BR122020009898B1 - PROCESSES FOR MANUFACTURING COMPOUNDS - Google Patents

Abstract

The present invention relates to a process for preparing a compound of formula (I) wherein R1 is as defined herein, which is useful as an intermediate in the preparation of active pharmaceutical compounds.

Description

DIVIDED OF BR 11 2016 011048-0, DEPOSITED ON 11/13/2014 RELATED REQUEST

[001] This application claims priority to European Patent Application 13193030.7 filed on November 15, 2013, the entirety of which is incorporated herein by reference.

FIELD OF INVENTION

[002] The present invention relates to processes for the preparation of pyrimidinylcyclopentane compounds that are useful as intermediates in the preparation of AKT protein kinase inhibitors with therapeutic activity against diseases such as cancer.

BASICS OF THE INVENTION

[003] The protein kinase B/Akt enzymes are a group of serine/threonine kinases that are overexpressed in certain human tumors. International Patent Application WO 2008/006040 and US Patent 8,063,050 discuss a number of AKT inhibitors, including the compound (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)- 7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (ipatasertib, GDC- 0068), which is being investigated in clinical trials for the treatment of several cancers.

[004] Although the processes described in WO 2008/006040 and US 8,063,050 are useful in providing hydroxylated cyclopenta[d]pyrimidine compounds as AKT protein kinase inhibitors, alternative or improved processes are needed, including for large-scale manufacturing of these compounds.

SUMMARY OF THE INVENTION

[005] The present invention provides processes for preparing a compound of formula (I) or salts thereof, which comprise the coupling reaction of a compound of formula (II) with a compound of formula (III) wherein R1, R2 and M are as described herein.

DETAILED DESCRIPTION OF THE INVENTION

[006] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that normally understood by a person skilled in the art to which this invention belongs. Although similar or equivalent methods and materials to those described herein may be used in practicing or testing the invention, suitable methods and materials are described below.

[007] The nomenclature used in this Request is based on the IUPAC systematic nomenclature, unless otherwise indicated.

[008] Any open valence appearing on a carbon, oxygen, sulfur or nitrogen in the structures here indicates the presence of a hydrogen atom, unless otherwise indicated.

[009] When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the largest possible number of substitutions, that is, replacement of a hydrogen atom until the replacement of all hydrogens by substituents. .

[010] The term “optional” or “optionally” means that a subsequently described event or circumstance may, but need not occur, and that the description includes cases where the event or circumstance occurs and examples where it does not.

[011] The term “pharmaceutically acceptable salts” means salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition and base salts.

[012] The term “pharmaceutically acceptable acid addition salt” means those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p -toluenesulfonic acid, and salicylic acid.

[013] The term “pharmaceutically acceptable base addition salt” means those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including substituted naturally occurring amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine. , tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine resins, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine .

[014] The stereochemical definitions and conventions used here generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. When describing an optically active compound, the prefixes D and L, or R and S, are used. to designate the absolute configuration of the molecule around its chiral center. The substituents attached to the chiral center under consideration are classified according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and (-) are used to designate the rotational sign of light in the plane polarized by the compound, with (-) or L designating that the compound is levorotatory. A compound with the prefix (+) or D is dextrorotatory.

[015] The term “stereoisomer” designates a compound that has identical molecular connectivity and bond multiplicity, but which differs in the arrangement of its atoms in space.

[016] The term “chiral center” indicates a carbon atom bonded to four non-identical substituents. The term “chiral” designates the ability to not superimpose with the mirror image, while the term “achiral” refers to modalities that are superimposed with their mirror image. Chiral molecules are optically active, that is, they have the ability to rotate the plane of plane-polarized light.

[017] The compounds of the present invention may have one or more chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. Whenever a chiral center is present in a chemical structure, it is intended that all stereoisomers associated with that chiral center are encompassed by the present invention.

[018] The term “enantiomers” designates two stereoisomers of a compound that are non-superimposable mirror images of each other.

[019] The term “diastereomer” designates a stereoisomer with two or more chirality centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, for example melting points, boiling points, spectral properties, and reactivities.

[020] The term “diastereoisomeric excess” (de) indicates diastereoisomeric purity, that is, (diastereoisomer A - diastereoisomer B)/(diastereoisomer A + diastereoisomer B) (% by area).

[021] The term “enantiomeric excess” (ee) indicates enantiomeric purity, that is, (enantiomer A - enantiomer B)/(enantiomer A + enantiomer B) (% in area).

[022] The terms “halo” and “halogen” are used interchangeably here and denote fluorine, chlorine, bromine, or iodine.

[023] The term “halide” represents a halogen ion, especially fluoride, chloride, bromide or iodide.

[024] The term “alkyl” denotes a branched saturated hydrocarbon group of 1 to 12 linear or monovalent carbon atoms. In particular embodiments, alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.

[025] The term “alkenyl” denotes a branched hydrocarbon group of 2 to 7 carbon atoms with at least one monovalent double or linear bond. In particular embodiments, alkenyl has 2 to 4 carbon atoms with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, and iso-butenyl.

[026] The term “alkynyl” denotes a branched saturated hydrocarbon group of 2 to 7 carbon atoms, comprising one, two or three linear or monovalent triple bonds. In particular embodiments, alkynyl has 2 to 4 carbon atoms comprising one or two triple bonds. Examples of alkynyl include ethynyl, propynyl and n-butynyl.

[027] The term “alkoxy” denotes a group with the general formula -O-R', where R' is an alkyl group. Examples of alkoxy radicals include methoxy, ethoxy, isopropoxy and tert-butoxy.

[028] The term “haloalkyl” denotes an alkyl group in which at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, for example, 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term “perhaloalkyl” denotes an alkyl group in which all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms.

[029] The term “haloalkoxy” means an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of haloalkoxy include monofluoro-, difluoro- or trifluoro-methoxy, ethoxy or propoxy, for example, 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy,fluoromethoxy, or trifluoromethoxy. The term “perhaloalkoxy” means an alkoxy group in which all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.

[030] The term “cycloalkyl” denotes a monocyclic or bicyclic saturated monovalent hydrocarbon group of 3 to 10 carbon atoms in the ring. In particular embodiments cycloalkyl designates a monocyclic saturated monovalent hydrocarbon group of 3 to 8 carbon atoms in the ring. Bicyclic means consisting of two saturated carbocycles with one or more carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of bicyclic cycloalkyl are bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl.

[031] The term “heterocycloalkyl” indicates a saturated or partially unsaturated monovalent mono or bicyclic ring system of 3 to 9 ring atoms, which comprises 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a saturated monocyclic monocyclic ring system of 4 to 7 ring atoms, which comprises 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of saturated monocyclic heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thio morpholinyl, 1,1- dioxo- thiomorpholin-4-yl, azepanil, diazepanil, homopiperazinil, or oxazepanil. Examples of saturated bicyclic heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3- oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, or dihydropyranyl.

[032] The term “aryl” indicates a monovalent mono or bicyclic aromatic carbocyclic ring system comprising 6 to 10 carbon atoms in the ring. Examples of aryl radicals include phenyl and naphthyl. In particular aryl is phenyl.

[033] The term “heteroaryl” denotes a monovalent aromatic mono or bicyclic heterocyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl radicals include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indole il , isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[034] “Leaving group” refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction. Examples of leaving groups include, but are not limited to, hydrogen, halogen, hydroxyl groups, sulfhydryl groups, amino groups (e.g., -NRR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, or heterocyclyl and R is independently optionally substituted), silyl groups (e.g. -SiRRR, where R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted), -N(R)OR (where R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted), alkoxy groups (e.g. - OR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted ), thiol groups (e.g., -SR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted), sulfonyloxy groups (e.g., -OS(O)1-2R, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted), sulfamate groups (e.g., -OS(O)1-2NRR, wherein R is independently alkyl, alkenyl, alkynyl , cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted), carbamate groups (e.g. -OC(O)2NRR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted) , and carbonate groups (e.g. -OC(O)2R, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl and R is independently optionally substituted). Examples of carbonate groups include tert-butyl carbonate. Examples of sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (tosylate group) and p- nitrosulfonyloxy (nosylate group)). Other examples of leaving groups include substituted and unsubstituted amino groups, such as amino, alkylamino, dialkylamino, hydroxylamino, alkoxylamino, N-alkyl-N-alkoxyamino, acylamino, sulfonylamino, t-butyloxy and the like.

[035] The term “protecting group” means the group that selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively in another unprotected reactive site in the meaning conventionally associated with this synthetic chemistry. Protection groups can be removed at the appropriate point. Examples of protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy radical protecting groups.

[036] The term “amino protecting group” denotes groups intended to protect an amino group and includes benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), Fmoc (9-fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl ( BOC), and trifluoroacetyl. Other examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, “Protective Groups in Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, “Protective Groups in Organic Synthesis”, John Wiley and Sons, New York, NY, 1981. The term “protected amino group” refers to an amino group substituted by an amino protecting group. Particular example of an amino protecting group is tert-butoxycarbonyl (BOC).

[037] The term “deprotection” or “deprotect” designates the process by which a protecting group is removed after the selective reaction is completed. Deprotection reagents include acids, bases or hydrogen, in particular potassium or sodium carbonates, lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid, trifluoroacetic acid, palladium or boron tribromide catalysts. Particular deprotection reagent is hydrochloric acid.

[038] The term “buffer” means an excipient, which stabilizes the pH of a preparation. Suitable buffers are well known in the art and can be found in the literature. Pharmaceutically acceptable buffers include histidine buffers, arginine buffers, citrate buffers, succinate buffers, acetate buffers and phosphate buffers. Regardless of the buffer used, the pH can be adjusted with an acid or base known in the art, for example, hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide.

[039] The term “alkali metal” refers to the chemical elements of Group 1 of the Periodic Table, that is, lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), and francium (Fr). Particular examples of alkali metals are Li, Na and K, more particularly Na.

[040] The term “alkaline earth metal” refers to the chemical elements of Group 2 of the Periodic Table, that is, beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radio (Ra). Particular examples of alkaline earth metals are Mg and Ca.

[041] The term “transition metal” denotes chemical elements whose atoms have an incomplete d subshell.

[042] The present invention provides a process for preparing a compound of formula (I) or salts thereof, which comprises the coupling reaction of a compound of formula (II) with a compound of formula (III), wherein R1, R2 and M are as described herein (Scheme 1 below).

[043] An additional aspect of the present invention relates to the process for manufacturing compounds of formula (II) which comprises the asymmetric hydrogenation of a compound of formula (IV) using a complex metal catalyst (C) (Scheme 1 below) .

[044] One aspect of the present invention relates to the process for manufacturing compounds of formula (III) that comprises the asymmetric reduction of the compound of formula (V) catalyzed by an oxidoreductase (Scheme 1 below).

[045] An additional aspect of the present invention relates to the process for manufacturing compounds of formula (VI) or pharmaceutically acceptable salts thereof, in which a compound of formula (I) is deprotected (Scheme 1 below). SCHEME 1

[046] In one embodiment of the invention, R1 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl.

[047] In a particular embodiment of the invention, R1 is tert-butoxycarbonyl (BOC).

[048] In one embodiment of the invention, R2 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and trifluoroacetyl.

[049] In a particular embodiment of the invention, R2 is tert-butoxycarbonyl (BOC).

[050] In one embodiment of the invention, M is a metal ion selected from the list of alkali metal ion, alkaline earth metal ion and transition metal ions.

[051] In a particular embodiment of the invention, M is a metal ion, in particular an alkali metal ion, alkaline earth metal ion or transition metal ion with the proviso that it is not K+.

[052] In a particular embodiment of the invention, M is an alkali metal ion.

[053] In a particular embodiment of the invention, M is Li+, K+ or Na+.

[054] In a particular embodiment of the invention, M is not K+.

[055] In the most particular embodiment of the invention, M is Na+.

[056] WO 2008/006040 discloses amino acids of formula (II-pa) and methods of manufacturing them, in which R6 and R9 can have several alternatives and t is 0 to 4.

[057] This discloses processes for the preparation of compounds of formula (II-pa), involving a) the non-enantioselective reaction of an alkylamine with 2-arylacrylate to produce a racemic mixture, or b) the asymmetric addition of an alkoxymethanamine to 2-phenylacetate containing an appropriate chiral auxiliary. Both processes do not involve an asymmetric hydrogenation, but an addition reaction. Therefore, both processes require additional steps for addition, cleavage and separation of the auxiliary.

[058] The synthesis according to method a) above proceeds through the formation of an intermediate racemic ester that is further hydrolyzed to racemic acid, coupled with a chiral auxiliary (for example, just as S enantiomer) to generate a mixture 50: 50 of R-amino acid/S-auxiliary and S-amino acid/S-auxiliary diastereoisomers. Diastereoisomers must be separated by chromatography. The yield of the desired S-S intermediate is only 38%. Furthermore, the S-S intermediate must be hydrolyzed to obtain the S-II acid (with loss of the other chiral component, the chiral auxiliary). This procedure is time-consuming and inefficient, once in one step 72% of the material is lost. In summary, the non-enantioselective addition of amine and acrylate presents the intrinsic problem of lack of stereoselectivity and thus mandatory separation of the racemic mixture by, for example, chromatography. Consequently, the yield is at least 100% lower compared to a stereoselective sequence.

[059] Furthermore, the asymmetric addition of an intermediate containing a chiral auxiliary (method b) above) requires additional steps for addition, cleavage and separation of the auxiliary. A precursor for the synthesis of the target acid is combined with a chiral auxiliary and the resulting intermediate is coupled with an alkoxymethanamine. The product then consists, at best, of a slightly enriched mixture of R/S and S/S diastereoisomers, if not a 1:1 mixture, which must be further treated, as mentioned above, to isolate the -( S) of the compound of formula (II-pa) in modestly better yield.

[060] There is, therefore, an unmet need for improved processes for the preparation of compounds of formula (II) that provide better stereoselectivity by creating a subsequent chiral chromatography void, which requires fewer reaction steps, which provide a higher yield. high and are therefore more efficient, more ecological and less expensive.

[061] The inventors of the present invention have discovered a new process for manufacturing compounds of formula (II) that comprises the asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C).

[062] This new process for manufacturing compounds of formula (II) presents a series of pertinent advantages in relation to processes known in the art: • A highly stereoselective reaction is introduced into the synthesis; • Subsequent purification using chiral chromatography is null; • The number of reaction steps is reduced; • Overall performance is improved; • The global reaction is more efficient, more ecological and less expensive.

[063] The particular metal complex catalysts of the present invention have been shown to be much more efficient and much more active and selective than other known catalysts, in the sense that, under similar reaction conditions (i.e., without additives) in a molar ratio of substrate to catalyst (S/C) up to 10,000 can be employed whereas other known catalysts need to be used at an S/C of 200-250. Thus, using 40-50 times less catalyst has a substantial impact on efficiency, costs and sustainability.

[064] Certain known catalysts require a large amount of LiBF4 as an additive (up to 5.8% in moles for the hydrogenation substrate, up to 100 molar equivalents in relation to the catalyst) to increase the activity of catalysts. High amounts of LiBF4 are disadvantageous for an industrial process, because the presence of this large amount of fluoride ions (up to 23.2% of the hydrogenation substrate) poses a problem regarding corrosion of scale-up steel pressure reactors. On the other hand, even with LiBF4 additive the catalyst does not reach the activity of our new catalysts (for example, up to S/C 10,000).

[065] Homogeneously catalyzed reactions such as, for example, asymmetric hydrogenations known in the art require very laborious processing procedures, which comprise several extraction and solution concentration cycles. Furthermore, asymmetric hydrogenations as known in the art require the removal of metal catalysts with a sequestrant (e.g., thiol resins) in large quantities (up to 6% by weight relative to the hydrogenation substrate; up to 193 times the weight of the catalyst ). Such removal of ruthenium contaminants using sequestering resins is by far not easy and quite expensive. Furthermore, the ruthenium content is only partially reduced (e.g. to about 50 ppm) and is carried out through the following step, thus increasing the potential for by-product formation. This adds material and labor costs and opens up discussion about possible impurities.

[066] In conclusion, the effectiveness of known purification and isolation processes of the hydrogenation product from catalysts and additives is low.

[067] In contrast, the process according to the invention provides salts of the compound of formula (II), which are precipitated directly from the hydrogenation mixture and which can be easily removed by filtration. Said isolation and purification of the hydrogenation product provides high yields (> 94%) with 100% ee and ruthenium with content below the detection limit of 5 ppm. Processing the asymmetric hydrogenation reaction product as found by the present inventors is therefore substantially simpler, cheaper and more useful than conventional processes.

[068] One aspect of the present invention relates to a compound of formula (II) wherein R1 and M are as defined herein.

[069] One aspect of the present invention relates to a compound of formula (II) which is sodium (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate.

[070] One aspect of the present invention relates to the process for manufacturing compounds of formula (II) which comprises the asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C) where M are as defined herein.

[071] In one embodiment of the invention, the metal complex catalyst (C) is a ruthenium complex catalyst.

[072] In one embodiment of the invention, the ruthenium complex catalyst comprises ruthenium characterized by oxidation number II.

[073] In one embodiment of the invention, the ruthenium complex catalyst comprises a chiral phosphine ligand (D).

[074] In one embodiment of the invention, the ruthenium complex catalyst comprises ligands, particularly neutral ligands (L) and/or anionic ligands (Z).

[075] Examples of neutral ligands (L) are olefins, such as ethylene or propylene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cycloctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene , and p-cymene or also solvents such as tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol.

[076] Examples of anionic ligands (Z) are acetate (CH3COO-), trifluoroacetate (CF3COO-), n5-2,4-pentadienyl, n5-2,4-dimethyl-pentadienyl, and halogen, such as fluorine, chloride, bromide, or iodide.

[077] If the ruthenium complex catalyst is charged, it also comprises non-coordination anions (Y). Examples of non-coordination anions (Y) are halogen ions such as fluoride, chloride, bromide, or iodide, BF4-, ClO4-, SbF6-, PF6-, B(phenyl)4-, B(3,5-di- trifluoromethyl-phenyl)4-, CF3SO3-, and C6H5SO3-.

[078] The ruthenium complex catalyst can also optionally be coordinated with a Lewis acid, such as AlCl3.

[079] In one embodiment of the invention, the ruthenium complex catalyst is selected from a compound of formula (C1), (C2) or (C3): Ru(Z)2D (C1) [Ru(Z)2 -p(D)(L)m](Y)p (C2) Ru(E)(E')(D)(F) (C3) where: D is a chiral phosphine ligand; L is a neutral ligand selected from C2-7 alkene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cycloctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol; Z is an anionic ligand selected from hydride, fluoride, chloride, bromide, n5-2,4-pentadienyl, n5-2,4-dimethyl-pentadienyl or the group A-COO-, with the proviso that when two Z are linked to the Ru atom can be the same or different; A is C1-7 alkyl, C1-7 haloalkyl, aryl, or haloaryl; Y is a non-coordination anion selected from fluoride, chloride, bromide, BF4-, ClO4-, SbF6-, PF6-, B(phenyl)4-, B(3,5-di-trifluoromethyl-phenyl)4-, CF3SO3-, and C6H5SO3-; F is an optionally chiral diamine; E and E' are both halogen ions, or E is hydride and E' is BH<; m is 1, 2, 3 or 4; p is 1 or 2.

[080] In a particular embodiment of the invention, the ruthenium complex catalyst is selected from a compound of formula (C1) or (C2) in which Z, D, L, Y, m and p are as described herein.

[081] In a particular embodiment of the invention, the ruthenium complex catalyst is selected from a compound of formula (C1), where Z and D are as described herein.

[082] In a particular embodiment of the invention, the ruthenium complex catalyst is Ru(Z)2D, where Z and D are as described herein.

[083] In a particular embodiment of the invention, the ruthenium complex catalyst is selected from a compound of formula (C2), where Z, D, L, Y, m and p are as described herein.

[084] In a particular embodiment of the invention, the ruthenium complex catalyst is selected from a compound of formula (C3), where E, E', D and F are as described herein.

[085] In a particular embodiment of the invention, the anionic ligand (Z) is independently selected from chloride, bromide, iodide, OAc, and TFA.

[086] In a particular embodiment of the invention, the anionic ligand (Z) is A-COO-.

[087] In a particular embodiment of the invention, A is -CF3.

[088] In a particular embodiment of the invention, the anionic ligand (Z) is trifluoroacetate (TFA).

[089] In a particular embodiment of the invention, the neutral ligand (L) is independently selected from benzene (C6H6), p-cymene (pCym), and acetonitrile (AN).

[090] In a particular embodiment of the invention, the neutral ligand (L) is benzene (C6H6).

[091] In a particular embodiment of the invention, the non-coordination anion (Y) is selected from chloride, bromide, iodide and BF4-.

[092] In a particular embodiment of the invention, the non-coordination anion (Y) is BF4-.

[093] In a particular embodiment of the invention, m is 1 or 4.

[094] In a particular embodiment of the invention, m is 1.

[095] In a particular embodiment of the invention, m is 4.

[096] In a particular embodiment of the invention, p is 1.

[097] In a particular embodiment of the invention, p is 2.

[098] In a particular embodiment of the invention, E and E' are both chloride.

[099] In a particular embodiment of the invention, the chiral diamine F is (1S,2S)-1,2 diphenylethylenediamine (S,S-DPEN).

[0100] In a particular embodiment of the invention, the ruthenium complex catalyst is coordinated to a Lewis acid, especially AlCl3.

[0101] In one embodiment of the invention, the chiral phosphine ligand D is selected from a compound of formula (D1) to (D12): wherein: R11 is C1-7 alkyl, C1-7 alkoxy, benzyloxy, hydroxy or C1-7 alkyl-C(O)O-; R12 and R13 are each independently hydrogen, C1-7 alkyl, C1-7 alkoxy or di(C1-7 alkyl)amino; or R11 and R12 which are attached to the same phenyl group, or R12 and R13 which are attached to the same phenyl group taken together are -X-(CH2)rY-, where X is -O-, or -C(O)O -, Y is -O-, -N(lower alkyl)-, or -CF2- and r is an integer from 1 to 6; or two R11 taken together are -O-(CH2)sO- or O-CH(CH3)-(CH2)s- CH(CH3)-O-, where s is an integer from 1 to 6; or R11 and R12, or R12 and R13, together with the carbon atoms to which they are attached, form a naphthyl, tetrahydronaphthyl or dibenzofuran ring; R14 and R15 are each independently C1-7 alkyl, C3-8 cycloalkyl, phenyl, naphthyl or heteroaryl, optionally substituted with 1 to 7 substituents independently selected from the group consisting of C1-7 alkyl, C1-7 alkoxy, di(C1 -7 alkyl)amino, morpholinyl, phenyl, tri(C1-7 alkyl)silyl, C1-7 alkoxycarbonyl, hydroxycarbonyl, hydroxysulfonyl, (CH2)t-OH and (CH2)t-NH2, where t is an integer of 1 to 6; R16 is C1-7 alkyl; R17 is C1-7 alkyl; and R18 independently is aryl, heteroaryl, C3-8 cycloalkyl or C1-7 alkyl.

[0102] In a particular embodiment of the invention, the chiral phosphine ligand (D) is selected from the compound of formula (D1), wherein R11 to R15 are as described herein.

[0103] In a particular embodiment of the invention, the chiral phosphine ligand (D) is selected from (R)-3,5-Xyl-BINAP, (R)-BINAP, (S)-2- Furyl-MeOBIPHEP , (S)-BINAP, (S)-BINAPHANE, (S)-BIPHEMP, (S)-MeOBIPHEP, (S)-pTol-BINAP), (S)-TMBTP and (S,S)-iPr-DUPHOS.

[0104] In a particular embodiment of the invention, the chiral phosphine ligand (D) is selected from (S)-BIPHEMP, (S)-BINAP, and (S)-MeOBIPHEP.

[0105] In a particular embodiment of the invention, the chiral phosphine ligand (D) is (S)-BINAP.

[0106] In a particular embodiment of the invention, the chiral phosphine ligand (D) is (S)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl.

[0107] In a particular embodiment of the invention, the chiral phosphine ligand (D) is

[0108] In a particular embodiment of the invention, the ruthenium complex catalyst is selected from the group of: Ru(TFA)2((R)-3,5-Xyl-BINAP), Ru(OAc)2(( S)-2-Furyl-MeOBIPHEP), Ru(OAc)2((S)-BINAP), [Ru(OAc)2((S)-BINAP)]AlCl3, Ru(TFA)2((S)-BINAP ), Ru(TFA)2((S)-BINAPHANE), Ru(TFA)2((S)-BIPHEMP), Ru(OAc)2((S)-MeOBIPHEP), Ru(TFA)2((S) -TMBTP), Ru(TFA)2((S,S)-iPr-DUPHOS), [Ru((R)-BINAP)(pCym)(AN)](BF4)2, [RuBr((S)-BINAP )(C6H6)]Br, [RuCl((S)-BINAP)(C6H6)]BF4, [RuCl((S)-BINAP)(C6H6)]Cl, [RuI((S)-BINAP)(C6H6)] I, [Ru((S)-BINAP)(AN))4](BF4)2, and RuCl2((S)-pTol-BINAP)(S,S-DPEN).

[0109] In a particular embodiment of the invention, the ruthenium complex catalyst is selected from the group of: Ru(TFA)2((R)-3,5-Xyl-BINAP), Ru(OAc)2(( S)-2-Furyl-MeOBIPHEP), Ru(OAc)2((S)-BINAP), [Ru(OAc)2((S)-BINAP)]AlCl3, Ru(TFA)2((S)-BINAP ), Ru(TFA)2((S)-BINAPHANE), Ru(TFA)2((S)-BIPHEMP), Ru(OAc)2((S)-MeOBIPHEP), Ru(TFA)2((S) -TMBTP), Ru(TFA)2((S,S)-iPr-DUPHOS), [Ru((R)-BINAP)(pCym)(AN)](BF4)2, [RuBr((S)-BINAP )(C6H6)]Br, [RuCl((S)-BINAP)(C6H6)]BF4, [RuI((S)-BINAP)(C6H6)]I, [Ru((S)-BINAP)(AN)) 4](BF4)2, and RuCl2((S)-pTol-BINAP)(S,S-DPEN).

[0110] In a particular embodiment of the invention, the ruthenium complex catalyst is a compound of formula (C1) selected from the group of: Ru(TFA)2((R)-3,5-Xyl-BINAP), Ru(OAc)2((S)-2-Furyl-MeOBIPHEP), Ru(OAc)2((S)-BINAP), [Ru(OAc)2((S)-BINAP)]AlCl3, Ru(TFA) 2((S)-BINAP), Ru(TFA)2((S)-BINAPHANE), Ru(TFA)2((S)-BIPHEMP), Ru(OAc)2((S)-MeOBIPHEP), Ru( TFA)2((S)-TMBTP), and Ru(TFA)2((S,S)-iPr-DUPHOS).

[0111] In a particular embodiment of the invention, the ruthenium complex catalyst is a compound of formula (C2) selected from the group of: [Ru((R)-BINAP)(pCym)(AN)](BF4) 2, [RuBr((S)-BINAP)(C6H6)]Br, [RuCl((S)-BINAP)(C6H6)]BF4, [RuCl((S)-BINAP)(C6H6)]Cl, [RuI( (S)-BINAP)(C6H6)]I, and [Ru((S)-BINAP)(AN)4](BF4)2.

[0112] In a particular embodiment of the invention, the ruthenium complex catalyst is a compound of formula (C3), particularly RuCl2((S)-pTol-BINAP)(S,S-DPEN)).

[0113] In a particular embodiment of the invention, the ruthenium complex catalyst is Ru(TFA)2((S)-BINAP).

[0114] In a particular embodiment of the invention, the ruthenium complex catalyst is [RuCl(S-BINAP)(C6H6)]Cl.

[0115] In a particular embodiment of the invention, the ruthenium complex catalyst is not [RuCl(S-BINAP)(C6H6)]Cl.

[0116] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out in a solvent selected from alcohols, hydrocarbons, chlorinated hydrocarbons, fluorinated hydrocarbons and polyfluorinated aliphatic or aromatic hydrocarbons, supercritical carbon dioxide or liquid , THF, water or mixtures thereof.

[0117] Particular solvents for asymmetric hydrogenation are alcohols, chlorinated hydrocarbons and THF.

[0118] Particular solvents for asymmetric hydrogenation are selected from the list of MeOH, EtOH, i-PrOH, EtOH/cyclopentyl methyl ether, EtOH/CH2Cl2, EtOH/EtOAc, EtOH/THF, EtOH/H2O, CH2Cl2 and THF.

[0119] The most particular solvent for asymmetric hydrogenation is ethanol (EtOH).

[0120] Solvents can be used alone or as a mixture of solvents mentioned above.

[0121] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out at a concentration of the compound of formula (IV) of 1 to 50% by weight, in particular 5% by weight, 10 % by weight, 20% by weight or 30% by weight.

[0122] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out at a concentration of 10 to 25% by weight of the compound of formula (IV).

[0123] It has surprisingly been found that, in special cases, the addition of certain additives improves the asymmetric hydrogenation of a compound of formula (IV). It is assumed that the activity as well as the stability of the ruthenium catalyst are substantially improved and therefore the amount of catalyst required is reduced. Smaller quantities of catalyst employed result in simplified work and reduced costs.

[0124] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) further comprises one or more additives selected from the list of LiBF4, LiPF6, LiO3SCF3, NaCl, NaBr, NaI, KCl, KBr, KI , LiCl, LiBr, LiI, HBF4, HCl, HBr, H2SO4, and CH3SO3H.

[0125] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) does not comprise LiBF4, LiPF6 or LiO3SCF3 as an additive. Due to their highly corrosive character, such fluorine-containing additives are difficult to handle and thus are not preferred.

[0126] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) additionally comprises one or more additives selected from the list of NaCl, NaBr, KCl, KBr, HCl and HBr.

[0127] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) additionally comprises one or more additives selected from the list of LiBF4, HBF4, HCl, H2SO4, and CH3SO3H.

[0128] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) further comprises one or more additives selected from the list of LiBF4, NaCl, NaBr, LiCl, LiBr, LiI, HBF4, HCl, HBr , H2SO4, and CH3SO3H.

[0129] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out with hydrogen as the hydrogen source.

[0130] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out under hydrogen pressure of 1 to 150 bar, particularly 10 to 30 bar, more particularly 17 to 21 bar.

[0131] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out at a temperature of 10 to 120°C, particularly 20 to 90°C.

[0132] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out over a period of time from 5 to 30 h, particularly from 6 to 25 h, more particularly, from 6 to 23 h.

[0133] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out at a substrate/catalyst ratio (S/C) of 5 to 100'000, particularly 100 to 15'000, more particularly 100 to 10'000.

[0134] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out in batches.

[0135] In a particular embodiment of the invention, the asymmetric hydrogenation of a compound of formula (IV) is carried out in a continuous manner.

[0136] One aspect of the present invention relates to the process for manufacturing compounds of formula (II) which comprises the asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C), followed by the formation of a salt by addition to the hydrogenation reaction mixture of an alcoholic solution of a metal alkoxide of formula C1-7 alkyl-OM, wherein R1 and M are as here defined.

[0137] One aspect of the present invention relates to the process for manufacturing compounds of formula (II) which comprises the asymmetric hydrogenation of a compound of formula (IV) using a complex metal catalyst (C), followed by the formation of a salt by addition to the hydrogenation reaction mixture of an alcoholic solution of a metal alkoxide of formula C1-7 alkyl-OM, without prior isolation or purification of the acidic intermediate, wherein R1 and M are as defined herein.

[0138] In a particular embodiment of the invention, the metal alkoxide used in the salt formation step is MeOM, Etom, iPrOM, nPrOM, nBuOM, iBuOM tBuOM or, more particularly EtOM.

[0139] In a particular embodiment of the invention, the alcohol used as a solvent in the salt formation step is C1-7 alkyl-OH, more particularly, MeOH, EtOH, iPrOH, nPrOH, nBuOH, iBuOH or tBuOH, more particularly EtOH.

[0140] One aspect of the present invention relates to the process for the manufacture of compounds of formula (II) which comprises the asymmetric hydrogenation of a compound of formula (IV) using a complex metal catalyst (C), followed by the formation of a salt by adding to the hydrogenation reaction mixture of an ethanolic solution of sodium ethoxide.

[0141] Compounds of formula (IV) can be prepared according to methods known to those skilled in the art. A general method of specific preparation of compounds of formula (IV) is described in Scheme 2. For a more detailed description of the individual reaction steps, see the Examples section below. SCHEME 2

[0142] A compound of formula (IVa), wherein R3 is optionally substituted C1-7 alkyl, in particular ethyl, is condensed under basic conditions with a compound HCO2R4, wherein R4 is optionally substituted C1-7 alkyl, particularly ethyl , to form a compound of formula (IVb). Furthermore, condensation of compounds of formula (IVb) with an amine HN(isopropyl)R5, where R5 is hydrogen, C 1-7 alkyl or an amino protecting group, forms compounds of formula (IVc). When R5 is hydrogen, in compounds of formula (IVc), additional protection of the amine can be done to form protected compounds of formula (IVc) (for example, where R5 is an amino protecting group, such as Boc) . Hydrolysis of the ester of compound (IVc) provides compounds of formula (IV).

[0143] The ruthenium complex catalysts of the invention can, in principle, be prepared in a manner known per se. They can be isolated or used directly (in situ preparation), for example according to B. Heiser et al., Tetrahedron: Asymmetry 1991, 2, 51; or N. Feiken et al., Organometallics 1997, 16, 537; or J.-P. Genet, Acc. Chem. Res. 2003, 36, 908; or K. Mashima et al., J. Org. Chem. 1994, 53, 3064;Angew. Chem. Int. Ed. 1998, 37, 1703-1707; or M. P. Fleming et al., US 6,545,165 B1, and references cited therein; as well as O. Briel et al. in Catalysis of Organic Reactions, CRC Press, Boca Raton, 2009 specifically for ferrocene-based Ru complexes, the disclosures of all these documents are incorporated herein by reference in their entirety for all purposes.

[0144] The synthesis of [Ru(TFA)2((S)-BINAP)] is disclosed in B. Heiser et al, Tetrahedron: Asymmetry 1991, 2, 51.

[0145] Ruthenium complex catalysts can be prepared in situ, that is, immediately before use and without isolation. The solution in which such a catalyst is prepared may already contain the substrate for enantioselective hydrogenation or the solution may be mixed with the substrate immediately before the hydrogenation reaction is initiated.

[0146] WO 2008/006040 discloses 5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ols of formula (71) and methods of manufacturing the same, in which R5 can have several alternatives.

[0147] In particular, WO 2008/006040 discloses the asymmetric reduction of 5-methyl-5,6-dihydrocyclopenta[d]pyrimidin-7-ones to (R) or (S)-5-methyl-6,7 -dihydro-5H-cyclopenta[d]pyrimidin-7-ols using a chiral catalyst in the presence of hydrogen, a Corey-Bakshi-Shibata (CBS) catalyst, a borohydride reducing agent in the presence of a chiral ligand, or a non-chiral reducing agent (e.g. H2, Pd/C).

[0148] Methods known in the art for producing compounds of formula (III) exhibit the intrinsic disadvantages that require drastic reaction conditions (e.g., high pressures), the use of heavy metals and chiral auxiliaries, and the diastereoselectivity obtained is only limited (i.e. 88% of) thus requiring additional purification steps.

[0149] The inventors of the present invention have discovered new enzymatic processes for the preparation of compounds of formula (III), where R2 is as described herein.

[0150] These new processes for manufacturing compounds of formula (III) according to the present invention present a number of relevant advantages, compared to the process as is known in the art. The advantages of enzymatic reduction are its catalytic nature, the very high diastereoselectivity avoiding the potential need for subsequent resolution of the formed diastereoisomers, and the mild reaction conditions. Furthermore, no heavy metal auxiliaries and chiral auxiliaries are required.

[0151] The enzymatic reduction of the present invention simplifies technical requirements, reduces the number and quantities of ingredients and allows for greater space-time yield. The advantages of the present invention are exemplified as the improved pertinent technical criteria, such as increasing substrate concentration (up to 25%), increasing product concentration (up to 25%), decreasing cofactor loading (up to 1/3000 of compound of formula (V)) and a simpler cofactor regeneration system with a 2-propanol as final reductant. The cofactor regeneration system with 2-propanol as the final reductant avoids a second enzyme, reduces viscosity, prevents continuous neutralization of gluconic acid as the oxidized co-substrate and allows continuous removal of the formed acetone.

[0152] One aspect of the present invention relates to the process for manufacturing compounds of formula (III) comprising the asymmetric reduction of the compound of formula (V) catalyzed by an oxidoreductase, where R2 is as defined herein.

[0153] In one aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a ketoreductase.

[0154] In one aspect of the invention, oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereoselectivity of at least a diastereoisomeric excess of at least 95% (of), particularly with a diastereoselectivity of at least 98% of, more particularly, with a diastereoselectivity of at least 99% of.

[0155] In one aspect of the invention, the asymmetric reduction of a compound of formula (V) with a compound of formula (III) is catalyzed by an oxidoreductase in the presence of a cofactor.

[0156] In one aspect of the invention, the cofactor that is oxidized in the asymmetric reduction of a compound of formula (V) with a compound of formula (III) is NADH or NADPH.

[0157] In one aspect of the invention, the cofactor that is oxidized in the asymmetric reduction of a compound of formula (V) with a compound of formula (III) is regenerated in situ by applying enzyme-coupled cofactor regeneration (e.g., based in glucose as the final reductant and glucose dehydrogenase) or substrate-coupled regeneration (e.g., using a secondary alcohol as a cosubstrate).

[0158] In one aspect of the invention, the cofactor that is oxidized in the asymmetric reduction of a compound of formula (V) to a compound of formula (III) in situ is regenerated by enzyme-coupled cofactor regeneration using glucose and glucose dehydrogenase as cosubstrate.

[0159] In one aspect of the invention, the cofactor that is oxidized in the asymmetric reduction of a compound of formula (V) with a compound of formula (III) is regenerated in situ by substrate-coupled regeneration using a secondary alcohol as a cosubstrate.

[0160] In one aspect of the invention, the secondary alcohol as a co-substrate for substrate-coupled regeneration is selected from 2-propanol, 2-butanol, butan-1,4-diol, 2-pentanol, pentan-1,5 -diol, 4-methyl-2-pentanol, 2-hexanol, hexan-1,5-diol, 2-heptanol or 2-octanol, particularly 2-propanol.

[0161] Particularly useful is 2-propanol for the regeneration of the cofactor in the same enzyme also catalyzes the target reaction and the continuous removal of the acetone formed.

[0162] In one aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase.

[0163] In one aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of: KRED-NADPH- 111 (from Codexis Inc., Redwood City, CA, USA), KRED-NADPH-112 (from Codexis Inc., Redwood City, CA, USA), KRED-NADPH-113 (from Codexis Inc., Redwood City, CA, USA), KRED-NADPH-114 (from Codexis Inc., Redwood City, CA, USA), KRED-NADPH-115 (from Codexis Inc., Redwood City, CA, USA), KRED-NADPH-121 (from Codexis Inc ., Redwood City, CA, USA), KRED-NADPH-123 (from Codexis Inc., Redwood City, CA, USA), KRED-NADPH-145 (from Codexis Inc., Redwood City, CA, USA), KRED- NADPH-155 (from Codexis Inc., Redwood City, CA, USA), A231 (from Almac Group Ltd. Craigavon, UK), and KRED-NADPH-136 (from Enzysource, Hangzhou, China).

[0164] Another suitable oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) are diastereoselective NADPH-dependent oxidoreductases selected from the list of: KRED-X1, a ketoreductase modified from Lactobacillus kefir as disclosed in PCT Int. Publication WO2010/025238 A2 and identified as SEQ. ID. AT THE. 34, and KRED-X2, a modified ketoreductase from Sporobolomyces salmonicolor as disclosed in PCT Int. Publication WO2009/029554A2 and identified as SEQ. ID. AT THE. 138.

[0165] Another suitable oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) are variants of KRED-X1, which are commercially available (from Codexis Inc., Redwood City, CA , USA).

[0166] Particularly useful is the modified ketoreductase “KRED-X1-P1B06”, a KRED “P1B06” variant of Codexis KRED, a specialty plate product “KRED-X1-SPECIALTY-PLT”.

[0167] Another suitable oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) are variants of KRED-X1, which are commercially available (from Codexis Inc., Redwood City, CA , USA). Particularly useful are the following modified ketoreductases from Codexis KRED, a specialty plate product “KRED-X1.1-B06-SPECIALTY-PLT”: “KRED-X1.1-P1F01” (variant KRED P1F01), “KRED-X1.1 -P1H10” (KRED P1H10 variant), “KRED-X1.1-P1G11” (KRED P1G11 variant), “KRED-X1.1-P1C04” (KRED P1C04 variant), “KRED-X1.1-P1C11” (KRED variant KRED P1C11), and “KRED-X1.1-P1C08” (KRED P1C08 variant).

[0168] Particularly useful are the modified ketoreductases “KRED-X1.1-P1C04” and “KRED-X1.1-P1F01”. More particular ketoreductase is the modified ketoreductase “KRED-X1.1-P1F01”.

[0169] PCT Int. Publications WO2010/025085A2 and WO2009/029554A2 are incorporated herein by reference in their entirety for all purposes, in particular aspects therein relating to the preparation and use of oxidoreductases.

[0170] All of the enzymes mentioned above can also use the cofactor NADH.

[0171] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-NADPH- 111, KRED-NADPH-112, KRED-NADPH-113, KRED-NADPH-114, KRED-NADPH-115, KRED-NADPH-121, KRED-NADPH-123, KRED-NADPH-145, KRED-NADPH- 155, A231, KRED-NADPH-136, KRED-X1, KRED-X2, KRED-X1-P1B06, KRED-X1.1-P1F01, KRED-X1.1-P1H10, KRED-X1.1-P1G11, KRED-X1. 1-P1C04,KRED-X1.1-P1C11, and KRED-X1.1-P1C08.

[0172] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1, KRED-X2, KRED- and KRED-X1.1-P1C08.

[0173] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1, KRED-X2, KRED-X1-P1B06, KRED-X1.1-P1C04 and KRED-X1.1-P1F01.

[0174] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1, KRED-X1-P1B06, KRED-X1.1-P1C04 and KRED-X1.1-P1F01.

[0175] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1 and KRED-X2.

[0176] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1 and KRED-X1- P1B06.

[0177] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of KRED-X1. 1-P1C04 and KRED-X1.1-P1F01.

[0178] In a particular aspect of the invention, the oxidoreductase that catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is the diastereoselective NADPH-dependent oxidoreductase KRED-X1.1-P1F01.

[0179] In one aspect of the invention, the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is carried out in an aqueous medium in the presence of one or more organic co-solvents.

[0180] In one aspect of the invention, the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is carried out in an aqueous medium in the presence of one or more organic co-solvents, wherein the organic co-solvents are present in a total concentration of 1 to 50%V, particularly 4 to 40%V.

[0181] In one aspect of the invention, the cosolvents present in the asymmetric reduction of a compound of formula (V) to a compound of formula (III) are selected from the list of glycerol, 2-propanol, diethylether, tert-butylmethylether, diisopropylether, dibutylether, methyl tetrahydrofuran, ethyl acetate, butylacetate, toluene, heptane, hexane, cyclohexene and mixtures thereof; particularly 2-propanol.

[0182] 2-propanol is particularly useful as a co-solvent, as it can serve as a final reductant for substrate-coupled cofactor regeneration.

[0183] In one aspect of the invention, the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is carried out at a reaction temperature between 1°C and 50°C, particularly between 20°C and 45°C.

[0184] Temperatures in the upper range increase the reaction speed and facilitate the removal of acetone.

[0185] In one aspect of the invention, the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is carried out at a pH between 5.5 and 8.5.

[0186] In one aspect of the invention, the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is carried out in an aqueous buffer. Suitable buffers are known to the person skilled in the art. Particular buffers are 2-(N-morpholino)ethanesulfonic acid (MES) or potassium dihydrogen phosphate (PBS).

[0187] The ideal pH range, and therefore any suitable buffers, are dependent on the particular oxidoreductase employed.

[0188] One aspect of the invention relates to the asymmetric reduction of a compound of formula (V) to a compound of formula (III), wherein the compound of formula (V) is initially present at a concentration of 1 to 25% in weight, particularly 10 to 20% by weight.

[0189] One aspect of the invention relates to the asymmetric reduction of a compound of formula (V) to a compound of formula (III), in which the reaction concentration (total concentration of ketone of formula (V) and the chiral alcohol of formula (III) in the reaction mixture) is between 1 and 25% by weight, particularly between 10 and 20% by weight.

[0190] One aspect of the present invention relates to the process for manufacturing compounds of formula (III) which comprises the asymmetric reduction of the compound of formula (V) catalyzed by an oxidoreductase followed by processing by extraction or filtration.

[0191] One aspect of the invention relates to the asymmetric reduction of a compound of formula (V) to a compound of formula (III) catalyzed by an oxidoreductase, wherein the product is conventionally processed by extraction or filtration.

[0192] The purity of the crude product can be further increased through crystallization or used as such in the subsequent reaction sequence for the manufacture of compounds of formula (I).

[0193] One aspect of the present invention relates to the process for manufacturing compounds of formula (III) which comprises the asymmetric reduction of the compound of formula (V) catalyzed by an oxidoreductase, followed by processing by extraction or filtration and additionally by crystallization.

[0194] One aspect of the invention relates to the asymmetric reduction of a compound of formula (V) to a compound of formula (III), wherein the product is conventionally processed by extraction or filtration and also by crystallization.

[0195] One aspect of the present invention relates to the process for manufacturing compounds of formula (IVc): or a salt thereof, wherein R1 and R3 are as defined herein, comprising contacting a compound of formula (IVd): or a salt thereof, with R1-X, wherein X is a leaving group, under conditions sufficient to generate a compound of formula IVc or a salt thereof.

[0196] In one embodiment, the process comprises the manufacture of ethyl (E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylate, or a salt thereof, wherein R 1 is BOC protecting group, R3 is ethyl, and where R1-X is (BOC)2O.

[0197] In a particular embodiment, the process comprises contacting a compound of formula IVd or a salt thereof, with less than about 8 equivalents of (Boc)2O, particularly less than about 4 equivalents, more particularly about 3 equivalents, under conditions that generate a compound of formula IVc or a salt thereof, in yields greater than about 50%, particularly about 75% or more yield, in a polar solvent mixture comprising DMF.

[0198] In a more particular embodiment, the conditions comprise contacting a compound of formula IVd or a salt thereof, with about 3 equivalents of (Boc)2O, and a basic mixture comprising about 2 equivalents each of tributylamine and dimethylaminopyridine (DMAP), in a polar solvent mixture comprising DMF. In one embodiment, the process further comprises removing a portion of the liquid from the reaction mixture under vacuum during the addition of (Boc)2O.

[0199] The compounds of formula (V) can be prepared according to methods known to those skilled in the art. A general method of specific preparation of compounds of formula (V) is described in Scheme 3. For a more detailed description of the individual reaction steps, see the Examples section below. SCHEME 3

[0200] The reaction of a compound of formula (Va) with an iodinating agent (for example iodide salt, such as NaI and, optionally, with an acid) generates a diiodopyrimidine of formula (Vb), which can be additionally reacted with a monoprotected piperazine, to generate a compound of formula (Vc). The compound of formula (Vc) is metallated with a metallating agent, such as a Grignard reagent (e.g., a C1-7alkylmagnesium halide, such as iPrMgCl) to form a compound of formula (Vd), which is further cyclized to form a cyclopentyl ketone of formula (V), wherein R2 is as described herein, G is Li or Mg, R6 is Cl or OH, R7 is -CN, -COORa or -CONRaRb, wherein Ra and Rb are independently selected from the list of hydrogen, -OH, C1-7 alkoxy, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-8 cycloalkyl, phenyl or 3- to 12-membered heterocycloalkyl; or Ra and Rb are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycloalkyl.

[0201] WO 2008/006040 discloses methods of manufacturing compounds of formula (73, in which compounds of formula (71) after deprotection using an acid are acylated with the appropriate amino acid, in which R and R5 can have several alternatives.

[0202] Acylation reactions as described in the prior art present the following drawbacks: • A process using HBTU as a coupling agent is not suitable for a large-scale commercial manufacturing process. HBTU raises serious industrial hygiene concerns as cases of anaphylaxis and occupational allergic contact dermatitis are described in the literature (Hannu T. et al, Occup Med, 2006, 56(6), 430-433 and M. A. Aleer et al, Contact Dermatitis, 2010 62, 2 123); • A process employing dichloromethane as a solvent is not suitable for a large-scale commercial production process as it is classified as a hazardous air pollutant (HAP) in the USA. Additionally, dichloromethane is evaluated by the International Conference on Harmonization (ICH) as a Class 2 solvent with a Fair Allowable Daily Exposure (PDE), due to its inherent toxicity; • Purification of a product using chromatography is not an acceptable purification method for small molecule manufacturing on a bulk scale due to its high solvent consumption and low yield; • In case a commercial bulk scale reaction process involves more than one solvent in a mixture, the solvents require sufficiently distinct boiling points apart from each other in order to allow separation from each other and recycling using distillation. Processes that involve four solvents in the same step (for example, with cyclopentyl methyl ether (PCEM)), which are not recyclable because the mixture is inseparable, are not suitable for large-scale production; • Processing products that require numerous aqueous extractions (e.g., six), all of which contain concentrated inorganic salts, results in significant amounts of contaminated wastewater. Such process conditions result in an environmentally disadvantageous production process.

[0203] The inventors of the present invention have discovered a new improved process for manufacturing a compound of formula (I), which comprises coupling a compound of formula (II), which is a salt particularly a sodium salt, to a compound of formula (III). It has been found that the use of the compound of formula (II) as the salt, particularly a sodium salt, substantially facilitates and simplifies such a process, compared to the use of a free amino acid.

[0204] The process for manufacturing compounds of formula (I) according to the invention presents a series of relevant advantages, as compared to processes described in the art, for example, among others: • Processing of the compound of formula ( I) is considerably improved. Only three solvents (isopropanol, toluene and heptane) are used that are well separable; • Propylphosphinic anhydride (T3P) is a non-toxic coupling agent, without allergenic and sensitizing properties; • The by-products of the reaction are soluble in water and can therefore be easily removed, for example, by three-fold aqueous phase extraction.

[0205] One aspect of the present invention provides a process for preparing a compound of formula (I) coupling of a compound of formula (II) with a compound of formula (III) wherein R1, R2 and M are as defined herein.

[0206] One aspect of the present invention provides a process for preparing a compound of formula (I) or salts thereof, which comprises the coupling reaction of a compound of formula (II) with a compound of formula (III) wherein R1, R2 and M are as defined herein, which comprises the following reaction steps: a) Deprotection of the compound of formula (III) in a solvent under acidic conditions; b) adjust to an alkaline pH using a base; c) adding a solution comprising the compound of formula (II) in a solvent; d) adding a solution comprising a coupling agent in a solvent.

[0207] In one aspect of the invention, deprotection in step a) is carried out using hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid.

[0208] In a particular aspect of the invention, the deprotection in step a) is carried out using hydrochloric acid.

[0209] In one aspect of the invention, the solvent used for deprotection in step a) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.

[0210] In a particular aspect of the invention, the solvent used for deprotection in step a) is selected from n-propanol or isopropanol.

[0211] In one aspect of the invention, the deprotection in step a) is carried out at a temperature of 50 to 100°C, particularly at 80°C.

[0212] In one aspect of the invention, deprotection in step a) is carried out during a reaction time of 0.1 to 24 hours, particularly during a reaction time of 1 to 2 hours.

[0213] In one aspect of the invention, the base in step b) is a liquid base selected from N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), diisopropylethylamine (DIPEA), pyridine and lutidine.

[0214] In one aspect of the invention, the base in step b) is N-ethylmorpholine (NEM).

[0215] In one aspect of the invention, in step b) 4 to 8 equivalents of base are added, in relation to the compound of formula (III), particularly 6 to 7 equivalents of base, more particularly 6.5 equivalents of base .

[0216] In one aspect of the invention, the solvent used in step c) is identical to the solvent used in step a).

[0217] In one aspect of the invention, the solvent used in step c) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.

[0218] In a particular aspect of the invention, the solvent in step c) is selected from n-propanol or isopropanol.

[0219] In one aspect of the invention, the coupling agent used in step d) is propylphosphonic anhydride (T3P).

[0220] In one aspect of the invention, the solvent used in step d) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride, dichloromethane, dichloroethane, diethyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, N,N-dimethyl acetamide, N-methyl pyrrolidone, dioxane, tetrahydropyran, pyridine, 2-propanone, 2-butanone, dimethyl ether of ethylene glycol, ethyl acetate, butyl acetate, isopropyl acetate, and mixtures of the above.

[0221] In a particular aspect of the invention, the solvent used in step d) is selected from a mixture of propanol and n-toluene or isopropanol and toluene, more particularly a mixture of n-propanol and toluene.

[0222] In one aspect of the invention, the coupling reaction in step d) is carried out at a temperature of -10 to 50°C, particularly 0 to 25°C.

[0223] In one aspect of the invention, the coupling reaction in step d) is carried out during a reaction time of 0.1 to 24 hours, particularly during a reaction time of 1 to 4 hours.

[0224] One aspect of the present invention relates to the coupling reaction of a compound of formula (II) with a compound of formula (III), in which after step d), the product is processed by aqueous extraction.

[0225] In a particular aspect of the invention, the above processing of the product after step d) comprises one to six water extractions, particularly three water extractions.

[0226] One aspect of the present invention relates to the process for manufacturing compounds of formula (VI) or the pharmaceutically acceptable salts thereof, in which a compound of formula (I) is deprotected where R1 is as defined here.

[0227] One aspect of the present invention relates to the process for manufacturing compounds of formula (VI) or pharmaceutically acceptable salts thereof, in which a compound of formula (I) is deprotected, in which R1 is as defined herein, which comprises the following reaction steps: i) Deprotection of the compound of formula (I) in a solvent under acidic conditions; ii) pH adjustment, using a base in a solvent; iii) optionally, crystallization of the compound of formula (VI).

[0228] In one aspect of the invention, deprotection in step i) is carried out using hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid.

[0229] In a particular aspect of the invention, deprotection in step i) is carried out using hydrochloric acid.

[0230] In one aspect of the invention, the solvent used for deprotection in step i) is selected from water, methanol, ethanol, n-propanol, isopropanol and tert-butanol or mixtures thereof.

[0231] In a particular aspect of the invention, the solvent used for deprotection in step i) is selected from n-propanol, isopropanol and a 1:1 mixture of n-propanol/water.

[0232] In one aspect of the invention, the deprotection in step i) is carried out at a temperature of 30 to 100°C, particularly at 80°C.

[0233] In one aspect of the invention, the deprotection in step i) is carried out during a reaction time of 1 to 24 hours, particularly during a reaction time of 1 to 4 hours.

[0234] In one aspect of the invention, the base in step ii) is NaOH in a 1:1 mixture of n-propanol/water.

[0235] In one aspect of the invention, the base in step ii) is ammonia.

[0236] In one aspect of the invention, the solvent used in step ii) is identical to the solvent used in step i).

[0237] In one aspect of the invention, the solvent used in step ii) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol or mixtures thereof.

[0238] In a particular aspect of the invention, the solvent in step ii) is selected from n-propanol, isopropanol and a 1:1 mixture of n-propanol/water.

[0239] In a particular aspect of the invention, pH adjustment is carried out by dropwise addition of a solution of ammonia (2-4% by weight, particularly 3.8% by weight) in isopropanol or a solution of NaOH (5-10M, particularly 7M) in a 1:1 n-propanol/water mixture.

[0240] In a particular aspect of the invention, the final pH after adjustment in step ii) is above pH 6, especially between pH 6 and 7.

[0241] In one aspect of the invention, crystallization in step iii) is carried out by a change of solvent to a suitable crystallization solvent for crystallization of the compound of formula (VI).

[0242] In a particular aspect of the invention, the crystallization solvent in step iii) is selected from toluene, heptane, tetrahydrofuran, 2-propanone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate , isopropyl acetate and mixtures thereof.

[0243] In a particular aspect of the invention, the crystallization solvent in step iii) is ethyl acetate.

[0244] One aspect of the invention relates to compounds obtained by any process as described herein.

[0245] One aspect of the invention relates to pharmaceutical compositions comprising compounds that can be obtained by any process as described herein.

[0246] One aspect of the invention relates to a compound of formula (VI) as described herein comprising between 1 ppb and 100 ppm of the compound of formula (I), wherein R1 is as defined herein.

[0247] One aspect of the invention relates to a compound of formula (VI) as described herein comprising between 1 ppb and 1 ppm of the compound of formula (I), wherein R1 is as defined herein.

[0248] One aspect of the invention relates to a pharmaceutical composition comprising compounds of formula (VI) as described herein.

[0249] One aspect of the invention relates to a compound of formula (I) as described herein comprising between 1 ppb and 100 ppm of the compound of formula (II), wherein R1 and M are as defined herein.

[0250] One aspect of the invention relates to a compound of formula (I) as described herein comprising between 1 ppb and 1 ppm of the compound of formula (II), wherein R1 and M are as defined herein.

[0251] One aspect of the invention relates to a compound of formula (I) as described herein comprising between 1 ppb and 100 ppm of the compound of formula (III), wherein R1 and R2 are as defined herein.

[0252] One aspect of the invention relates to a compound of formula (I) as described herein comprising between 1 ppb to 1 ppm and of the compound of formula (III), wherein R1 and R2 are as defined herein.

[0253] One aspect of the invention relates to a compound of formula (I) as described herein comprising between 1 ppb and 100 ppm of the compound of formula (II) and between 1 ppb and 100 ppm of the compound of formula (III), in that R1, R2 and M are as defined herein.

[0254] One aspect of the invention relates to a compound of formula (I) as described herein comprising between 1 ppb and 1 ppm of the compound of formula (II) and between 1 ppb and 1 ppm of the compound of formula (III), in that R1, R2 and M are as defined herein.

EXAMPLES

[0255] The following examples 1-15 are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

[0256] In a solution of ethyl formate (123.9 L, 1538.9 mol) in MTBE (189 L) ethyl 4-chlorophenylacetate (120 kg, 604.1 mol) was added. The mixture was stirred at 15-30°C for 30 min and then a mixture of t-BuOK (136.8 kg, 1219.1 mol) in MTBE (1215.8 L) was added while maintaining the internal temperature below 5°C. The mixture was stirred at 010°C for 1.5 h. The reaction mixture was added to an aqueous hydrochloric acid solution (35%, 99.8 L in 560 L H2O) maintaining the internal temperature below 10°C. The mixture was stirred for 30 min at 0-10°C, until a final pH = 2 was observed. The layers were separated and the organic layer was washed with 25% NaCl solution (496 L).

[0257] The mixture was cooled to -5°C and then isopropylamine (107.2 L, 1251.9 mol) and AcOH (70.5L, 1233.3 mol) were added slowly keeping the temperature <10°C. The mixture was stirred for 3 hours at 0-10°C and then the organic layer was washed with H2O (760 L), 15% aqueous Na2CO3 solution (424 L) and then 25% aqueous NaCl (650L). The aqueous layer was separated and DMF (443 L) and DMAP (14.4 kg, 117.9 mol) were added to the organic solution. The mixture was then heated to 6065°C, followed by slow addition of (Boc)2O (951.6 L, 4.142 mol), DMF (228.6 L) and triethylamine (263.0 L, 1821.8 mol) to the over 24 hours. After stirring ~6 h, the mixture was cooled to room temperature and MTBE (1434 L), water (1010 L) and 10% aqueous citric acid (938 L) were added. The aqueous layer was separated and the mixture was washed with 25% aqueous NaCl (984 L). The organic layer was then concentrated by distillation to a minimum working volume (~240 L), maintaining the temperature below 50°C. The organic layer was then stirred for 5 h at 0-5°C and filtered. The filter cake was washed with heptane (20.6 L) and dried to obtain (E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (148.55 kg, 63% yield over three steps) as a white solid.

[0258] (E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (133.5 kg, 362.9 mol) was added to a mixture of H2O (252 L), NaOH (58.25 kg, 1456 mol) and EtOH (383.5 L), stirred at room temperature. The mixture was heated at 40-45°C for 2.5 hours until a clear solution formed. The mixture was concentrated to a minimum working volume, keeping the temperature below 50°C. The mixture was then cooled to 10-25°C and an HCl solution was added (842 L of 2N HCl and 11 L of 35% HCl) until a final pH = ~2-4 was obtained. The aqueous layer was separated and the organic layer was washed with 25% aqueous NaCl (810 L). n-Heptane was added during distillation to form a suspension. The product was collected and washed with n-heptane and dried at 4045°C for ~10 hours to obtain 110.7 kg (90.5% yield) of (E)-3-(tert-butoxycarbonyl(isopropyl) acid amino)-2-(4-chlorophenyl)acrylic with 99.9% purity by HPLC. The E configuration was confirmed using single crystal X-ray analysis.

[0259] A concentrated solution of ethyl 2-(4-chlorophenyl)-3-(isopropylamino) acrylates (prepared as above in Example 1 from 120 kg of ethyl 2-(4-chlorophenyl) acetate, 0.604 kmol) was DMF (354 kg) was added and the batch was concentrated until 3 volumes were obtained. DMAP (14.0 kg, 114.6 mol) and n-Bu3N (224.21 kg, 1.21 kmol) were added and the mixture was heated to 70-75°C and a solution of (Boc)2O (330 kg, 1.51 kmol) in DMF (169 kg) solution was added over 2 h at 70-75°C. After the addition was complete about 200 L of DMF was removed under vacuum over 3 h below 75°C. The addition of (Boc)2O (68.6 kg, 0.314 kmol) in DMF solution (32.4 kg) was maintained over 0.5 h at 70-75°C. After the addition was complete, the batch was concentrated at a temperature below 75°C and then cooled to about 23.5°C. MTBE (899.6 kg) was charged and then the mixture was cooled to about 12.6°C. Citric acid monohydrate (197.4 kg) in a water solution (702 kg) was added at 10-20°C. The layers were separated and the organic layer was washed with 5% aqueous NaCl (582 kg). The layers were cut and the organic layer was concentrated to 240-360 L at less than 50°C. After n-heptane (77 kg) was charged, the mixture was concentrated to 240-360 L below 50°C. After n-heptane (70 kg) was charged, the suspension was stirred for 4 hours at 0-10°C and the product was collected by centrifugation. The cake was washed with n-heptane (28.2 kg) and (E)-ethyl 3-(amino(tert-butoxycarbonyl)(isopropyl))-2-(4-chlorophenyl)acrylate was obtained (170.6 kg, 77% yield, 99.8% HPLC), which can be used as above in this Example 1 to prepare (E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic acid . EXAMPLE 2 (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL)SODIUM PROPANOATE

[0260] In a fume hood with gloves (O2 content <2 ppm), in a 50 ml autoclave was charged with 6.8 g (20.0 mmol) of acid (E)-2-(4-chlorophenyl)- 3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid, 34 ml of ethanol and 4.81 mg (0.0051 mmol, S/C 4'000) of [ Ru(TFA)2((S)-BINAP]. Asymmetric hydrogenation was carried out for 7 h at 60°C under 18 bar hydrogen. After cooling to room temperature, the pressure was released from the autoclave and a sample of the yellow reaction was analyzed to show >99% conversion of (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an enantiomeric S/N ratio of 99, 3 to 0.7. The hydrogenation mixture was transferred with the help of 100 ml of tert-butyl methyl ether into a 1 L glass reactor under argon, which contained the crude reaction mixture from 6 analogous experiments of hydrogenation (in total 47.9 g of (E)-2-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid), in Then, an ethanol solution of sodium ethoxide (52.3 ml, 140 mmol) was added dropwise at 50°C under stirring. A yellowish precipitate formed, which was stirred at the same temperature and then at room temperature overnight. The precipitated product was filtered, washed with a mixture of t-butyl methyl ether/ethanol 4:1 (300 ml) and with t-butyl methyl ether (200 ml), dried under vacuum until constant weight to give (S)- Sodium 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate in a yield of 96.3% (49.03 g) and with an enantiomeric S/N ratio of >99.9 to <0.1%, as white crystals. 1H- NMR (D2O): δ 7.32 (d, 2H), 7.22 (d, 2H), 3.65-3.85 two bs, aryl-CH and N- CH(CH3)2), 3 .55 (m, 2H), 1.29 (s, 9H), 1.00 (d, 3H), 0.80 (bs, 3H).

[0261] The enantiomeric ratio was determined by HPLC using a Chiralpak-AD-3 column, 150 mm*4.6 mm. Eluents: A) n-heptane with 0.10% trifluoroacetic acid, B) ethanol, flow: 1.25 mL/min, 25°C, injection volume 5 μl, 220 nm. Retention times: (S)-3-(tert-Butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid 2.48 min, (R)-3-(tert-Butoxycarbonyl-isopropyl acid -amino)-2-(4-chloro-phenyl)-propionic acid 2.77 min, (E)-2-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2 acid -ylamino]prop-2-enoic 3.16 min. EXAMPLE 3 (S)-3-(TERT-BUTOXYCARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL) SODIUM PROPANOATE

[0262] In a fume hood with gloves (O2 content <2 ppm), a 185 ml autoclave was charged with 17.0 g (50.0 mmol) of acid (E)-2-(4-chlorophenyl)- 3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid, 70 ml of ethanol and 4.74 mg (0.005 mmol, S/C 10'000) of [Ru( TFA)2((S)-BINAP]. Asymmetric hydrogenation was performed for 22 h at 70°C under 18 bar hydrogen. After cooling to room temperature, the pressure was released from the autoclave and a sample of the reaction solution yellow was analyzed to show >99% conversion to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an enantiomeric S/N ratio of 98.2 to 1.8. The hydrogenation mixture was transferred with the help of 200 ml of tert-butyl methyl ether in a 400 ml glass reactor under argon atmosphere, then an ethanol solution of sodium ethoxide (18. 7 ml, 50 mmol) was added dropwise at 50 ° C under stirring. A yellowish precipitate formed, which was stirred at the same temperature and then at room temperature for a total of 3.5 h. The precipitated product was filtered, washed with a mixture of t-butyl methyl ether/ethanol 4:1 (80 ml) and with t-butyl methyl ether (20 ml), dried under vacuum until constant weight to give (S)- Sodium 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate in a yield of 94.6% (17.35 g) and with an enantiomeric S/N ratio of 100 to 0% in forms white crystals.EXAMPLE 3A (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL)SODIUM PROPANOATE

[0263] In a glove hood (O2 content <2 ppm), a 185 ml autoclave was charged with 10.0 g (29.4 mmol) of (E)-2-(4-chlorophenyl)-3 acid -[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid, 125 ml of ethanol, 0.118 ml of a solution of NaBr in water (1 M) and 5.77 mg (0.006 mmol, S/C 5'000) of [Ru(TFA)2((S)-BINAP]. Asymmetric hydrogenation was carried out for 22 h at 60°C under 18 bar of hydrogen. After cooling to room temperature, the pressure was released from the autoclave and a sample of the yellow reaction solution was analyzed to show >99% conversion of (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an enantiomeric S/N ratio of 98 to 2. The hydrogenation mixture was transferred with the aid of 10 mL of ethanol to a 0.5 L reactor. The reaction mixture was evaporated at 45 ° C in vacuum to a residual volume of 65 mL.

[0264] 70 ml of tert-butyl methyl ether were added at 45°C. Then, an ethanol solution of sodium ethoxide (11.4 g, 35 mmol) was added dropwise at 45°C under stirring. The funnel was washed with 1.3 g of ethanol. A yellowish precipitate formed, which was stirred at the same temperature for 1 h and then at room temperature for 1 h. The precipitated product was filtered, washed with a 1:1 t-butyl methyl ether/ethanol mixture (13.6 g) and with t-butyl methyl ether (16 g), dried under vacuum until constant weight to give (S) Sodium -3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate in a yield of 89% (9.52 g) and with an enantiomeric S/N ratio of 100 to 0% in the form of white crystals. EXAMPLE 3B (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL) SODIUM PROPANOATE

[0265] In a glove hood (O2 content <2 ppm), a 185 ml autoclave was charged with 10.0 g (29.4 mmol) of (E)-2-(4-chlorophenyl)-3 acid -[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid, 120 ml of ethanol (distilled under Ar), 0.118 ml of NaCl solution in water (1 M) and 5, 8 mg (0.006 mmol, S/C 5'000) of [Ru(TFA)2((S)-BINAP]. Asymmetric hydrogenation was carried out for 12 h at 60°C under 18 bar of hydrogen. After cooling to room temperature , pressure was released from the autoclave and a sample of the yellow reaction solution was analyzed to show >99% conversion to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro) acid. -phenyl)-propionic acid with an enantiomeric S/N ratio of 99 to 1. The hydrogenation mixture was transferred with the help of 10 ml of ethanol to a 0.5 L reactor. The reaction mixture was evaporated at 45°C in vacuum to a residual volume of 65 mL.

[0266] 70 ml of tert-butyl methyl ether were added at 20°C. Then, a solution of sodium ethoxide (21% (m/m), 9.5 g, 29.4 mmol) in ethanol was added dropwise at 45°C under stirring. The funnel was washed with 1.3 g of ethanol. A precipitate formed, which was stirred at the same temperature for 1 h and then at room temperature for 1 h. The precipitated product was filtered, washed with a 1:1 t-butyl methyl ether/ethanol mixture (13.6 g) and with t-butyl methyl ether (16 g), dried under vacuum until constant weight to give (S) Sodium -3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate in a yield of 89% (9.5 g) and with an enantiomeric S/N ratio of 100 to 0% in the form of white crystals.EXAMPLE 3C (S)-3-(TERT-BUTOXYCARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL)- PROPIONIC ACID

[0267] In a fume hood with gloves (O2 content <2 ppm), a 185 ml autoclave was charged with 17.1 g (50.0 mmol) of acid (E)-2-(4-chlorophenyl)- 3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid and 75 ml of ethanol. In a separate vial a mixture of 4.79 mg (0.005 mmol, S/C 10'000) of [Ru(TFA)2((S)-BINAP] and 8.3 ml of ethanol was treated with 1.67 ml (0.10 mmol) of a solution of 60 millimolar HCl in water, the resulting suspension was stirred for 30 min and then added to the autoclave. After sealing the autoclave, asymmetric hydrogenation was carried out for 12 h at 60°C under 18 bar hydrogen. After cooling to room temperature, the pressure was released from the autoclave and a sample of the yellow reaction solution was analyzed to show 99.5% conversion of (S)-3-(tert-butoxycarbonyl-) acid. isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an enantiomeric ratio of 98.7-1.3 S/N. 3D EXAMPLE (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO) ACID -2-(4-CHLOROPHENIL)- PROPIONIC

[0268] The procedure of Example 3c was repeated using HBr as an additive. Hydrogenation proceeded with 99.8% conversion, the desired acid (S) was isolated in quantitative yield with an enantiomeric S/R ratio of 98.7:1.3. EXAMPLE 3E (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL)- PROPIONIC ACID

[0269] In a glove hood (O2 content <2 ppm), a 185 ml autoclave was charged with 17.0 g (50.0 mmol) of (E)-2-(4-chlorophenyl)-3 acid -[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid and 75 ml of ethanol. In a separate vial a mixture of 9.59 mg (0.010 mmol, S/C 5'000) of [Ru(TFA)2((S)-BINAP] and 9.8 ml of ethanol was treated with 0.20 ml (0.20 mmol) of a 1 molar solution of HCl solution in water, the resulting suspension was stirred for 30 min and then added to the autoclave. After sealing the autoclave asymmetric hydrogenation was carried out for 12 h at 60°C under 18 bar of hydrogen. After cooling to room temperature, the pressure was released from the autoclave and a sample of the yellow reaction solution was analyzed to show 99.7% conversion of (S)-3-(tert-) acid. butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic with an enantiomeric ratio of 99.0-1.0 S/N. EXAMPLE 3F (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL) ACID AMINO)-2-(4-CHLOROPHENYL)- PROPIONIC

[0270] The procedure in example 3f was repeated using LiBr as an additive. Hydrogenation proceeded with 98.9% conversion, the desired acid (S) was isolated in quantitative yield, with an enantiomeric S/R ratio of 98.5: 1.5. EXAMPLE 4 (S)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL)-PROPIONIC ACID

[0271] In a glove hood (O2 content <2 ppm), a 35 mL autoclave equipped with a glass insert and a magnetic stir bar was charged with 400 mg (1.18 mmol) of acid (E )-2-(4-chlorophenyl)-3-[(2-methylpropan-2-yl)oxycarbonyl-propan-2-ylamino]prop-2-enoic acid, 5.92 mg (0.00589 mmol) of [Ru( TFA)2((S)-BINAP)](S/C 200) and 4 ml of ethanol. The autoclave was sealed and pressurized with 20 bar of hydrogen, asymmetric hydrogenation was carried out under stirring for 14 hours at 60°C. After cooling to room temperature, pressure was released from the autoclave, the ethanol solution was evaporated in vacuum to generate (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl) acid )-propionic acid with a quantitative yield and an enantiomeric S/N ratio of 99:1. The conversion was >= 99.9%. EXAMPLE 5.1 TO 5.17 (S) OR (R)-3-(TERT-BUTOXICARBONYL(ISOPROPYL)AMINO)- 2-(4-CHLOROPHENYL)PROPIONIC ACID

[0272] The procedure of Example 4 was repeated using different chiral ruthenium catalysts to produce corresponding (R) and (S) isomers of 3-(tert-Butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl) acid -propionic. The results are shown in Table 1, together with the catalyst, % conversion and enantiomeric S/N ratio. The scale of the reaction was, in all experiments (unless specifically indicated in the footnote) 400 mg, the temperature was 60°C, the hydrogen pressure was 20 bar with an S/C ratio of 200, the time reaction time was 14 h. The reactor was a 35 ml autoclave. The indicated amount of additive is intended in relation to the amount of metal catalyst.TABLE 1 35 ml autoclave, scale 1.7 g; S/C 250, 22 h. b) scale 1.7 g, S/C 250.14 h; c) 6.8 g of substrate in 50 ml of autoclave, S/C 1500, 5 h. d) Catalyst prepared in situ by stirring 2.56 mg of [Ru(COD)(TFA)2]2 and 2.2 molar equivalents of chiral diphosphine in a fume hood with gloves in 3 ml of ethanol for 3 h at 50°C EXAMPLE 6.1 TO 6.8 (S) OR (R)-3-(TERT-BUTOXYCARBONYL(ISOPROPYL)AMINO)-2-(4-CHLOROPHENYL)PROPIONIC ACID

[0273] In a manner analogous to Examples 5.1-5.16, the following hydrogenations were carried out using various substances as additives to generate the isomers (R) and (S) of 3-(tert-Butoxycarbonyl-isopropyl-amino)-2- acid (4-chloro-phenyl)-propionic in the purity and enantiomeric purity indicated in Table 2. The scale of the reaction was in all experiments (unless specifically indicated in the footnote) 400 mg, the temperature was 60 ° C, the hydrogen pressure was 18 to 20 bar for 4 h and S/C ratio was 200. The reactor was a 35 ml autoclave. The indicated amount of additive is intended in relation to the amount of metal catalyst.TABLE 2 For a) reaction time 14 h; b) S/C 4000, 18 h, scale 6.8 g in a 185 ml autoclave; c) S/C 200, 14 h, scale 1.18 g, 30 ml autoclave, 20 bar H2. EXAMPLE 7.1-7.11 ACID (S) OR (R)-3-(TERT-BUTOXICARBONYL(ISOPROPYL) )AMINO)-2-(4- CHLOROPHENIL)PROPIONIC

[0274] The procedure of Examples 5.1-5.16 was repeated, but the reaction conditions were varied in terms of hydrogen pressure, concentration and solvent to produce corresponding acid isomers (R) and (S) of 3-(tert-Butoxycarbonyl -isopropyl-amino)-2-(4-chloro-phenyl)-propionic. The results are shown in Table 3, reaction scale was, in all experiments (unless specifically indicated in the footnote) 400 mg in 4 ml of solvent, the temperature was 60°C at the S/C ratio of 200 , the reaction time was 14 h. The reactor was a 35 ml autoclave, the catalyst was Ru(TFA)2((S)-BINAP).TABLE 3 For a) reaction time 4 h; b) 200 mg of substrate in 4 ml of ethanol; c) 600 mg of substrate in 2 ml of ethanol; d) catalyst prepared in situ by stirring 2.56 mg of [Ru(COD)(TFA)2]2 and 4.0 mg of (S)-BINAP in a box with gloves, in 3 ml of ethanol for 3 h 50 °C. EXAMPLE 8 (R)-TER-BUTYL-4-(5-METHYL-7-OXO-5,6-DI-HYDRO-5H-CYCLOPENTA[D] PYRIMIDIN-4-YL)PIPERAZINE-1-CARBOXYLATE (R)-METHYL3-(4,6-DICHLOROPYRIMIDIN-5-YL)BUTANOATE

[0275] In a mixture of (R)-methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate (1.00 kg, 4.70 mol), toluene (4.00 L), and 2 ,6-lutidine (0.550 L, 4.70 mol) was added phosphorus oxychloride (0.960 L, 10.6 mol) at 50°C slowly. The mixture was stirred at 70°C for 24 h. The solution was cooled to 0°C. To the mixture, 20% aqueous sodium hydroxide (about 40.0 mol, 1.60 kg of 8.00 L H2O) was slowly added, maintaining the internal temperature below 30°C, to obtain a final pH value between 5 and 6. Ethyl acetate (2.50 L) was added, and stirred for 0.5 h, and then the layers were separated. The aqueous phase was extracted with ethyl acetate (3 x 1.00 L). The organic products were combined and washed with 1N hydrochloric acid (2 x 2.50 L), and brine (2.50 L). The organic layers were combined and dried over sodium sulfate and filtered through a glass fiber filter. The solution was concentrated to about 3.00 ml/g, and diluted with acetonitrile to about 7.00 ml/g. The sequence was repeated twice to remove residual ethyl acetate and toluene (confirmed by 1H NMR analysis). The remaining crude solution was used directly in the next step without further purification or isolation.(R)-METHYL 3-(4,6-DIIODOPYRIMIDIN-5-YL)BUTANOATE

[0276] To a solution of (R)-methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (36.0 g, 145 mmol) in acetonitrile (540 mL) was added sodium iodide (152 g, 1.02 mol). The mixture was stirred at 25°C for 30 min and then cooled to about 5°C. Methanesulfonic acid (9.41 mL, 1.00 equiv) was added over 5 min. The mixture was stirred at about 5°C for 3 h. The reactor was cooled to about 5°C and N,N-diisopropylethylamine (20.3 mL, 116 mmol) was added. The mixture was stirred for 1 h while heating the mixture to 20°C. Saturated sodium sulfite solution was added until no color change was observed to remove iodine. Water (540 mL) was added and the pH was adjusted to between about 5 and 7. The two-phase mixture was concentrated under reduced pressure at a temperature below 40°C to remove acetonitrile. The aqueous suspension was filtered to give 48.8 g (78% yield) of an off-white solid product. (R)-TER-BUTYL 4-(6-IODO-5-(4-METHOXY-4-OXOBUTAN-2 -IL)PYRIMIDIN-4-IL)PIPERAZINE- 1-CARBOXYLATE

[0277] To a solution of (R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate (212 g, 491 mmol) and Boc-piperazine (101 g, 540 mmol) in methanol (424 mL) N,N-diisopropylethylamine (94.3 mL, 540 mmol) was added. The mixture was heated at 60°C for 24 h. Methanol was removed by distillation under reduced pressure below 40°C. To the mixture was added 318 ml of tetrahydrofuran. The above solvent exchange process was repeated twice. To the mixture were added 424 mL of tetrahydrofuran, 212 mL of saturated aqueous ammonium chloride, and 21.2 mL of water. The organic layer was washed with 212 ml (1.00 vol.) of saturated aqueous ammonium chloride. This tetrahydrofuran solution was used in the next step without further purification (91% weight assay yield). -PYRIMIDIN-5- IL)BUTANOIC

[0278] To a solution of (R)-tert-butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl) pyrimidin-4-yl)piperazine-1-carboxylate (219 g , 0.447 mol) in tetrahydrofuran (657 ml) was added, a solution of lithium hydroxide monohydrate (56.2 g, 1.34 mol) in 329 ml of water at 25°C was added. The mixture was stirred at 25°C for 5 h. The lower aqueous layer was discarded. The mixture was acidified with 1N hydrochloric acid at 5°C to give a final pH value of between about 1 to 2. The layers were separated. The upper layer was then extracted with isopropyl acetate (440 ml x 3), combined with the lower layer, and washed with water (220 ml x 2). The solvent was removed by distillation under reduced pressure below 50°C. The residual isopropyl acetate was subjected to azeotropic distillation with heptane under reduced pressure below 50°C. Product gradually precipitated and was filtered to give an off-white to light yellow powder (196 g, 84% yield). (R)-TERT-BUTYL-4-(6-IODO-5-(4-(METHOXY(METHYL)AMINO)-4-OXOBUTAN-2-YL)PYRIMIDIN- 4-YL)PIPERAZINE-1 -CARBOXYLATE

[0279] To a solution of (R)-3-(4-(4-(tert-butoxycarbonyl) piperazin-1-yl)-6-iodo-pyrimidin-5-yl)butanoic acid (100 g, 210 mmol) in tetrahydrofuran (700 mL) 1,1'-carbonyldiimidazole (40.9 g, 252 mmol) was added in portions. The reaction mixture was stirred at 20°C for 1 h and cooled to 5°C. N,O-dimethylhydroxyamine hydrochloride (41.0 g, 420 mmol) was added in portions, followed by N-methylmorpholine (6.94 mL, 63.0 mmol). The mixture was stirred at 5°C for about 1 h, slowly warmed to room temperature, and stirred for 24 h. Saturated aqueous ammonium chloride (500 mL) and water (150 mL) were added to obtain clear phase separation. The organic layer was washed with saturated aqueous ammonium chloride (500 mL) and brine (200 mL). The wastewater was subjected to azeotropic distillation to less than 500 ppm by co-evaporation with tetrahydrofuran. The product, as a solution in tetrahydrofuran, was used for the next step without further purification or isolation (assay weight yield: > 99%). (R)-TERT-BUTYL 4-(5-METHYL-7-OXO-6,7-DI-HYDRO-5H-CYCLOPENTA[D] PYRIMIDIN-4- IL)PIPERAZINE-1 -CARBOXYLATE

[0280] A solution of (R)-tert-butyl 4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1 -carboxylate (109 g, 210 mmol) in tetrahydrofuran (600 mL) was purged with nitrogen for 30 min. Isopropyl magnesium chloride solution (159 mL, 210 mmol, 1.32 M in tetrahydrofuran) was added dropwise at -15°C. The mixture was stirred at -10°C for 1 h and slowly transferred to a cold 20 wt% aqueous ammonium chloride solution (600 mL) with stirring, maintaining the internal temperature below 10°C. The organic layer was then washed with saturated aqueous ammonium chloride (500 mL). Tetrahydrofuran was removed by distillation under reduced pressure below 40°C. Methyl tert-butyl ether (350 mL) was slowly added while maintaining the internal temperature between 35°C and 40°C, followed by heptane (350 mL). The mixture was slowly cooled to 20°C and the product gradually precipitated during the process. The slurry was filtered and the cake was dried at 40°C under vacuum to give a gray solid (52.3 g, 75% yield in two steps). 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 3.92-3.83 (m, 2H), 3.73-3.49 (m, 7H), 2.96 (dd, J= 16.5, 7.2 Hz, 1H), 2.33 (dd, J = 16.5, 1.8 Hz, 1H), 1.50 (s, 9H), 1.32 (d, J = 6.9 Hz, 3H), HRMS calculated for C17H25N403 [M+H]+: 333.1921, found 333.1924. EXAMPLE 9 TERC-BUTYL-4-[(5R,7R)-7HYDROXY-5-METHYL- 6,7-DIHYDROCYCLOPENTA[D]PYRIMIDIN-4- IL]PIPERAZINE-1 –CARBOXYLATE

[0281] A weak yellow suspension of 3 g of tert-butyl-4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1- carboxylate in 21 ml of aqueous buffer (100 mM 2-(N-morpholino)ethanesulfonic acid, pH 5.8), 6 ml of 2-propanol and 3 mg of oxidized NADP cofactor [Roche] formed under vigorous stirring. The reaction solution was heated to 40°C and stirred for 5 min. and subsequently the reduction started with the addition of 30 mg KRED-X1--P1B06. The pH was adjusted to 5.6 to 5.8. During the course of the reaction at 40°C within 21.5 h reaching almost complete conversion (IPC: 0.6% of the educt area), the pH rose to 6.4. In the reaction, 30 ml of isopropyl acetate were added and stirred vigorously for 15 min. Phase separation occurred spontaneously. The separated aqueous phase was extracted twice with 50 ml of isopropyl acetate, total of 100 ml of isopropyl acetate. The combined organic phases were dried over MgSO4, filtered and evaporated under vacuum at 50°C to obtain 3.07 g (102%) of light red foam as a crude product of the title compound containing about 4% isopropyl acetate. GC-EI-MS: 334.2 (M+H)+; Chiral HPLC: 99.88% (R,R), 0.12% (R,S) [254 nm; Chiralpak IC-3; 150*4.6 mm, 3μm, flow 0.8 ml, 30°C, A: 60% n-heptane, B: 40% EtOH + 0.1 DEA, 0-15 min 100% B, 15 -17 min 100% B, 17.1 min 40% B]; Chemical purity by HPLC: 99.2% by area (contains 0.6% by area of educt). 1H NMR (600 MHz, CDCl3) δ ppm 1.17-1.22 (m, 3H) 1,451.51 (m, 9H) 2.02 (s, 1H), 2.12-2.24 (m, 2H) 3.43-3.83 (m, 9H) 3.85-4.08 (m, 1H) 5.12 (t, J = 7.2Hz, 1H) 8.53 (s, 1H) (contains ~4% isopropyl acetate) -1 -CARBOXYLATE

[0282] For examples 9.1-9.6, the procedure of Example 9 was repeated, but the cofactor ratio (NADP [Roche]) was varied as indicated in the table below and a different variant of ketoreductase was applied, i.e. KRED-X1 was applied. TABLE 4 EXAMPLE 11 TERC-BUTYL 4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDROCYCLOPENTA[D]PYRIMIDIN-4- ILl-PIPERAZINE-1 -CARBOXYLATE

[0283] A weak yellow suspension of 6 g of tert-butyl-4-[(5R)-5-methyl-7-oxo-5,6-hydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate in 18 ml of aqueous buffer (100 mM 2-(N-morpholino)ethanesulfonic acid, pH 5.8), 6 ml of 2-propanol and 6 mg of oxidized NADP cofactor [Roche] was formed under vigorous stirring. The reaction solution was heated to 40°C and stirred for 5 min. and, subsequently, the reduction started with the addition of 60 mg of KRED-X1-P1B06. The pH was adjusted from 5.5 to 5.8. During the course of the reaction at 40°C within 2 d achieving almost complete conversion (IPC: 1d 1.3% in educt area, 2d 1.2% in educt area), the pH rose to 6.0 . In the reaction, 30 ml of isopropyl acetate was added and stirred vigorously for 15 min. Phase separation occurred spontaneously. The separated aqueous phase was extracted twice with 50 ml of isopropyl acetate, total of 100 ml of isopropyl acetate. The combined organic phases were dried over MgSO4, filtered and evaporated under vacuum at 50°C to obtain 6.02 g (99.7%) of light red foam as a crude product of the title compound containing about 4% sodium acetate. isopropyl. GC-EI-MS: 334.2 (M+H)+; Chiral HPLC: 99.88% (R,R), 0.12% (R,S) [254 nm; Chirapakl IC-3; 150*4.6 mm, 3μm, flow 0.8 ml, 30°C, A: 60% n-heptane, B: 40% EtOH + 0.1 DEA, 0-15 min 100% B, 15-17 min 100% B, 17.1 min 40% B]; chemical purity by HPLC: 98.4% by area (contains 1.3% by area of educt), 1H NMR (600 MHz, CDCl3) δ ppm 1.2 (d, J=7.1 Hz 3 H) 1, 49 (s, 9 H) 2.14 - 2.23 (m, 2 H) 3.46 - 3.59 (m, 5 H) 3.64 (ddd, J=13.1, 6.9, 3 .3 Hz, 2 H) 3.78 (ddd J=13.1, 7.2, 3.3 Hz, 2H) 5.12 (t, J=7.2 Hz, 1 H) 8.53(s , 1 H) (contains ~4% isopropyl acetate). IL]PIPERAZINE-1 -CARBOXYLATE

[0284] A weak yellow suspension of 3 g of tert-butyl-4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1- carboxylate in 21 ml aqueous buffer (100 mM potassium dihydrogen phosphate pH 7.2; 2 mM magnesium chloride), 6 ml 2-propanol and 3 mg oxidized NADP cofactor [Roche] formed under vigorous stirring . The reaction solution was heated to 40°C and stirred for 5 min. and subsequently the reduction started with the addition of 30 mg KRED-X1-P1B06. The pH was adjusted from 7.5 to 7.2. During the course of the reaction at 40°C within 18.5 h reaching almost complete conversion (IPC: 0.8% in educt area) the pH decreased to 7.15. In the reaction, 30 ml of isopropyl acetate was added and stirred vigorously for 15 min. Phase separation occurred spontaneously. The separated aqueous phase was extracted twice with 50 ml of isopropyl acetate, total of 100 ml of isopropyl acetate. The combined organic phases were dried over MgSO4, filtered and evaporated under vacuum at 50°C to obtain 3.06 g (102%) of light red foam as a crude product of the title compound containing about 4% isopropyl acetate. GC-EI-MS: 334.2 (M+H)+; Chiral HPLC: 99.76% (R,R), 0.24% (R,S) [254 nm; Chirapakl IC-3; 150*4.6 mm, 3μm, flow 0.8 ml, 30°C, A: 60% n-heptane, B: 40% EtOH + 0.1 DEA, 0-15 min 100% B, 15-17 min 100% B, 17.1 min 40% B]; chemical purity by HPLC: 98.9% by area (contains 0.8% by area of educt), 1H NMR (600 MHz, CDCl3) δ ppm 1.16-1.22 (m, 3 H) 1.45- 1.53 (m, 9H) 2.12 - 2.25 (m, 2H) 3.42 - 3.86 (m, 9H) 4.13 (br. s., 1H) 5.12 ( t, J=7.2 Hz, 1H) 8.44 - 8.59 (m, 1 H) (contains ~4% isopropyl acetate). EXAMPLE 13.1-13.7 TERC-BUTYL 4-[(5R,7R)-7HYDROXY -5-METHYL-6,7-DIHYDROCYCLOPENTA[D]PYRIMIDIN-4- IL]PIPERAZINE-1 -CARBOXYLATE

[0285] 10 mg of tert-butyl-4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate dissolved in a mixture of 50 μl DMSO and 50 μl of 2-propanol were added to each well of a deep well plate containing 300 μl of MES buffer (100 mM, 2 mM MgCl2; pH 5.8) 1 mg of NADP and KRED- variants X1. After stirring for 1.5 h at room temperature, 0.5 ml of MeOH was added to each well and analyzed by HPLC. The results of the best variants are listed in the following table. TABLE 5 EXAMPLE 13A TERC-BUTYL 4-[(5R,7R)-7-HYDROXY-5-METHYL-6,7-DIHYDROCYCLOPENTA[D]PYRIMIDIN-4-YL]PIPERAZINE-1-CARBOXYLATE

[0286] A suspension of 50 g (150 mmol) of tert-butyl-4-[(5R)-5-methyl-7-oxo-5,6-hydrocyclopenta[d]-pyrimidin-4-yl]piperazine-1 -carboxylate in 100 ml aqueous buffer (100 mM potassium dihydrogen phosphate pH 7.2), 78 g of 2-propanol and 50 mg of NAD (75μmol) was formed under vigorous stirring. The reduction began with the addition of 500 mg KRED-X1.1-P1F01. The reaction mixture is sparged with nitrogen and heated at 40°C for 22 hours. After completion of the reaction, 174 g of isopropyl acetate are added, stirred, the phases are separated and the aqueous phase is removed. The aqueous phase was extracted again with 174 g of isopropyl acetate. The aqueous phase was removed and the organic phases were combined and concentrated at 35°C in vacuo to a final volume of 115 mL. At the same temperature 212 g of heptane is added within 1 hour, the suspension is aged for 1 hour and cooled to 10°C within 6 hours. The suspension is filtered and washed with 68g of heptane. After drying the filter cake for 4 hours at 50°C and 41.1 g (yield 82%, area purity 100%) white crystals are obtained. EXAMPLE 13B TERC-BUTYL 4-[(5R,7R) -7-HYDROXY-5-METHYL-6,7-DIHYDROCYCLOPENTA[D]PYRIMIDIN-4- IL]PIPERAZINE-1 -CARBOXYLATE

[0287] A suspension of 40 g (150 mmol) of tert-butyl-4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[d]-pyrimidin-4-yl]piperazine -1-carboxylate in 240 ml aqueous buffer (containing 3.3 g KH2PO4 and 8.4 g K2HPO4), 26 g glucose and 40 mg NAD was formed under vigorous stirring. Reduction heated to 35°C and started by adding 400 mg KRED-X1.1-P1F01 and 400 mg GDH-101. During the course of the reaction (26 hours) the pH was maintained at 7.0 using 58.8 mL of an aqueous KOH solution (10% (m/m)). After completion of the reaction 290 g of isopropyl acetate and 117 g of NaSCN are added, stirred, the phases separated and the aqueous phase removed. The organic phase is washed with 200 g of water and filtered using a Filtrox filter plate, the aqueous phase was washed with 175 g of isopropyl acetate. The combined organic phases are concentrated at 25°C in vacuum to a final volume of 100 mL. At 25°C 383 g of heptane are added and within 1 hour. The suspension is cooled to 0°C over 30 minutes and aged for 30 minutes, the suspension is filtered and washed with 91 g of heptane. After drying the filter cake for 16 hours at 50°C and 30.9 g (76% yield, 100% area purity) white crystals are obtained. EXAMPLE 14 TERC-BUTYL ((S)-2-(4-CHLOROPHENYL)-3-(4-((5R,7R)-7HYDROXY-5-METHYL-6,7-DI-DI-HYDROCYCLOPENTA[D]PYRIMIDIN- 4-IL)PIPERAZIN-1-IL)-3- OXOPROPYL)(ISOPROPYL)CARBAMATE

[0288] To a 500 mL three-neck reactor, equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer was charged tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6 ,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (16.7 g, 52.5 mmol) and 2-propanol (65 mL). The solution was heated to 55°C. Then, 20.8% (m/m) HCl in 2-propanol (24.6 g, 140 mmol) was added over 10 minutes at 55°C. The suspension was stirred until the reaction was complete. The reaction mixture was cooled to 10°C and 4-methylmorpholine (32.9 g, 325 mmol) was added. The mixture was stirred at 15°C for 30 min. (S)-3-((tert-Butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid sodium salt (19.1 g, 52.5 mmol) and 2-propanol (73 g) were added and the reaction mixture was cooled to 5°C. Propane phosphonic anhydride (T3P) (50 wt% (m/m) in toluene) (35 g, 57.3 mmol) was added at a rate maintaining the temperature at 5°C. After completion of the reaction, 20 g of water was added. The solution was concentrated by distillation at 45°C and 150 mbar, to a final volume of 100 mL. Toluene (260 g) was added. The solution was concentrated again by distillation at 45°C and 150 mbar, to a final volume of 300 mL. Water (150 g) was added and the suspension was stirred for 15 minutes. The phases were separated for 15 minutes and the aqueous phase was removed. Water (100 g) was added and the suspension was stirred for 15 minutes. The phases were separated for 15 minutes and the aqueous phase was removed. Water (100 g) was added again and the suspension was stirred for 15 minutes. The phases were separated for 15 minutes and the aqueous phase was removed. The solution was concentrated by distillation at 45°C and 150 mbar, to a final volume of 100 mL. n-Heptane (34 g) was added, the solution was cooled to 0°C within 1 hour to allow crystallization of tert-butyl ((S)-2-(4-chlorophenyl)-3-(4-(( 5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate. More n-heptane (170 g) was added. The suspension was left to stand for 2 hours, filtered and washed with a mixture of toluene (6.4 g) and n-heptane (29.2 g), followed twice by heptane (68.4 g each). The filter cake was dried at <55°C to generate tert-butyl((S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6 ,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl)carbamate as an off-white solid, isolated 23.9 g, 86% yield . (1H NMR (600 MHz, CDCl3) δ ppm 0.68 (br, s,, 3 H) 0.94 - 1.08 (m, 3 H) 1.14 (d, J=7.0 Hz, 3 H) 1.47 (s, 10 H) 2.06 - 2.27 (m, 2 H) 3.30 (br, s,, 1 H) 3.38 - 3.53 (m, 5 H) 3 .56 -3.73 (m, 4 H) 3.78 (br, s,, 3 H) 4.62 (br, s,, 1 H) 5.10 (t, J=7.1 Hz, 1 H) 7.24 (s, 1 H) 8.49 (s, 1H) EXAMPLE 15 (S)-2-(4-CHLOROPHENYL)-1 -(4-((5R,7R)-7-HYDROXY- 5-METHYL-6,7-DI-HYDRO-5H- CYCLOPENTA[D]PYRIMIDIN-4-IL)PIPERAZIN-1-IL)-3-(ISOPROPYLAMINO)PROPAN-L-ONE MONOCHLORHYDRATE

[0289] To a 500 mL reactor, equipped with a mechanical stirrer, a nitrogen inlet, a thermometer and a pH meter, tert-butyl ((S)-2-(4-chlorophenyl)-3-(4 -((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl) carbamate (50 g) and 2-propanol (128 g). The solution was heated to 50°C. A solution of HCl in 2-propanol (21% by weight (m/m), 46.7 g) was added at 50°C. The solution was maintained at 50°C until completion of the reaction and the mixture was cooled to 25°C. Ammonia solution in 2-propanol (2 M, 66.6 g, 1.66 eq) was added within approx. 1 hour until pH 6.7 is reached. The suspension was cooled to 0°C and filtered. The cake was washed with 2-propanol (39 g). The filtrate was concentrated by distillation at 50°C and 150 mbar, to a final volume of 100 mL. Ethyl acetate (130 g) was added to the solution. The paste was solvent exchanged at 40°C, at constant volume (300 ml) using ethyl acetate (670 g). The suspension was cooled to 5°C and the slurry filtered. The filter cake was washed with EtOAc (105 mL) and dried under vacuum at 100°C for 16 hours to provide (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7 -hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one monohydrochloride as an off-white solid : (82% yield) 36.4 g. (1H NMR (600 MHz, D2O) δ ppm 0.92 (d, J=7.1 Hz, 3 H) 1.23 (t, J=6.4 Hz, 6H) 1.89 - 2.15 ( m, 2 H) 2.85 - 3.06 (m, 1 H) 3.17 - 3.59 (m, 10 H) 3.83 (d, J=10.5 Hz, 2 H) 4.33 (dd, J=8.5, 4.9 Hz, 1 H) 4.98 (t, J=7.0 Hz, 1 H) 7.23 (d, J=8.5 Hz, 2 H) 7 .36 (d, J=8.7 Hz, 2 H) 8.10 - 8.35 (m, 1 H), LCMS [M+H]+ 458.2). EXAMPLE 16 (S)-2-(4-CHLOROPHENYL)-1 -(4-((5R,7R)-7HYDROXY-5-METHYL-6,7-DI-HYDRO-5H- CYCLOPENTA[D]PYRIMIDIN-4- IL)PIPERAZIN-1-IL)-3-(ISOPROPYLAMINO)PROPAN-1-ONE MONOCHLORHYDRATE

[0290] To a 500 mL reactor, equipped with a mechanical stirrer, a nitrogen inlet, a thermometer and a pH meter, tert-butyl ((S)-2-(4-chlorophenyl)-3-(4 -((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl)(isopropyl) carbamate (50 g) and 1-propanol (131 g). The solution was heated to 60°C. HCl solution in 1-propanol (22% by weight (m/m), 38.0 g) was added at 60°C. The solution was maintained at 50°C until completion of the reaction and the mixture was cooled to 25°C. aq. NaOH (28%) (16 g) was added until a pH of 6 was reached. The suspension was concentrated at 60°C in vacuum until a final volume of 100 ml was reached. The suspension is cooled to 20°C, 90 g of ethyl acetate is added and filtered with a Filtrox plate. Reactor and filter unit are washed with 41 g of 1-propanol/ethyl acetate. The solution is filtered at 20°C through charcoal filter pads, the reactor and filter are washed with 82 g of 1-propanol/ethyl acetate. At 60°C, the solution is concentrated under vacuum to a final volume of 300 mL. Distillation is continued at 60°C and simultaneously 1.260 g of ethyl acetate are added keeping the volume constant.

[0291] The suspension was cooled to 5°C and the paste filtered. The filter cake was washed with EtOAc (105 mL) and dried under vacuum at 60°C for 16 hours to generate (S)-2-(4-chlorophenyl)-1-(4-((5R, 7R)-7 -hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one as an off-white solid: 36.5 g (yield 81%, purity 91.4% (m/m), assay 99.9% (area))

Claims (9)

1. PROCESS FOR MANUFACTURING COMPOUNDS, of formula (II): characterized by comprising the asymmetric hydrogenation of a compound of formula (IV): using a metal complex catalyst (C) in which, R1 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl; and M is a metal ion selected from the list of alkali metal ions, alkaline earth metal ions and transition metal ions, wherein the metal complex catalyst (C) is a ruthenium complex catalyst selected from from a compound of formula (C1), (C2) or (C3): where: D is a chiral phosphine ligand; L is a neutral ligand selected from C2-7 alkene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cycloctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol; Z is an anionic ligand selected from hydride, fluoride, chloride, bromide, n5-2,4-pentadienyl, n5-2,4-dimethyl-pentadienyl or the group A-COO-, provided that when two Z are attached to the atom of Ru, they can be the same or different; A is C1-7 alkyl, C1-7 haloalkyl, aryl or haloaryl; Y is a non-coordination anion selected from fluoride, chloride, bromide, BF4-, ClO4-, SbF6-, PF6-, B(phenyl)4-, B(3,5-di-trifluoromethyl-phenyl)4, CF3SO3- and C6H5SO3-; F is an optionally chiral diamine; E and E' are both halogen ions or E is hydride and E' is BH4-; m is 1, 2, 3 or 4; ep is 1 or 2. 2. PROCESS, according to claim 1, characterized in that R1 is tert-butoxycarbonyl (BOC). 3. PROCESS, according to any one of claims 1 to 2, characterized in that M is an alkali metal ion, or in which M is Na+. 4. PROCESS, according to any one of claims 1 to 3, characterized in that the anionic ligand (Z) is independently selected from chloride, bromide, iodide, OAc and TFA. 5. PROCESS, according to any one of claims 1 to 3, characterized in that the non-coordination anion (Y) is BF4-. 6. PROCESS according to any one of claims 1 to 3, characterized by the chiral diamine F being (1S,2S)-1,2-diphenylethylenediamine (S,S-DPEN). 7. PROCESS, according to any one of claims 1 to 3, characterized in that the chiral phosphine ligand D is selected from a compound of formula (D1) to (D12): wherein: R11 is C1-7 alkyl, C1-7 alkoxy, hydroxy or C1-7 alkyl-C(O)O-; R12 and R13 are each independently hydrogen, C1-7 alkyl, C1-7 alkoxy or di(C1-7 alkyl)amino; or R11 and R12 which are bonded to the same phenyl group, or R12 and R13 which are bonded to the same phenyl group taken together are -X-(CH2)rY-, where X is -O-, or -C(O) O-, Y is -O-, -N(lower alkyl)-, or -CF2- and er is an integer from 1 to 6; or two R11 taken together are -O-(CH2)sO- or O-CH(CH3)- (CH2)s-CH(CH3)-O-, where s is an integer from 1 to 6; or R11 and R12, or R12 and R13, together with the carbon atoms to which they are attached, form a naphthyl, tetrahydronaphthyl or dibenzofuran ring; R14 and R15 are each independently C1-7 alkyl, C3-8 cycloalkyl, phenyl, naphthyl or heteroaryl, optionally substituted with 1 to 7 substituents independently selected from the group consisting of C1-7 alkyl, C1-7 alkoxy, di(C1 -7 alkyl)amino, morpholinyl, phenyl, tri(C1-7 alkyl)silyl, C1-7 alkoxycarbonyl, hydroxycarbonyl, hydroxysulfonyl, (CH2)t-OH and (CH2)t-NH2, where t is an integer of 1 to 6; R16 is C1-7 alkyl; R17 is C1-7 alkyl; and R18 independently is aryl, heteroaryl, C3-8 cycloalkyl or C1-7 alkyl. 8. PROCESS, according to any one of claims 1 to 7, characterized in that the chiral phosphine ligand (D) is (S)-BINAP. 9. PROCESS according to any one of claims 1 to 3, characterized in that the ruthenium complex catalyst is selected from the group of. Ru(TFA)2((R)-3,5-Xyl-BINAP), Ru(OAc)2((S)-2-Furyl-MeOBIPHEP), Ru(OAc)2((S)-BINAP), [ Ru(OAc)2((S)-BINAP)]AlCl3, Ru(TFA)2((S)-BINAP), Ru(TFA)2((S)-BINAPHANE), Ru(TFA)2((S) -BIPHEMP), Ru(OAc)2((S)-MeOBIPHEP), Ru(TFA)2((S)-TMBTP), Ru(TFA)2((S,S)-iPr-DUPHOS), [Ru( (R)-BINAP)(pCym)(AN)](BF4)2, [RuBr((S)-BINAP)(C6H6)]Br, [RuCl((S)-BINAP)(C6H6)]BF4, [RuI ((S)-BINAP)(C6H6)]I, [Ru((S)-BINAP)(AN))4](BF4)2, and RuCl2((S)-pTol-BINAP)(S,S-DPEN ); or wherein the ruthenium complex catalyst is Ru(TFA)2((S)-BINAP).