ITMI20130487A1 - SELECTIVE ALCHILATION OF CYCLOPENTILALCULES - Google Patents

Description

Description of the industrial invention entitled:

"SELECTIVE ALKYLATION OF CYCLOPENTYLALLCHOLS"

Field of the invention

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

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

State of the art

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

This compound, manufactured by AstraZeneca (under the 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 an inhibitor of platelet aggregation and indicated for the prevention of thrombosis.

Ticagrelor and other similar compounds are described in international application WO 00/034283.

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

In international application WO 00/034283 the hydroxyethyl chain is introduced by alkylating an intermediate with methyl (trifluoromethylsulfonyloxy) 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 primary alcohol with diisobutyl aluminum hydride (Dibal-H, a pyrophoric reducing agent). This synthetic approach has many disadvantages: methyl glycolate triflate is not a commercial product and its preparation requires the use of triflic anhydride at cryogenic temperatures. Triflical anhydride is an expensive, highly corrosive and reactive product 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 due to the pyrophoric characteristics of the reagent in question. Furthermore, the reduction with Dibal-H produces a stoichiometric quantity of aluminum salts which must be disposed of appropriately, resulting in additional costs. In addition to the practical disadvantages described above, the introduction of the hydroxyethyl chain using methyl glycolate triflate is not optimal from an atomic economy point of view, defined by the ratio of (molecular weight of the desired product) / (molecular weight of all reagents used) X 100.

International application WO 01/092263 describes a more convergent process for the synthesis of Ticagrelor.

The five-membered carbohydrate-cyclic portion is introduced using the protected hydroxyethyl amino triol as acetonide, shown below:

The use of this intermediate avoids the reduction of the ester group to 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, ie for the protection of the amino group, alkylation with an ester of bromoacetic acid, reduction of the ester to 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 Γ N- (benzyloxycarbonyloxy) succinimide (also known as Cbz-OSu), a very expensive reagent and consequently not suitable for preparations on an industrial scale. The reduction of the ester is carried out with lithium borohydride and the deprotection of benzyl carbamate is achieved using palladium on carbon and hydrogen. The latter reaction, if carried out on an industrial scale, requires specialized reactors (hydrogenators), the handling of a pyrophoric catalyst and to be economically acceptable it must provide for 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 is known on Ticagrelor, for example, in international application WO 13/023511:

This step is carried out, according to the teaching of this question, by treating the alcohol dissolved in tetrahydrofuran with potassium tert-butylate and then with ethyl bromoacetate, leading to a completely unsatisfactory yield (9%).

The purpose of this invention is to provide a method for the synthesis of an allosteric antagonist of ADP receptors, in particular Ticagrelor, which is carried out in a lower number of synthetic steps than those of the known processes, in excellent yields and which provides Ticagrelor of adequate purity for pharmaceutical use.

Summary of the invention

These objectives have been achieved with the present invention which, in its first aspect, concerns a selective alkylation reaction of amino alcohols to oxygen without resorting to the protection of the amino group. In a second aspect, the invention relates to a process which comprises as a first step the selective alkylation reaction to oxygen, and subsequently one or more steps of transformation of the O-alkylation product into an allosteric antagonist of 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, 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 forth below and are to be applied uniformly to the entire description and claims, unless otherwise indicated.

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 - (wedge bond) present in some formulas of the description and claims indicates that the substituent is directed above the plane of the sheet.

Compounds prepared by the processes of the present invention can have one or more stereocenters and can exist, be used or be 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 "*" (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. These formulas may refer 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 "enantiomeric excess" or e. E. Which is defined, for example for the (S) enantiomer, as [(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 or by polarimetry).

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

The term "enantiomerically enriched" as used in the present application means that one of the enantiomers is present in excess with respect to the other enantiomer. The term "purified (S) or (R) enantiomer" means that its enantiomeric purity is usually 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 can represent its salt or its co-crystal.

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

in which:

- R <1> and R <2> are chosen, independently of each other, between H and C1-C6 alkyl; alternatively R <1> and R <2> together can form a spiro-fused ring of 5 to 6 terms, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl;

- R <3> is chosen between H and OR <5>;

- R <4> is selected from H, C1-C6 alkyl, a protective group of the alcohols removable by treatment in acidic conditions, or together with R <5> it forms a C2-C3 alkylene radical optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl;

- R <5> is C1-C6 alkyl or forms together with R <4> a C2-C3 alkylene radical, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl;

- X is one of the leaving groups known to the skilled person, for example selected from a halogen (preferably Cl, Br or I) or an optionally substituted alkyl or aryl sulfonate (preferably mesylate, benzenesulfonate or tosylate); with the proviso that when R <3> is H, R <4> is H or a protecting group of the alcohols; and that when R <3> is OR <5>, R <4> is a C1-C6 alkyl or alternatively forms together with R <5> a C2-C3 alkylene radical, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl.

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

The selective alkylation reaction with oxygen is carried out by 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 from dimethylformamide, / V-methylpyrrolidone or, preferably, dimethylacetamide, then adding a compound of formula (IV) at a temperature between -20 and 25 ° C, preferably at 0 ° C.

Sodium hydride is used in a super-close-in amount with respect 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 about 4 equivalents.

Compound (IV) is used in an amount ranging from 1 to 5 equivalents with respect to the amount of amino alcohol of formula (I) used, preferably in amounts of about 2.5 equivalents.

The quantity of sodium hydride used and the method of addition of the compound of formula (IV) determine a greater or lesser selectivity towards the formation of the O-alkylated product (II).

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

Reaction

The amount of compound of formula (IV) to be added in the individual portions and the timing of the additions themselves can be easily determined by an average technician by carrying out an analytical check on the reaction mass, calculating the conversion percentage achieved and proceeding to the next addition if in two subsequent analytical checks no progress in the degree of conversion is observed.

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

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

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

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

in which the substituents R <1>, R <2>, R <3> and R <4> take on the meanings reported above.

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

The second operation, B), of the process of the invention, can be carried out according to two alternative synthetic schemes, indicated below as B.i), B.ii).

The synthetic scheme B.i) can be realized when R <3> is equal to OR <5> and R <4> is a C1-C6 alkyl or alternatively it forms together with R <5> a C2-C3 alkylene radical, optionally substituted 1, 2 or 3 substituents independently selected from C1-C6 alkyl; in the latter case, called alkylene radical, the two oxygen atoms to which it is bonded and the carbon atom bonded to the two oxygen atoms, can form, for example, a 1, 3-dioxolane or 1, 3-dioxane ring . This brief outline includes the following steps:

B.i.1) convert the O-alkylated product (II) into aldehyde (III ")

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

In step B.i.1) the O-alkylated product (II) is converted to aldehyde (III ") through the use of acidic conditions, for example using one of those described in T. W. Green, Protective Groups in Organic Synthesis, Wiley (1999 ) for the deprotection of acetals and ketals. Acids useful for this purpose are mineral acids, for example hydrochloric acid, aqueous solutions of sulfuric acid or phosphoric acid, optionally in combination with one or more organic solvents miscible with water, for example methanol, ethanol, isopropanol, tetrahydrofuran , 1, 4-dioxane or a mixture thereof. Preferably, this step is carried out in an aqueous solution of hydrochloric acid in combination with methanol. Alternatively this step can be carried out using a solution of one or more inorganic acids in an alcohol, for example anhydrous hydrogen chloride in methanol, or using organic, for example carboxylic acids (such as formic, acetic or trifluoroacetic acid) or sulphonic acids. (such as methanesulfonic, camphorsulfonic or para-toulenesulfonic acid) optionally in admixture with an organic solvent such as an alcohol (for example methanol, ethanol or isopropanol), an ether (for example tetrahydrofuran or 1, 4-dioxane) or one of them mixture and optionally in the presence of water. Optionally, this step can be carried out by isolating the reaction intermediates of formula (II ·) and (II "):

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

Suitable reducing agents 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 boron hydride or sodium triacetoxy boron hydride), 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 carried out using sodium dithionite (Na2S204) as the reducing agent.

The reduction of aldehyde (III ") into an allosteric antagonist of ADP receptors, (III), can be carried out in a very wide variety of solvents, for example an alcohol (preferably methanol, ethanol or isopropanol), 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 realized when R <3> is H and R <4> is H or a protective group of the alcohols which can be removed by treatment in acidic conditions, for example an ether, preferably tetrahydropyran-2-yl, or a trialkylsilyl, preferably trimethylsilyl. This synthetic scheme includes the transformation of compound (II) into an allosteric antagonist (III) of ADP receptors by acid treatment, for example one of those described above to carry out operation B.i.1).

Preferably this step is carried out using an aqueous solution of a mineral acid selected from hydrochloric acid, sulfuric acid or phosphoric acid, or an aqueous solution of a carboxylic acid or a sulphonic acid in the presence of a water-miscible solvent, for example methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane or a mixture thereof.

Optionally, this step can be carried out by isolating the intermediate compounds of formula (V ') and (V "), produced during the reaction:

Preferably, in step A) of the process of the invention, the enantiomerically enriched amino alcohol with formula (la) is used as the starting compound, leading to the formation of Ticagrelor:

Compound (III ") is new and is a further object of the present invention. Compound (II), with the condition that R <3> is equal to OR <5> and R <4> is a C1-C6 0 alkyl alternatively forms a C2-C3 alkylene radical together with R <5>, optionally replaced by 1, 2 or 3 substituents independently selected from C1-C6 alkyl, is in 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 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.

The invention will be further illustrated through the following examples.

Example 1

Preparation of N - ((1 R2S) -2- (3,4-difluorophenyl) cyclopropyl) -3 - ((3aS, 4R.6S.6aR) -2.2-dimethyl-6- (2 - ((tetrahydro-2H- pyran-2-yl) oxy) ethoxy) tetrahydro-3a / y-cyclopentarc / iri .3T dioxol-4-yl) -5- (propylthio) -3 / - / - H .2.31triazoloi4.5-c / lpirimidin- 7-amine (compound 2).

In this example, compound (1), compound of formula (I) in which R <1> and R <2> are both methyl and the stereogenic centers have the indicated configuration, and compound (4), composed of formula (IV) where R <3> is hydrogen, R <4> is 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 brought to 25 ° C and is left under stirring for 1 hour.

The mixture is cooled to 0 ° C and 2- (2-bromoethoxy) tetrahydro-2/7-pyran (4) (96%, 104 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (0.5 mL) is added . At the end of the addition it is maintained under magnetic stirring at 0 ° C, checking the course of the reaction using the HPLC method reported below. When two subsequent analytical controls show no progress in the degree of conversion (after about 2 hours), a second portion of compound (4) (104 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (0.5 mL) is added and keeps under magnetic stirring at 0 ° C, controlling the course of the reaction in HPLC.

A third portion of compound (4) is then added (after about 19 hours) (52 mg, 0.24 mmol) dissolved in anhydrous dimethylacetamide (0.25 mL) and kept under magnetic stirring at 0 ° C, controlling the course of the reaction in HPLC. After 22 hours. The HPLC analysis shows: compound (1) 1.5%, compound (2) 88.0%, / V-alkylated 0.2%, di-alkylated 10.3%, the latter having the following structural formulas:

/ V-alkylated di-alkylated

A saturated aqueous solution of NH4CI (5 mL) and water (5 mL) is then added, 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 on Na2SO4, filtered, concentrated to 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 an HPLC purity of 58%, corresponding to 38 mg of pure product. Overall yield 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, 1H), 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, 1H), 3.83 - 3.70 (m, 1H), 3.70 - 3.58 (m, 2H), 3.58 - 3.47 (m, 1H), 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, 1H), 1.86 -1.24 (m, 10H), 1.52 (s, 3H), 1.34 (s, 3H) 0.94 (t, J = 7.3 Hz, 3H).

<13> C 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, 117.94 (d, J = 17 Hz), 116.65 (d, J = 17 Hz), 113.58, 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. 1), 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 C18250 x 4.6mm 5pm or equivalent

Flow: 1.0 mL / min

Injection volume: 5 pL

Wavelength: 210 and 220 nm

T column: 30 ° C

Mobile phase:

Phase A: 0.1% aqueous solution of H3P04

Phase B: acetonitrile

Gradient:

Retention times (minutes):

Compound (1): 27.9

A / -alkylate: 33.1

Compound (2): 33.4

di-alkylate: 40.1

Example 2

Preparation of N - (('\ R2S) -2- (3,4-difluorophenyl) cyclopropyl) -3 - ((3aS, 4R, 6S, 6aR) -6- (2,2-dimethosethoxy) -2.2-dimethyltetrahydro- 3a / - / - cyclopentarc / 1f1,31 dioxol-4-yl) -5- (propylthio) -3 / - / - n, 2,31triazolor4,5-c / lpirimidin-7-amine (compound 3)

In this example the compound (1) of Example 1 and the compound (5), compound of formula (IV) in which R <3> is a methoxy radical, R <4> a methyl 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 brought to 25 ° C and is left under stirring for 30 minutes.

The mixture is cooled to 0 ° C and bromoacetaldehyde dimethyl acetal (5) (97%, 84 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (0.5 mL) is added. At the end of the addition it is maintained under magnetic stirring at 25 ° C, checking the course of the reaction using the HPLC method reported previously.

When two successive analytical controls show no progress in the degree of conversion (after about 20 hours), the mixture is cooled to 0 ° C, a second portion of compound (5) is added (97%, 84 mg, 0.48 mmol) dissolved in anhydrous dimethylacetamide (0.5 mL) and maintained under magnetic stirring at 25 ° C, controlling the course of the reaction in 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) is added, extracted with ethyl acetate (3 x 10 mL). The combined organic phases are washed with water (2 x 10 µL) and brine (10 mL), then dried on Na2SO4, filtered, concentrated to residue and purified by flash chromatography eluting with ethyl acetate / hexane 1: 1 obtaining the product pure (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, 1H), 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, 1H), 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).

<13> C 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, 118.05 (rotamer 1), 117.82 (rotamer 2), 116.74 (rotamer 1), 116.51 (rotamer 2), 113.70, 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 the compound (2) produced as described in example 1, and following the preferred synthetic scheme B.ii).

Compound (2) (500 mg, 0.77 mmol) is dissolved in methanol (5 mL), cooled to 0 ° C and aqueous 6N HCl (1.0 mL) slowly added. Once the addition is complete, it is brought to room temperature. The mixture is stirred at this temperature for 4 hours and 30 minutes, neutralized (pH = 7) with NaOH 1 N, the methanol is removed under reduced pressure, the residue is taken up with ethyl acetate (5 mL) and washed with water ( 5 mL); the phases are separated, the aqueous phase is re-extracted 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 sulphate, filtered and concentrated to the residue to obtain Ticagrelor (390 mg, 97%) as a white solid.

Example 4

Preparation of Ticagrelor

In this example, Ticagrelor is prepared starting from the 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 an acetic acid-water mixture (1: 1, 1.7 mL) and heated under reflux for two hours, following the course of the reaction in TLC ( AcOEt, Rf (3) = 0.87; Rf (product) = 0.25). The mixture is cooled to room temperature, ethyl acetate (5 mL) is added, the phases are separated, the organic phase is washed with water (2 x 5 mL) and with a saturated sodium bicarbonate solution (2 x 5 mL ), then again with water (2 x 5 mL) and finally with brine (5 mL).

The organic phase is dried on sodium sulphate, the solvent is evaporated to residue and taken up with methanol (1 mL), cooled to 0 ° C and NaBH4 (10 mg, 0.28 mmol) is added. The mixture is stirred for 30 minutes at 0 ° C and for 16 hours at room temperature.

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

Claims (18)

CLAIMS 1. Reaction of selective alkylation to oxygen of an amino alcohol of general formula (I) with a compound of general formula (IV) to give an 0-alkylated compound of general formula (II), according to the scheme: in which: - R <1> and R <2> are chosen, independently of each other, between H and C1-C6 alkyl; alternatively R <1> and R <2> together can form a spiro-fused ring of 5 to 6 terms, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl; - R <3> is chosen between H and OR <5>; - R <4> is selected from H, C1-C6 alkyl, a protective group of the alcohols removable by treatment in acidic conditions, or together with R <5> it forms a C2-C3 alkylene radical optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl; - R <5> is C1-C6 alkyl or forms together with R <4> a C2-C3 alkylene radical, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl; - X is a leaving group; with the proviso that when R <3> is H, R <4> is H or a protecting group of the alcohols; and that when R <3> is OR <5>, R <4> is a C1-C6 alkyl or alternatively forms together with R <5> a C2-C3 alkylene radical, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl, said reaction comprising the treatment of the compound of formula (I) with sodium hydride in a quantity comprised between 2 and 6 equivalent with respect to the compound of formula (I) at a temperature comprised between -20 and 25 ° C in a solvent selected from dimethylformamide, / V-methylpyrrolidone or dimethylacetamide, and the subsequent addition of the compound of formula (IV) in a quantity comprised between 1 and 5 equivalent with respect to the quantity of compound of formula (I) at a temperature comprised between -20 and 25 ° C. 2. Reaction according to claim 1, wherein when R <4> is a protecting group of the alcohols, said group is an ether or a trialkylsilyl. 3. A reaction according to claim 2, wherein said ether is tetrahydropyran-2-yl and said trialkylsilyl is trimethylsilyl. 4. Reaction according to any one of the preceding claims, wherein said leaving group X is selected from a halogen or an optionally substituted alkyl or aryl sulfonate. 5. Reaction according to claim 4 wherein said halogen is selected from Cl, Br and I and said alkyl or aryl sulfonate is selected from mesylate, benzenesulfonate and tosylate. 6. Reaction according to any one of the preceding claims, wherein said alkylene radical, the two oxygen atoms to which it is bonded and the carbon atom bonded to the two oxygen atoms, together form a 1, 3-dioxolane or 1 ring , 3-dioxane. 7. Reaction according to any one of the preceding claims, in which the addition of the compound of formula (IV) is carried out in successive portions. 8. Reaction according to any one of claims 1 to 7, 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 (IIa): 9. Process for the preparation of an allosteric antagonist of ADP receptors, (III), including the operations: A) transform the amino alcohol (I) into the O-alkylated product (II) according to any one of claims 1 to 7: wherein the substituents R <1>, R <2>, R <3> and R <4> have the meanings reported in claim 1; And B) transform the O-alkylated product (II) into an allosteric antagonist of ADP receptors, (III): 10. Process according to claim 9 wherein, when R <3> is equal to OR <5> and R <4> is a C1-C6 alkyl or alternatively forms a C2-C3 alkylene radical together with R <5>, optionally replaced by 1, 2 or 3 substituents independently selected from C1-C6 alkyl, operation B is carried out according to a synthetic scheme B.i) comprising the following steps: B.i.1) convert the O-alkylated product (II) into aldehyde (III ") by operating in acidic conditions: B.i.2) reduce aldehyde (III ") to obtain an allosteric antagonist of ADP receptors (III). 11. Process according to claim 10, wherein step B.i.1) is carried out using an acid selected from a mineral acid, a carboxylic acid and a sulphonic acid. 12. Process according to any one of claims 10 or 11, in which the reaction intermediates of formula (ΙΓ) and (II ") are isolated: 13. Process according to any one of claims 10 to 12, wherein step B.i.2) is carried out by treatment with a reducing agent, optionally after correction of the pH of the reaction mixture. 14. Process according to claim 9 wherein, when R <3> is H and R <4> is H or a protective group of an alcohol, operation B is carried out according to the synthetic scheme B.ii) by treatment of the compound (II) with an aqueous solution of a mineral acid selected from hydrochloric acid, sulfuric acid or phosphoric acid, or an aqueous solution of a carboxylic acid or a sulphonic acid in the presence of a water-miscible solvent. 15. Process according to claim 14, in which the reaction intermediates of formula (V ') and (V ") are isolated: 16. Process according to any one of claims 9 to 15, in which the starting compound used in operation A), is an enantiomerically enriched amino alcohol with formula (la), and said process leads to the formation of Ticagrelor: 17. Compound with general formula (III "): 18. Compound of general formula (II): in which: - R <1> and R <2> are chosen, independently of each other, between H and C1-C6 alkyl; alternatively R <1> and R <2> together can form a spiro-fused ring of 5 to 6 terms, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl; - R <3> is chosen between H and OR <5>; - R <4> is selected from H, C1-C6 alkyl, a protective group of the alcohols removable by treatment in acidic conditions, or together with R <5> it forms a C2-C3 alkylene radical optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl; - R <5> is C1-C6 alkyl or forms together with R <4> a C2-C3 alkylene radical, optionally substituted by 1, 2 or 3 substituents independently selected from C1-C6 alkyl.