ITMI20121142A1 - CHEMOENZYMATIC PROCESS FOR THE PRODUCTION OF FENYL CYCLOPROPYLAMINE - Google Patents

Description

Description

CHEMOENZYME PROCESS FOR THE PRODUCTION OF PHENYL CYCLOPROPYLAMINS

Field of invention

The present invention relates to a chemoenzymatic process for the industrial production of phenyl cyclopropylamines, their salts and the use of these compounds as intermediates for the preparation of active pharmaceutical ingredients.

State of the art

Phenyl cyclopropylamines are a very interesting class of compounds for the preparation of a large number of active pharmaceutical ingredients, such as 3- [7 - [[(1R, 2S) -2- (3,4-difluorophenyl) -cyclopropyl] - amino] -5- (propylthio) -3 / - / - 1,2,3-triazol [4,5-d] -pyrimidin-3-yl] -5- (2-hydroxyethoxy) - (1S, 2S, 3R, 5S) -cyclopentan-1, 2-diol (known as Ticagrelor). This compound, produced by AstraZeneca (with the trade names of Brilinta <®> in the United States and Brilique <®> or Poesia <®> in Europe) is an allosteric antagonist of the P2YI2 subtype of ADP receptors, useful as an inhibitor of platelet aggregation and indicated for the prevention of thrombosis. Ticagrelor and other similar compounds are described in international applications WO 99/05143 A1 and WO 00/34283 A1. These documents report a method for the preparation of phenyl cyclopropylamine (1), one of the key intermediates for the preparation of Ticagrelor:

Phenyl cyclopropylamine (1) is obtained by condensing Oppolzer's sultame with 3,4-difluorophenyl acrylic acid and subsequent cyclopropanation with diazomethane in the presence of a palladium-based catalyst.

On an industrial scale, the use of this synthesis route has numerous disadvantages, such as the high cost of Oppolzer's sultame or the known problems deriving from the use of diazomethane due to its high instability and toxicity.

An alternative synthetic method for the preparation of phenyl cyclopropylamine (1) is reported in the international patent application WO 01/92200 A1, in which the (-) - menthyl-3,4-difluorophenyl acrylate is subjected to a diasteroselective cyclopropanation according to Corey -Chaykovsky.

Problems related to this method are the high number of synthetic steps, the use of dangerous and / or explosive reagents, such as NaN3 or trimethylsulfoxonium iodide, and a very poor overall yield (about 30%).

A new synthetic approach for the preparation of phenyl cyclopropylamine (1) is reported in international applications WO 2008/018822 A1 and WO 2008/018823 A1.

The purpose of this invention is to provide a new and alternative synthetic method for the preparation of phenyl cyclopropylamines characterized by excellent yields and high optical and chemical purity.

Summary of the invention

These objectives have been achieved with the present invention which relates to the preparation of phenyl cyclopropylamines and their salts, as well as their use for the preparation of active pharmaceutical ingredients.

A first aspect of the invention relates to a new synthetic method for the preparation of phenyl cyclopropylamines.

In a first embodiment, the process of the invention includes the following steps:

a) transforming a cyclopropyl ketone of formula (I) into a cyclopropyl kethoxime of formula (II):

(l) (The)

b) subjecting to a Beckmann rearrangement the cyclopropyl ketoxime of formula (II) or one of its derivatives selected from one of its activated form of formula (II ') or an alkyl carbonate of formula (VI):

O R <9>

R <3> (II) R <3> (vi)

to obtain a phenyl cyclopropylamine amide of formula (III): N R <6>

c) transforming the amide of phenyl cyclopropylamine of formula (III) into phenyl cyclopropylamine (IV) or a salt thereof:

* NH.

(IV)

in which the substituents have the following meanings:

R <1>, R <2>, R <3>, R <4> and R <5> are, independently of each other, hydrogen or halogen, with the condition that at least one of them is a halogen;

R <6> is an optionally substituted linear or branched C1-C6 alkyl or an optionally substituted phenyl;

R <7> is a leaving group selected from a halogen or an aryl or alkyl sulfonate; And

R <9> is a linear or branched C1-C6 alkyl optionally substituted.

Preferably the starting compound for step a) of the process is a racemic mixture of the trans-cyclopropyl ketone of formula (IA):

(±) -trans- (iA)

With racemic mixture (±) -trans it is meant that the two radicals bound to the cyclopropyl, the substituted phenyl and Tacyl -C (0) R <6>, are directed towards opposite parts of the plane defined by the cyclopropyl itself and that both enantiomers of the product in equal quantities.

In this case the process leads to the obtainment of the racemic mixture of transphenyl cyclopropylamine with the formula (IVA):

(±) -trans- (NA)

Even more preferably, the process of the present invention leads to the formation of a phenyl cyclopropylamine of formula (1) with the specified stereochemistry:

Detailed description of the invention

All terms used in this application, unless otherwise indicated, must be understood in their ordinary meaning as far as known in the field. Other more detailed specifications for some terms used in the present application are set out below and are to be applied uniformly to the entire description and claims, unless otherwise indicated.

Compounds prepared by the processes of the present invention can have one or more stereocenters and can exist, be used or isolated in enantiomerically enriched forms or as racemic mixtures, as well as in diastereoisomerically pure forms or diastereoisomeric mixtures. It should be understood that the processes of the present invention can give rise to racemic mixtures or to enantiomerically enriched mixtures. It should also be understood that the products of the present invention can be isolated as racemic mixtures or in enantiomerically enriched form. The procedures for purification and characterization of these compounds are known to the skilled person and include for example crystallization techniques or chiral stationary phase chromatography.

The symbol â € œ * "(asterisk) present in some formulas of the description and claims indicates a stereogenic center (of asymmetry), however the absence of asterisks does not necessarily imply that there are no stereocenters in the compound. reference to a racemic or enantiomerically enriched mixture or to a mixture of diastereomers.

A mixture of enantiomers (R, S) can contain the two enantiomers in any ratio to each other. The enantiomeric purity is generally expressed as â € œenantiomeric excessâ € or ee, which is defined, for example for the enantiomer (S), as:

ee = [(S-R) / {R + S)) x 100

where S and R are the respective quantities of the two enantiomers (S) and (R) (as determined for example by HPLC or GC on chiral stationary phase).

The enantioselectivity factor E, which reflects the relative rate of reaction of the two enantiomers in an enzymatic kinetic resolution, is defined as:

E = In {(1-ees) (eep) / (eep) / ees + eep} / In {(1 + ees) (eep) / ees + eep}

where ees is the enantiomeric excess of the substrate and eepà the enantiomeric excess of the product.

The term "racemic" refers to a sample of a chiral compound that contains equal amounts of the two optical isomers (+) and (-).

The term â € œenantiomerically enrichedâ € as used in the present application means that one of the enantiomers is present in excess of the other enantiomer.

The term "purified (S) or (R) enantiometer" means that its enantiomeric purity is usually at least 96%, preferably 99%, even more preferably 99.5%.

The symbol . (dashed link) present in some formulas of the description and claims indicates that the substituent is directed below the plane of the sheet. The symbol â € ”(wedge bond) present in some formulas of the description and claims indicates that the substituent is directed above the plane of the sheet.

The compounds obtained through the processes of the present invention can be used in the subsequent steps without further purification or they can be separated and purified by one of the methods known to the skilled person, such as crystallization, chromatography, or by transforming them into a salt or a co- crystal, or by washing with an organic solvent or aqueous solution, optionally changing the pH.

It should also be understood that each compound described in the present invention can describe a salt or a co-crystal thereof.

Step a) of the process of the invention consists in the preparation of a cyclopropyl ketoxime of formula (II) starting from the cyclopropyl ketone of formula (I):

in which the substituents take on the meanings seen above.

Step a) of the process can be carried out for example by treating the cyclopropyl ketone of formula (I) with hydroxylamine, optionally in salified form (preferably as hydrochloride, sulphate or phosphate), in a polar protic solvent, such as for example an alcohol ( preferably ethanol or methanol), optionally mixed with water. This reaction is normally carried out in the presence of an organic or inorganic base (if the hydroxylamine used is in salified form), for example a carbonate (preferably Na2C03, U2CO3, K2C03), a hydroxide (preferably LiOH, KOH, NaOH), an acetate (preferably sodium acetate) or a tertiary amine (cyclic or acyclic), for example triethylamine, r / V, A / -diisopropylethylamine, Î "N, N-diisopropylmethylamine, la / V- methylpyrrolidine, la / V-methylmorpholine, Î "Λ /, Î ›/ - dicyclohexylmethylamine, A /, A / -dìethylaniline, 2,6-dimethylpyridine or 2,4,6-trimethylpyridine, at a temperature between the room temperature and the reflux temperature of the selected solvent.

The quantity of hydroxylamine and base useful for the purpose can vary between 1 and 2 equivalents, preferably 1.25 equivalents, with respect to the molar quantity of cyclopropyl ketone of formula (I).

In the subsequent step b) the cyclopropyl ketoxime of formula (II) is subjected to a Beckmann rearrangement to obtain an amide of phenyl cyclopropylamine of formula (III):

N R <6>

R <3> (il) (III) in which the substituents R <1> -R <6> take on the meanings seen above.

Optionally, ketoxime (II) can be used in a form of its derivative, in particular its activated form of formula (II) or an alkyl carbonate of formula (VI):

wherein R 7 represents one of the leaving groups known in the art such as a halogen, an aryl or alkyl sulfonate, such as for example a mesylate, a tosylate, a triflate, a nonapflate, a fluorosulfonate or a nosylate; and R <9> is an optionally substituted linear or branched C1-C6 alkyl. Compounds (II ') and (VI) can optionally be isolated before subjecting them to said rearrangement.

The Beckmann rearrangement is normally carried out in the presence of a promoter optionally under microwave irradiation or by supporting the promoter on mineral oxides (for example on silica (Si02) or alumina (Al203)) or in the presence of ionic liquids. Said promoter can be a strong acid, for example sulfuric acid, hydrochloric acid, poi [phosphoric acid, para-toluenesulfonic acid, a Lewis acid, for example iron trichloride, bismuth trichloride, cerium trichloride, zinc chloride, aluminum trichloride, indium trichloride, stannous chloride (SnCI2), etherate boron trifluoride (BF3 * Et20), or an activating reagent selected from phosphorus, tosyl chloride, mesyl chloride or propylphosphonic anhydride (T3P).

When the promoter used for the Beckmann rearrangement is a Lewis acid, the reaction is carried out in an aprotic polar solvent, preferably acetonitrile, dichloromethane, dichloroethane, in an apolar solvent (preferably toluene) or a mixture thereof.

If said promoter is phosphorus oxychloride, the reaction can optionally be carried out in the presence of an organic base, such as a tertiary amine (preferably triethylamine) or pyridine.

If the promoter used is tosyl chloride, the reaction can take place in the presence of organic or inorganic bases, preferably organic, for example triethylamine or pyridine.

In the event that the cyclopropyl kethoxime of formula (II) is transformed into the activated form of formula (IIâ € ™) the subsequent Beckmann rearrangement usually takes place spontaneously under the same conditions necessary for the activation of the cyclopropyl ketoxime of formula (II) . Alternatively, when the cyclopropyl ketoxime of formula (II) is converted into an alkyl carbonate of formula (VI), the Beckmann rearrangement is carried out by treatment with acids (preferably trifluoroacetic acid) or Lewis acids (such as BF3 * Et20) in a suitable solvent, for example chlorinated solvents (preferably dichloromethane). The quantity of promoter necessary for the reaction can vary between 1 and 15 equivalents, preferably 3, with respect to the molar quantity of cyclopropyl ketoxime of formula (II), of its activated form of formula (ll ') or of the alkyl carbonate of formula ( YOU).

In case of use of the ketoxime in its activated form of formula (ll '), R <7> can be a sulfonate or a halogen.

When R <7> is a sulfonate, such as a mesylate, a trifluoromethanesulfonate (triflate) or a tosylate, its preparation can be carried out by one of the methods generally known in the art, for example by treating the substrate with the corresponding sulfonyl halide or the corresponding sulphonic anhydride, in the presence of an organic base and in a suitable solvent. Preferably the base is a tertiary amine (cyclic or acyclic) for example triethylamine, N, N-diisopropylethylamine, N, N -diisopropylmethylamine, N -methylpyrrolidine, N-methylmorpholine, N, N -dicyclohexylmethylamine, N, N -diethylaniline, 2,6-dimethylpyridine or 2,4,6-trimethylpyridine or 4-dimethylaminopyridine. Useful solvents for this purpose are, for example, chlorinated solvents (dichloromethane) or aprotic polar solvents, such as an ether, or a mixture thereof. The amount of sulfonyl halide or sulphonic anhydride used is between 1 and 1.5 equivalents, preferably 1.2 equivalents, with respect to the molar amount of cyclopropyl ketoxime of formula (II). Alternatively, if R <7> is a halogen, the activated form (II ') of the ketoxime can be prepared by treating the cyclopropyl kethoxime of formula (II) with halogenated reagents, for example, thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, or phosphorus tribromide in a chlorinated solvent, such as dichloromethane, or in an aprotic polar solvent, such as an acetate (preferably an alkyl acetate, e.g. ethyl acetate), an ether (preferably tetrahydrofuran or 1, 4-dioxane) or a hydrocarbon, for example toluene, or a mixture thereof, optionally in the presence of an organic base (preferably pyridine). The activated form (IIâ € ™) in which R <7> is halogen can also be prepared starting from ketoxime (II) by treatment with I2, / V-CI-succinimide in the presence of phosphines (preferably triphenylphosphine), Nal in presence of a Lewis acid (preferably AICI3) or with pivaloyl chloride.

Alternatively, the cyclopropyl ketoxime of formula (II) can be converted into the corresponding alkyl carbonate of formula (VI) (preferably methyl, ethyl or benzyl carbonate), by treatment with the corresponding alkyl chloroformate, in the presence of an organic base and in a suitable solvent, such as for example a chlorinated solvent (preferably dichloromethane) or an aprotic polar solvent, such as an ether, or a mixture thereof.

The necessary basis for the reaction is a tertiary amine (cyclic or acyclic) for example triethylamine, A /, / \ / - diisopropylethylamine, \ â € ™ N, N-diisopropylmethylamine, A / -methylpyrrolidine, / V-methylmorpholine, \ â € ™ N, N-dicyclohexylmethylamine, A /./ V-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine or 4-dimethylaminopyridine.

The next step c) of the process of the invention consists in the transformation of the amide of phenyl cyclopropylamine of formula (III) into phenyl cyclopropylamine (IV) or one of its salt:

** NH

The transformation from amide (III) to amine (IV) can be accomplished by one of the methods generally known in the art, for example one of those reported in the book Protective Groups in Organic Synthesis, edited by Theodora W. Green, John Wiley & Sons ( 1999). Such hydrolytic conditions preferably provide for treatment with aqueous mineral acids (for example HCI) at a concentration varying between 1 and 20% by weight and at a temperature varying between room temperature and reflux temperature.

This synthetic step can optionally be conducted under biocatalyzed hydrolytic conditions. Preferably these biocatalyzed conditions include the use of an enzyme belonging to the class of hydrolases, for example a lipase, an esterase or a protease. These conditions also make it possible to improve the enantiomeric excess of phenyl cyclopropylamine (IV) when that of the corresponding amide (III) is unsatisfactory.

In the event that phenyl cyclopropylamine (IV) or any of the other compounds described in the present application is obtained with an unsatisfactory chemical and / or optical purity to be used in the preparation of a medicament, it is possible to subject it to purification, for example by chromatography or crystallization, optionally after the formation of an addition compound, such as for example a salt or a co-crystal.

In step d), optional with respect to the process of the invention, phenyl cyclopropylamine (IV) or one of its salt are converted into Ticagrelor, one of its salt or an intermediate useful for its synthesis by one of the processes known in literature. The starting compound of the synthetic process of the present invention, the cyclopropyl ketone of formula (I), can be produced prior to the process of the invention by following various synthetic approaches accessible to the average person.

A possible way of synthesis of the compound of formula (I) starts from an ester of phenyl cyclopropane of formula (V) or from the corresponding acid of formula (Vâ € ™):

in which the substituents take on the meanings given above and R <8> is an optionally substituted linear or branched C1-C6 alkyl or an optionally substituted phenyl. An ester of phenyl cyclopropane of formula (V) (where R <1> = R <2> = F, R <3> = R <4> = R <5> = H, R <8> = ethyl) can be produced for example using the method described in international applications WO 2008/018822 A1 and WO 2008/018823 A1, wherein, Î ™ Ί.2-difluorobenzene is reacted with chloroacetyl chloride in the presence of aluminum trichloride to obtain 2- chloro-1- (3,4-difluorophenyl) ethanone, which is subsequently reduced using borane in the presence of (S) -diphenylprolinol and trimethyl borate to give 2-chloro- (1S) - (3,4-difluorophenyl) ethanol. This compound by reaction with triethylphosphonoacetate in the presence of sodium hydride leads to ethyl- (1 R, 2R) -trans -2- (3,4-difluorophenyl) cyclopropyl carboxylate:

CICOCH2CI BH3-DMS

B (OMe) 3 F

EtO-P.

Toluene

t GOOD / Toluene

Ethyl- (1R, 2R) -trans -2- (3,4-difluorophenyl) cyclopropyl carboxylate is converted into the corresponding carboxylic acid, using hydrolytic conditions, optionally bio-catalyzed, according to the following scheme:

to Hydrolysis

Hydrolytic conditions useful for this purpose are normally accessible to the average technician. By way of example, this reaction can be carried out using one of the methods described in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), preferably by treatment with an alkali metal hydroxide or carbonate (such as K2C03 , Na2CC> 3, Li2C03, Cs2C03, KOH, NaOH, LiOH) in a water-miscible solvent, preferably methanol, ethanol, tetrahydrofuran, dioxane or a mixture thereof, in the presence of water.

The quantity of alkali metal hydroxide or carbonate used is normally between 1 and 5 equivalents, preferably 3, with respect to the quantity of the phenyl cyclopropane ester of formula (V)

When the process described leads to obtaining a racemic mixture of the phenyl cyclopropane derivative of formula (V), for example in the case in which the reduction of 2-chloro-1- (3,4-difluorophenyl) ethanone is carried out in non-stereoselective conditions using for example sodium boron hydride (NaBH4) as a reducing agent, said mixture can be converted into the corresponding enantiomerically enriched form of the carboxylic acid of formula (Vâ € ™ a) or (V'b), or into an enantiomerically enriched with the ester of formula (Vb) or (Ve), by the action of a hydrolase, for example a lipase or an esterase:

Biocatalysis

Desired product

Racemic mixture-frans Biocatalysis (S) 'CO2H

(Vb) Desired product

In the formulas of the scheme reported above, the substituents have the meanings reported above and with the stereochemics at the stereocenters specified.

Enzymes useful for this purpose are for example AH-4 (lipase derived from Pseudomonas stutzeri), AH-5 (lipase derived from Pseudomonas cepacia), AH-7 (lipase D derived from Alcaligenes sp.), AH-8 (lipase E derived from Alcaligenes sp.), AH-9 (lipase B derived from Candida rugosa), AH-18 (neutral protease A), AH-20 (acid protease A), AH-27 (lipase derived from Aspergillus niger), AH-36 ( lipase A derived from Burkholderia cepacia), AH-38 (lipase A derived from Rhizomucor mihei), AH-39 (lipase derived from Candida antarctica), AH-40 (lipase derived from Thermomyces lanuginosus), AH-42 (lipase B derived from Antarctic Candida (liq)), AH-45 (lipase derived from Thermomyces lanuginosus), AH-46 (lipase C derived from Rhizomucor mihei); preferential conditions foresee the use of AH-45 as lipase.

These enzymes are commercially available for example from Almac Sciences, Craigavon, BT63 5QD, UK.

The acid of phenyl cyclopropane of formula (Vâ € ™) is converted into the cyclopropyl ketone of formula (I) with one of the methods generally known to the skilled person, for example, by treatment with an organolithium compound (preferably MeLi and phenyllithium) in an aprotic polar solvent for example a cyclic or acyclic ether (preferably diethyl ether, dibutyl ether, methyl cyclopentyl ether methyl ferz-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane or a mixture thereof) at a temperature between -78 and 0 ° C, preferably between -20 and -30 ° C.

The quantity of organolithium compound necessary for the reaction can vary between 2 and 4 equivalents, preferably 2.2, with respect to the molar quantity of the phenyl cyclopropane acid of formula (V).

Alternatively, the cyclopropyl ketone of formula (I) can be prepared by condensing the acid of phenyl cyclopropane of formula (Vâ € ™) with the Î ›/, Ο-dimethylhydroxylamine or with morpholine (optionally salified), and treating the resulting amide of Weinreb or morpholinamide with an alkyl or arylmagnesium halide.

The preparation of Weinreb's amide or morpholinamide is carried out after activating the phenyl cyclopropane acid of formula (V ') by transforming it into the corresponding acyl chloride, the corresponding mixed anhydride or using one of the acid activating agents generally known in the field peptide synthesis (for example those reported in Chem. Soc. Rev., (2009), 38, 606-631), preferably carbonyl diimidazole (CD1), dicyclohexyl carbodiimide (DCC), re-ethyl-3- (3 -dimethylaminopropyl) carbodiimide (EDC), benzotriazol-1 -yloxytyripyrrolidinphosphonium hexafluorophosphate (PyBOP), lâ € ™ 0- (7-azabenzotriazol-1-il) -Î ›/, Λ /, Î ›/ ', / V' -tetramethyluronium hexafluorophosphate (HATU) or 6-chloro-1 - ((dimethylamino) (morpholin) -methylen) -1 H-benzotriazolium 3-oxide hexafluorophosphate (6-HDMCB). The reaction is carried out in an aprotic polar solvent, for example dichloromethane, acetonitrile, dimethylacetamide, dimethylformamide, tetrahydrofuran, an alkylacetate or a mixture thereof, at a temperature between 0 ° C and room temperature.

The next step involves the treatment of the activated form of phenyl cyclopropane acid of formula (V) with Î ›/, Ο-dimethylhydroxylamine or with morpholine (optionally salified) in the presence of a tertiary amine (cyclic or acyclic) ), for example triethylamine, IW, / \ / - diisopropylethylamine, Î "N, N-diisopropylmethylamine, la / V-methylpyrrolidine, la / V-methylmorpholine, Î" N, N-dicyclohexylmethylamine, la /V.N- diethylaniline, la 2,6-dimethylpyridine or 2,4,6-trimethylpyridine; the reaction can optionally be carried out in the presence of an additive, such as Î "W-hydroxybenzotriazole (HOBT), 5-aza-1-hydroxybenzotriazole (5HOAT), IW-hydroxysuccinimide (HOSu), n-hydroxy-2-phenylbenzimidazole (HOBI ) and ethyl 2-cyano-2- (hydroxyimino) acetate (Oxyma).

This step is normally carried out under the same conditions and in the same solvent in which the activation reaction of the acid derivative of phenyl cyclopropane of formula (V) took place.

The amount of Î ›/, Ο-dimethylhydroxylamine or morpholine (optionally salified) required for the reaction can vary between 2 and 4 equivalents, preferably 2.5, with respect to the molar amount of the acid of the phenyl cyclopropane of formula (Vâ € ™).

The quantity of tertiary amine necessary for the reaction can vary between 2 and 4 equivalents, preferably 3, with respect to the molar quantity of the phenyl cyclopropane acid of formula (V).

Alternatively, the corresponding Weinreb amide or morpholinamide can be prepared by reaction of the phenyl cyclopropane ester of formula (V) with Î ›/, Ο-dimethylhydroxylamine or morpholine or a salt thereof, in the presence of trimethylaluminium, dimethylaluminium chloride or isopropyl magnesium chloride or bromide. Conditions compatible with the reaction foresee the use of chlorinated solvents (preferably dichloromethane), ethers (cyclic or acyclic), preferably diethyl ether or tetrahydrofuran, hydrocarbons, aromatic or aliphatic (preferably toluene, hexane or heptane) or a mixture thereof with a variable temperature between -50 ° C and the reflux temperature of the selected solvent, preferably variable between -30 and 0 ° C.

The quantity of trimethylaluminium, dimethylaluminium chloride or isopropyl magnesium chloride or bromide can vary between 2 and 5 equivalents, preferably 3, with respect to the molar quantity of the ester of phenyl cyclopropane of formula (V).

The amides thus obtained are converted, in the subsequent synthetic step, into the cyclopropyl ketone of formula (I), by treatment with an alkyl or arylmagnesium halide (preferably a methyl, ethyl or phenylmagnesium halide). This reaction is normally carried out in an aprotic polar solvent, for example a cyclic or acyclic ether (preferably diethyl ether, dibutyl ether, methyl terzbutyl ether, methyl cyclopentyl ether, tetrahydrofuran, dioxane, methyl tetrahydrofuran or a mixture thereof) at a temperature between -78 ° C and the ambient temperature, preferably at 0 ° C.

The necessary quantity of alkyl halide or arylmagnesium can vary between 1 and 3 equivalents, preferably 1.5, with respect to the molar quantity of the amide.

The cyclopropyl ketane of formula (I) can be prepared in an alternative embodiment of the present invention, by treatment of the epoxide (VII) with a 2-ketophosphonate of formula (VIII), according to the following scheme:

o o

R <3> (VII) R <3> (1) in which the substituents R <1> -R <6> have the meanings seen above and R <10> represents an optionally substituted linear or branched C1-C6 alkyl.

This reaction is carried out in the presence of an organic or inorganic base, preferably sodium, lithium or potassium hydrides (NaH, UH or KH), bis (trimethylsilyl) sodium, lithium or potassium amides (NaHMDS, LiHMDS or KHMDS), lithium diisopropylamide (LDA) or sodium, lithium or potassium hydroxides (NaOH, LiOH, KOH), in a solvent selected from an aromatic hydrocarbon (preferably toluene, xylene or ethylbenzene), a cyclic or acyclic ether (preferably tetrahydrofuran, methyl tetrahydrofuran ) or a mixture thereof, at a variable temperature between 0 ° C and the reflux temperature of the selected solvent.

The necessary quantity of 2-ketophosphonate of formula (VIII) can vary between 1 and 1.5 equivalents, preferably 1.2 equivalents, with respect to the molar quantity of epoxide (VII).

The quantity of base useful for this purpose can vary between 1 and 1.5 equivalents, preferably 1.2 equivalents, with respect to the molar quantity of epoxide (VII). A further aspect of the present invention is represented by the new compounds (IA), (HA), (MAâ € ™), (VIA) and their enantiomerically enriched isomers:

_7

(HA) OH (MA ') R <7> (VIA) O R <9> The present invention will be further illustrated by the following examples.

EXAMPLE 1

Synthesis of 1 - ((1R, 2ft) -2- (3,4-difluorophenyl) cyclopropyl) ethanone

MeLi (1.6 M in Et20, 630 pl_, 1.0 mmol) drop by drop. The reaction mixture is stirred at -78 ° C for 15 min, then 1 h at 0 ° C. H20 is added, the phases are separated and the aqueous phase is extracted with Et20. The combined organic phases are dried with Na2SO4, filtered and the solvent is removed under reduced pressure. The product is purified by flash chromatography with a petroleum ether / ethyl acetate elution gradient 100: 0-> 50:50 obtaining the title product as a colorless oil (80 mg, 82%).

<1> H NMR (400 MHz, CDCI3): 57.11-6.96 (m, 1H), 6.91-6.76 (m, 2H), 2.47 (ddd, J = 9.4, 6.8, 3.6 Hz, 1H), 2.27 (s, 3H), 2.19-2.10 (m, 1H), 1.64 (ddd, J = 9.2, 5.4, 2.8 Hz, 1 H), 1.29 (ddd, J = 8.3, 6.6, 4.4 Hz, 1 H) ppm.

<13> C NMR (100 MHz, CDCI3): 5206.4, 150.2 (dd, J = 247.9, 12.8 Hz), 149.0 (dd, J = 246.7, 12.6 Hz), 137.5 (dd, J = 5.5, 3.9 Hz), 122.2 (dd, J = 5.9, 3.4 Hz), 117.1 (d, J = 17.3 Hz), 114.9 (d, J = 17.7 Hz), 32.5, 30.7, 27.7, 18.9.ppm.

[<x] D: -391.0 (c = 1.00, CHCl3, 25 ° C).

EXAMPLE 2

Synthesis of 1 - ((1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl) ethanone oxime

NH2OH * HCI (83 mg, 1.20 mmol), the methyl ketane obtained in example 1 (196 mg, 1.0 mmol), and NaOH (48 mg, 1.20 mmol) are solubilized in EtOH 95% (3 mL) and the mixture it is heated under reflux for 12 h. 1N HCl is added and extracted with EtOAc. The combined organic phases are dried with Na2SO4, filtered and the solvent is removed under reduced pressure. The product is purified by flash chromatography with a petroleum ether / ethyl acetate elution gradient 100: 0-> 50:50 obtaining the title product as a white solid (143 mg, 68%).

<1> H NMR (400 MHz, CDCI3): £ 9.62 (bs, 1H) 7.04-6.97 (m, 1H), 6.89-6.79 (m, 2H), 2.18-2.13 (m, 1H), 1.82 (s, 3H), 1.80-1.77 (m, 1H), 1.38-1.35 (m, 1H), 1.15-1.11 (m, 1H) ppm.

<13> C NMR (100 MHz, CDCI3): £ 157.4, 149.9 (dd, J = 246.2 and 12.4 Hz), 148.6 (dd, J = 244.7 and 12.2 Hz), 138.0, 121.7, 116.6 (d, J = 15.4 Hz), 114.5 (d, J = 17.4 Hz), 26.5, 21.9, 13.8, 11.5 ppm.

Pf: 77-79 ° C.

EXAMPLE 3

Synthesis of A / - ((1 / ?, 2S) -2- (3,4-difluorophenyl) cyclopropyl) acetamide

POCI3 (680 Î1⁄4Î ™ _, 7.3 mmol) is added to a solution of oxime obtained in example 2 (100 mg, 0.47 mmol) in 10 mL of pyridine placed under an atmosphere of N2; the mixture is stirred for 1 h at room temperature. H20 is slowly added and the aqueous phase is extracted with EtOAc. The combined organic phases are washed with 1 N HCl, subsequently with a saturated solution of NaCl, dried with Na2SO4, filtered and the solvent removed under reduced pressure to obtain the title product as a slightly yellow solid (95 mg, 95%).

<1> H NMR (400 MHz, CDCI3): Î ́ 6.91-6.86 (m, 2H), 6.81-6.78 (m, 1H), 6.66 (s, 1H), 2.74-2.71 (m, 1H), 1.97- 1.91 (m, 4H), 1.13-1.06 (m, 2H) ppm.

<13> C NMR (100 MHz, CDCI3): £ 171.3, 149.7 (dd, J = 246.3 and 12.6 Hz), 148.4 (dd, J = 244.5 and 12.5 Hz), 137.2, 122.1, 116.5 (d, J = 16.9 Hz), 114.5 (d, J = 17.4 Hz), 31.7, 23.6, 22.5, 14.9 ppm.

Pf: 93-95 ° C.

[a] D: -73.1 (c = 1.00, CHCI3, T = 25 ° C)

EXAMPLE 4

Synthesis of (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine hydrochloride

To the compound obtained in example 3 (80 mg, 0.38 mmol) HCI 2N (1.50 mL) is added and heated under reflux for 12 h. The solvent is removed under reduced pressure to obtain the product as a white solid (78 mg, 99%).

<1> H NMR (400 MHz, CDCI3): 57.18-7.07 (m, 2H), 7.02-6.98 (m, 1H), 2.85-2.81 (m, 1H), 2.46-2.41 (m, 1H), 1.50- 1.46 (m, 1H), 1.31-1.28 (m, 1H) ppm.

Pf: 192-194 ° C.

[a] D: -54.7 (c = 1.00, MeOH)

Free base [a] D: -79.5 (c = 1.00, CHCl3)

EXAMPLE 5

Synthesis of 1 - ((1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl) ethanone

A solution of (1R2R) -2- (3,4-difluorophenyl) cyclopropanecarboxylic acid (500 mg, 2.52 mmol) in dichloromethane (10 mL) is treated at 0 ° C with carbonyldiimidazole (450 mg, 2.77 mmol). After 2 hours at the same temperature, Î, Ο-dimethylhydroxylamine hydrochloride (614 mg, 6.3 mmol) is added and it is left to react for 18 hours at room temperature, then the reaction mixture is filtered on a Celite panel washing with dichloromethane. The filtrate is washed with water and then dried on Na2SO4e concentrated to residue obtaining the corresponding Weinreb amide in quantitative yield as a white solid, which after drying is dissolved under nitrogen in 10 mL of anhydrous tetrahydrofuran. To this solution, cooled to -15 ° C, a solution of methyl magnesium bromide (1.2 M in THF, 4.6 mL, 5.52 mmol) is added. At the end of the addition, the temperature is allowed to rise up to room temperature. After 12 hours, an ammonium chloride solution is added under nitrogen, the phases are separated, the THF is evaporated and the aqueous phase is extracted with ethyl acetate. After drying on sodium sulphate the residue is evaporated. The product is purified by flash chromatography with a petroleum ether / ethyl acetate elution gradient 100: 0â † ’50: 50 obtaining the title product as a colorless oil (410 mg, 83%).

EXAMPLE 6

Enzymatic synthesis of ethyl (1R, 2R) -2- (3,4-difluorophenyl) cyclopropan carboxylate

25 mg of lipase AH45 (Almac Sciences, Craigavon, BT63 5QD, UK) is placed in a 1.5 mL Eppendorf tube. AH45 is a recombinant lipase derived from Thermomyces lanuginosus which has been cloned into Aspergillus oryzae. The enzyme is suspended in methyl tert-butyl ether (MTBE, 0.5 mL) and ethyl (±) - (trans) ethyl 2- (3,4-difluorophenyl) cyclopropan carboxylate (6 mg) is added and the reaction is ̈ incubated at 30 ° C, following the course of the reaction in HPLC with chiral stationary phase. Column: Chiracel OJ-H, mobile phase: n-hexane: isopropanol 95: 5. Monitoring Î »= 210 nm. Retention times (min): ethyl ester (R, R) 6.3 min; ethyl ester (S, S) 6.9; acid (R, R) 10.1; acid (S, S) 12.6.

After 110 hours, the enantiomeric excess of the starting product (ee = 71.8%, ester (1R.2R) major product) and of the target product (ee = 98.8, acid (1S.2S) major product) are measured. AND> 200. Conversion calculated 42%.

EXAMPLE 7

Synthesis of 1 - ((1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl) pentan-1-one

NBuLi (2.5 M in hexane, 4.0 mL, 10.0 mmol) drop by drop. The reaction mixture is stirred at -78 ° C for 15 min, then 1 h at 0 ° C. H20 is added, the phases are separated and the aqueous phase is extracted with Et20. The combined organic phases are dried with Na2SO4, filtered and the solvent is removed under reduced pressure. The product is purified by flash chromatography with a petroleum ether / ethyl acetate elution gradient 100: 0 ^ 50: 50 obtaining the title product as a colorless oil (840 mg, 70%).

<1> H NMR (400 MHz, CDCl3): 57.05-6.98 (m, 1H), 6.85-6.80 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 2.44-2.40 (m, 1H) , 2.13-2.10 (m, 1H), 1.60-1.54 (m, 3H), 1.33-1.20 (m, 3H), 0.90 (t, J = 7.2 Hz, 3H) ppm.

EXAMPLE 8

Synthesis of 1 - ((1R, 2R) -2- (3,4-difluorophenyl) cyclopropyl) pentan-1-one oxime

NH2OH HCI (140 mg, 2.01 mmol), the butyl ketone obtained in example 7 (400 mg, 1.68 mmol), and NaOH (80 mg, 2.01 mmol) are solubilized in EtOH (5 mL) and the mixture is heated to reflux for 12 h. 1N HCl is added and extracted with EtOAc. The combined organic phases are dried with Na2SO4, filtered and the solvent is removed under reduced pressure. The product is purified by flash chromatography with a petroleum ether / ethyl acetate elution gradient 100: 0â † ’50: 50 obtaining the title product as a white solid (220 mg, 52%).

<1> H NMR (400 MHz, CDCI3): 59.62 (bs, 1H) 7.05-6.99 (m, 1H), 6.89-6.82 (m, 2H), 2.45-2.31 (m, 2H), 2.16-2.14 (m , 1H), 1.67-1.65 (m, 1H), 1.55-1.50 (m, 2H), 1.41-1.34 (m, 3H), 1.19-1.17 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H) ppm.

EXAMPLE 9

Synthesis of W - ((1 R, 2S) -2- (3,4-difluorophenyl) cyclopropyl) pentanamide

POCI3 (670 Î1⁄4L, 7.3 mmol) is added to a solution of the oxime obtained in example 8 (120 mg, 0.47 mmol) in 10 mL of pyridine placed under an atmosphere of N2; the mixture is stirred for 1 h at room temperature. H20 is slowly added and the aqueous phase is extracted with EtOAc. The combined organic phases are washed with 1 N HCl and a saturated solution of NaCl, dried with Na2SO4, filtered and the solvent removed under reduced pressure to obtain the expected product as a faintly yellow solid (110 mg, 92%).

<1> H NMR (400 MHz, CDCI3): Î ́ 6.94-6.88 (m, 2H), 6.82-6.74 (m, 1H), 6.52 (bs, 1H), 2.74-2.71 (m, 1H), 2.11 ( t, J = 7.6 Hz, 2H), 1.95-1.91 (m, 1H), 1.58-1.50 (m, 2H), 1.29-1.20 (m, 2H)), 1.18-1.11 (m, 2H), 0.88 ( t, J = 7.6 Hz, 3H) ppm.

EXAMPLE 10

Synthesis of (1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine hydrochloride

To the compound obtained in example 9 (99 mg, 0.39 mmol) HCI 2N (1.50 mL) is added and heated under reflux for 12 h. The solvent is removed under reduced pressure obtaining the expected product as a white solid (80 mg, 99%).

EXAMPLE 11

Synthesis of 1 - ((1 R, 2R) -2- (3,4-difluorophenyl) cyclopropyl) ethanone

Diethyl (2-oxopropyl) phosphonate) (diethyl acetonyl phosphonate) (2.8 mL, 14.1 mmol) keeping the temperature below 5 ° C. After the end of the addition, it is left to react for 15 minutes at room temperature and then a solution of (S) -2- (3,4-difluorophenyl) oxirane (1.84 g, 11.8 mmol) in xylene (8 mL) is added ). The mixture is heated under reflux (about 85 ° C) for 18 hours, then it is cooled to room temperature, water is added, the phases are separated and the organic phase is washed with 1N HCl. The organic phase is anhydrated on sodium sulphate and the product is purified by flash chromatography eluting with hexane-ethyl acetate 85:15, obtaining the product (1.15 g, yield 50%) as a colorless oil, with the same spectroscopic characteristics and the same power. optical rotation of the product obtained in Example 1.

Claims (1)

CLAIMS 1. Process for the preparation of a phenyl cyclopropylamine or a salt thereof, which includes the following steps: a) transforming a cyclopropyl ketone of formula (I) into a cyclopropyl kethoxime of formula (II): R <6> b) subjecting to a Beckmann rearrangement the cyclopropyl ketoxime of formula (II) or one of its derivatives selected from one of its activated form of formula (II) or an alkyl carbonate of formula (VI): R <6> R <7> R <9> to obtain an amide of phenyl cyclopropylamine of formula (III): c) transform the amide of phenyl cyclopropylamine of formula (III) into phenyl cyclopropylamine (IV) or one of its salt: ** NH. in which the substituents have the following meanings: R <1>, R <2>, R <3>, R <4> and R <5> are, independently of each other, hydrogen or halogen, with the condition that at least one of them is a halogen; R <6> is an optionally substituted linear or branched C1-C6 alkyl or an optionally substituted phenyl; R <7> is a leaving group selected from a halogen or an aryl or alkyl sulfonate; And R <9> is an optionally substituted linear or branched C1-C6 alkyl 2. Process according to claim 1 wherein the starting material used in step a) is a racemic mixture of the frans-cyclopropyl ketone of formula (IA): (±) -trans- {lA) 3. Process according to claim 2 wherein the compound having the structural formula (1Aâ € ̃) is transformed into the compound having the structural formula (1), as indicated in the following scheme: 4. Process according to any one of the preceding claims in which said step a) is carried out by treating the cyclopropyl ketone of formula (I) with hydroxylamine or a salt thereof in a quantity comprised between 1 and 2 equivalent to said ketone. 5. Process according to claim 4 wherein, when said hydroxylamine is used in the form of a salt thereof, step a) is carried out in the presence of an organic or inorganic base in a quantity comprised between 1 and 2 equivalents with respect to said ketone. 6. Process according to any one of the preceding claims in which said step b) is carried out in the presence of a promoter selected from a strong acid, a Lewis acid, or an activating reactive, in quantities ranging from 1 to 15 equivalent with respect to the molar quantity of cyclopropyl ketoxime of formula (II), of its activated form of formula (Î ™ Î ") or of alkyl carbonate of formula (VI). 7. Process according to claim 6 wherein said strong acid is selected from sulfuric acid, hydrochloric acid, polyphosphoric acid and paratoluenesulfonic acid; said Lewis acid is selected from iron trichloride, bismuth trichloride, cerium trichloride, zinc chloride, aluminum trichloride, indium trichloride, stannous chloride and etherate boron trifluoride (BF3 * Et20); and said activating reagent is selected from phosphorus oxychloride, tosyl chloride, mesyl chloride or propylphosphonic anhydride. 8. Process according to claim 7 wherein, when said promoter is phosphorus oxychloride, the reaction is carried out in the presence of an organic base. 9. Process according to any one of the preceding claims, wherein said step c) is carried out by treating the amide of formula (III) with an aqueous mineral acid at a variable temperature between the ambient temperature and the reflux temperature. 10. Process according to any one of the preceding claims, in which said step c) is carried out under biocatalyzed hydrolytic conditions. 11. Process according to claim 10 in which said biocatalyzed hydrolytic conditions include the use of enzymes belonging to the class of hydrolases selected from lipase, esterase or protease. Process according to any one of the preceding claims, comprising a further step d) in which phenyl cyclopropylamine (IV) or one of its salt are converted into Ticagrelor, one of its salt or an intermediate useful for its synthesis. 13. Process according to any one of the preceding claims, further comprising a preliminary step of preparing the ketane (I) according to the following reaction scheme: or Ο R <3> (VII) in which the substituents R <1> -R <6> have the meanings seen above and R <10> represents an optionally substituted linear or branched C1-C6 alkyl, and in which an epoxide of formula (VII) is reacted with a 2-ketophosphonate of formula (VIII), in the presence of an organic or inorganic base. 14. Process according to claim 13, wherein said base is selected from sodium hydride, lithium hydride, potassium hydride, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bis (trimethylsilyl) amide, lithium or potassium, or lithium diisopropylamide. 15. Compound of formula (IA) and its enantiomerically enriched isomers: wherein R <6> is an optionally substituted linear or branched C1-C6 alkyl or an optionally substituted phenyl. 16. Compound of formula (MA) and its enantiomerically enriched isomers: (HA) "OH wherein R <6> is an optionally substituted linear or branched C1-C6 alkyl or an optionally substituted phenyl. 17. Compound of formula (HAâ € ™): (MA ') <'> R <7> wherein R <6> is an optionally substituted linear or branched C1-C6 alkyl or an optionally substituted phenyl and R <7> is a leaving group selected from a halogen or an aryl or alkyl sulfonate. 18. Compound with general formula (EIA): (VIA) ÎŒ wherein R <6> is an optionally substituted linear or branched C1-C6 alkyl or optionally substituted phenyl and R <9> is an optionally substituted linear or branched C1-C6 alkyl. (MP / lm)