oil. 1 H NMR (CDCI 3 , 500 MHz) : δ 1 .41 (m, 1 H), 1 .53 (m, 1 H), 1 .64 (m, 1 H), 2.60 (m, 1 H), 6.87 (m, 1 H), 6.92 (m, 1 H), 7.10 (m, 1 H). Example 16: Preparation of frans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (VII)

A mixture of trans-2-(3,4-difluorophenyl)cyclopropanecarbonitrile (VIb) (7.70 g) and 4 M aqueous lithium hydroxide (281 ml_) was stirred at reflux temperature for 3.5 hours. The resulting mixture was cooled down and acidified with 4 M aqueous HCI to pH 1 and the product was extracted with MTBE (200 + 2 χ 150 ml_). Combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure to give 8.12 g (95 %) of frans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (VII) as a solid. 1 H NMR (CDCI 3 , 500 MHz) : δ 1 .36 (m, 1 H), 1 .68 (m, 1 H), 1 .87 (m, 1 H), 2.57 (m, 1 H), 6.86 (m, 1 H), 6.92 (m, 1 H), 7.08 (m, 1 H).

Example 17: Preparation of lithium frans-2-(3,4-difluorophenyl)cyclopropanecarboxylate (Vila)

VIb Vila A mixture of trans-2-(3,4-difluorophenyl)cyclopropanecarbonitrile (VIb) (0.2 g) and 4 M aqueous lithium hydroxide (7.3 ml_) was stirred at reflux temperature for 1 .5 hours. The resulting mixture was cooled down, the solid was filtered off, washed with cold water to give 0.15 g (66 %) of lithium frans-2-(3,4-difluorophenyl)cyclopropanecarboxylate (Vila) as a solid. 1 H NMR (DMSO- d6, 500 MHz): δ 0.89 (m, 1 H), 1 .21 (m, 1 H), 1 .53 (m, 1 H), 2.12 (m, 1 H), 6.89 (m, 1 H), 7.05 (m, 1 H), 7.24 (m, 1 H).