WO2014154908A1

WO2014154908A1 - Selective alkylation of cyclopentyl alcohols

Info

Publication number: WO2014154908A1
Application number: PCT/EP2014/056417
Authority: WO
Inventors: Marcello Rasparini; Anna Maria PIATEK; Katharine Ann POWLES; Luca Carcone; Giuseppe D'arienzo
Original assignee: Chemo Research, S.L.
Priority date: 2013-03-29
Filing date: 2014-03-31
Publication date: 2014-10-02
Also published as: ITMI20130487A1

Abstract

There is described an oxygen-selective alkylation reaction of an amino alcohol of general formula (I) with a compound of general formula (IV) to produce an O-alkylated compound of general formula (II), avoiding the need to protect the amino group of the starting compound, according to the scheme. There is also described a process for the preparation of allosteric antagonists of ADP receptors, in particular Ticagrelor, or of intermediates useful for their preparation, which uses the oxygen-selective alkylation reaction.

Description

SELECTIVE ALKYLATION OF CYCLOPENTYL ALCOHOLS

Field of the invention

The present invention relates to a process for the production of triazol[4,5-c | pyrimidines and the use of these compounds as intermediates for the preparation of pharmaceutical active ingredients.

In particular, this invention relates to industrially applicable and advantageous processes for the preparation of allosteric antagonists of ADP receptors, in particular Ticagrelor, or of intermediates useful for the preparation thereof.

State of the art

Triazol[4,5-c | pyrimidines are a very interesting class of compounds for the preparation of a large number of pharmaceutical active ingredients, such as 3-[7- [[(1 f?,2S)-2-(3,4-difluorophenyl)-cyclopropyl]-amino]-5-(propylthio)-3/-/-1 ,2,3-triazol [4,5-c |-pyrimidin-3-yl]-5-(2-hydroxyethoxy)-(1 S,2S,3F?,5S)-cyclopentan-1 ,2-diol (known as Ticagrelor), having the following structural formula:

This compound, manufactured by AstraZeneca (with trade names of Brilinta in the United States and Brilique^® or Possia^® in Europe) is an allosteric antagonist of the P2Y-I2 subtype of ADP receptors, useful as inhibitor of platelet aggregation and indicated for the prevention of thrombosis.

Ticagrelor and other similar compounds are described in international application WO 00/34283 A1 .

One of the structural features of Ticagrelor is the presence of a hydroxyethyl chain, linked to one of the hydroxyls present on the five-membered carbocyclic portion.

In international application WO 00/34283 A1 , the hydroxyethyl chain is introduced by alkylating an intermediate with methyl(trifluoromethylsulfoniloxy)acetate (the triflate of methyl glycolate), obtaining a modest yield (42%). In subsequent steps of the synthesis, the ester group thus introduced is reduced to a primary alcohol with diisobutyl aluminum hydride (Dibal-H, a pyrophoric reducing agent). This synthetic approach has many disadvantages: the triflate of methyl glycolate is not a commercial product and its preparation requires the use of triflic anhydride at cryogenic temperatures. Triflic anhydride is an expensive product, highly corrosive and reactive and therefore difficult to handle, especially on an industrial scale. The reduction of the ester group to a primary alcohol group with Dibal-H should be avoided on an industrial scale because it is a pyrophoric reagent. Furthermore, the reduction with Dibal-H produces a stoichiometric amount of aluminum salts which must be disposed of properly, resulting in additional costs. In addition to the disadvantages of a practical nature described above, the introduction of the hydroxyethyl chain using the triflate of methyl glycolate is not desirable for the atom economy of the process, defined by the ratio of (molecular weight of the desired product)/(molecular weight of all reagents used) x 100.

International application WO 01 /92263 A1 describes a more convergent process for the synthesis of Ticagrelor.

The hydroxylated five-membered carbocyclic portion is introduced using hydroxyethyl amino triol protected as acetonide, as follows:

The use of this intermediate avoids the reduction of the ester group to a primary alcohol in the final steps of the synthesis; however, the introduction of the hydroxyethyl group in Ticagrelor is carried out in an indirect way, i.e. by protection of the amino group, alkylation with an ester of bromoacetic acid, reduction of the ester to a primary alcohol, and finally deprotection of the amino group.

The protection of the amine (as benzyl carbamate) is carried out with benzyl chloroformate, a carcinogenic reagent, or alternatively with N- (benzyloxycarboniloxy) succinimide (also known as Cbz-OSu), a very expensive reagent and therefore not suitable for industrial scale preparations. The reduction of the ester is carried out with lithium borohydride and the deprotection of the benzyl carbamate is performed using palladium on carbon and hydrogen. This latter reaction, if carried out on an industrial scale, requires specialized reactors (hydrogenators), the handling of a pyrophoric catalyst and in order to be economically acceptable it must contemplate recycling operations of the exhausted catalyst. This sequence of protection and deprotection of the amino group is therefore disadvantageous in the economy of the synthesis process of Ticagrelor.

An oxygen alkylation reaction in the presence of an unprotected secondary amine in the synthesis of Ticagrelor is known, for example, from international application WO 2013/02351 1 A1 :

This step is performed, according to the teaching of this application, treating the alcohol dissolved in tetrahydrofuran with potassium terf-butylate followed by ethyl bromoacetate, leading to a wholly unsatisfactory yield (9%).

The object of this invention is to provide a method for the synthesis of an allosteric antagonist of the ADP receptors, in particular Ticagrelor, involving less synthetic steps than the known processes, with excellent yields and which provides Ticagrelor of adequate purity for pharmaceutical use.

Summary of the invention

These objects are achieved with the present invention which, in a first aspect thereof, relates to an oxygen-selective alkylation reaction of amino alcohols that avoids the need of protecting the amino group. In a second aspect thereof, the invention relates to a process which comprises as first step the oxygen-selective alkylation reaction and subsequently one or more steps to transform the O- alkylation product into an allosteric antagonist of the ADP receptors, in particular Ticagrelor; finally, the invention relates to intermediate compounds obtained in the process.

Detailed description of the invention

All terms used in this application, unless otherwise indicated, shall be understood in their ordinary meaning as known in the art. More detailed specifications for some of the terms used in this application are listed below and must be applied uniformly to the entire specification and claims, unless otherwise indicated.

The symbol (dashed bond) present in some of the formulas of the specification and claims indicates that the substituent is directed below the plane of the sheet. The symbol — (wedge bond) present in some of the formulas of the specification and claims indicates that the substituent is directed above the plane of the sheet. The compounds prepared by the processes of the present invention may have one or more stereocenters, and may exist, be used or be isolated in enantiomerically enriched forms or as racemic mixtures as well as in diastereomerically pure forms or as diastereomeric mixtures. It should be understood that the processes of the present invention may give rise to racemic mixtures or enantiomerically enriched mixtures. The procedures for the purification and characterization of these compounds are known to the man skilled in the art and include, for example, crystallization techniques or chromatography on chiral stationary phase.

The symbol "*" (asterisk) present in some formulas of the specification and claims indicates a chiral center; however, the absence of asterisks does not necessarily imply that there are no stereocenters in the compound. These formulas may refer to a racemic or enantiomerically enriched mixture or to a mixture of diastereoisomers.

A mixture of enantiomers {R, S) may contain the two enantiomers in any ratio. The enantiomeric purity is usually expressed as "enantiomeric excess" or e.e. which is defined, for example for the enantiomer (S), as [(S-R)/{R+S)] x 100, where S and R are the amounts of the two enantiomers (S) and (R) (as determined for example by HPLC or GC on chiral stationary phase or by polarimetry).

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

The term "enantiomerically enriched" as used in this application means that one of the enantiomers is present in excess over the other enantiomer.

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

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

According to a first aspect, the present invention relates to an oxygen-selective alkylation reaction of an amino alcohol of general formula (I) with a compound of general formula (IV) to produce an O-alkylated compound of general formula (II), without protection of the amino group of the starting compound, according to the scheme:

wherein:

- R¹ and R² are selected, independently of one another, among H and C1 -C6 alkyl; alternatively, R¹ and R² together may form a 5- or 6-membered spiro- fused ring, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl;

- R³ is selected between H and OR⁵;

- R⁴ is selected among H, C1 -C6 alkyl, a protective group (Pg) of alcohols removable by treatment in acidic conditions, or together with R⁵ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl;

- R⁵ is C1 -C6 alkyl or together with R⁴ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl;

- X is a leaving group selected among a halogen or an optionally substituted alkyl- or aryl-sulfonate;

with the proviso that when R³ is H, then R⁴ is H or a protecting group (Pg) of alcohols; and that when R³ is OR⁵, then R⁴ is a C1 -C6 alkyl or alternatively together with R⁵ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl.

The compound of formula (I), used as starting material in the oxygen-selective alkylation reaction of the invention, is known and can be obtained for example using the procedure described in the international application WO 00/034283; the compounds related to the general formula (IV) are commercial or can be synthesized according to current techniques in organic synthesis.

The oxygen-selective alkylation reaction is carried out transforming the amino alcohol of formula (I) into a reactive form thereof by treatment with sodium hydride (NaH) at a temperature between -20 and 25 °C, in a solvent selected among dimethylformamide, /V-methylpyrrolidone, or preferably dimethylacetamide, and then adding a compound of formula (IV) at a temperature between -20 and 25 °C, preferably at 0 °C.

Sodium hydride is used in over-stoichiometric amount compared to the amount of amino alcohol of formula (I) used; amounts of NaH useful for the purposes of the invention are between 2 and 6 equivalents, preferably between about 4 and 5 equivalents.

Compound (IV) is used in an amount between 1 and 5 equivalents relative to the amount of amino alcohol of formula (I) used, preferably in an amount between about 2.5 and 2.7 equivalents.

Preferably, the compound of formula (IV) is added in successive portions to limit the elimination side reaction according to the following scheme:

The amount of compound of formula (IV) to be used in any addition and the timing of the additions themselves can be easily determined by the man skilled in the art by performing analytical controls at different times on the reaction mass, calculating the conversion at each control, and adding compound of formula (IV) if further conversion is not observed in two successive analytical controls.

Preferably, the starting compound used in the oxygen-selective alkylation reaction described so far is an enantiomerically enriched amino alcohol of formula (la) and the reaction leads to the formation of an enantiomerically enriched O-alkylated product of formula (Ma):

In a second aspect thereof, the invention relates to a process for the preparation of an allosteric antagonist (III) of the ADP receptors, in particular Ticagrelor, comprising:

A) transforming the amino alcohol (I) into the O-alkylated product (II):

B) transforming the O-alkylated product (II) into an allosteric antagonist (III) of ADP receptors:

wherein substituents R¹, R², R³ and R⁴ have the meanings given above.

The first operation A) of the process corresponds to the oxygen-selective alkylation reaction described above.

The second operation, B), of the process of the invention can be carried out according to two alternative synthetic schemes, referred to below as B.i) and B.ii). Synthetic scheme B.i) can be carried out when R³ is OR⁵ and R⁴ is a C1 -C6 alkyl, or alternatively forms, together with R⁵, a C2-C3 alkylene radical, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl; in the latter case, said alkylene radical, the two oxygen atoms to which it is bound and the carbon atom bonded to two oxygen atoms, may form for example a 1 ,3- dioxolane or 1 ,3-dioxane ring. This synthetic scheme includes the following steps: B.i.1 ) converting the O-alkylated product (II) into aldehyde (IN"),

B.i.2) reducing the aldehyde (IN") to obtain an allosteric antagonist (III) of ADP receptors.

In step B.i.1 ), the O-alkylated product (II) is converted into aldehyde (IN") through the use of acidic conditions, for example using one of the methods for the deprotection of acetals and ketals described in T.W. Green, Protective Groups in Organic Synthesis, Wiley (1999), pages 297-328, incorporated herein by reference. Acids useful for the purpose are the mineral acids, for example hydrochloric acid, sulfuric acid or phosphoric acid, optionally in combination with one or more organic solvents miscible with water, for example methanol, ethanol, /^'sopropanol, tetrahydrofuran, 1 ,4-dioxane or a mixture thereof. Preferably, such a step is conducted using hydrochloric acid and methanol. Alternatively, this step can be conducted using a solution of one or more inorganic acids in an alcohol, for example anhydrous hydrogen chloride in methanol, or using organic acids, for example carboxylic acids (such as formic, acetic or trifluoroacetic acid) or sulfonic (such as methanesulfonic, camphorsulfonic or para-toulensulfonic acid) in admixture with an organic solvent such as an alcohol (for example methanol, ethanol or /sopropanol), an ether (for example tetrahydrofuran or 1 ,4-dioxane) or a mixture thereof and optionally in the presence of water. Optionally, such a step can be conducted by isolating the reaction intermediates of formula (Ι ) and (Ι ):

In step B.i.2), aldehyde (IN") (optionally isolated) is converted into an allosteric antagonist (III) of the ADP receptors by treatment with a reducing agent.

Reducing agents suitable for the purpose are generally known in the art and are described, for example, in S.D. Burke (Ed.), Handbook of Reagents for Organic Synthesis, Oxidizing and Reducing Agents, Wiley (1999); preferably, this step is carried out using as reducing agent a boron hydride (for example sodium, lithium or potassium borohydride or sodium triacetoxyborohydride), or borane complexed with a Lewis base, for example ammonia, an amine (primary, secondary or tertiary), a pyridine, a sulfide, a phosphine or an ether. Alternatively, this step can be conducted using as the reducing agent sodium dithionite (Na₂S₂0₄).

The reduction of the aldehyde (IN") into an allosteric antagonist (III) of the ADP receptors can be conducted in a very wide variety of solvents, for example an alcohol (preferably methanol, ethanol or /sopropanol), an ether (preferably tetrahydrofuran or 1 ,4-dioxane), a carboxylic acid (preferably acetic acid) or a mixture thereof, optionally in the presence of water.

The preferred synthetic scheme B.ii) can be carried out when R³ is H and R⁴ is H or a protecting group (Pg) of alcohols removable by treatment in acidic conditions, for example an ether, such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), para-methoxybenzyloxymethyl ether (p-OMe-BOM), 2- methoxyethoxymethyl ether (MEM), 1 -etoxyethyl ether, or preferably tetrahydropyran-2-yl ether (THP); or a trialkylsilyl ether, such as triethylsilyl, tri-/^'so propylsilyl or preferably trimethylsilyl ether. This synthetic scheme comprises the transformation of compound (II) into an allosteric antagonist (III) of the ADP receptor via acid treatment, for example one of those described above to perform step B.i.1 ).

Preferably, this step is carried out using an aqueous solution of a mineral acid selected among hydrochloric acid, sulfuric acid or phosphoric acid, or an aqueous solution of a carboxylic acid or a sulfonic acid in the presence of a solvent miscible with water, for example methanol, ethanol, /^'sopropanol, tetrahydrofuran, 1 ,4- dioxane or a mixture thereof.

Optionally, this step can be conducted by isolating the intermediate compounds of formula (V) and (V):

In the preferred case of use of the enantiomerically enriched amino alcohol of formula (la) as starting material, this synthetic scheme leads to the formation of Ticagrelor:

Compound (IN") is new and is a further object of the present invention. Compound (II), with the proviso that R³ is OR⁵ and R⁴ is a C1 -C6 alkyl or alternatively forms together with R⁵ a C2-C3 alkylene radical, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl, is in its turn new and constitutes an additional object of the present invention.

The compounds obtained through the processes of the present invention can be used in subsequent steps without further purification or can be separated and purified by one of the methods known by the man skilled in the art, such as crystallization, chromatography, or transforming them into a salt or a co-crystal, or by washing with an organic solvent or an aqueous solution, optionally adjusting the pH. The invention will be further described by the following examples. In the examples, when a mixture of solvents is used as eluent, the indicated ratio of solvents is by volume.

Example 1

Preparation of A/-((1 /⁼?,2S)-2-(3,4-difluorophenyl)cvclopropyl)-3-((3aS,4/⁼?.6S,6a/⁼?)- 2.2-dimethyl-6-(2-((tetrahvdro-2/-/-pyran-2-yl)oxy)ethoxy)tetrahvdro-3a/-/- cvclopenta[c/|[1 ,31dioxol-4-yl)-5-(propylthio)-3/-/-[1 ,2,3]triazol[4,5-c/|pyrimidin-7- amine (compound 2).

In this example, as reagents are used compound (1 ), compound of formula (I) in which R¹ and R² are both methyl and the chiral centers have the configuration shown, and compound (4), compound of formula (IV) in which R³ is hydrogen, R⁴ is a radical tetrahydropyran-2-yl, and X is Br.

Compound (1 ) (250 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (1 .0 ml_) is added, under nitrogen and at 0 °C, to a suspension of NaH (60% in mineral oil) (77 mg, 1 .92 mmol) in anhydrous dimethylacetamide (1 .0 ml_). At the end of the addition, the mixture is warmed to 25 °C and stirred for 1 hour.

The mixture is cooled to 0 °C and 2-(2-bromoethoxy)tetrahydro-2/-/-pyran (4) (96%, 104 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (0.5 ml_) is added. After complete addition, the mixture is stirred at a temperature between 0 and 5 °C monitoring the reaction using the HPLC method below. When two subsequent analytical checks show no further conversion (after about 2 hours), a second portion of the compound (4) (104 mg, 0.48 mmol) in anhydrous dimethylacetamide (0.5 ml_) is added. The mixture is stirred at the same temperature monitoring the reaction by HPLC.

After about 19 hours, a third portion of the compound (4) (52 mg, 0.24 mmol) dissolved in anhydrous dimethylacetamide (0.25 ml_) is added. The mixture is stirred at the same temperature monitoring the reaction by HPLC. After 22 hours, the HPLC analysis shows: compound (1 ) 1 .5%, compound (2) 88.0%, N-alkyl-derivative 0.2%, di-alkyl-derivative 10.3%, the latter two compounds having the following structural formulas:

/V-alkyl-derivative di-alkyl-derivative

A saturated aqueous solution of NH₄CI (5 mL) and water (5 mL) are then added. The mixture is extracted with ethyl acetate (3 x 10 mL). The combined organic phases are washed with water (2 x 10 mL) and brine (10 mL), then dried over Na₂S0₄, filtered, concentrated to a residue and purified by flash chromatography eluting with ethyl acetate/hexane 1 :1 , obtaining the pure product (2) (207 mg, 67%) and 65 mg of product with a HPLC purity of 58%, corresponding to 38 mg of pure product. Overall yield is 79%.

¹ H NMR (300 MHz, CD₃OD, mixture of 2 diastereomers) δ 7.29 - 6.97 (m, 3H), 5.54 (dd, J = 6.7, 3.3 Hz, 1 H), 5.07 (td, J = 6.8, 3.3 Hz, 1 H), 4.79 (dt, J = 4.5, 2.0 Hz, 1 H), 4.51 (t, J = 3.1 Hz, 0.5H, diast. 1 ), 4.48 (t, J = 3.1 Hz, 0.5H, diast 2), 4.08 - 3.97 (m, 1 H), 3.83 - 3.70 (m, 1 H), 3.70 - 3.58 (m, 2H), 3.58 - 3.47 (m, 1 H), 3.47 - 3.33 (m, 2H), 3.20 - 2.86 (m, 3H) 2.64 (t, J = 6.4, Hz, 2H), 2.20 - 2.07 (m, 1 H), 1 .86 - 1 .24 (m, 10H), 1 .52 (s, 3H), 1 .34 (s, 3H) 0.94 (t, J = 7.3 Hz, 3H).

1³C NMR (75 MHz, CD₃OD, mixture of 2 diastereomers) δ 172.01 , 155.61 , 151 .46 (dd, J = 246, 14 Hz), 150.63, 150.13 (dd, J = 245, 12 Hz) 139.94, 124.56, 123.97, 1 17.94 (d, J = 17 Hz), 1 16.65 (d, J = 17 Hz), 1 13.58, 100.22 (diast. 1 ), 100.12 (diast. 2), 85.54, 84.78, 83.54, 69.88 (diast. 1 ), 69.81 (diast. 2), 67.68 (diast. 1 ), 67.63 (diast. 2), 63.90, 63.05 (diast. 1 ), 62.97 (diast. 2), 36.52 (diast. 1 ), 36.45 (diast. 2), 34.58, 34.10, 31 .57, 27.21 , 26.50, 25.53, 24.93, 23.91 , 20.37 (diast. 1 ), 20.34 (diast. 2), 15.80, 13.83.

HPLC method

Column: Symmetry C18 250 x 4.6 mm 5μιτι or equivalent

Flow: 1 .0 mL/min Injection volume: 5 μΙ_

Wavelength: 210 and 220 nm

Column T: 30 °C

Mobile phase: Phase A: 0.1 % aqueous solution of H₃P0₄

Phase B: acetonitrile

Gradient:

Retention times (minutes):

Compound (1 ):

/V-alkyl-derivative

Compound (2):

di-alkyl -derivative

Example 2

Preparation of A/-((1 /⁼?,2S)-2-(3,4-difluorophenyl)cvclopropyl)-3-((3aS,4/⁼?,6S,6a/⁼?)-

6-(2₁2-dimethoxyethoxy)-2₁2-dimethyltetrahvdro-3a/-/-cvclopenta[c |[1 ₁31dioxol-4- yl)-5-(propylthio)-3/-/-[1 ,2,31triazol[4,5-c lpyrimidin-7-amine (compound 3)

In this example, compound (1 ) of example 1 and compound (5), compound of formula (IV) in which R³ is a methoxy radical, R⁴ a methyl and X is Br, are used as reagents.

Compound (1 ) (250 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (1 .0 mL) is added, under nitrogen and at 0 °C, to a suspension of NaH (60% in mineral oil) (77 mg, 1 .92 mmol) in anhydrous dimethylacetamide (1 .0 mL). At the end of the addition, the mixture is warmed to 25 °C for 30 minutes.

The mixture is cooled to 0 °C and bromoacetaldehyde dimethyl acetal (5) (97%, 84 mg, 0.48 mmol) in anhydrous dimethylacetamide (0.5 mL) is added. After complete addition the mixture is stirred at 25 °C checking the reaction using the HPLC method above.

When two subsequent analytical checks show no progress in the degree of conversion (after about 20 hours), the mixture is cooled to 0 °C, and a second portion of the compound (5) (97%, 84 mg, 0.48 mmol) in anhydrous dimethylacetamide (0.5 mL) is added. The mixture is warmed to 25 °C, checking the reaction by HPLC. After 22 hours, the HPLC analysis shows: compound (1 ) 29.3%, compound (3) 70.7%.

A saturated aqueous solution of NH₄CI (5 mL) and water (5 mL) are then added. The mixture is extracted with ethyl acetate (3 x 10 mL). The combined organic phases are washed with water (2 x 10 mL) and brine (10 mL), then dried over Na₂S0₄, filtered, concentrated to a residue and purified by flash chromatography eluting with ethyl acetate/hexane 1 :1 , obtaining the pure product (3) (175 mg, 60%).

¹ H NMR (301 MHz, CD₃OD) δ 7.27 - 6.89 (m, 3H), 5.48 (dd, J = 6.7, 3.3 Hz, 1 H), 5.04 (td, J = 6.9, 3.4 Hz, 1 H), 4.23 (t, J = 5.1 Hz, 1 H), 3.98 (td, J = 5.9, 2.2 Hz, 1 H), 3.46 (dd, J = 10.4, 5.2 Hz, 1 H), 3.34 (dd, J = 10.4, 5.2 Hz, 1 H), 3.28 (s, 3H), 3.23 (s, 3H), 3.12 - 2.83 (m, 3H), 2.60 (t, J = 6.5 Hz, 2H), 2.14 - 2.04 (m, 1 H), 1 .69 - 1 .53 (m, 2H), 1 .53 - 1 .26 (m, 6H), 1 .49 (s, 3H), 1 .32 (s, 3H), 0.91 (t, J = 7.3 Hz, 3H).

¹³C NMR (76 MHz, CD₃OD) δ 172.07, 155.67, 151 .49 (dd, J = 245, 13 Hz), 150.65, 150.15 (dd, J = 245, 13 Hz), 149.86, 139.95, 124.61 , 123.97, 1 18.05 (rotamer 1 ), 1 17.82 (rotamer 2), 1 16.74 (rotamer 1 ), 1 16.51 (rotamer 2), 1 13.70, 104.15, 85.55, 85.03, 83.55, 70.18, 63.81 , 54.48, 36.33, 34.57, 34.10, 27.18, 25.56, 24.90, 23.92, 15.78, 13.79.

Retention times (minutes): Compound (1 ): 27.9

Compound (3): 31 .3

Example 3

Preparation of Ticagrelor

In this example, Ticagrelor is prepared starting from compound (2) produced as described in e B.ii).

A solution of compound (2) (500 mg, 0.77 mmol) in methanol (5 mL) is prepared and kept at 0 °C; to this solution, aqueous HCI 6N (1 .0 mL) is slowly added. At the end of the addition, the mixture is warmed to room temperature and stirred at this temperature for 4 hours and 30 minutes, then it is neutralized (pH = 7) with 1 N NaOH, methanol is removed under reduced pressure, the residue is taken up in ethyl acetate (5 mL) and washed with water (5 mL); the phases are separated, the aqueous phase is extracted again with ethyl acetate (3 x 10 mL). The organic phase is washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to a residue obtaining Ticagrelor (390 mg, 97%) as a white solid.

Example 4

Preparation of Ticagrelor

In this example, Ticagrelor is prepared starting from compound (3) produced as described in example 2, and following the synthetic scheme B.i).

Compound (3) (170 mg, 0.28 mmol) is dissolved in a mixture of acetic acid and water (1 :1 , 1 .7 mL) and heated to reflux for two hours, monitoring the reaction by TLC (AcOEt, R_f (3) = 0.87; R_f (product) = 0.25). The mixture is cooled to room temperature, ethyl acetate is added (5 mL), the phases are separated, the organic phase is washed with water (2 x 5 mL) and with a saturated solution of sodium bicarbonate (2 x 5 mL), then again with water (2 x 5 mL) and finally with brine (5 mL).

The organic phase is dried over sodium sulfate, the solvent is evaporated to a residue, which is taken up in methanol (1 mL) and cooled to 0 °C. To the resultant solution, NaBH₄ is added (10 mg, 0.28 mmol). The mixture is stirred for 30 minutes at 0 °C then for 16 hours at room temperature.

Afterwards, a saturated solution of ammonium chloride (2 mL) and ethyl acetate (10 mL) are added. The mixture is stirred for 30 minutes, the phases are separated, the organic phase is washed with brine (2 mL), dried over sodium sulfate and concentrated to a residue which is purified by flash chromatography eluting with dichloromethane/methanol 95:5, obtaining Ticagrelor (80 mg, 55%) as a white solid.

Example 5

Large scale preparation of A/-((1 ff,2S)-2-(3,4-difluorophenyl)cvclopropyl)-3- ((3aS,4/⁼?,6S,6a/⁼?)-2,2-dimethyl-6-(2-((tetrahvdro-2H-pyran-2- yl)oxy)ethoxy)tetrahydro-3a/-/-cvclopenta[c |[1 ,31dioxol-4-yl)-5-(propylthio)-3/-/- [1 ,2,31triazo -c |pyrimidin-7-amine (compound 2).

Compound (1 ) (1 18.0 g, 0.23 mol) dissolved in anhydrous dimethylacetamide (472 ml_) is added in one hour, under nitrogen and at 0 °C, to a suspension of NaH (60% in mineral oil) (45.6 g, 1 .14 mol) in anhydrous dimethylacetamide (472 ml_). At the end of the addition, the mixture is stirred one hour at 0 °C, then 2-(2- bromoethoxy)tetrahydro-2/-/-pyran (4) (1 19.0 g, 0.57 mol) is added in one hour. The mixture is stirred at 0 °C for 24 hours and a HPLC analysis is performed on the reaction mixture using the method reported above.

The composition of the mixture is the following: compound (1 ) 2.0%, compound (2) 80.0%, /V-alkyl derivative 0.5%, di-alkyl-derivative 17.5%.

The reaction mixture is poured on a stirred mixture of water (1890 ml_), /^'sopropyl acetate (950 ml_) and acetic acid (35 g) chilled at 0 °C. After complete quenching the mixture is warmed to room temperature and the phases are separated; the aqueous phase is re-extracted with /^'sopropyl acetate (450 ml_). The combined organic phases are filtered on Celite; the filtrate is concentrated to a residue by distillation under reduced pressure.

The residue is taken up with methanol (150 ml_) and distilled to a residue twice. The crude product (220 g) is analyzed, resulting suitable for use in the production of Ticagrelor according to the procedure described in example 3.

Claims

1 . Oxygen-selective alkylation reaction of an amino alcohol of general formula (I) with a compound of general formula (IV) to produce an O-alkylated compound of general formula (II), according to the scheme:

w ere

- R¹ and R² are selected, independently of one another, among H and C1 - C6 alkyl; alternatively, R¹ and R² together may form a 5- or 6-membered spiro-fused ring, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl;

- R³ is selected between H and OR⁵;

- R⁴ is selected among H, C1 -C6 alkyl, a protecting group (Pg) of alcohols removable by treatment in acidic conditions, or together with R⁴ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl;

- R⁵ is C1 -C6 alkyl or together with R⁴ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among_C1 -C6 alkyl;

with the proviso that when R³ is H, then R⁴ is H or a protecting group (Pg) of alcohols; and that when R³ is OR⁵, then R⁴ is a C1 -C6 alkyl or alternatively together with R⁵ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl,

said reaction comprising the treatment of the compound of formula (I) with sodium hydride in an amount between 2 and 6 equivalents with respect to the compound of formula (I) at a temperature between -20 and 25 °C in a solvent selected among dimethylformamide, /V-methylpyrrolidone or dimethylacetamide, and the subsequent addition of the compound of formula (IV) in an amount between 1 and 5 equivalents with respect to the compound of formula (I) at a temperature between -20 and 25 °C.

Reaction according to claim 1 , wherein when R⁴ is a protecting group (Pg) of alcohols, said group is an ether or a trialkylsilyl ether.

Reaction according to claim 2, wherein said ether is selected among methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), para- methoxybenzyloxymethyl ether (p-OMe-BOM), 2-methoxyethoxymethyl ether (MEM), 1 -etoxyethyl ether, and tetrahydropyran-2-yl ether (THP), and said trialkylsilyl ether is selected among triethylsilyl ether, tri-/^'sopropylsilyl ether and trimethylsilyl ether.

Reaction according to claim 1 wherein said halogen is selected among CI, Br and I and said alkyl- or aryl-sulfonate is selected among mesylate, benzenesulfonate and tosylate.

Reaction according to any one of the preceding claims, wherein said alkylene radical, the two oxygen atoms to which it is linked, and the carbon atom bonded to the two oxygen atoms, together form a 1 ,3-dioxolane or a 1 ,3- dioxane ring.

Reaction according to any one of the preceding claims, wherein the addition of the compound of formula (IV) is carried out in successive portions.

Reaction according to any one of the preceding claims, wherein the starting compound is an enantiomerically enriched amino alcohol of formula (la) and said reaction leads to the formation of an enantiomerically enriched O- alkylated product of formula (Ma):

8. Process for the preparation of an allosteric antagonist of ADP receptors, (III), comprising the operations:

A) transforming the amino alcohol (I) into the O-alkylated product (II) according to any one of claims 1 to 7:

wherein substituents R¹, R², R³ and R⁴ have the meanings given in claim 1 ; and

Process according to claim 8 wherein, when R³ is OR⁵ and R⁴ is a C1 -C6 alkyl or alternatively forms together with R⁵ a C2-C3 alkylene radical, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl, operation B is carried out according to a synthetic scheme B.i) comprising the following steps:

B.i.1 ) converting the O-alkylated product (II) into aldehyde (IN") operating under acidic conditions:

B.i.2) reducing aldehyde (IN") in order to obtain an allosteric antagonist (III) of ADP receptors.

10. Process according to claim 9, wherein step B.i.1 ) is carried out using an acid selected among a mineral acid, a carboxylic acid and a sulfonic acid.

1 1 . Process according to any one of claims 9 or 10, wherein the reaction intermediates of formula (Ι ) and (II") are isolated:

12. Process according to any one of claims 9 to 1 1 , wherein step B.i.2) is accomplished by treatment with a reducing agent.

13. Process according to claim 8 wherein, when R³ is H and R⁴ is H or a protecting group (Pg) of an alcohol, operation B is carried out according to synthetic scheme B.ii) by treatment of compound (II) with an aqueous solution of a mineral acid selected among hydrochloric acid, sulfuric acid or phosphoric acid, or an aqueous solution of a carboxylic acid or of a sulfonic acid in the presence of a solvent miscible with water.

14. Process according to claim 13, wherein the reaction intermediates of formula (V) and (V") are isolated:

wherein substituents R¹, R² have the meanings given above and Pg is one of the alcohol protecting groups removable by treatment in acidic conditions. 15. Process according to any one of claims 8 to 14, wherein the starting compound used in operation A) is an enantiomerically enriched amino alcohol of formula la), and sai f Ticagrelor:

16. Compound of general formula (IN"):

1 7. Compound of general formula (II):

wherein :

- R¹ and R² are selected, independently of each other, among H and C1 -C6 alkyl ; alternatively, R¹ and R² together may form a 5- or 6-membered spiro-fused ring, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl ;

- R³ is OR⁵;

- R⁴ is selected among H, C1 -C6 alkyl, a protecting group (Pg) of alcohols removable by treatment in acidic conditions, or together with R⁵ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl ;

- R⁵ is C1 -C6 alkyl or together with R⁴ it forms a C2-C3 alkylene radical optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl,

with the proviso that R⁴ is a C1 -C6 alkyl or alternatively forms together with R⁵ a C2-C3 alkylene radical, optionally substituted by 1 , 2 or 3 substituents independently selected among C1 -C6 alkyl.