WO2013144295A1

WO2013144295A1 - Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts

Info

Publication number: WO2013144295A1
Application number: PCT/EP2013/056703
Authority: WO
Inventors: Borut ZUPANCIC; Parven Kumar Luthra; Rashid Khan; Raji Nair; Tonmoy Das; Sanket Gudekar; Aziz SYED
Original assignee: Sandoz Ag; Lek Pharmaceuticals D.D.
Priority date: 2012-03-30
Filing date: 2013-03-28
Publication date: 2013-10-03
Also published as: CN104603098B; CN104603098A

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.

Description

Synthesis of 2-{3,4-difluorophenyl)cyclopropanamine derivatives and salts

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 ?,2Sj-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3/-/-'/.2.3-triazolo[4.5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)-(1 S.2S,3R,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).

All synthetic approaches mentioned above utilize as one of the key intermediates the intermediate CPA ((1 R.2S)-2-(3,4-difluorophenyl)cyclopropylamine) of formula

CPA

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

According to WO 01 /92200 and WO 01/92263 CPA is prepared as shown in Scheme 1. 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- d (fluorophenyl )-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 2S,5R)-2-isopropyl-5-methylcyclohexyl (£)-3-(3,4-difluorophenyl)-2- propenoate, which is with dimethylsulfoxonium methylide, sodium iodide and NaOH in DMSO converted to (1 f?.2S,5/?)-2-isopropyl-5-methylcyclohexyl frans-2-(3,4-difluorophenyl)- cyclopropanecarboxylate. The latter is then hydrolyzed to (1 R,2R)-2-(3,4-difluorophenyl)- cyclopropanecarboxylic acid, which is subsequently converted to (1 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 iert-butylammonium bromide, which is finally converted to CPA.

Pyridine

Toluene NaN₃ Bu₄NBr, SOCi₂ Na₂C0₃

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

The eight steps synthesis described in Scheme 1 is very long and uses toxic compounds like sodium azide and pyridine. In addition, inorganic azides are potentially explosive. 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 (1 f?,2S)-2-(3,4-difluorophenyl)cyclopropylamine 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. CICO;,Et. Et_jN, 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 sultam 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. A process described in WO 1 1/017108 represents an improvement of the process described above in Scheme 2. Use of the most hazardous reagents has been omitted, in situ formation of diazomethane and expensive diphenylphosphoryl azide, (2R)-bornane-10.2-sultam and palladium acetate, however, still do not satisfy the need for safe and cheap industrial process. The overall approach of the improved process is presented in Scheme 3. a

Scheme 3: Synthesis of CPA as described in WO 1 1/017108.

According to WO 08/018822 and WO 08/018823, CPA is prepared as shown in Scheme 4. 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 (1 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 4: 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.

Another synthetic route for preparing CPA is described in WO 1 1/132083 (Scheme 5). 1.2- Difluorobenzene is reacted with 3-chloropropionyl chloride to produce 3-chloro-1 -(3',4'- difluorophenyl)-propan-1 -one, which is by addition of NJV-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- A/.A/-diethyl aniline complex in the presence of tetrahydrofurane. The obtained (1 R)-1 - (3\4'-difluorophenyl)-3-nitro-propan-1-ol is then added to a mixture of triphenylphosphine and diethylazodicarboxylate in benzene to yield (1 S,2R)-2-(3',4'-difluorophenyl)-1-nitrocyclopropane, which is in the last step converted to CPA by reduction of the nitro group by catalytic hydrogenation with palladium catalyst and zink dust.

Scheme 5: Synthesis of CPA as described in WO 1 1/132083. 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. 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 (1 f?,2R)-2-(3.4-difluorophenyl)-1- cyclopropanecarboxylate, which is converted to (1 2f?)-2-(3,4-difluorophenyl)-1 - cyclopropanecarboxylic acid by hydrolysis in the presence of sodium hydroxide and methanol. The obtained carboxylic acid is with aqueous hydroxylamine solution further converted to (1 R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxamide, which is mixed with pyridine and acetic anhydride to yield (1 2f?)-A/-(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 that environmentally unfriendly reagents are used, which makes the prior art processes unsuitable for large scale preparation of CPA. A need therefore remains for an alternative but commercially viable process for preparation of CPA which would at the same time be less hazardous and more environmentally friendly. Summary of the Invention

The object of the present invention was to provide an industrially applicable and economical process for obtaining (1 R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (CPA), an important intermediate in preparation of ticagrelor (TCG).

The present invention provides a process for the preparation of a compound of formula IX or a salt thereof

IX

wherein the chiral center * is in its (R) or (S) configuration,

comprising the steps of:

(i) providing a compound of formula V

V wherein the chiral center * is in its (R) or (S) configuration,

(ii) converting the hydrazide of formula V to an azide of formula VI

VI wherein the chiral center * is in its (R) or (S) configuration, and

(iii) converting the obtained compound of formula VI to provide the compound of formula IX or a salt thereof.

The process defined above allows for preparation or synthesis of (1 R,2S)-2-(3,4- difluorophenyl)cyclopropylamine with an industrially applicable and economical process while using environmentally friendly and non-explosive reagents. Preferred embodiments will be described below. Furthermore, the present invention provides for isolation of crystalline (1 R,2S)-2-(3,4- difiuorophenyl)cyclopropylamine hydrochloride (CPA.HCI) without previous isolation of CPA base.

The present invention further provides novel compounds that are useful as an intermediate the preparation of ticagrelor (TCG).

Brief Description of the Figures Fig. 1 shows an X-Ray diffraction pattern of crystalline (1 2S)-2-(3,4-difluorophenyl)- cyclopropylamine hydrochloride (CPA.HCI) prepared according to example 18.

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 one embodiment, the azide compound of formula VI is converted to a compound of formula IX directly or through a compound of formula Vlll as shown in Scheme 7.

lllb Curtius vlll

·_»· . \ Hydrazide rearrangement

Fstenfication \ formation /

Deprotection

Carbox lic

IV V VI IX

chirai center * is in its (R) or (S) configuration

Scheme 7: General representation of the basic synthetic concept of the invention.

Alternatively, the compound of formula VI can be converted to a compound of formula Vlll through isocyanate VII

VIS wherein the chiral center * is in its (R) or (S) configuration.

As presented in Scheme 7, the hydrazide V is prepared from frar?s-2-(3,4-difluorophenyl)- cyclopropanecarboxyiic acid IV directly or optionally via ester compound 1Mb.

According to another embodiment of the present invention, ?rans-2-(3,4-difluorophenyl)- cyclopropanecarboxylic acid IV is prepared as shown in Scheme 8.

Condensation

I II III IV

chiral center ^* is in its (R) or (S) configuration Scheme 8: General representation of the basic synthetic concept of the invention.

The process is based on cyciopropanation of alkene II, which can be prepared from 3,4- difluorobenzaldehyde I through aldol condensation or Wittig reaction. The cyciopropanation is carried out with a suitable reagent, for example with trimethylsulfoxonium iodide. The substituent Q in compounds of formula II and III can be any group that can be converted to either carboxylic group and allows cyciopropanation of II. Preferably, Q is selected from the group selected of Ci-C₆-alkyl carboxylic ester, carboxylic ester with a chiral alcohol such as L- menthol, N-substituted or unsubstituted carboxamide, cyano, hydroxymethyl, formyl, aldehyde, trihalomethyl, imide such as phthalimide etc. Cyclopropane III is then hydrolysed under acidic or basic conditions or oxidized to give frans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid IV.

The process of Scheme 8 selectively leads to irans-substituted racemic cyclopropanes. The enantiomers can be separated from the obtained racemic mixture in any step of preparation of compound IX, using principles in the art such as chromatographic separation, or crystallisation technics after preparation of diastereoisomers by introduction of a chiral moiety or by preparation diastereoisomeric salts with chiral counterion. For example, if Q is COO(L-menthyl) the racemic compound III can be separated to enantiomers by crystallisation as described in WO 01 /092200. In this case (fR_;2S_;5R)-2-isopropyl-5-methylcyclohexyl-2-(3,4-difluorophenyl)- cyclopropanecarboxylate is then hydrolysed to ( 7 2f?)-2-(3,4-difluorophenyl)cyclopropane- carboxylic acid (( 1R,2R) enantiomer of compound IV). In a particularly preferred embodiment presented in Scheme 9, the synthesis of trans-2-(3A- difluorophenyl)-cyclopropanecarboxylic acid IV begins with reacting 1 ,2-difluorobenzaldehyde and acetonitrile in the presence of a base, preferably KOH or BuLi, to give (E)-3-(3,4- difluorophenyl)acrylonitrile Ila as a white solid. Ila is then transformed to Ilia by cyclopropanation using trimethylsulfoxonium iodide and NaH or NaOH in DMSO. Enantiomerically enriched Ilia can be formed from Ila using methods for asymmetric cyclopropanation as described in the literature. In the next step, Ilia is hydrolyzed using basic or acidic conditions, preferably base, most preferably LiOH, to give frans-2-(3,4-difluorophenyl)- cyclopropanecarboxylic acid IV.

chiral center ^* is in its (R) or (S) configuration

Scheme 9: Synthesis of ?rans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid representing a particularly preferred embodiment of the invention.

In another preferred embodiment, methyl frans-2-(3.4-difluorophenyl)cyclopropanecarboxylate Illb is prepared from 1 ,2-difluorobenzaldehyde (Scheme 10). In the first step (£)-3-(3,4- difluorophenyl)acrylic acid Mb is prepared according to the procedure described in WO 01/92200 and WO 01/92263. This is followed by esterification, for which any acid in MeOH can be used, preferably H₂S0₄, to give lie as white solid, which is subsequently cyclopropanated using trimethylsulfoxonium iodide and NaH or NaOH in DMSO. Again, the enantiomerically enriched Illb can be formed from lie using methods for asymmetric cyclopropanation as described in the literature.

lib lie Illb

chiral center * is in its ( ) or (S) configuration

Scheme 10: Synthesis of methyl frans-2-(3,4-difluorophenyl)cyclopropanecarboxylate Illb

representing the embodiment of the invention.

In the next step, the carboxylic acid IV is transformed to irans-2-(3.4-difluorophenyl)- cyclopropanecarbonyl azide VI (Scheme 1 1 ). IV can be converted directly to hydrazide V or through ester lllb, which can be prepared by cyclopropanation of lie as described above, or by esterification of IV using any acid in MeOH, preferably H₂S0₄.

Hydrazide V can be prepared as a white solid compound directly from the carboxylic acid IV by heating it with SOCI₂ in any aprotic solvent, preferably toluene, followed by reaction with hydrazine. Alternatively, hydrazide V is prepared by stirring ester lllb and hydrazine in any solvent, preferably solvent from Ci-C₆ alcohols, most preferably methanol, in a temperature range from 0 to 150 C, preferably the temperature is 70 C.

Hydrazide V can be then reacted with nitrite, preferably NaN0₂ in acidic media, preferably in AcOH, to form frans-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI.

IV lllb

chiral center * is in its (R) or (S) configuration

Scheme 11 : Synthesis of frans-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI from irans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid IV representing the embodiment of the invention.

The procedure of Scheme 1 1 does not use explosive inorganic or organic azides. Furthermore, the intermediate hydrazide of formula V is solid and can be optionally purified by crystallisation if needed.

As discussed above, the preferred enantiomer can be obtained from the racemic mixture in any step of preparation of compound IX using principles well known in the art. In a preferred embodiment, the carboxylic acid of formula IV is provided in enantiomerically pure form (1 /?,2f?)-2-(3.4-difluorophenyl)cyclopropanecarboxylic acid (IV). Use of enantiomerically pure carboxylic acid IV gives (1 ,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide (compound VI') according to Scheme 12.

Scheme 12: Synthesis of (1 R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide VI' from

(1 R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid IV representing the embodiment of the invention.

The enantiomerically pure (1 2f?)-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI' or racemic frans-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide VI can then be directly transformed to (1 2S)-2-(3,4-difluorophenyl)cyclopropanamine (CPA) or trans-2-(3A- difluorophenyl)cyclopropanamine IX, respectively, by a one-pot reaction as described in WO 01 /92200 and WO 01 /92263.

Alternatively, the carbamate protected amine VIII can also be prepared directly from VI or through isocyanate VII (Scheme 13), which can be prepared by simple heating of compound VI in any aprotic solvent, preferably toluene, at a temperature falling into the range of 25 to 150 C, preferably the temperature is 80 C. VII is then transformed to Villa by reaction with iBuOH at 25 to 150 C, preferably at the temperature of reflux, or by reacting KOfBu in any aprotic solvent at a temperature falling in the range of -50 to 100 C, preferably at 0 C.

chiral center ^* is in its (R) or (S) configuration

Synthesis of frans-2-(3,4-difluorophenyl)cyclopropanamine (IX) and its Boc protected analog Villa from irans-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide VI representing the embodiment of the invention. Analogously, in a preferred embodiment presented in Scheme 14 the enantiomerically pure chiral azide (1 2f?)-2-(3,4-difluorophenyl)cyclopropanecarbonyl (VI') is converted to (1 R,2R)-2- (3,4-difluorophenyl)cyclopropanamine hydrochloride (CPA) Villa or Villa' can also be prepared through one-pot transformation starting from VI or VI', respectively, according to the same reaction conditions as described above.

Scheme 14: Synthesis of (1 2S)-2-(3.4-difluorophenyl)cyclopropanamine (CPA) and its Boc protected analog Villa' from (1 2f?)-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI' representing the embodiment of the invention.

The intermediate Villa or Villa' is hydrolysed by hydrochloric acid in the mixture of methanol and water. This mixture is preferred due to unexpected lower solubility of hydrochloride salt in water. Said hydrochloride salt is provided in crystalline form and smoothly precipitates from the mixture, giving the product in high yield. Such approach is advantageous over the prior art process described in CN102249929, in which hydrolysis occurs in ethyl acetate/water mixture and the product is finally isolated following the neutralization, as a base from the organic phase. The crystalline hydrochloride salt of CPA can be prepared also in the absence of water by introducing gaseous hydrogen chloride, optionally dissolved in an organic solvent, preferably diethyl ether, to a solution comprising CPA base in an organic solvent such as aromatic hydrocarbons or ethers. According to another embodiment of the present invention, the compound of formula V is prepared by reaction of cyclopropanation from a compound of formula B as shown in Scheme 15. Suitable reagents for this reaction are for example trimethyl sulfoxonium iodide, trimethyl sulfoxonium bromide, trimethyl sulfonium iodide and trimethyl sulfonium bromide. Preferred reagent is trimethyl sulfoxonium iodide. ,o

c

hydrolysis

hydrazine hydrate

IV Illb

chiral center ^* is in its ( ) or (S) configuration

Scheme 15: Synthetic steps showing the embodiment of the present invention.

The compound of formula A is prepared as shown in Scheme 15. (E)-3-(3.4-Difluorophenyl) acrylic acid (lib), prepared for example as described in WO 01/92200 and WO 01/92263, is converted into its acid halide, for example chloride (lid). Said acid chloride is then reacted with N. O-dimethyl hydroxylamine hydrochloride to obtain (£)-3-(3,4-difluorophenyl)-/V-methoxy-A/- methylacrylamide (A).

The compound of formula B is further converted to the hydrazide compound of formula V. This step can be performed directly by reacting the compound of formula V with hydrazine hydrate. Alternatively, the compound of formula B can be hydrolyzed into 2-(3.4- difluorophenyl)cyclopropanecarboxylic acid (IV), which is then converted into its ester (Illb). Said ester, which is for example ester with a linear or branched alkyl, preferably Ci to C₆ alkyl ester, is then reacted with hydrazine hydrate giving the compound of formula V.

According to another embodiment, the compound of formula IX can be further converted to a stereochemicaily pure (1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine in a form of a salt, for example by chiral resolution of the racemic amine IX with an optically active acid. A preferred optically active acid is R-mandelic acid.

chiral center ^* is in its (R) or (S) configuration

Scheme 16 showing the preferred embodiment of the present invention.

Scheme 16 represents a preferred embodiment of the present invention. (£)-3-(3,4- Difluorophenyl) acrylic acid (lib) is converted into its acid chloride by reaction with thionyl chloride or oxalyl chloride in DM F. The obtained acid chloride (lid) is reacted with N.O-dimethyl hydroxylamine hydrochloride in the presence of pyridine to obtain (£)-3-(3.4-difluorophenyl)-A/- methoxy-AZ-methylacrylamide (A). This compound is then cyclopropanated with trimethyl sulfoxonium iodide in sodium hydride and DMSO to give 2-(3.4-difluorophenyl)-A/-methoxy-/V- methylcyclopropanecarboxamide (B). Alternatively, sodium hydroxide can be used instead of sodium hydride to perform this step. The intermediate B can be converted into 2-(3,4- difluorophenyl)cyclopropanecarbohydrazide (V) by either

(i) reacting B with hydrazine hydrate to directly obtain V, or

(ii) hydrolyzing B into 2-(3.4-difluorophenyl)cyclopropanecarboxylic acid (IV), which is then converted into its methyl ester and then further reacted with hydrazine hydrate to obtain V.

2-(3.4-difluorophenyl)cyclopropanecarbohydrazide (V) is then reacted with sodium nitrite in the presence of HCI to obtain the corresponding acyl azide (VI) which is then subjected to the Curtius rearrangement to give VII. In the next step, the compound VII is hydrolyzed to obtain 2- (3,4-difluorophenyl)cyclopropanamine (IX). The reaction path from V to IX is carried in the same pot, without isolating intermediates VI and VII. The desired isomer (1 ?,2S)-2-(3,4- difluorophenyl)cyclopropanamine is then isolated in the form of its salt (IX') by reacting with R- mandelic acid.

Further aspect of the present invention resides in the provision of a valuable intermediate trans- 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide (compound of formula V), useful in the synthesis of ticagrelor (TCG):

V

wherein the chiral center ^* is in its (R) or (S) configuration.

In a preferred embodiment the intermediate is enantiomerically pure (1 ?,2 ?)-2-(3,4- difluorophenyl)cyclopropanecarbohydrazide (V)

V

Further aspect of the present invention resides in the provision of intermediate compounds of formula A and B useful in the synthesis of ticagrelor (TCG):

A B

wherein the chiral center ^* is in its (R) or (S) configuration.

Yet further aspect of the present invention resides in the provision of crystalline trans-2-(3,4- difluorophenyl)cyclopropanamine hydrochloride (IX.HCI), wherein the chiral center ^* is in its (R) or (S) configuration.

IX.HCI

Further particularly preferred aspect of the present invention resides in the provision of crystalline (1 f?,2S)-2-(3.4-difluorophenyl)cyclopropanamine hydrochloride (CPA.HCI).

CPA.HCI

In the following the present invention will be described in further detail by illustrative, non- limiting examples.

Examples

Example 1 : Preparation of (£)-3-(3.4-difluorophenyl)acrylonitrile (Ila)

Ila To a mixture of KOH (3.3 g, 50 mmol, 85%) and MeCN (40 mL) was heated to 80 C, and then I (7.1 g, 50 mmol) was added. The resulting reaction mixture was stirred at 80 C for 1 h, then it was poured into ice (50 g), and water (100 mL) was then added. After extraction with MeTHF (3 x 50 mL), combined organic layers were dried over MgS0₄, and then concentrated to afford crude product, which was then recrystallized from hexane to give title compound Ila as colorless crystals (1.67 g, 20% yield). DSC (Onset): 70 C; ¹H NMR (CDCI₃): 5.83 (d, 1 H, J 16.7), 7.19- 7.26 (m, 2H), 7.26-7.35 (m, 2H); ¹⁹F NMR (CDCI₃): -136.6 (m, 1 F), -133.2 (m, 1 F); MS (ESI) m/z: 166 [MH]\

Example 2: Preparation of (E)-methyl 3-(3.4-difluorophenyl)acrylate (lie)

lib lie

The compound Mb was prepared through procedure described in (WO 2001/92200 and WO 2001/92263).

A mixture of Mb (20.0 g, 109 mmol) and H₂S0₄ (96%, 0.50 g) in MeOH (150 mL) was stirred at 60 C for 3 days, then half of the MeOH was evaporated, 20 mL saturated aq. solution of NaHC0₃ was added, and water (50 mL) was added. White precipitate was then filtered off, washed with water and dried to afford title compound lie as white powder (20.7 g, 90% yield). DSC (Onset): 76 C; ¹H NMR (CDCI₃): 3.82 (s, 3H), 6.36 (d, 1 H, J 16.0), 7.19 (m, 1 H), 7.26 (m, 1 H), 7.35 (m, 1 H), 7.60 (d, 1 H, J 16.0): MS (ESI) mlz: 199 [MHf. Preparation of frans-2-(3,4-difluorophenyl)cyclopropanecarbonitrile (Ilia)

Ha Ilia

To a solution of tnmethylsulfoxonium iodide (0.80 g, 3.64 mmoi) in dry DMSO (10 mL) was added at 25 C NaH (60%, 0.15 g, 3.64 mmoi). The resulting reaction mixture was stirred 30 min at 25 C, then lia (0.50 g, 3.03 mmoi) was added at 0 C, and reaction mixture was stirred at 25 C for 16 h. Water (80 mL) was added, and product was extracted to MeTHF (3 x 20 mL). Combined organic layers were dried over MgS0₄, and then concentrated to afford crude product, which was then purified by chromatography (Si0₂, hexane:EtOAc) to give title compound Ilia as colorless oil (0.29 g, 53% yield). ¹ H NMR (CDCI₃): 1.41 (m, 1 H), 1.54 (m, 1 H), 1.65 (m, 1 H), 2.61 (m, 1 H), 6.87 (m, 1 H), 6.92 (m, 1 H), 7.1 1 (m, 1 H); MS (ESI) m/z: 213 [MH]\

Example 4: Preparation of methyl ?rans-2-(3.4-difluorophenyl)cyclopropanecarboxylate (Illb)

lie Illb

To a solution of tnmethylsulfoxonium iodide (5.55 g, 25.2 mmoi) in dry DMSO (40 mL) was added at 25 C NaH (60%, 1.0 g, 25.2 mmoi). The resulting reaction mixture was stirred 30 min at 25 C, then lie (5.0 g, 25.2 mmoi) was added at 0 C, and reaction mixture was stirred at 25 C for 16 h. Water (200 mL) was added, and product was extracted to MeTHF (3 x 50 mL).

Combined organic layers were dried over MgSO.₍, and then concentrated to afford crude product, which was then purified by chromatography (Si0₂, hexane:EtOAc) to give title compound Illb as colorless oil (4.0 g, 75% yield). ¹ H NMR (CDCI₃): 1 .26 (m, 1 H), 1.60 (m, 1 H),

1.85 (m, 1 H), 2.49 (m, 1 H), 3.72 (s, 3H), 6.83 (m, 1 H), 6.89 (m, 1 H), 7.06 (m, 1 H); ¹⁹F NMR

(CDCI₃): -137.8 (m, 1 F), -140.8 (m, 1 F); MS (ESI) m/z: 213 [MH]\

Example 5: Preparation of frans-2-(3.4-difluorophenyl)cyclopropanecarboxylic acid (IV)

Ilia IV

A mixture of Ilia (1.1 g. 6.14 mmoi) and 4 M aq. LiOH (35 mL) in /PrOH (20 mL) was stirred at reflux temperature for 3.5 hours. Slowly 10% aq. HCI (70 mL) was added, and product was extracted to MeTHF (3 x 20 mL). Combined organic layers were dried over MgS0₄, and then concentrated to afford title compound (IV) as white solid (1.15 g, 95% yield).¹H NMR (CDCI₃):

I.38 (m, 1H), 1.69 (m, 1H), 1.88 (m, 1H), 2.59 (m, 1H), 6.87 (m, 1H), 6.93 (m, 1H), 7.11 (m, 1H),

II.94 (brs, 1H); ¹⁹F NMR (CDCI₃): -137.5 (m, 1F), -140.4 (m, 1F); MS (ESI) m/z: 199 [MH]\

Example 6: Preparation of methyl frans-2-(3.4-difluorophenyl)cyclopropanecarboxylate (Illb)

IV Illb

To a solution of IV (2.0 g, 10.1 mmol) in MeOH (40 mL) H₂S0₄ (0.2 g, 96%) was added at 0 C. The resulting reaction mixture was stirred at 60°C for 2 h, then saturated solution of NaHC0₃ (5 mL) was added, and product was extracted to THF (3 x 20 mL). Combined organic layers were dried over MgS0₄, and then concentrated to afford title compound (Illb) as colorless oil (2.1 g, 98% yield).¹H NMR (CDCI₃): 1.26 (m, 1H), 1.60 (m, 1H), 1.85 (m, 1H), 2.49 (m, 1H), 3.72 (s, 3H), 6.83 (m, 1H), 6.89 (m.1H), 7.06 (m, 1H); ¹⁹F NMR (CDCI₃): -137.8 (m, 1F), -140.8 (m, 1F); MS (ESI) m/z: 213 [MH]\

Example 7: Preparation of frans-2-(3,4-difluorophenyl)cyclopropanecarbohydrazide (V)

Illb V^COHH2

To a solution of Illb (2.1 g, 9.90 mmol) in MeOH (15 mL) NH₂NH₂ (1.74 mL, 52% in water) was added at 25 C The resulting reaction mixture was stirred at 70 C for 16 h, then 1 M NaOH (50 mL) was added, product (V) was filtered off, washed with water (50 mL), and dried in vacuum. White powder was obtained (1.8 g, 86% yield). DSC (Onset): 128.5 C; ¹H NMR (DMSO-d₆): 1.24 (m, 1H), 1.34 (m, 1H), 1.76 (m, 1H), 2.27 (m, 1H), 4.22 (br s, 2H), 6.98 (m, 1H), 7.20 (m, 1H), 7.30 (m, 1H). 9.18 (br s, 1H); ¹⁹F NMR (DMSO-d₆): -140.0 (m, 1F), -143.6 (m, 1F); MS (ESI) m/z: 213 [MH]\

Example 8: Preparation irans-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide (VI)

VI To a solution of V (1 .0 g, 4.71 mmol) in AcOH (10 mL) was added under stirring at 25 C NaN0₂ (0.36 g, 5.18 mmol). Resulting reaction mixture was stirred at 25 C for 30 min, then water (100 mL) was added, product was extracted to EtOAc (3 x 30 mL), combined organic layers were dried over MgS0₄, then concentrated to afford crude compound, which was then purified by chromatography (Si0₂, hexane:EtOAc) to afford title compound (VI) as colorless oil (0.65 g, 62% yield). ¹H NMR (CDCI₃): 1.40 (m, 1 H), 1.72 (m, 1 H), 1 .86 (m, 1 H), 2.60 (m, 1 H), 6.84 (m, 1 H), 6.89 (m, 1 H), 7.08 (m, 1 H); ¹⁹F NMR (CDCI₃): -138.3 (m, 1 F), -141 .1 (m, 1 F).

Example 9: Preparation of 1 ,2-difluoro-4-(frans-2-isocyanatocyclopropyl)benzene (VII)

VI VII

A solution of VI (1 .31 g, 5.88 mmol) in toluene (10 mL) was stirred at 80 C for 2 h. Evaporation of the solvent afforded title compound VII as colorless oil (1.07 g, 93% yield). ¹H NMR (CDCI₃): 1.20 (m, 1 H), 1.33 (m, 1 H), 2.18 (m, 1 H), 2.90 (m, 1 H), 6.81 (m, 1 H), 6.86 (m, 1 H), 7.09 (m, 1 H); ¹⁹F NMR (CDCI₃): -137.6 (m, 1 F), -140.8 (m, 1 F).

Example 10: Preparation of ferf-butyl £rans-2-(3,4-difiuorophenyl)cyclopropyl)carbamate (Villa)

VII Villa

A solution of VII (1.0 g, 5.12 mmol) in iBuOH (15 mL) was stirred at 80 C for 24 h. Then water (50 mL) was added, and white solid material was filtered off and dried to afford title compound Villa as white powder (1 .20 g, 87% yield). ¹H NMR (CDCI₃): 1.08-1 .17 (m, 2H), 1.45 (s, 9H), 2.01 (m, 1 H), 2.64 (m, 1 H), 4.89 (br s, 1 H), 6.89 (m, 1 H), 6.96 (m, 1 H), 7.03 (m, 1 H); ¹⁹F NMR (CDCI₃): -139.3 (m, 1 F), -142.8 (m, 1 F); MS (ESI) mlz: 270 [MH]\

Example 11 : Preparation of irans-2-(3.4-difluorophenyl)cyclopropanamine hydrochloride salt

(IX.HCI)

V^llla IX.HCI To a solution of Villa (0.15 g, 0.56 mmol) in MeOH (3 mL) was added 2 mL of 37% HCI. Resulting reaction mixture was stirred at 25 C for 2 h, then water (5 mL) was added, white precipitate was filtered off, washed with water (2 mL), and dried to afford title compound IX as HCI salt. DSC (Onset): 153°C; ¹H NMR (DMSO-d₆): 1 .20 (m, 1 H), 1 .45 (m, 1 H), 2.40 (m, 1 H), 2.78 (m, 1 H), 7.05 (m, 1 H), 7.25 (m, 1 H), 7.32 (m, 1 H), 8.76 (br s. 3H); ¹⁹F NMR (DMSO-d₆): - 138.9 (m, 1 F), -142.1 (m, 1 F).

Preparation of methyl (1 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate

(Illb')

The compound IV was prepared through procedure described in WO 2001/92200 and WO 2001/92263.

To a solution of IV (4.0 g, 20.2 mmol) in MeOH (60 mL) H₂S0₄ (0.2 g, 96%) was added at OX. The resulting reaction mixture was stirred at 60 C for 2 h, then saturated solution of NaHC0₃ (10 mL) was added, and product was extracted to THF (3 x 30 mL). Combined organic layers were dried over MgS0₄, and then concentrated to afford title compound (Illb') as colorless oil (3.94 g, 92% yield). ¹ H NMR (CDCI₃): 1 .26 (m, 1 H), 1 .60 (m, 1 H), 1 .85 (m. 1 H), 2.49 (m, 1 H), 3.72 (s, 3H), 6.83 (m, 1 H), 6.89 (m, 1 H), 7.06 (m, 1 H); ¹⁹F NMR (CDCI₃): -137.8 (m, 1 F), -140.8 (m, 1 F); MS (ESI) m/z: 213 [MHf.

Example 13: Preparation of (1 R,2f?)-2-(3.4-difluorophenyl)cyclopropanecarbohydrazide (V)

Illb' V

To a solution of 1Mb' (3.15 g, 14.9 mmol) in MeOH (25 mL) NH₂NH₂ (2.61 mL, 52% in water) was added at 25 C. The resulting reaction mixture was stirred at 70 C for 16 h, then 1 M NaOH (70 mL) was added, product (V) was filtered off, washed with water (100 mL), and dried in vacuum. White powder was obtained (2.7 g, 86% yield). Melting point: 129 C; ¹H NMR (500 MHz, DMSO-de): 1.24 (m, 1 H), 1.34 (m, 1 H), 1.76 (m, 1 H), 2.27 (m, 1 H), 4.22 (br s, 2H), 6.98 (m, 1 H), 7.20 (m, 1 H), 7.30 (m, 1 H), 9.18 (br s, 1 H); ¹⁹F NMR (470 MHz, DMSO-d₆): -140.0 (m, 1 F), -143.6 (m, 1 F); MS (ESI) m/z: 213 [MHf. Example 14: Preparation (1 R,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide (VI')

VI'

To a solution of V (1.7 g, 8.0 mmol) in AcOH (15 mL) was added under stirring at 25 C NaN0₂ (0.61 g, 8.8 mmol). Resulting reaction mixture was stirred at 25 C for 30 min, then water (200 mL) was added, product was extracted to MeTHF (3 x 30 mL), combined organic layers were dried over MgS0₄, then concentrated to afford crude compound, which was then purified by chromatography (Si0₂, hexane:EtOAc) to afford title compound (VI') as colorless oil (1 .32 g, 74% yield). ¹H NMR (CDCI₃): 1.40 (m, 1 H), 1.72 (m, 1 H), 1 .86 (m, 1 H), 2.60 (m, 1 H), 6.84 (m, 1 H), 6.89 (m, 1 H), 7.08 (m, 1 H); ¹⁹F NMR (CDCI₃): -138.3 (m. 1 F), -141 .1 (m, 1 F).

Example 15: Preparation of terf-butyl (1 R,2S)-2-(3,4-difluorophenyl)cyclopropyl)carbamate

(Villa')

A solution of VI' (2.6 g, 1 1.6 mmol) in toluene (20 mL) was stirred at 80 C for 16 h. Then volatile components were evaporated and fBuOH (10 mL) was added. Resulting reaction mixture was stirred at 80 C for 6 days. Then water (50 mL) was added, and white solid material was filtered off and dried to afford title compound Villa' as white powder (1 .72 g, 55% yield). DSC (Onset): 1 10°C; ¹ H NMR (CDCI₃): 1.08-1 .17 (m, 2H), 1.45 (s, 9H), 2.01 (m, 1 H), 2.64 (m, 1 H), 4.89 (br s, 1 H), 6.89 (m, 1 H), 6.96 (m, 1 H), 7.03 (m, 1 H); ¹⁹F NMR (CDCI₃): -139.3 (m, 1 F), -142.8 (m, 1 F); MS (ESI) mlz 270 [MH]⁺.

Example 16: Preparation of (1 2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride salt (CPA.HCI)

V^illa' CPA.HCI

To a solution of Villa' (0.30 g, 1.12 mmol) in MeOH (10 mL) was added 4 mL of 37% HCI. Resulting reaction mixture was stirred at 25 C for 2 h, then MeOH was partly evaporated, water (10 mL) was added, white precipitate was filtered off, washed with water (5 mL), and dried to afford title compound CPA as HCI salt (0.18 g, 76% yield). DSC (Onset): 200 C; ¹H NMR (DMSO-de): 1.20 (m, 1 H), 1.45 (m, 1 H), 2.40 (m, 1 H), 2.78 (m, 1 H), 7.05 (m, 1 H), 7.25 (m, 1 H), 7.32 (m, 1 H), 8.76 (br s, 3H); ¹⁹F NMR (DMSO-d₆): -138.9 (m, 1 F), -142.1 (m. 1 F).

Example 17: Preparation of (1 2S)-2-(3,4-difluorophenyl)cyclopropanamine (CPA)

To a 1 M NaOH (20 mL) was added under stirring at 25 C CPA.HCI (0.15 g, 0.78 mmol). Resulting reaction mixture was stirring at 25 C for 15 min, then the product was extracted to MeTHF (3 x 5 mL). Combined organic layers were dried over Na₂S0₄, then concentrated to afford CPA as yellowish oil (125 mg, 95% yield). ¹ H NMR (CDCI₃): 0.88 (m, 1 H), 1 .02 (m, 1 H), 1.66 (br s, 2H), 1.79 (m, 1 H), 2.46 (m, 1 H), 6.68-6.77 (m, 2H), 6.98 (m, 1 H); ¹⁹F NMR (CDCI₃): -139.6 (m, 1 F), -143.8 (m, 1 F);

Example 18: Preparation of (1 2S)-2-(3,4-difiuorophenyl)cyclopropanamine hydrochloride salt (CPA.HCI)

CPA was prepared as above or through procedure described in WO 2001/92200 and WO 2001/92263.

To an ice-cold 37% HCI (30 mL) was slowly added (1 f?,2S)-2-(3,4-difluorophenyl)- cyclopropanamine (CPA, 5.0 g, 29.6 mmol). Resulting reaction mixture was stirred at OX, for 15 min, then white precipitate was filtered off, washed with water (10 mL) and dried. Filtrate was concentrated to -50% of starting volume, white precipitate was again filtered off and dried. White crystals were obtained (5.28 g, 87% yield). XPRD, characteristic angles (2Θ, in °): 15.6 ± 0.2, 18.4 ± 0.2, 21.3 ± 0.2, 23.1 ± 0.2, 23.6 ± 0.2, 28.4 ± 0.2, 29.1 ± 0.2, 31 .3 ± 0.2; DSC (Onset): 200 C; ¹H NMR (DMSO-d₆): 1.20 (m, 1 H), 1.45 (m, 1 H), 2.40 (m, 1 H), 2.78 (m, 1 H), 7.05 (m, 1 H), 7.25 (m, 1 H), 7.32 (m, 1 H), 8.76 (br s, 3H); ¹⁹F NMR (DMSO-d₆): -138.9 (m, 1 F), -142.1 (m, 1 F).

Example 19: Preparation of (1 2S)-2-(3,4-difluorophenyl)cyclopropanamine hydrochloride salt (CPA.HCI)

CPA HCI

To a stirred mixture of (1 2R)-2-(3,4-difluorophenyl)cyclopropanecarbohydrazide (V) (1 .67 g, 7.87 mmol), toluene (30 mL), MeTHF (10 mL) and 2 M HCI (aq., 30 mL) at 20 C was added NaN0₂ (0.60 g, 8.66 mmol). Resulting reaction mixture was stirred at 20 C for 1 h, then water layer was separated and organic layer was dried over MgS0₄. Salts were filtered off and filtrate was stirred while heating at 100 C for 1 h. Reaction mixture was then cooled to 20°C and it was slowly added to a stirred mixture of 37% HCI (aq., 30 mL) and water (10 mL) at 60 C. When all of the solution was added, the reaction mixture was stirred at 60 C for additional 15 min, then it was cooled to 20 C, and organic layer was separated. Water layer was then washed with MeTHF/toluene mixture (2:1 , 3 x 30 mL) and neutralized with Na₂C0₃. CPA was then extracted to the toluene (2 x 20 mL), combined organic layers were dried over Na₂S0₄, salts were filtered off, and to the filtrate HCI (1 M solution in diethyl ether, 7 mL) was added. White precipitate was filtered off, washed with toluene (2 x 5 mL) and dried to afford title compound (CPA. HCI) as white powder (0.71 g, 44% yield). ¹H NMR (DMSO-d₆): 1.20 (m, 1 H), 1 .45 (m, 1 H), 2.40 (m, 1 H), 2.78 (m, 1 H), 7.05 (m, 1 H), 7.25 (m, 1 H), 7.32 (m, 1 H), 8.76 (br s, 3H); ¹⁹F NMR (DMSO-d₆): -138.9 (m. 1 F). -142.1 (m, 1 F).

Example 20: Preparation of (E)-3-(3,4-difluorophenyl)-A/-methoxy-A/-methylacrylamide (A)

Preparation of (E)-3-(3, 4-difluorophenyl)acryloyl chloride

100 g (0.54 moles) of (£)-3-(3,4-Difluorophenyl) acrylic acid was dissolved in 250 ml dichloromethane at about 25 to 30 C. A solution of the 276 g of oxalyl chloride (2.17 moles) in 100 ml dichloromethane was added slowly to reaction mixture in about 15 minutes. This was followed by the addition of a solution of 20 ml. DMF in 150 ml dichloromethane at 25°C to 30 C in about 15 minutes. The reaction mixture stirred for about 2 h, solvent was distilled under reduced pressure below 40 C to obtain product in the form of a semisolid.

The semisolid obtained was dissolved in about 100 ml acetone and used as such in next step.

Conversion of (E)-3-(3,4-difiuorophenyl)acryloyl chloride into (2E)-3-(3,4-difluorophenyl)-N- methoxy-N-methylacryiamide

In another reaction flask, was prepared a solution of 59 g (0.597 moles) Ν,Ο-dimethyl hydroxylamine hydrochloride in acetone. The solution was cooled to 0 to 5 C. Pyridine 128 g (1.62 moles) was added to this solution and the reaction mixture was stirred at 25 C to 30 C for about 10 minutes. The solution of the acid chloride in acetone previously prepared was added slowly to the reaction mixture maintaining the temperature between 0 to 5 C. After completion of the reaction solvent from the reaction mixture was distilled out under vacuum below 40 C. To the residue was added 500 ml dichloromethane followed by hydrochloric acid (dilute) till pH of aqueous layer was about 2 to 3. The resultant biphasic mixture was stirred for about 15 minutes and then the layers were allowed to settle for about 10 minutes. The lower organic layer was separated and washed 500 ml with saturated bicarbonate solution followed by 250 ml water. The solvent was distilled under reduced pressure below 40 C to obtain 1 14.5 g of product.

1H NMR in (400MHz, CDCI₃) 6 3.30 (3H.s), 3.76 (3H,s), 6.91-6.95 ( 1 H, d), 7.12-7.19

(1 H, m), 7.26- 7.28 (1 H, m), 7.34-7.40 ( 1 H, m), 7.59-7.63 ( 1 H, d) Example 21 : Preparation of 2-(3,4-difluorophenyl)- V-methoxy- \/-methylcyclopropanecarbox- amide (B)

To 500 ml of dimethylsulphoxide was added 242 g (1.1 moles) of trimethylsulphoxonium iodide at 25 C to 30 C. To the resultant slurry was charged 17 g (0.66 moles) of sodium hydride in portions carefully to avoid exotherm. The reaction mixture was then stirred at 25°C to 30 C for about 1 hr. Then, to the reaction mixture was added a solution of 100 g (£)-3-(3,4- difluorophenyl)-A/-methoxy-A/-methylacrylamide as obtained above dissolved in 100 ml of dimethylsulphoxide, slowly between 25 C and 30 C.

The reaction mixture was stirred at 25 C to 30 C for 3 h and diluted with about 2.5 L water and extracted with toluene. The toluene solution was washed with brine followed by water and distilled under vacuum to obtain 106 g of the cyclopropanated product in the form of oil. This oil was used as such for the next step.

H NMR in (400MHz,DMSO d₆) 5 1.33-1 .37 (1 H,m), 1.40-1 .44 (1 H,m), 2.32- 2.39 ( 2H, m), 3.13 (3H,s ), 3.65 ( 3H, s ), 7.04-7.08 ( 1 H, m), 7.25 -7.33 ( 2H, m)

Example 22: Preparation of 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide (V)

To the oil obtained in the above example were added 250 ml of methanol and 140.25 (2.8 moles) g of hydrazine hydrate. The resultant reaction mixture was heated to about 60 C to 65 C for 12 h. After completion of the reaction, solvent was distilled from reaction mixture under reduced pressure. The reaction mixture was diluted with ethyl acetate and washed with brine.

The ethyl acetate was distilled completely under reduced pressure to obtain 62 g (yield = 70%) product in the form of a solid.

1H NMR in (400MHz, DMSO d₆) δ 1 .27-1 .37 (2H, m), 1.74- 1.78 (1 H, m), 2.25-2.28

(1 H, m), 4.22(2H, s), 7.00 (1 H, m), 7.19-7.34( 21-1, m), 9.10 ( 1 H, s)

Example 23: Preparation of 2-(3,4-difluorophenyl)cyclopropanamine (IX) 20 g (94.3 mmoles) 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide was added to 50 ml of water and the slurry was cooled to 0-5 ' C. 100 ml (6N) Hydrochloric acid was added slowly and stirred to dissolve the solid. To the resultant clear solution sodium nitrite solution (6.5 g dissolved in 100 ml) was added slowly at 0-5 C over a period of 30 min followed by 200 ml of toluene. The reaction mixture was stirred for 15 min, stirring stopped to separate layers. Toluene layer containing azide intermediate collected and was added slowly over one hour to 50 ml of toluene at 1 10 °C. The reaction mixture was refluxed for 1 h at 1 10 C and the hot toluene solution was transferred to 200 ml (6N) hydrochloric acid at 100 C under stirring and the reflux continued for another 2 hr. The reaction mixture was cooled to 25 °C and the layers were allowed to separate. Aqueous layer collected and the pH was adjusted to 10. 200 ml of methylene dichloride was added and stirred for 15 min. The dichloromethane layer separated and concentrated under vacuum below 40 C to get 10 g of 2-(3.4-difluorophenyl)- cyclopropanamine as an oil.

Example 24: Preparation of (1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine R-mandelic acid salt (IX')

To a solution of 9 g R-mandelic acid in 300 ml of methanol at 45 C, was added a solution of 10 g of 2-(3.4-difluorophenyl)cyclopropanamine in 300 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25 C, stirred for 1 h, then further cooled slowly to 18 C and maintained for another 1 h. The crystalized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 7.56 g of product as a white crystalline solid.

¹H NMR in (400MHz, DMSO d₆) 5 1 .13 -1 .16 (2H, m), 1.25 - 1.28 (2H, m), 2.20-2.23

(1 H, m), 2.65 - 2.67 (1 H, m), 4.64(1 H, s), 6.94 -6.96 (1 H, m). 7.1 1 -7.36 (8H, m)

Example 25: Preparation of 2-(3,4-difluorophenyl)cyclopropane carbohydrazide (V) from 2- (3.4-difluorophenyl)cyclopropanecarboxylic acid (IV)

Preparation of 2-( 3, 4-difluorophenyl)cyclopropanecarboxylic acid

To 9 g ( 0.420 moles) of 2-(3,4-difluorophenyl)-A/-methoxy-A/-methylcyclopropane carboxamide in 120 ml of methanol was added a solution of 180 ml HCI in dioxane (0.720 moles) at 25- 30 C. The resulting clear solution was stirred at 25- 30 C for 16 h and then concentrated under vacuum. The resulting oil was dissolved in aqueous 1.5 N potassium hydroxide solution (160 ml) and heated to 50 C for 3 h. After cooling to 25- 30 C the mixture was diluted with water 500 ml and 10 % aqueous HCI was added till pH 3 to 4. The solid that separated out was filtered and dried under vacuum to obtain 7.35g (90%) product. Conversion of 2-(3,4-difluorophenyi)cyclopropanecarboxylic acid into 2-(3, 4-difluorophenyl)- cyclopropanecarbohydrazide

To 200 ml of methylene dichloride was added 20 g (100 mmoles) 2-(3.4-difluorophenyl)- cyclopropane carboxylic acid, 1.0 ml of DMF at ambient temperature and to the solution slowly added 10 ml of (1 16 mmoles) oxalyl chloride over a period of 30 min under stirring. After completion of reaction, 200 ml methanol was added slowly over 30-45 min. The reaction mixture was then subjected to vacuum distillation at 60-65 C to get yellow oil. To the oil was added 100 ml methanol slowly under stirring followed by 40 ml of hydrazine hydrate was added with vigorous stirring at 20-25 C. After complete addition the reaction mixture was refluxed at 65 C for 3 h. The reaction mixture was distilled at 60-65 C to remove solvent completely. A concentrated reaction mass was obtained. To the residue was added 200 ml water followed by 200 ml dichloromethane and stirred to dissolve the solid. The organic layer was separated and washed with 200 ml water. The organic layer was then concentrated under vacuum at 35-40 C to give 20 g of 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide (87% of theory).

¹H MR in (400MHz,DMSO d₆) 5 1 .27-1.37 (2H, m), 1.74- 1 .78 (1 H, m), 2.25-2.28

(1 H, m), 4.22(2H, s), 7.00 (1 H, m), 7.19-7.34 (2H, m), 9.10 (1 H, s)

Example 26: Preparation of 2-(3,4-difluorophenyl)cyclopropanamine (IX)

To 50 ml of water was added 20 g (94.3 mmoles) 2-(3,4-difluorophenyl)cyclopropane- carbohydrazide and the slurry was cooled to 0-5 C. 100 ml (6N) Hydrochloric acid was added slowly to the above slurry and stirred to dissolve the solid. To the resultant clear solution was then added sodium nitrite solution (6.5 g dissolved in 100 ml) slowly at 0-5 °C over a period of 30 min followed by 200 ml toluene. The reaction mixture was stirred for 15 min and then the layers were separated. The organic layer containing azide intermediate was then added slowly to 50 ml of hot toluene at 1 10 C over a period of 1 h. The reaction mass was refluxed for 1 h at 1 10 C and then transferred to 200 ml (6N) hydrochloric acid at 1 10 under stirring. The reflux was continued for 2 hrs. After completion of reaction the reaction mixture was cooled to 25 °C and the layers were separated. To the aqueous layer, sodium hydroxide solution was added to adjust to pH 10. 200 ml Methylene dichloride was added and stirred for 15 min. The layers were separated and the organic layer was distilled under vacuum below 40 °C to get 10 g 2-(3,4- difluorophenyl)cyclopropanamine as an oil (yield= 63 % theory).

Example 27: Preparation of (1 2S)-2-(3,4-difluorophenyl)cyclopropanamine R-mandelic acid salt (IX')

To a solution of 4.5 g R-mandelic acid in 150 ml of methanol at 45 C, was added a solution of 5 g of 2-(3.4-difluorophenyl)cyclopropanamine in 150 ml of methanol slowly over a period of 30 minutes. The reaction mixture was slowly cooled to 25 C and stirred for 1 h, then further cooled slowly to 18 C and maintained for another 1 h. The crystallized product was filtered off and washed with 20 ml of chilled methanol. The product was dried under vacuum to obtain 3.8 g of product as a white crystalline solid.

(1 H, m), 2.65 - 2.67 (1 H, m), 4.64(1 H, s), 6.94 -6.96 (1 H, m), 7.1 1 -7.36 (8H, m) Analytical data in examples were obtained with the following hardware: X-Ray powder diffraction method:

Conditions for obtaining powder X-ray diffraction (XRD) patterns: The powder X-ray diffraction patterns were obtained by methods known in the art using Philips X'Pert PRO diffractometer with X'Celerator detector using CuKa radiation (tube operating at 45 kV and 40 mA) in the Bragg-Brentano (reflection) geometry. Data were recorded from 2 to 40 °2Θ in steps of 0.033 °2Θ and the measurement time of 50 seconds per step. Variable divergence and anti scatter slits were used to maintain 12 mm of sample length irradiated.

Differential Scanning Calorimetry:

Conditions for obtaining DSC thermograms: Thermograms were obtained with Mettler Toledo DSC822e differential scanning calorimeter. The sample (1 -10 mg) was placed in an unsealed aluminium pan with a hole and heated at 10°C/min in the temperature range from 30 °C to 250 °C.

NMR analysis:

All the NMR spectra were taken with Bruker Avance III 500 MHz spectrophotometer. ¹ H NMR spectra were obtained at 500 MHz and ¹⁹F NMR spectra were obtained at 470 MHz at 25 C in CDCI₃ (7.24 ppm in ¹ H spectrum) or DMSO-d₆ (2.50 ppm in ¹H spectrum). Chemical shifts are reported in ppm downfield from an internal TMS standard or relative to the residual solvent signal. Coupling constants (J) are given in hertz (Hz).

HPLC-MS analysis:

MS spectra were recorded with LC-MS system composed of Waters Alliance HPLC and Micromass Quattro micro mass spectrometer equipped with electrospray ionisation source.

Claims

1 . A process for the preparation of a compound of formula IX or a salt thereof

IX wherein the chiral center * is in its (R) or (S) configuration,

comprising the steps of:

(i) providing a compound of formula V

V wherein the chiral center * is in its (R) or (S) configuration,

(ii) converting the hydrazide of formula V to an azide of formula VI

wherein the chiral center * is in its (R) or (S) configuration, and

2. The process according to claim 1 , wherein the compound of formula VI obtained in step (ii) is first converted to a compound of formula VIII

VIII wherein the chiral center * is in its (R) or (S) configuration, and wherein R is linear or branched d-C₆ alkyl,

said compound VIII being converted to the compound of formula IX.

The process according to claim 2, wherein the compound of formula VI is first converted to a compound of formula VII

VII wherein the chiral center * is in its (R) or (S) configuration,

said compound VII being converted to the compound of formula VIII.

The process according to claim 2 or claim 3, wherein the process is conducted as a one-pot process.

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

(i) providing a compound of formula 111 t> or IV

nib IV wherein the chiral center * is in its (R) or (S) configuration and wherein Ri is linear or branched C^-Ce alkyl, and

(ii) converting the compound of formula 1Mb or IV to the compound of formula V.

The process according to claim 5, wherein the compound of formula IV is first converted to a compound of formula 1Mb, which is then converted to the compound of formula V.

The process according to claim 5, wherein the compound of formula IV is prepared by a process comprising:

(i) providing a compound of formula I

(ii) converting the compound of formula I to give an alkene of formula II

II wherein Q is a group convertible to carboxyl group, ester group, amine or amine salt, converting the obtained alkene of formula II by reaction of cyclopropanation to give a compound of formula III

III wherein the chiral center * is in its (R) or (S) configuration and wherein Q is as defined above,

(iv) converting the obtained compound of formula III to the compound of formula IV

IV wherein the chiral center * is in its (R) or (S) configuration, and

(v) optionally separating the obtained frans-racemate of IV to provide the enantiomerically pure (1 R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid.

The process according to claim 5, wherein the compound of formula IV is the enantiomerically pure (1 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid, the process comprising:

(i) providing a compound of formula I

(ϋ) converting the compound of formula I to give an alkene of formula II

III wherein the chiral center * is in its {R) or (S) configuration and wherein Q is as defined above, separating the obtained frans-racemate of III to provide the enantiomerically pure compound of formula III', and

III'

(v) converting the obtained compound of formula III' to (1 2f?)-2-(3,4- difluorophenyl)cyclopropanecarboxylic acid.

(i) providing a compound of formula lib

(ii) converting the compound of formula lib to give a compound of formula lid

reacting the obtained compound of formula lid with Ν,Ο-dimethylhydroxylamine hydrochloride to yield the compound of formula A

(iii) converting the compound of formula A by reaction of cyclopropanation to give a compound of formula B

B wherein the chiral center * is in its (R) or (S) configuration, and (iv) converting the compound of formula B to give a compound of formula V.

10. The process according to claim 9, wherein the compound of formula B is first converted to a compound of formula IV

IV

wherein the chiral center * is in its (R) or (S) configuration, or a methyl ester thereof, said compound IV being converted to the compound of formula V.

1 1. The process according to claim 1 , wherein the salt of IX is (1 ?,2S)-2-(3,4-difluorophenyl)- cyclopropanamine R-mandelic acid salt (IX')

IX'

12. The process according to claim 1 , wherein the salt of IX is a crystalline hydrochloride salt

CPA.HCI

13. A compound of the following formula V and stereochemical isomeric forms thereof.

14. A compound of formula A or B and stereochemical isomeric forms thereof.

B

15. A crystalline hydrochloride salt of the following formula

CPA.HCI

16. Use of any of the compounds of claims 13 to 15 in the preparation of ticagrelor.