ESTER COMPOUND Field of the Invention

The present invention relates to a method for the preparation of a chiral amine, in particular ethyl (2S,

3S)-3-aminobicyclo[2.2.2]octane-2-carboxylate.

Background of the Invention

Compound (I) or a salt thereof, such as the HCl salt thereof (Compound (Ia)),

is a key intermediate in a synthetic route of Compound (A), represented by the below structural

formula,

and salts and solvates thereof, such as the hydrochloride salt hemihydrate of Compound (A).

Compound (A) is also known as (2S,3S)-3-{[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3- yl)- pyrimidin-4-yl]amino}bicyclo[2.2.2]octane-2-carboxylic acid or under its INN as pimodivir.

Compound (A), as described in WO2010/148197, and pharmaceutically acceptable salts thereof and

solvates thereof, such as the hydrochloride salt hemihydrate, inhibit the replication of influenza

viruses.

The synthesis of the HCl salt of Compound (I) was previously reported in WO2015/073476 (Scheme

1) and in the review J. Med. Chem.2014, 57, 6668.

Scheme 1: Synthesis of the HCl salt of Compound (I) as described in WO2015/073476 The synthesis method described in WO2015/073476 involved numerous chemical transformations and the use of sensitive reagents. Enantiomer resolution was accomplished using an asymmetric ethanolysis of a cyclic anhydride in the presence of quinine followed by epimerization at the a-ester position to form the acid-ester compound shown above. Installation of the protected amine was performed via a Curtius rearrangement in the presence of diphenylphosphoryl azide (DPPA).

Diastereoselective catalytic hydrogenation of the double bond was performed in the presence of hydrogen gas (H ₂ ) and palladium on carbon (Pd/C). This method presents several drawbacks. First, the resolution, amine installation, and hydrogenation are performed over multiple steps. Second, the Curtius rearrangement employed undesirable azide reagents. Indeed, it is known that azide reagents are i) thermal and light sensitive, ii) unstable, and iii) have a potential explosive character. Third, the hydrogenation step was carried out under high pressure. Fourth, palladium is a hazardous reagent. Working under high pressure presents also a risk of explosion of the reactor or of the reaction vessel in the case of an over-pressurizing. Moreover, hydrogen is a highly flammable gas and palladium is a pyrophoric reagent.

WO2005/028419 describes a synthesis method for producing an amino acid derivative by reacting a keto acid derivative with ammonia or an amine or a salt thereof in the presence of a chiral catalyst and molecular hydrogen. The described method uses hydrogen gas at high pressure and thus presents the same safety drawbacks mentioned above. Additionally, said method yields only moderate enantiomer selectivity, also referred to by enantiomer excess (ee), as reported in the examples section below. Consequently, there is a need for a synthesis method for chiral cyclic beta-amino esters such as Compound (I) and salts thereof that at least overcomes the above-mentioned drawbacks. This problem has been solved as described herein through a highly enantio- and diastereoselective transfer hydrogenation of an imine formed from a cyclic beta-keto ester. Described herein is a method of preparing a compound of Formula (Ib) or a salt thereof:

wherein

R ¹ is C _1-6 alkyl;

comprising treating a racemic compound of Formula (IIb):

with HCO ₂ NH ₄ and a chiral transfer hydrogenation catalyst to form the compound of Formula (Ib). In one aspect, the present invention provides a method of preparing Compound (I) or a salt thereof:

comprising treating racemic Compound (II):

with HCO ₂ NH ₄ and a chiral transfer hydrogenation catalyst to form the compound of Formula (I) or a salt thereof.

Also described herein is a method of preparing Compound (A) or a salt or solvate thereof comprising treating a racemic compound of Formula (IIb) or Compound (II) with HCO ₂ NH ₄ and a chiral transfer hydrogenation catalyst to form a compound of Formula (Ib) or Compound (I), or a salt thereof, and converting the compound of Formula (Ib) or Compound (I), or a salt thereof, to Compound (A) or a salt or solvate thereof.

In another aspect, the present invention relates to a compound of Formula (III):

wherein R ¹ is C _1-6 alkyl. One of ordinary skill will recognize that the compound of Formula (III) can exist in the enamine form as shown, or in the corresponding imine tautomer form (III’), or as a mixture thereof.

In another aspect, the present invention relates to a mixture of a racemic compound of Formula (IIa) or racemic Compound (II) and HCO ₂ NH ₄ and optionally a chiral transfer hydrogenation catalyst. The method of the present invention presents several advantages compared to the methods of the prior art. The method of the invention leads to high selectivity or ee. Additionally, it is safer as it is devoid of azide reagents thereby eliminating the need for the storage and the use of sensitive reagents. The method of the invention is also devoid of hydrogenation step under high pressure as hydrogen is provided from a different source, i.e. ammonium formate. Thus, the method of the invention is more efficient in term of diastereo- and enantioselectivity, shorter and safer compared to the existing synthesis routes.

Detailed Description of the Invention

As used herein,“Compound (A)” refers to the free base form of Compound (A) and“Compound (I)” refers to the free base form of Compound (I). A salt of Compound (A) or Compound (I) refers to a salt composed of a 1:1 ratio of the compound and the acid component of the salt. The“HCl salt of Compound (A),” the“HCl salt of Compound (I),” and“Compound (Ia)” refer to a 1:1 ratio of the HCl and the compound free base components.

As used herein, the term“alkyl” refers to a saturated, straight or branched chain hydrocarbon group. The term“C _x-y ” refers to a hydrocarbon group with from x to y carbon atoms in the hydrocarbon group. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

As used herein, a“chiral transfer hydrogenation catalyst” is a hydrogenation catalyst comprising a metal (II) complex, wherein the metal is ruthenium, rhodium, or iridium, and preferably ruthenium. The catalyst also comprises a chiral ligand chelated to the metal atom, such as a chiral bisphosphine ligand. The catalyst serves to catalyze the asymmetric transfer of hydrogen from a hydrogen donor, such as formate, to an achiral imine intermediate, thereby catalyzing an asymmetric transfer hydrogenation. In some embodiments, the imine is formed by reaction of a ketone with ammonia. In some embodiments, the source of both the ammonia and the formate is ammonium formate. In some embodiments, the imine substrate for the asymmetric transfer hydrogenation with formate is formed in situ from a ketone by reaction of the ketone with ammonia or ammonium formate.

Suitable salts of the compounds described herein include acid addition salts of amino compounds. For example, suitable salts include hydrochloride, hydrobromide, acetate, phosphate, and other salts. The compounds described herein, and salts thereof, can exist in solvated forms, such as hydrates, including hemihydrates.

As used herein, cis and trans refer to the relative orientation of the amino and ester groups in, for example, Compound (I) or (Ib) (trans, one group axial and one equatorial) and the diastereomer thereof (cis, both groups axial or both groups equatorial).

In one aspect is a method of preparing a compound of Formula (Ib) or a salt thereof:

wherein

R ¹ is C _1-6 alkyl;

comprising treating a racemic compound of Formula (IIb):

with HCO ₂ NH ₄ and a chiral transfer hydrogenation catalyst to form the compound of Formula (Ib). In some embodiments of Formula (Ib) and (IIb), R ¹ is methyl, ethyl, propyl, or isopropyl. In some embodiments, R ¹ is methyl or ethyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl.

In one aspect is a method of preparing Compound (I) or a salt thereof:

comprising treating racemic Compound (II): with HCO ₂ NH ₄ and a chiral transfer hydrogenation catalyst to form the compound of Formula (I) or a salt thereof.

In another aspect is a method of preparing Compound (A) or a salt or solvate thereof comprising treating a racemic compound of Formula (IIb) or racemic Compound (II) with HCO ₂ NH ₄ and a chiral transfer hydrogenation catalyst to form a compound of Formula (Ib) or Compound (I), or a salt thereof, and converting the compound of Formula (Ib) or Compound (I), or a salt thereof, to

Compound (A) or a salt or solvate thereof. In some embodiments, the racemic compound of Formula (IIb) is Compound (II) and the compound of Formula (Ib) is Compound (I). In some embodiments, the method is used to prepare Compound (A) hydrochloride salt or Compound (A) hydrochloride salt hemihydrate.

In another aspect, the present invention relates to a compound of Formula (III), or a tautomer thereof, or a mixture of tautomers thereof: wherein R ¹ is C _1-6 alkyl. In some embodiments, R ¹ is methyl, ethyl, propyl, or isopropyl. In some embodiments, R ¹ is methyl or ethyl. In some embodiments, R ¹ is ethyl. One of ordinary skill in the art will recognize that the imine is formed as an intermediate in the asymmetric transfer

hydrogenation process described herein.

In another aspect, the present invention relates to composition comprising a racemic compound of Formula (IIb) or racemic Compound (II) and HCO ₂ NH ₄ and optionally a chiral transfer hydrogenation catalyst.

In some embodiments, the present invention relates to a method for the preparation of Compound (I)

, comprising the step of asymmetric reductive transfer hydrogenation from the racemic bicyclic b- ketoester (II), by reacting said b-ketoester Compound (II)

,

with ammonium formate in a solvent in the presence of a ruthenium catalyst.

In some embodiments, he methods described produce the compound of Formula (Ib) or Compound (I) in high enantio- and diastereoselectivity:

- in a yield of at least 80%, preferably at least 80%, more preferably at least 89%, even more preferably at least 93%, most preferably at least 98%,

- with a diastereoselectivity > 32:1 trans/cis ratio, preferably > 35:1 trans/cis ratio, more

preferably > 40:1 trans/cis ratio, most preferably > 45:1 trans/cis ratio, and

- with an ee > 85%, preferably > 90%, more preferably > 95% and most preferably > 99%. The chiral transfer hydrogenation catalyst for the transfer hydrogenation serves to transfer hydrogen from a hydrogen donor, such as formate, to an imine substrate. In some embodiments, the chiral transfer hydrogenation catalyst is a chiral ruthenium, rhodium, or iridium hydrogenation catalyst. In some embodiments, the chiral transfer hydrogenation catalyst is a chiral ruthenium hydrogenation catalyst. In some embodiments, the chiral transfer hydrogenation catalyst comprises a ruthenium (II) complex chelated to a chiral bisphosphine ligand. In some embodiments, the ruthenium catalyst is a ruthenium (II) complex. In some embodiments, the ruthenium catalyst comprises a ruthenium (II) complex chelated to a chiral bisphosphine ligand. In some embodiments, the ruthenium (II) complex is Ru(OAc)2 or RuCl2. In some embodiments, the chiral bisphosphine ligand is an atropisomeric aryl bisphosphine ligand. In some embodiments, the chiral bisphosphine ligand is a chiral binaphthalene bisphosphine ligand. In some embodiments, the chiral bisphosphine ligand is (S)-BINAP, (S)-(Xyl- BINAP), or (S)-(Tol-BINAP). In some embodiments, the chiral ruthenium hydrogenation catalyst is selected from (S)-Ru(OAc) ₂ (Tol-BINAP), (S)-Ru(OAc) ₂ BINAP, (S)-Ru(OAc) ₂ (Xyl-BINAP), (S)- RuCl[p-cymene(BINAP)]Cl, (S)-RuCl ₂ (Tol-BINAP), and (R)-RuCl ₂ (Tol-BINAP). In some embodiments, the chiral ruthenium hydrogenation catalyst is selected from (S)-Ru(OAc) ₂ (Tol- BINAP), (S)-Ru(OAc) ₂ BINAP, (S)-Ru(OAc) ₂ (Xyl-BINAP), and (S)-RuCl ₂ (Tol-BINAP). The chiral transfer hydrogenation catalyst or ruthenium catalyst can be used as such in the reaction mixture, or the catalyst can be pre-formed in-situ from a metal complex, such as a ruthenium (II) complex, in particular a ruthenium (II) complex chelated to an aryl ligand such as p-cymene (e.g., dichloro(p- cymene)ruthenium(II) dimer) and a bisphopshine ligand such as BINAP, a derivative of a BINAP ligand, or an analogous ligand. Preferably, the catalyst is a homogeneous ruthenium catalyst bearing a chiral bisphosphine ligand. In some embodiments, the chiral transfer hydrogenation catalyst is a homogeneous ruthenium (II) catalyst complexed to a chiral bisphosphine ligand. BINAP is 2,2¢- bis(diphenylphosphino)-1,1¢-binaphthyl.

In a preferred embodiment, the catalyst loading is comprised between 1 mol% and 6 mol%, preferably between 2 mol% and 5 mol%, more preferably, between 3 mol% and 4 mol%. In a preferred embodiment, the catalyst loading is in the range of about 1 mol% to 6 mol%, relative to the keto-ester starting material, preferably from about 2 mol% and 5 mol%, more preferably, from about 3 mol% and 4 mol%.

In some embodiments, the solvent is a C _1-4 alkanol, or a C _1-4 -fluoroalkanol, or a mixture thereof. The solvent is selected from trifluoroethanol, ethanol, methanol, and acetonitrile, or any combination thereof. In some embodiments, the solvent is trifluoroethanol or ethanol, or a mixture thereof. In some embodiments, the solvent is trifluoroethanol or a mixture of trifluoroethanol and ethanol. In a preferred embodiment, the solvent is a mixture of trifluoroethanol and ethanol. More preferably, the solvent is trifluoroethanol.

Wherein a mixture of solvent is used, the ratio between the solvents is comprised between 1:1 and 1:5. Preferably, the ratio ranges from 1:1 to 1:3. More preferably, the ratio is comprised between 1:1 and 1:2. When a mixture of solvent is used, the ratio between the solvents is in the range of about 1:1 and 1:5 by volume. Preferably, the ratio ranges from about 1:1 to 1:3 by volume. More preferably, the ratio is in the range of about 1:1 to 1:2 by volume. In some embodiments, the solvent is a mixture in the range of about 1:1 to 1:3 by volume of trifluoroethanol and ethanol. In some embodiments, the solvent is a mixture of about 1:1 by volume of trifluoroethanol and ethanol.

In a preferred embodiment, the volume of the solvent is comprised between 3 and 15 mL per g of ketoester (II), preferably between 5 and 12 mL per g of ketoester (II), more preferably between 7 and 11 mL per g of ketoester (II), most preferably between 9 and 10 mL per g of ketoester (II). In a preferred embodiment, the volume of the solvent is in the range of about 3 to 15 mL per g of

Compound (II) or the compound of Formula (IIb), preferably in the range of about 5 to 12 mL per g of Compound (II) or the compound of Formula (IIb), more preferably in the range of about 7 to 11 mL per g of Compound (II) or the compound of Formula (IIb), most preferably in the range of about 9 to 10 mL per g of Compound (II) or the compound of Formula (IIb).

The amount of ammonium formate is comprised between 1 and 15 equivalents. In a preferred embodiment, the amount of ammonium formate ranges from 3 to 14, preferably from 5 to 12 equivalents, more preferably from 8 to 10 equivalents. The amount of ammonium formate is in the range of about 1 to 15 equivalents relative to Compound (II) or the compound of Formula (IIb). In a preferred embodiment, the amount of ammonium formate ranges from about 3 to 14 equivalents, preferably from about 5 to 12 equivalents, more preferably from about 8 to 10 equivalents.

In some embodiments, the treating is performed in the presence of one or more additional additives. An additive may be added to the reaction. Said additive can be organic or inorganic base or an acid. In some embodiments, the one or more additives are selected from an organic base, an inorganic base, and an acid, and mixtures thereof. Wherein a base is used, in some embodiments it is selected from triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate, sodium formate, sodium acetate, and ammonia or a combination thereof. In a preferred embodiment the base is ammonia. In some embodiments, the additive is an organic base. In some embodiments, the organic base is ammonia, aqueous ammonia (e.g., about 15 to 40% aqueous ammonia, or about 20 to 35% aqueous ammonia), triethylamine, diisopropylethylamine, sodium formate, and sodium acetate. In some embodiments, the additive is an inorganic base. In some embodiments, the inorganic base is selected from potassium phosphate, and potassium carbonate. In some embodiments, the additive is aqueous ammonia, such as about 15 to 40% aqueous ammonia, or about 20 to 35% aqueous ammonia, or about 25% aqueous ammonia, or about 32% aqueous ammonia. Wherein an acid is used, in some embodiments it is selected from formic acid, benzoic acid and salicylic acid or any combination thereof. In some embodiments, the additive is an acid. In some embodiments, the acid is a carboxylic acid. In some embodiments, the carboxylic acid is formic acid.

The amount of the additive is comprised between 1 and 4 equivalents, preferably between 1.5 and 3 equivalents, more preferably the amount of additive is 2 equivalents. The amount of the additive is comprised in the range of about 1 to 4 equivalents relative to Compound (II) or the compound of Formula (IIb), preferably in the range of about 1.5 to 3 equivalents, more preferably the amount of additive is about 2 equivalents. In some embodiments, the additive is about 2 equivalents of about 20 to 35% aqueous ammonia, or about 25% aqueous ammonia, or about 32% aqueous ammonia.

The reaction is performed at a temperature comprised between 60 and 90°C, preferably between 70 and 85°C, more preferably between 75 and 80 °C. In some embodiments, the treating is performed at a temperature between about 0 °C and about 150 °C, or between about 60 °C and 90 °C, preferably between about 70 °C and 85 °C, more preferably between 75°C and 80 °C.

The reaction time is comprised between 10 and 20 hours (h). In an embodiment, the reaction time ranges from 5 to 20 hours. Preferably, the reaction time is between 8 and 18 hours. More preferably, the reaction time is comprised between 10 and 17 hours. Most preferably, the reaction time ranges from 12 to 16 hours. Particularly, the reaction time is 16 hours. The reaction time is in the range of about 10 to 20 hours (h), or about 5 to 20 hours, or about 8 and 18 hours, or about 10 and 17 hours, or about 12 to 16 hours, or about 16 hours. Examples

Example A: Comparative Hydrogenation Procedure

Compound (I) was synthesized using the method described in WO2005/028419 by mixing Compound (II) with (S)-Ru(OAc)2(Tol-BINAP) (1 mol%), ammonium acetate (3 equiv.), and trifluoroethanol (9 mL/g of Compound (II)). The mixture was stirred at 80 °C under a hydrogen pressure of 10 bar for 16 h until complete conversion of the imine/enamine intermediate was observed. The reaction yielded Compound (I) with an ee of 50% and a diastereoselectivity of 22:1 trans/cis.

The reaction was repeated with the same conditions except for the catalyst which was replaced by (R)-Cl-MeO-BIPHEP. Compound (I) was obtained with an ee of 58% and a diastereoselectivity of 17:1 trans/cis.

Example B: Chiral Transfer Hydrogenation

General Procedure: Chiral ruthenium catalyst (as shown in Table 1; 3 mol%) was added to a mixture of Compound (II) (1.0 equiv.) and ammonium formate (3 to 10 equiv. as shown in Table 1) in a solvent (solvent and amount shown in Table 1). The reaction mixture was stirred at 75 °C or 90 °C as shown in Table 1 and was monitored by gas chromatography (GC). The resulting yield, trans/cis ratio and % ee for each trial are shown in Table 1.

Procedure 1– Preformed Catalyst (Table 1, entry 29): Ru(OAc) ₂ (Tol-BINAP) (3 mol%) was added to a mixture of Compound (II) (1.0 equiv.), ammonium formate (10.0 equiv.), and ammonia (32% aq. solution, 2.0 equiv.) in 2,2,2-trifluoroethanol (10 mL/g of Compound (II)). The reaction mixture was stirred for 16 h at 75 °C until complete disappearance of the imine/enamine intermediate was observed.

Procedure 2– In situ Generated Catalyst (Table 1, entry 33): RuCl ₂ -p-cymene dimer (1 mol%) and (S)-Tol-BINAP (2 mol%) were mixed in 2,2,2-trifluoroethanol (1 mL/g of Compound (II)). The mixture was degassed and stirred at 80 °C for 1 hour. The reaction mixture was transferred into a mixture of Compound (II) (1.0 equiv.), ammonium formate (5.0 equiv.), and ammonia (25% aq. solution, 2 equiv.) in 2,2,2-trifluoroethanol (8 mL/g of Compound (II)). The reaction mixture was stirred for 12 h at 75 °C until complete conversion of the imine/enamine intermediate to the reduced product was observed.

aDetermined by GC analysis.