Method for preparing pyrimidinylcyclopentane compounds

Abstract

The present invention relates to a method for preparing a compound of formula (I), wherein R 1 As defined herein, the compounds are useful as intermediates in the preparation of active pharmaceutical compounds.

Description

[0001] This application is a divisional application of a Chinese patent application with application number 201480072954.1, invention name “Method for preparing pyrimidinylcyclopentane compounds” and application date November 13, 2014 (PCT application number PCT / US2014 / 065567).

[0002] Related Applications

[0003] This application claims the benefit of European Patent Application No. 13193030.7 filed on November 15, 2013, the entire contents of which are incorporated herein by reference. Field of the Invention

[0004] The present invention relates to a method for preparing pyrimidinylcyclopentane compounds useful as intermediates for preparing AKT protein kinase inhibitors having therapeutic activity against diseases such as cancer. Background of the Invention

[0005] 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 U.S. Patent No. 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 explored in clinical trials for the treatment of various cancers.

[0006] Although the methods described in WO 2008 / 006040 and US 8,063,050 are useful for providing hydroxylated cyclopenta[d]pyrimidine compounds as AKT protein kinase inhibitors, there is a need for alternative or improved methods, including methods for large-scale production of these compounds. SUMMARY OF THE INVENTION

[0007] The present invention provides a method for preparing a compound of formula (I)

[0008]

[0009] or a salt thereof, which comprises a compound of formula (II)

[0010]

[0011] With the compound of formula (III)

[0012]

[0013] The coupling reaction, where R 1 , R 2 and M as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although methods and materials similar or equivalent to those described herein can be used to implement or test the present invention, suitable methods and materials are described below.

[0015] Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

[0016] Unless otherwise indicated, any open valencies appearing on carbon, oxygen, sulfur, or nitrogen atoms in the structures herein indicate the presence of hydrogen.

[0017] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substitution, ie, replacement of one hydrogen by a substituent up to replacement of all hydrogens by substituents.

[0018] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0019] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0020] 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 the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes 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, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

[0021] The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts obtained from pharmaceutically acceptable organic non-toxic bases include salts of the following: primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclamines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

[0022] The stereochemical definitions and conventions used herein generally follow those in SP 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. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold, and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; Erratum 511). The prefixes D and L or (+) and (-) are used to specify the sign of the rotation of plane polarized light achieved by the compound, where (-) or L specifies that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0023] The term "stereoisomer" refers to compounds that have identical molecular connectivity and bonding multiplicity but differ with regard to the arrangement of its atoms in space.

[0024] The term "chiral center" refers to a carbon atom bonded to four non-identical substituents. The term "chiral" means non-superimposability with a mirror image, while the term "achiral" means that embodiments are superimposable with their mirror images. Chiral molecules are optically active, i.e., they are able to rotate the plane of plane-polarized light.

[0025] The compounds of the present invention may have one or more chiral centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g., such as racemates), optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Whenever a chiral center is present in a chemical structure, all stereoisomers associated with that chiral center are intended to be encompassed by the present invention.

[0026] The term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0027] The term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

[0028] The term "diastereomeric excess" (de) refers to the diastereomeric purity, ie (diastereomer A - diastereomer B) / (diastereomer A + diastereomer B) (in area %).

[0029] The term "enantiomeric excess" (ee) refers to the enantiomeric purity, ie (enantiomer A - enantiomer B) / (enantiomer A + enantiomer B) (in area %).

[0030] The terms "halo" and "halogen" are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.

[0031] The term "halide" denotes a halogen ion, in particular a fluoride, chloride, bromide or iodide ion.

[0032] The term "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon group having from 1 to 12 carbon atoms. In particular embodiments, the alkyl group has from 1 to 7 carbon atoms, and in more particular embodiments, has from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0033] The term "alkenyl" refers to a monovalent straight or branched hydrocarbon group having 2 to 7 carbon atoms and at least one double bond. In a particular embodiment, the alkenyl group has 2 to 4 carbon atoms and at least one double bond. Examples of alkenyl groups include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, and isobutenyl.

[0034] The term "alkynyl" refers to a monovalent straight or branched chain saturated hydrocarbon group having 2 to 7 carbon atoms, containing one, two or three triple bonds. In certain embodiments, the alkynyl group has 2 to 4 carbon atoms, containing one or two triple bonds. Examples of alkynyl groups include ethynyl, propynyl and n-butynyl.

[0035] The term "alkoxy" refers to a radical of the formula -O-R', wherein R' is an alkyl radical. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy and tert-butoxy.

[0036] The term "haloalkyl" means an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of haloalkyl groups include monofluoro, difluoro or trifluoromethyl, ethyl or propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term "perhaloalkyl" means an alkyl group in which all hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms.

[0037] The term "haloalkoxy" denotes an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by the same or different halogen atoms, in particular fluorine atoms. Examples of haloalkoxy groups include mono-, di- or trifluoromethoxy, ethoxy or propoxy, such as 3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, fluoromethoxy or trifluoromethoxy. The term "perhaloalkoxy" denotes an alkoxy group in which all hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms.

[0038] The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms. In a particular embodiment, a cycloalkyl group means a monovalent saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Particular cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutane, cyclopentane, cyclohexyl or cycloheptane. Examples of bicyclic cycloalkyl groups are bicyclo[2.2.1]heptane or bicyclo[2.2.2]octanyl.

[0039] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 9 ring atoms, including 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In a specific embodiment, heterocycloalkyl is a monovalent saturated monocyclic ring system having 4 to 7 ring atoms, including 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated 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 dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl or dihydropyranyl.

[0040] The term "aryl" means a monovalent aromatic carbocyclic monocyclic or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl. A specific aryl group is phenyl.

[0041] The term "heteroaryl" refers to a monovalent aromatic heterocyclic monocyclic or bicyclic ring system having 5 to 12 ring atoms, the ring atoms including 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, aza Base, diazepine yl, isoxazolyl, benzofuranyl, isothiazolyl, benzothiophenyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl or quinoxalinyl.

[0042] "Leaving group" refers to the part of the 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, sulfhydryl, amino (e.g., -NRR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclic radical, and R is independently optionally substituted), silyl (e.g., -SiRRR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclic radical, and R is independently optionally substituted), -N(R)OR (wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclic radical, and R is independently optionally substituted), alkoxy (e.g., -OR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclic radical, and R is independently optionally substituted), thiol group (e.g., -SR, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl The invention also includes alkyl, alkyl or heterocyclyl, and R is independently optionally substituted), sulfonyloxy (e.g., -OS(O)1-2R, wherein R is independently alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or heterocyclyl, and R is independently optionally substituted), aminosulfonate 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). Exemplary carbonate groups include tert-butyl carbonate. Exemplary sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (e.g., methylsulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (trifluoromethanesulfonate group)) and arylsulfonyloxy groups (e.g., p-toluenesulfonyloxy (toluenesulfonate group) and p-nitrosulfonyloxy (p-nitrobenzenesulfonate group)). Other examples of leaving groups include substituted and unsubstituted amino groups such as amino, alkylamino, dialkylamino, hydroxyamino, alkoxyamino, N-alkyl-N-alkoxyamino, acylamino, sulfonylamino, tert-butoxy, and the like.

[0043] The term "protecting group" refers to a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site, under the meaning conventionally associated with it in synthetic chemistry. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxyl protecting groups.

[0044] The term "amino protecting group" means a group intended to protect an amino group, and includes benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), Fmoc (9-fluorenylmethyloxycarbonyl), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl. Other examples of these groups are found in TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 2nd edition, John Wiley & Sons, Inc., New York, NY, 1991, Chapter 7; E. Haslam, "Protective Groups in Organic Chemistry", JGW McOmie, ed., Plenum Press, New York, NY, 1973, Chapter 5; and TW Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with an amino protecting group. A specific example of an amino protecting group is tert-butoxycarbonyl (BOC).

[0045] The term "deprotection" or "deprotecting" refers to the process used to remove the protecting groups after the selective reaction is complete. Deprotecting agents include acids, bases or hydrogen, particularly potassium carbonate or sodium carbonate, lithium hydroxide in alcohol solution, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalysts or boron tribromide. A specific deprotecting agent is hydrochloric acid.

[0046] The term "buffer" refers to an excipient that stabilizes the pH of the formulation. Suitable buffers are well known in the art and can be found in the literature. Specific pharmaceutically acceptable buffers include histidine buffers, arginine buffers, citrate buffers, succinate buffers, acetate buffers, and phosphate buffers. Independent of the buffer used, the pH can be adjusted with acids or bases known in the art, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid and citric acid, sodium hydroxide and potassium hydroxide.

[0047] The term "alkali metal" refers to chemical elements of Group 1 of the periodic table, namely lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs) and francium (Fr). Specific examples of alkali metals are Li, Na and K, most particularly Na.

[0048] The term "alkaline earth metals" refers to chemical elements of Group 2 of the periodic table, namely beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra). Specific examples of alkaline earth metals are Mg and Ca.

[0049] The term "transition metal" refers to chemical elements whose atoms have an incomplete d sub-shell.

[0050] abbreviation

[0051] Ac Acetyl

[0052] AcOH Acetic acid

[0053] AN Acetonitrile

[0054] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

[0055] BINAPHANE 1,2-Bis[4,5-dihydro-3H-binaphtho(1,2-c:2',1'-e)phosphaheptaphena]benzene

[0056] BIPHEMP (6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenylphosphine)

[0057] BOC tert-Butyloxycarbonyl

[0058] (Boc) 2 O Di-tert-butyl dicarbonate

[0059] CBS Corey Bakshi Shibata

[0060] (Corey-Bakshi-Shibata) Catalyst

[0061] CBZ benzyloxycarbonyl, benzyloxycarbonyl

[0062] COD 1,5-cyclooctadiene

[0063] CPME Cyclopentyl Methyl Ether

[0064] de Diastereomeric excess

[0065] DIPEA Diisopropylethylamine

[0066] DMAP dimethylaminopyridine

[0067] DMF N,N-Dimethylformamide

[0068] DPEN 1,2-Diphenylethylenediamine

[0069] ee enantiomeric excess

[0070] Et Ethyl

[0071] EtOAc Ethyl acetate

[0072] Fmoc 9-fluorenylmethyloxycarbonyl

[0073] (2-Furyl)-MeOBIPHEP (6,6'-dimethoxybiphenyl-2,2'-diyl)bis[bis(2-furyl)-phosphine]

[0074] HAP Hazardous Air Pollutants

[0075] HBTU N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate

[0076] iBu Isobutyl

[0077] ICM International Coordination Meeting

[0078] IPC Process Control

[0079] iPr Isopropyl

[0080] iPr-DUPHOS 1,2-Bis(2,5-di-isopropylphospholyl)benzene

[0081] Me Methyl

[0082] MeOBIPHEP (6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine)

[0083] MES 2-(N-morpholino)ethanesulfonic acid

[0084] MTBE Methyl tert-butyl ether

[0085] NAD Nicotinamide adenine dinucleotide

[0086] NADP Nicotinamide adenine dinucleotide phosphate

[0087] nBu n-butyl

[0088] NEM N-ethylmorpholine

[0089] nPr n-propyl

[0090] OAc Acetate

[0091] PBS Potassium dihydrogen phosphate buffer

[0092] pCym p-cymene

[0093] PDE Permitted Daily Exposure

[0094] Ph Phenyl

[0095] pTol p-Tolyl

[0096] pTol-Binap 2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl

[0097] S / C substrate to catalyst molar ratio

[0098] T3P Propylphosphonic anhydride

[0099] tBu tert-butyl

[0100] t-BuOK Potassium tert-butoxide

[0101] TEA Triethylamine

[0102] TFA trifluoroacetate

[0103] THF Tetrahydrofuran

[0104] TMBTP 2,2',5,5'-Tetramethyl-4,4'-bis(diphenylphosphino)-3,3'-bithiophene

[0105] TPA tri(n-propyl)amine

[0106] Xyl 3,5-dimethylphenyl

[0107] 3,5-Xyl,4-MeO-MeOBIPHEP (6,6'-dimethoxybiphenyl-2,2'-diyl)bis[bis(3,5-dimethyl-4-methoxyphenyl)phosphine]

[0108] 3,5-Xyl-BINAP 2,2'-Bis[di(3,5-xylyl)phosphine]-1,1'-binaphthyl

[0109] 3,5-Xyl-MeOBIPHEP (6,6'-dimethoxybiphenyl-2,2'-diyl)bis[bis(3,5-dimethylphenyl)phosphine]

[0110] The present invention provides a method for preparing a compound of formula (I) or a salt thereof, which comprises a coupling reaction of a compound of formula (II) with a compound of formula (III), wherein R 1 , R 2 and M are as described herein (Scheme 1 below).

[0111] Another aspect of the present invention relates to a process for making a compound of formula (II), which comprises asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C) (Scheme 1 below).

[0112] One aspect of the present invention relates to a process for making a compound of formula (III) comprising an asymmetric reduction of a compound of formula (V) catalyzed by an oxidoreductase (Scheme 1 below).

[0113] Another aspect of the present invention relates to a process for making a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is deprotected (Scheme 1 below).

[0114] Process 1

[0115]

[0116] In one embodiment of the present invention, R 1 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl.

[0117] In a particular embodiment of the invention, R 1 It is tert-butoxycarbonyl (BOC).

[0118] In one embodiment of the present invention, R 2 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl.

[0119] In a particular embodiment of the invention, R 2 It is tert-butoxycarbonyl (BOC).

[0120] In one embodiment of the present invention, M is a metal ion selected from the list of alkali metal ions, alkaline earth metal ions and transition metal ions.

[0121] In a particular embodiment of the invention, M is a metal ion, in particular an alkali metal ion, an alkaline earth metal ion or a transition metal ion, with the proviso that it is not K + .

[0122] In a particular embodiment of the invention, M is an alkali metal ion.

[0123] In a particular embodiment of the invention, M is Li + , K + Or Na + .

[0124] In a particular embodiment of the invention, M is not K +.

[0125] In a most specific embodiment of the invention, M is Na + .

[0126] WO 2008 / 006040 discloses an amino acid of formula (II-pa) and a method for producing the same, wherein R 6 and R 9 There can be various substitutions, and t is 0 to 4.

[0127]

[0128] The methods disclosed therein for making compounds of formula (II-pa) involve a) diastereoselective reaction of alkylamines with 2-aryl acrylates to produce racemic mixtures or b) asymmetric addition of alkoxymethylamines to 2-phenylacetic acid esters containing appropriate chiral auxiliary agents. Both methods do not involve asymmetric hydrogenation, but involve addition reactions. Therefore, both methods require additional steps for adding, cleaving and separating auxiliary agents.

[0129] The synthesis according to the above method a) is carried out by forming a racemic ester intermediate, which is further hydrolyzed into a racemic acid, coupled with a chiral auxiliary (only in the form of, for example, the S enantiomer) to produce a 50:50 mixture of diastereoisomers R-amino acid / S-auxiliary and S-amino acid / S-auxiliary. The diastereoisomers must be separated by chromatography. The yield of the required SS intermediate is only 38%. In addition, the SS intermediate must be hydrolyzed to provide S-II acid (with the loss of another chiral component chiral auxiliary). This procedure is tedious and inefficient because 72% of the material is lost in one step. In short, the diastereoselective addition of amines and acrylates exhibits a lack of stereoselectivity, and therefore the inherent problem of racemic mixtures must be separated by, for example, chromatography. Therefore, compared to the stereoselectivity order, the yield is at least 100% lower.

[0130] In addition, the asymmetric addition to the intermediate containing the chiral auxiliary (method b) above) requires additional steps for adding, cleaving and separating the auxiliary. The precursors in the synthesis of the targeted acid are combined with the chiral auxiliary and the resulting intermediate is coupled with the alkoxymethylamine. The product, if not consisting of a 1:1 mixture, at best consists of a slightly enriched mixture of diastereomers R / S and S / S, which must be further processed as mentioned above to separate the (S)-isomer of the compound of formula (II-pa) in at best moderate yields.

[0131] Thus, there is an unmet need for improved processes for preparing compounds of formula (II) that provide better stereoselectivity, thereby avoiding subsequent chiral chromatography; require fewer reaction steps; provide higher yields; and are therefore more efficient, greener and less costly.

[0132] The inventors of the present invention have discovered a novel process for producing a compound of formula (II) which comprises asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C).

[0133] This novel process for the manufacture of compounds of formula (II) is characterized by a number of associated advantages over processes known in the art:

[0134] Introducing highly stereoselective reactions into synthesis;

[0135] Avoid the use of chiral chromatography for subsequent purification;

[0136] The number of reaction steps is reduced;

[0137] Improved overall yield;

[0138] The overall reaction is more efficient, greener and less costly.

[0139] The specific metal complex catalysts of the present invention have been found 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), substrate to catalyst molar ratios (S / C) of up to 10'000 can be employed, whereas other known catalysts need to be used at S / Cs of 200-250. Thus, using 40-50 times less catalyst has a substantial impact on efficiency, cost, and greenness.

[0140] Some known catalysts require large amounts of LiBF 4 As an additive (up to 5.8 mol% relative to the hydrogenation substrate, up to 100 molar equivalents relative to the catalyst) to increase catalyst activity. High amounts of LiBF 4 This is disadvantageous for industrial processes, since the presence of such a large amount of fluoride ions (up to 23.2% of the hydrogenation substrate) would cause problems with corrosion of steel pressure reactors when scaling up. 4 Even with the additives, the catalysts do not reach the activity of our new catalysts (eg up to S / C 10'000).

[0141] For example, the homogeneous catalytic reaction of asymmetric hydrogenation as known in the art requires extremely arduous treatment procedures, which include extraction and concentration of solutions for many cycles. In addition, asymmetric hydrogenation as known in the art requires removal of metal catalysts with a large amount of (up to 6% by weight relative to the hydrogenation substrate; up to 193 times of the catalyst weight) scavengers (e.g., mercaptan resins). Such removal of ruthenium pollutants using scavenger resins is not easy so far, and is very expensive. In addition, ruthenium inclusions are only partially reduced (e.g., to about 50ppm), and proceed to the next step, thus increasing the possibility of by-product formation. This increases material and labor costs, and launches a discussion about potential impurities.

[0142] In general, the known methods for purifying and separating hydrogenation products from catalysts and additives are relatively inefficient.

[0143] In contrast, the method according to the present invention provides a salt of a compound of formula (II) which is directly precipitated from the hydrogenation mixture and can be easily filtered off. Such separation and purification of the hydrogenation product provides a high yield (>94%), wherein the ee is 100%, and the ruthenium content is below the detection limit of 5 ppm. The treatment of the asymmetric hydrogenation reaction product as discovered by the inventors is therefore substantially simpler, cheaper and more applicable than conventional methods.

[0144] One aspect of the present invention relates to a compound of formula (II)

[0145]

[0146] Where R 1 and M are as defined herein.

[0147] 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.

[0148] One aspect of the present invention relates to a process for producing a compound of formula (II)

[0149]

[0150] It comprises using a metal complex catalyst (C) to react a compound of formula (IV)

[0151]

[0152] Asymmetric hydrogenation, where R 1 and M are as defined herein.

[0153] In one embodiment of the present invention, the metal complex catalyst (C) is a ruthenium complex catalyst.

[0154] In one embodiment of the present invention, the ruthenium complex catalyst comprises ruthenium characterized by an oxidation number of II.

[0155] In one embodiment of the present invention, the ruthenium complex catalyst comprises a chiral phosphine ligand (D).

[0156] In one embodiment of the present invention, the ruthenium complex catalyst comprises ligands, in particular neutral ligands (L) and / or anionic ligands (Z).

[0157] Examples of neutral ligands (L) are olefins such as ethylene or propylene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene and p-cymene, or also solvents such as tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol.

[0158] An example of anionic ligands (Z) is acetate (CH 3 COO-), trifluoroacetate (CF 3 COO-), η 5 -2,4-pentadienyl, η 5 -2,4-dimethyl-pentadienyl and a halogen ion such as fluoride, chloride, bromide or iodide.

[0159] If the ruthenium complex catalyst is charged, it also contains a non-coordinating anion (Y). Examples of non-coordinating anions (Y) are halides (such as fluoride, chloride, bromide or iodide), BF 4 -、ClO 4 -、SbF 6 -PF 6 -、B(phenyl) 4 -、B(3,5-bis-trifluoromethyl-phenyl) 4 -、CF 3 SO 3 - and C 6 H 5 SO 3 -.

[0160] The ruthenium complex catalyst may optionally be further coordinated to a Lewis acid such as AlCl 3 .

[0161] In one embodiment of the present invention, the ruthenium complex catalyst is selected from the compounds of formula (C1), (C2) or (C3):

[0162] Ru(Z) 2 D (C1)

[0163] [Ru(Z) 2-p(D)(L) m ](Y) p (C2)

[0164] Ru(E)(E')CD)(F) (C3)

[0165] in:

[0166] D is a chiral phosphine ligand;

[0167] L is a neutral ligand selected from the following: C 2-7 ene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene, and methanol;

[0168] Z is an anionic ligand selected from the group consisting of hydride, fluoride, chloride, bromide, 5 -2,4-pentadienyl, η 5 -2,4-dimethyl-pentadienyl or group A-COO - , provided that when two Z are attached to the Ru atom, they may be the same or different;

[0169] A is for C 1-7 Alkyl, C 1-7 haloalkyl, aryl or haloaryl;

[0170] Y is a non-coordinating anion selected from the group consisting of fluoride, chloride, bromide, BF 4 - , ClO 4 - , SbF 6 - PF 6 - 、B(phenyl) 4 - 、B(3,5-bis-trifluoromethyl-phenyl) 4 - CF 3 SO 3 - and C 6 H 5 SO 3 - ;

[0171] F is an optional chiral diamine;

[0172] E and E' are both halogen ions, or E is a hydride ion and E' is BH 4 - ;

[0173] m is 1, 2, 3, or 4:

[0174] p is 1 or 2.

[0175] In a particular embodiment of the present invention, the ruthenium complex catalyst is selected from compounds of formula (C1) or (C2), wherein Z, D, L, Y, m and p are as described herein.

[0176] In a particular embodiment of the present invention, the ruthenium complex catalyst is selected from compounds of formula (C1), wherein Z and D are as described herein.

[0177] In a particular embodiment of the present invention, the ruthenium complex catalyst is Ru(Z) 2 D, wherein Z and D are as described herein.

[0178] In a particular embodiment of the present invention, the ruthenium complex catalyst is selected from compounds of formula (C2), wherein Z, D, L, Y, m and p are as described herein.

[0179] In a particular embodiment of the present invention, the ruthenium complex catalyst is selected from compounds of formula (C3), wherein E, E', D and F are as described herein.

[0180] In a particular embodiment of the present invention, the anionic ligands (Z) are independently selected from chloride, bromide, iodide, OAc and TFA.

[0181] In a particular embodiment of the present invention, the anionic ligand (Z) is A-COO - .

[0182] In a particular embodiment of the invention, A is -CF 3 .

[0183] In a particular embodiment of the present invention, the anionic ligand (Z) is trifluoroacetate (TFA).

[0184] In a particular embodiment of the present invention, the neutral ligands (L) are independently selected from benzene (C 6 H 6 ), p-cymene (pCym) and acetonitrile (AN).

[0185] In a particular embodiment of the present invention, the neutral ligand (L) is benzene (C 6 H 6 ).

[0186] In a particular embodiment of the present invention, the non-coordinating anion (Y) is selected from the group consisting of chloride, bromide, iodide and BF 4 - .

[0187] In a particular embodiment of the invention, the non-coordinating anion (Y) is BF 4 - .

[0188] In a particular embodiment of the invention, m is 1 or 4.

[0189] In a particular embodiment of the invention, m is 1.

[0190] In a particular embodiment of the invention, m is 4.

[0191] In a particular embodiment of the invention, p is 1.

[0192] In a particular embodiment of the invention, p is 2.

[0193] In a particular embodiment of the present invention, E and E' are both chloride ions;

[0194] In a particular embodiment of the present invention, the chiral diamine F is (1S,2S)-1,2-diphenylethylenediamine (S,S-DPEN).

[0195] In a particular embodiment of the invention, the ruthenium complex catalyst is coordinated to a Lewis acid, in particular AlCl 3 .

[0196] In one embodiment of the present invention, the chiral phosphine ligand D is selected from the compounds of formula (D1) to (D12):

[0197]

[0198] in:

[0199] R 11 It is C 1-7 Alkyl, C 1-7 Alkoxy, benzyloxy, hydroxyl or C 1-7 Alkyl-C(O)O-;

[0200] R 12 and R 13 are independently hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy or di(C 1-7 alkyl)amino; or

[0201] R connected to the same phenyl group 11 and R 12 or R connected to the same phenyl group 12 and R 13 Together is -X-(CH 2 ) r-Y-, wherein X is -O- or -C(O)O-, and Y is -O-, -N(lower alkyl)- or -CF 2 -, and r is an integer from 1 to 6; or

[0202] Two R's 11 Together is -O-(CH 2 ) s -O- or O-CH(CH 3 )-(CH 2 ) s -CH(CH 3 )-O-, wherein s is an integer from 1 to 6; or

[0203] R 11 and R 12 or R 12 and R 13 Together with the carbon atoms to which they are attached, they form a naphthyl, tetrahydronaphthyl or dibenzofuran ring;

[0204] R 14 and R 15 Each is independently C 1-7 Alkyl, C 3-8 Cycloalkyl, phenyl, naphthyl or heteroaryl, optionally substituted with 1 to 7 substituents independently selected from the group consisting of: C 1-7 Alkyl, C 1-7 Alkoxy, di(C 1-7 alkyl)amino, morpholinyl, phenyl, tri(C 1-7 alkyl) silyl, C 1-7 Alkoxycarbonyl, hydroxycarbonyl, hydroxysulfonyl, (CH 2 ) t -OH and (CH 2 ) t -NH 2 , wherein t is an integer from 1 to 6;

[0205] R 16 It is C 1-7 alkyl;

[0206] R 17 It is C 1-7 Alkyl; and

[0207] R 18 are independently aryl, heteroaryl, C 3-8 Cycloalkyl or C 1-7 alkyl.

[0208] In a particular embodiment of the present invention, the chiral phosphine ligand (D) is selected from compounds of formula (D1), wherein R 11 To R 15 As described in this article.

[0209] In a particular embodiment of the present invention, the chiral phosphine ligand (D) is selected from (R)-3,5-Xyl-BINAP, (R)-BINAP, (S)-2-furanyl-MeOBIPHEP, (S)-BINAP, (S)-BINAPHANE, (S)-BIPHEMP, (S)-MeOBIPHEP, (S)-pTol-BINAP), (S)-TMBTP and (S,S)-iPr-DUPHOS.

[0210] In a particular embodiment of the present invention, the chiral phosphine ligand (D) is selected from (S)-BIPHEMP, (S)-BINAP and (S)-MeOBIPHEP.

[0211] In a particular embodiment of the present invention, the chiral phosphine ligand (D) is (S)-BINAP.

[0212] In a particular embodiment of the present invention, the chiral phosphine ligand (D) is (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0213] In a particular embodiment of the present invention, the chiral phosphine ligand (D) is

[0214]

[0215] In a particular embodiment of the present invention, the ruthenium complex catalyst is selected from the group consisting of:

[0216] Ru(TFA) 2 ((R)-3,5-Xyl-BINAP),

[0217] Ru(OAc) 2 ((S)-2-Furyl-MeOBIPHEP),

[0218] Ru(OAc) 2 ((S)-BINAP),

[0219] [Ru(OAc) 2 ((S)-BINAP)]AlCl 3 ,

[0220] Ru(TFA) 2 ((S)-BINAP),

[0221] Ru(TFA) 2 ((S)-BINAPHANE),

[0222] Ru(TFA) 2((S)-BIPHEMP),

[0223] Ru(OAc) 2 ((S)-MeOBIPHEP),

[0224] Ru(TFA) 2 ((S)-TMBTP),

[0225] Ru(TFA) 2 ((S,S)-iPr-DUPHOS),

[0226] [Ru((R)-BINAP)(pCym)(AN)](BF 4 ) 2 ,

[0227] [RuBr((S)-BINAP)(C 6 H 6 )]Br、

[0228] [RuCl((S)-BINAP)(C 6 H 6 )]BF 4 ,

[0229] [RuCl((S)-BINAP)(C 6 H 6 )]Cl,

[0230] [RuI((S)-BINAP)(C 6 H 6 )]I.

[0231] [Ru((S)-BINAP)(AN) 4 ](BF 4 ) 2 and

[0232] RuCl 2 ((S)-pTol-BINAP)(S,S-DPEN).

[0233] In a particular embodiment of the present invention, the ruthenium complex catalyst is selected from the group consisting of:

[0234] Ru(TFA) 2 ((R)-3,5-Xyl-BINAP),

[0235] Ru(OAc) 2 ((S)-2-Furyl-MeOBIPHEP),

[0236] Ru(OAc) 2((S)-BINAP),

[0237] [Ru(OAc) 2 ((S)-BINAP)]AlCl 3 ,

[0238] Ru(TFA) 2 ((S)-BINAP),

[0239] Ru(TFA) 2 ((S)-BINAPHANE),

[0240] Ru(TFA) 2 ((S)-BIPHEMP),

[0241] Ru(OAc) 2 ((S)-MeOBIPHEP),

[0242] Ru(TFA) 2 ((S)-TMBTP),

[0243] Ru(TFA) 2 ((S,S)-iPr-DUPHOS),

[0244] [Ru((R)-BINAP)(pCym)(AN)](BF 4 ) 2 ,

[0245] [RuBr((S)-BINAP)(C 6 H 6 )]Br、

[0246] [RuCl((S)-BINAP)(C 6 H 6 )]BF 4 ,

[0247] [RuI((S)-BINAP)(C 6 H 6 )]I.

[0248] [Ru((S)-BINAP)(AN) 4 ](BF 4 ) 2 and

[0249] RuCl 2 ((S)-pTol-BINAP)(S,S-DPEN).

[0250] In a particular embodiment of the present invention, the ruthenium complex catalyst is a compound of formula (C1) selected from the group consisting of:

[0251] Ru(TFA) 2 ((R)-3,5-Xyl-BINAP),

[0252] Ru(OAc) 2 ((S)-2-Furyl-MeOBIPHEP),

[0253] Ru(OAc) 2 ((S)-BINAP),

[0254] [Ru(OAc) 2 ((S)-BINAP)]AlCl 3 ,

[0255] Ru(TFA) 2 ((S)-BINAP),

[0256] Ru(TFA) 2 ((S)-BINAPHANE),

[0257] Ru(TFA) 2 ((S)-BIPHEMP),

[0258] Ru(OAc) 2 ((S)-MeOBIPHEP),

[0259] Ru(TFA) 2 ((S)-TMBTP) and

[0260] Ru(TFA) 2 ((S,S)-iPr-DUPHOS).

[0261] In a particular embodiment of the present invention, the ruthenium complex catalyst is a compound of formula (C2) selected from the group consisting of:

[0262] [Ru((R)-BINAP)(pCym)(AN)](BF 4 ) 2 ,

[0263] [RuBr((S)-BINAP)(C 6 H 6 )]Br、

[0264] [RuCl((S)-BINAP)(C 6 H 6 )]BF 4 ,

[0265] [RuCl((S)-BINAP)(C 6H 6 )]Cl,

[0266] [RuI((S)-BINAP)(C 6 H 6 )]I and

[0267] [Ru((S)-BINAP)(AN) 4 ](BF 4 ) 2 .

[0268] In a particular embodiment of the present invention, the ruthenium complex catalyst is a compound of formula (C3), in particular RuCl 2 ((S)-pTol-BINAP)(S,S-DPEN)).

[0269] In a particular embodiment of the present invention, the ruthenium complex catalyst is Ru(TFA)2((S)-BINAP).

[0270] In a particular embodiment of the present invention, the ruthenium complex catalyst is [RuCl(S-BINAP)(C 6 H 6 )]Cl.

[0271] In a particular embodiment of the present invention, the ruthenium complex catalyst is not [RuCl(S-BINAP)(C 6 H 6 )]Cl.

[0272] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out in a solvent selected from alcohols, hydrocarbons, chlorinated hydrocarbons, fluorinated and polyfluorinated aliphatic or aromatic hydrocarbons, supercritical or liquid carbon dioxide, THF, water or mixtures thereof.

[0273] Particular solvents for asymmetric hydrogenations are alcohols, chlorinated hydrocarbons and THF.

[0274] The specific solvent for the asymmetric hydrogenation is selected from MeOH, EtOH, i-PrOH, EtOH / cyclopentyl methyl ether, EtOH / CH 2 Cl 2 , EtOH / EtOAc, EtOH / THF, EtOH / H 2 O、CH 2 Cl 2 and a list of THF.

[0275] The most specific solvent for asymmetric hydrogenation is ethanol (EtOH).

[0276] The solvent may be used alone or as a mixture of the above-mentioned solvents.

[0277] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out at a concentration of 1 to 50% by weight, in particular 5%, 10%, 20% or 30% by weight of the compound of formula (IV).

[0278] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of the formula (IV) is carried out at a concentration of the compound of the formula (IV) of 10 to 25% by weight.

[0279] It has been surprisingly found that in special cases, the addition of certain additives improves the asymmetric hydrogenation of compounds of formula (IV). It is assumed that the activity and stability of the ruthenium catalyst are substantially improved, and therefore the amount of catalyst required is reduced. The use of lower amounts of catalyst leads to simplified handling and reduced costs.

[0280] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) further comprises one or more selected from LiBF 4 、LiPF 6 、LiO 3 SCF 3 , NaCl, NaBr, NaI, KCl, KBr, KI, LiCl, LiBr, LiI, HBF 4 , HCl, HBr, H 2 SO 4 and CH 3 SO 3 H is a list of additives.

[0281] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) does not include LiBF 4 、LiPF 6 or LiO 3 SCF 3 As additives. In view of the highly corrosive nature of the fluoride-containing additives, they are difficult to handle and are therefore not preferred.

[0282] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) further comprises one or more additives selected from the list of NaCl, NaBr, KCl, KBr, HCl and HBr.

[0283] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) further comprises one or more selected from LiBF 4 HBF 4 , HCl, H 2 SO 4 and CH 3 SO 3 H is a list of additives.

[0284] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) further comprises one or more selected from LiBF 4 , NaCl, NaBr, LiCl, LiBr, LiI, HBF 4 , HCl, HBr, H 2 SO 4 and CH 3 SO 3 H is a list of additives.

[0285] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out using hydrogen gas as hydrogen source.

[0286] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out at a hydrogen pressure of 1 to 150 bar, in particular 10 to 30 bar, most in particular 17 to 21 bar.

[0287] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out at a temperature of from 10 to 120°C, in particular from 20 to 90°C.

[0288] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out during a period of 5 to 30 hours, in particular 6 to 25 hours, more in particular 6 to 23 hours.

[0289] In a particular embodiment of the invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out at a substrate / catalyst ratio (S / C) of 5 to 100'000, in particular 100 to 15'000, most in particular 100 to 10'000.

[0290] In a particular embodiment of the present invention, the asymmetric hydrogenation of the compound of formula (IV) is carried out batchwise.

[0291] In a particular embodiment of the present invention, the asymmetric hydrogenation of compounds of formula (IV) is carried out in a continuous manner.

[0292] One aspect of the present invention relates to a process for producing a compound of formula (II)

[0293]

[0294] It comprises using a metal complex catalyst (C) to react a compound of formula (IV)

[0295]

[0296] Asymmetric hydrogenation is then carried out by adding to the hydrogenation reaction mixture a compound of formula C 1-7Alkyl-OM metal alkoxide alcohol solution to form a salt, wherein R 1 and M are as defined herein.

[0297] One aspect of the present invention relates to a process for preparing a compound of formula (II), which comprises asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C), followed by addition of a compound of formula (C) to the hydrogenation reaction mixture without prior isolation or purification of the acid intermediate. 1-7 Alkyl-OM metal alkoxide alcohol solution to form a salt, wherein R 1 and M are as defined herein.

[0298] In a particular embodiment of the present invention, the metal alkoxide employed in the salt formation step is MeOM, EtOM, iPrOM, nPrOM, nBuOM, iBuOM or tBuOM, most particularly EtOM.

[0299] In a particular embodiment of the present invention, the alcohol used as solvent in the salt formation step is C 1-7 Alkyl-OH, more particularly MeOH, EtOH, iPrOH, nPrOH, nBuOH, iBuOH or tBuOH, most particularly EtOH.

[0300] One aspect of the present invention relates to a process for making a compound of formula (II), which comprises asymmetric hydrogenation of a compound of formula (IV) using a metal complex catalyst (C), followed by salt formation by adding an ethanolic solution of sodium ethoxide to the hydrogenation reaction mixture.

[0301] Compounds of formula (IV) can be prepared according to methods known to those skilled in the art. One particular general method for preparing compounds of formula (IV) is depicted in Scheme 2. For a more detailed description of the individual reaction steps, see the Examples section below.

[0302] Process 2

[0303]

[0304] The compound of formula (IVa) (wherein R 3 is an optionally substituted C 1-7 Alkyl groups, especially ethyl groups) and compounds HCO 2 R 4 (where R 4 is an optionally substituted C1-7 alkyl group, especially an ethyl group) is condensed under basic conditions to form a compound of formula (IVb). The compound of formula (IVb) is reacted with an amine HN(isopropyl)R 5 (where R 5 It is hydrogen, C 1-7alkyl or amino protecting group) is further condensed to form a compound of formula (IVc). When R 5 When R is hydrogen, the amine may be additionally protected to form a protected compound of formula (IVc) (e.g., wherein R 5 is an amino protecting group such as Boc). Hydrolysis of the ester of compound (IVc) provides a compound of formula (IV).

[0305] The ruthenium complex catalysts according to the invention can in principle be prepared in a manner known per se. They can be isolated or used directly (prepared in situ) 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 MP Fleming et al., US 6,545,165 B1 and the references cited therein; and in particular for ferrocene-based Ru complexes O. Briel et al., Catalysis of Organic Reactions, CRC Press, Boca Raton, 2009, the disclosure contents of all these documents are incorporated herein by reference in their entirety for all purposes.

[0306] [Ru(TFA) 2 The synthesis of ((S)-BINAP)] is disclosed in B. Heiser et al., Tetrahedron: Asymmetry 1991, 2, 51.

[0307] The ruthenium complex catalysts can be prepared in situ, ie just before use and without isolation. The solution in which such catalysts are prepared can already contain the substrate for the enantioselective hydrogenation, or the solution can be mixed with the substrate just before initiating the hydrogenation reaction.

[0308] WO 2008 / 006040 discloses 5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol of formula (71) and a method for producing the same, wherein R 5 Various alternatives are possible.

[0309]

[0310] Specifically, WO 2008 / 006040 discloses the use of 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 an achiral reducing agent (e.g., H 2 , Pd / C), to asymmetric reduce 5-methyl-5,6-dihydrocyclopenta[d]pyrimidin-7-one to (R) or (S)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol.

[0311] The processes known in the art to produce compounds of formula (III) exhibit inherent disadvantages, namely they require harsh reaction conditions (e.g. high pressure), use heavy metals and chiral auxiliaries, and the diastereomeric selectivity obtained is only limited (i.e. 88% de), thus requiring additional purification steps.

[0312] The inventors of the present invention have found a method for producing a 2 Novel enzymatic methods for preparing compounds of formula (III) as described herein.

[0313]

[0314] The novel methods for making compounds of formula (III) according to the present invention are characterized in that they have many relevant benefits compared to methods as known in the art. The advantage of enzymatic reduction is its catalytic properties, which avoids the extremely high diastereoselectivity and mild reaction conditions of the diastereomers that are potentially required to be subsequently split. In addition, heavy metals and chiral auxiliary agents are not required.

[0315] The enzymatic reduction of the present invention simplifies the technical requirements, reduces the number and quantity of components, and enables a higher space-time yield. The advantages of the present invention are exemplified by technical related criteria improvements, such as increased substrate concentration (up to 25%), increased product concentration (up to 25%), reduced cofactor loading (down to 1 / 3000 of the compound of formula (V)), and a simpler cofactor regeneration system using 2-propanol as the final reductant. The cofactor regeneration system using 2-propanol as the final reductant avoids a second enzyme, reduces viscosity, avoids continuous neutralization of gluconic acid as an oxidation cosubstrate, and allows continuous removal of formed acetone.

[0316] One aspect of the present invention relates to a process for producing a compound of formula (III)

[0317]

[0318] It comprises the step of oxidoreductase-catalyzed reaction of a compound of formula (V)

[0319]

[0320] Asymmetric reduction, where R2 As defined herein.

[0321] In one aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is a ketoreductase.

[0322] In one aspect of the invention, the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereomeric selectivity of at least 95% diastereomeric excess (de), particularly with a diastereomeric selectivity of at least 98% de, more particularly with a diastereomeric selectivity of at least 99% de.

[0323] In one aspect of the invention, the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is catalyzed by an oxidoreductase in the presence of a cofactor.

[0324] In one aspect of the invention, the cofactor oxidized in the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is NADH or NADPH.

[0325] In one aspect of the invention, the cofactor oxidized in the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is regenerated in situ using enzyme-coupled cofactor regeneration (e.g. based on glucose and glucose dehydrogenase as the final reducing agent) or substrate-coupled regeneration (e.g. using a secondary alcohol as a co-substrate).

[0326] In one aspect of the invention, the cofactor oxidized in the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is regenerated in situ by enzyme coupled cofactor regeneration using glucose and glucose dehydrogenase as cosubstrates.

[0327] In one aspect of the invention, the oxidized cofactor in the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is regenerated in situ by substrate coupling regeneration using a secondary alcohol as a cosubstrate.

[0328] In one aspect of the present invention, the secondary alcohol used as a co-substrate for substrate coupling regeneration is selected from 2-propanol, 2-butanol, butane-1,4-diol, 2-pentanol, pentane-1,5-diol, 4-methyl-2-pentanol, 2-hexanol, hexane-1,5-diol, 2-heptanol or 2-octanol, in particular 2-propanol.

[0329] Particularly suitable is 2-propanol for regeneration of the cofactor and continuous removal of the acetone formed in the presence of the same enzyme which also catalyzes the target reaction.

[0330] In one aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase.

[0331] In one aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of:

[0332] KRED-NADPH-111 (from Codexis Inc., Redwood City, CA, USA),

[0333] KRED-NADPH-112 (from Codexis Inc., Redwood City, CA, USA),

[0334] KRED-NADPH-113 (from Codexis Inc., Redwood City, CA, USA),

[0335] KRED-NADPH-114 (from Codexis Inc., Redwood City, CA, USA),

[0336] KRED-NADPH-115 (from Codexis Inc., Redwood City, CA, USA),

[0337] KRED-NADPH-121 (from Codexis Inc., Redwood City, CA, USA),

[0338] KRED-NADPH-123 (from Codexis Inc., Redwood City, CA, USA),

[0339] KRED-NADPH-145 (from Codexis Inc., Redwood City, CA, USA),

[0340] KRED-NADPH-155 (from Codexis Inc., Redwood City, CA, USA),

[0341] A231 (from Almac Group Ltd. Craigavon, United Kingdom) and

[0342] KRED-NADPH-136 (from Enzysource, Hangzhou, China).

[0343] Other suitable oxidoreductases catalyzing the asymmetric reduction of compounds of formula (V) to compounds of formula (III) are diastereoselective NADPH-dependent oxidoreductases selected from the list of:

[0344] KRED-X1, an engineered ketoreductase from Lactobacillus kefir, as disclosed in PCT International Publication No. WO2010 / 025238A2 and identified as SEQ.ID.NO.34, and

[0345] KRED-X2, an engineered ketoreductase from Sporobolomyces salmonicolor, as disclosed in PCT International Publication No. WO2009 / 029554A2 and identified as SEQ.ID.NO.138.

[0346] Other suitable oxidoreductases catalyzing the asymmetric reduction of compounds of formula (V) to compounds of formula (III) are commercially available variants of KRED-X1 (from Codexis Inc., Redwood City, CA, USA).

[0347] Particularly suitable is the engineered ketoreductase "KRED-X1-P1B06", a KRED variant "P1B06" from the Codexis KRED specialty plate product "KRED-X1-SPECIALTY-PLT".

[0348] Other suitable oxidoreductases that catalyze the asymmetric reduction of compounds of formula (V) to compounds of formula (III) are commercially available variants of KRED-X1 (from Codexis Inc., Redwood City, CA, USA). Particularly suitable are the following engineered ketoreductases from the Codexis KRED specialty plate product "KRED-X1.1-B06-SPECIALTY-PLT":

[0349] "KRED-X1.1-P1F01" (KRED variant P1F01),

[0350] "KRED-X1.1-P1H10" (KRED variant P1H10),

[0351] "KRED-X1.1-P1G11" (KRED variant P1G11),

[0352] "KRED-X1.1-P1C04" (KRED variant P1C04),

[0353] "KRED-X1.1-P1C11" (KRED variant P1C11) and

[0354] "KRED-X1.1-P1C08" (KRED variant P1C08).

[0355] Particularly suitable are the engineered ketoreductases "KRED-X1.1-P1C04" and "KRED-X1.1-P1F01". The most specific ketoreductase is the engineered ketoreductase "KRED-X1.1-P1F01".

[0356] PCT International Publication Nos. WO 2010 / 025085 A2 and WO 2009 / 029554 A2 are hereby incorporated by reference in their entirety for all purposes, particularly with respect to making and using oxidoreductases.

[0357] All of the above mentioned enzymes may also use the cofactor NADH.

[0358] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the 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-12 3. 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.

[0359] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the 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-P1F01, KRED-X1.1-P1H10, KRED-X1.1-P1G11, KRED-X1.1-P1C04, KRED-X1.1-P1C11 and KRED-X1.1-P1C08.

[0360] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the 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.

[0361] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the 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.

[0362] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of: KRED-X1 and KRED-X2.

[0363] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of: KRED-X1 and KRED-X1-P1B06.

[0364] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is a diastereoselective NADPH-dependent oxidoreductase selected from the list of: KRED-X1.1-P1C04 and KRED-X1.1-P1F01.

[0365] In a particular aspect of the invention, the oxidoreductase catalyzing the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is the diastereoselective NADPH-dependent oxidoreductase KRED-X1.1-P1F01.

[0366] 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.

[0367] In one aspect of the invention, the asymmetric reduction of compounds of formula (V) to compounds of formula (III) is carried out in 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%.

[0368] In one aspect of the invention, the co-solvent present in the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is selected from the following list: glycerol, 2-propanol, diethyl ether, tert-butyl methyl ether, diisopropyl ether, dibutyl ether, methyltetrahydrofuran, ethyl acetate, butyl acetate, toluene, heptane, hexane, cyclohexene and mixtures thereof; in particular 2-propanol.

[0369] 2-Propanol is particularly useful as a co-solvent because it can serve as the final reducing agent for regeneration of the substrate-coupling cofactor.

[0370] In one aspect of the invention, the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is carried out at a reaction temperature between 1°C and 50°C, in particular between 20°C and 45°C.

[0371] Temperatures in the upper range increase the reaction rate and facilitate acetone removal.

[0372] In one aspect of the invention, the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is carried out at a pH between 5.5 and 8.5.

[0373] In one aspect of the invention, the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is carried out in an aqueous buffer solution. Suitable buffers are known to experts in the art. Specific buffers are 2-(N-morpholino)ethanesulfonic acid (MES) or potassium dihydrogen phosphate (PBS).

[0374] The optimal pH range, and therefore any suitable buffer, depends on the specific oxidoreductase employed.

[0375] One aspect of the present 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% by weight, in particular 10 to 20% by weight.

[0376] One aspect of the present invention relates to the asymmetric reduction of a compound of formula (V) to a compound of formula (III), wherein the reaction concentration (total concentration of ketone of formula (V) and chiral alcohol of formula (III) in the reaction mixture) is between 1 and 25 weight %, in particular between 10 and 20 weight %.

[0377] One aspect of the invention relates to a process for the manufacture of a compound of formula (III) comprising an asymmetric reduction of a compound of formula (V) catalyzed by an oxidoreductase, followed by work-up by extraction or by filtration.

[0378] One aspect of the present 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 conveniently worked up by extraction or by filtration.

[0379] The crude product may be further increased in purity by crystallization or used as such in a subsequent reaction sequence for the preparation of compounds of formula (I).

[0380] One aspect of the present invention relates to a process for the manufacture of a compound of formula (III) comprising an asymmetric reduction of a compound of formula (V) catalyzed by an oxidoreductase, followed by work-up by extraction or by filtration and further by crystallization.

[0381] One aspect of the present invention relates to the asymmetric reduction of a compound of formula (V) to a compound of formula (III), wherein the product is conventionally worked up by extraction or by filtration and further by crystallization.

[0382] One aspect of the present invention relates to a method for producing a compound of formula (IVc):

[0383]

[0384] or a salt thereof, wherein R 1 and R 3 As defined herein, the method comprises treating a compound of formula (IVd):

[0385]

[0386] or its salts with R 1 -X under conditions sufficient to produce a compound of Formula IVc or a salt thereof, wherein X is a leaving group.

[0387] In one embodiment, the method comprises producing ethyl (E)-3-(tert-butoxycarbonyl(isopropyl)-amino)-2-(4-chlorophenyl)acrylate or a salt thereof, wherein R 1 is a BOC protecting group, R 3 is ethyl, and wherein R 1 -X is (BOC) 2 O.

[0388] In a particular embodiment, the method comprises reacting a compound of formula IVd or a salt thereof with less than about 8 equivalents, particularly less than about 4 equivalents, and more particularly about 3 equivalents of (BOC) 2 O in a polar solvent mixture comprising DMF under conditions to produce the compound of Formula IVc or a salt thereof in a yield of greater than about 50%, specifically about 75% or greater than 75%.

[0389] In a more specific embodiment, the conditions include reacting a compound of Formula IVd or a salt thereof with about 3 equivalents (BOC) in a polar solvent mixture comprising DMF. 2O and a basic mixture comprising about 2 equivalents of each of tributylamine and dimethylaminopyridine (DMAP). In one embodiment, the method further comprises adding (BOC) 2 During the reaction, a portion of the liquid was removed from the reaction mixture under vacuum.

[0390] Compounds of formula (V) can be prepared according to methods known to those skilled in the art. One particular general method for preparing compounds of formula (V) is depicted in Scheme 3. For a more detailed description of the individual reaction steps, see the Examples section below.

[0391] Process 3

[0392]

[0393] Compounds of formula (Va) are reacted with an iodinating agent (e.g., an iodide salt such as NaI, and optionally with an acid) to produce diiodopyrimidines of formula (Vb), which can be further reacted with monoprotected piperazine to provide compounds of formula (Vc). 1-7 The compound of formula (Vc) is metallated with an alkyl magnesium halide such as iPrMgCl) to form a compound of formula (Vd), which is further cyclized to form a cyclopentanone of formula (V), wherein

[0394] R 2 As stated in this article,

[0395] G is Li or Mg,

[0396] R 6 is Cl or OH,

[0397] R 7 Yes -CN, -COOR a or-CONR a R b , where R a and R b are independently selected from hydrogen, -OH, C 1-7 Alkoxy, C 1-7 Alkyl, C 2-7 Alkenyl, C 2-7 Alkynyl, C 3-8 cycloalkyl, phenyl or 3 to 12 membered heterocycloalkyl; or R a and R b Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocycloalkyl group.

[0398] WO 2008 / 006040 discloses a process for producing a compound of formula (73), wherein the compound of formula (71) is acylated with a suitable amino acid after deprotection using an acid, wherein R and R5 Various alternatives are possible.

[0399]

[0400] The acylation reaction as described in the prior art exhibits the following disadvantages:

[0401] • The method using HBTU as coupling reagent is not suitable for large-scale commercial manufacturing processes. HBTU poses serious industrial hygiene problems, as cases of allergy and occupational allergic contact dermatitis are described in the literature (Hannu T. et al., Occup Med, 2006, 56(6), 430-433 and MA Aleer et al., Contact Dermatitis, 2010 62, 2 123).

[0402] The method using methylene chloride as a solvent is not suitable for large-scale commercial manufacturing processes because methylene chloride is classified as a hazardous air pollutant (HAP) in the U.S. In addition, due to the inherent toxicity of methylene chloride, it is rated as a Class 2 solvent with a strict permitted daily exposure (PDE) by the International Conference on Harmonization (ICH).

[0403] • Purification of products using chromatography is not an acceptable purification method for large-scale small molecule manufacturing due to its extremely high solvent consumption and low throughput.

[0404] In the case of commercial large-scale reaction processes involving more than one solvent in a mixture, the solvents need to achieve sufficiently different boiling points from each other to allow separation and recycling from each other using distillation. Processes involving four solvents in the same step (such as in the case of cyclopentyl methyl ether (CPME)) are not suitable for large-scale manufacturing because the mixture cannot be separated and recycled.

[0405] The processing of the product requires numerous (e.g. six) aqueous extractions, all of which are accompanied by concentrated inorganic salts, thereby generating large amounts of contaminated wastewater. Such process conditions result in an environmentally unfavorable production process.

[0406] The inventors of the present invention have discovered a novel and improved process for preparing a compound of formula (I) which comprises coupling a compound of formula (II) as a salt, particularly a sodium salt, to a compound of formula (III). It has been found that the use of a compound of formula (II) in the form of a salt, particularly a sodium salt, substantially facilitates and simplifies such a process compared to the use of a free amino acid.

[0407] The process according to the invention for the manufacture of the compound of formula (I) is characterized by a number of advantages relative to the processes described in the art, such as, inter alia:

[0408] The handling of compounds of formula (I) is considerably improved. Only three well-separable solvents (isopropanol, toluene and heptane) are employed.

[0409] Propylphosphonic anhydride (T3P) is a non-toxic coupling agent that is non-allergenic and non-sensitizing.

[0410] • The by-products of the reaction are water-soluble and can therefore be easily removed by, for example, triple aqueous extraction.

[0411] One aspect of the present invention provides a method for preparing a compound of formula (I)

[0412]

[0413] or a salt thereof, which comprises a compound of formula (II)

[0414]

[0415] With the compound of formula (III)

[0416]

[0417] The coupling reaction, where R 1 , R 2 and M are as defined herein.

[0418] One aspect of the present invention provides a method for preparing a compound of formula (I) or a salt thereof, which comprises a coupling reaction of a compound of formula (II) with a compound of formula (III), wherein R 1 , R 2 and M are as defined herein, comprising the following reaction steps:

[0419] a) deprotecting the compound of formula (III) in a solvent under acidic conditions;

[0420] b) adjusting to alkaline pH using a base;

[0421] c) adding a solution comprising the compound of formula (II) in a solvent;

[0422] d) adding a solution comprising a coupling agent in a solvent.

[0423] In one aspect of the invention, the deprotection in step a) is carried out using hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid.

[0424] In a particular aspect of the invention, the deprotection in step a) is carried out using hydrochloric acid.

[0425] In one aspect of the present invention, the solvent used for the deprotection in step a) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.

[0426] In a particular aspect of the present invention, the solvent used for the deprotection in step a) is selected from n-propanol or isopropanol.

[0427] In one aspect of the invention, the deprotection in step a) is carried out at a temperature of 50 to 100 °C, in particular at 80 °C.

[0428] In one aspect of the present invention, the deprotection in step a) is carried out during a reaction time of 0.1 to 24 hours, in particular during a reaction time of 1 to 2 hours.

[0429] In one aspect of the present 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.

[0430] In one aspect of the invention, the base in step b) is N-ethylmorpholine (NEM).

[0431] In one aspect of the invention, in step b), 4 to 8 equivalents of base are added relative to the compound of formula (III), in particular 6 to 7 equivalents of base, most particularly 6.5 equivalents of base.

[0432] In one aspect of the invention, the solvent used in step c) is the same as the solvent used in step a).

[0433] In one aspect of the present invention, the solvent used in step c) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.

[0434] In a particular aspect of the present invention, the solvent in step c) is selected from n-propanol or isopropanol.

[0435] In one aspect of the present invention, the coupling agent used in step d) is propylphosphonic anhydride (T3P).

[0436] In one aspect of the present 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, dichloromethane, dichloroethane, diethyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, dioxane, tetrahydropyran, pyridine, 2-propanone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate, isopropyl acetate and a mixture of the above.

[0437] In a particular aspect of the invention, the solvent used in step d) is selected from a mixture of n-propanol and toluene or isopropanol and toluene, most particularly a mixture of n-propanol and toluene.

[0438] In one aspect of the present invention, the coupling reaction in step d) is carried out at a temperature of -10 to 50 °C, in particular 0 to 25 °C.

[0439] In one aspect of the present invention, the coupling reaction in step d) is carried out during a reaction time of 0.1 to 24 hours, in particular during a reaction time of 1 to 4 hours.

[0440] One aspect of the present invention relates to the coupling reaction of a compound of formula (II) with a compound of formula (III), wherein after step d), the product is worked up by aqueous extraction.

[0441] In a particular aspect of the present invention, the treatment of the product after step d) comprises extraction with water for 1 to 6 times, in particular for 3 times.

[0442] One aspect of the present invention relates to a method for preparing a compound of formula (VI)

[0443]

[0444] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I)

[0445]

[0446] Deprotection, where R 1 As defined herein.

[0447] One aspect of the present invention relates to a process for preparing a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein a compound of formula (I) is deprotected, wherein R 1 As defined herein, the reaction comprises the following steps:

[0448] i) deprotecting the compound of formula (I) in a solvent under acidic conditions;

[0449] ii) adjusting the pH using a base in the solvent;

[0450] iii) optionally crystallizing the compound of formula (VI).

[0451] In one aspect of the invention, the deprotection in step i) is carried out using hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid.

[0452] In a particular aspect of the invention, the deprotection in step i) is carried out using hydrochloric acid.

[0453] In one aspect of the present invention, the solvent used for deprotection in step i) is selected from water, methanol, ethanol, n-propanol, isopropanol and tert-butanol or a mixture thereof.

[0454] In a particular aspect of the present invention, the solvent used for the deprotection in step i) is selected from n-propanol, isopropanol and a 1:1 mixture of n-propanol / water.

[0455] In one aspect of the invention, the deprotection in step i) is carried out at a temperature of 30 to 100 °C, in particular at 80 °C.

[0456] In one aspect of the present invention, the deprotection in step i) is carried out during a reaction time of 1 to 24 hours, in particular during a reaction time of 1 to 4 hours.

[0457] In one aspect of the invention, the base in step ii) is NaOH in a 1:1 mixture of n-propanol / water.

[0458] In one aspect of the invention, the base in step ii) is ammonia.

[0459] In one aspect of the invention, the solvent used in step ii) is the same as the solvent used in step i).

[0460] In one aspect of the present invention, the solvent used in step ii) is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol or a mixture thereof.

[0461] In a particular aspect of the present invention, the solvent in step ii) is selected from n-propanol, isopropanol and a 1:1 mixture of n-propanol / water.

[0462] In a particular aspect of the invention, the pH adjustment is carried out by dropwise addition of a solution of ammonia in isopropanol (2-4% by weight, in particular 3.8% by weight) or a solution of NaOH in a 1:1 mixture of n-propanol / water (5-10 M, in particular 7 M).

[0463] In a particular aspect of the invention, the final pH after adjustment in step ii) is above pH 6, in particular between pH 6 and 7.

[0464] In one aspect of the present invention, the crystallization in step iii) is carried out by switching the solvent to a crystallization solvent suitable for crystallizing the compound of formula (VI).

[0465] In a particular aspect of the present 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.

[0466] In a particular aspect of the invention, the crystallization solvent in step iii) is ethyl acetate.

[0467] One aspect of the invention relates to compounds obtainable by any of the methods as described herein.

[0468] One aspect of the present invention relates to a pharmaceutical composition comprising a compound obtainable by any of the methods as described herein.

[0469] One aspect of the present invention relates to a compound of formula (VI) as described herein, comprising between 1 ppb and 100 ppm of a compound of formula (I), wherein R 1 As defined herein.

[0470] One aspect of the present invention relates to a compound of formula (VI) as described herein, comprising between 1 ppb and 1 ppm of a compound of formula (I), wherein R 1 As defined herein.

[0471] One aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (VI) as described herein.

[0472] One aspect of the present invention relates to a compound of formula (I) as described herein, comprising between 1 ppb and 100 ppm of a compound of formula (II), wherein R 1 and M are as defined herein.

[0473] One aspect of the present invention relates to a compound of formula (I) as described herein, comprising between 1 ppb and 1 ppm of a compound of formula (II), wherein R 1 and M are as defined herein.

[0474] One aspect of the present invention relates to a compound of formula (I) as described herein, comprising between 1 ppb and 100 ppm of a compound of formula (III), wherein R 1 and R 2 As defined herein.

[0475] One aspect of the present invention relates to a compound of formula (I) as described herein, comprising between 1 ppb and 1 ppm of a compound of formula (III), wherein R 1 and R 2 As defined herein.

[0476] One aspect of the present invention relates to a compound of formula (I) as described herein, comprising between 1 ppb and 100 ppm of a compound of formula (II) and between 1 ppb and 100 ppm of a compound of formula (III), wherein R 1 , R 2 and M are as defined herein.

[0477] One aspect of the present invention relates to a compound of formula (I) as described herein, comprising between 1 ppb and 1 ppm of a compound of formula (II) and between 1 ppb and 1 ppm of a compound of formula (III), wherein R 1, R 2 and M are as defined herein.

[0478] The present invention also relates to the following:

[0479] 1. A method for preparing a compound of formula (I)

[0480]

[0481] or a salt thereof, which comprises a compound of formula (II)

[0482]

[0483] With the compound of formula (III)

[0484]

[0485] The coupling reaction

[0486] R 1 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl.

[0487] R 2 is an amino protecting group selected from the list of benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl.

[0488] M is a metal ion selected from the list of alkali metal ions, alkaline earth metal ions and transition metal ions.

[0489] 2. The method according to item 1, wherein R 1 It is tert-butoxycarbonyl (BOC).

[0490] 3. The method according to any one of items 1 or 2, wherein R 2 It is tert-butoxycarbonyl (BOC).

[0491] 4. A method according to any one of items 1 to 3, wherein M is an alkali metal ion.

[0492] 5. A method according to any one of items 1 to 4, wherein M is Na + .

[0493] 6. The method according to any one of items 1 to 5, comprising the following reaction steps:

[0494] a) deprotecting the compound of formula (III) in a solvent under acidic conditions;

[0495] b) adjusting to alkaline pH using a base;

[0496] c) adding a solution comprising the compound of formula (II) in a solvent;

[0497] d) adding a solution comprising a coupling agent in a solvent.

[0498] 7. The process according to any one of items 1 to 6, wherein the deprotection in step a) is carried out using hydrochloric acid.

[0499] 8. The process according to any one of items 1 to 7, wherein the solvent used for deprotection in step a) is selected from n-propanol or isopropanol.

[0500] 9. A process according to any one of items 1 to 8, wherein the base in step b) is selected from N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), diisopropylethylamine (DIPEA), pyridine and lutidine.

[0501] 10. The process according to any one of items 1 to 9, wherein the base in step b) is N-ethylmorpholine (NEM).

[0502] 11. The process according to any one of items 1 to 10, wherein the solvent in step c) is selected from n-propanol or isopropanol.

[0503] 12. The process according to any one of items 1 to 11, wherein the coupling agent used in step d) is propylphosphonic anhydride (T3P).

[0504] 13. The process according to any one of items 1 to 12, wherein the solvent used in step d) is a mixture of n-propanol and toluene.

[0505] 14. The process according to any one of items 1 to 13, wherein after step d), the product is worked up by aqueous extraction.

[0506] 15. A method according to any one of items 1 to 14, which also includes a method for producing a compound of formula (II)

[0507]

[0508] It comprises using a metal complex catalyst (C) to react a compound of formula (IV)

[0509]

[0510] Asymmetric hydrogenation, where R 1and M is as defined in any one of items 1 to 5.

[0511] 16. A method for producing a compound of formula (II)

[0512]

[0513] It comprises using a metal complex catalyst (C) to react a compound of formula (IV)

[0514]

[0515] Asymmetric hydrogenation, where R 1 and M is as defined in any one of items 1 to 5.

[0516] 17. The method according to item 15 or 16, wherein the metal complex catalyst (C) is a ruthenium complex catalyst selected from compounds of formula (C1), (C2) or (C3):

[0517] Ru(Z) 2 D (C1)

[0518] [Ru(Z) 2-p (D)(L) m ](Y) p (C2)

[0519] Ru(E)(E')(D)(F) (C3)

[0520] in:

[0521] D is a chiral phosphine ligand;

[0522] L is a neutral ligand selected from the following: C 2-7 Olefins, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol;

[0523] Z is an anionic ligand selected from the group consisting of hydride, fluoride, chloride, bromide, 5 -2,4-pentadienyl, η 5 -2,4-dimethyl-pentadienyl or group A-COO - , provided that when two Z are attached to the Ru atom, they may be the same or different;

[0524] A is for C 1-7 Alkyl, C 1-7 haloalkyl, aryl or haloaryl;

[0525] Y is a non-coordinating anion selected from the group consisting of fluoride, chloride, bromide, BF4 - , ClO 4 - , SbF 6 - PF 6 - 、B(phenyl) 4 - 、B(3,5-bis-trifluoromethyl-phenyl) 4 - CF 3 SO 3 - and C 6 H 5 SO 3 - ;

[0526] F is an optional chiral diamine;

[0527] E and E' are both halogen ions, or E is a hydride ion and E' is BH 4 - ;

[0528] m is 1, 2, 3, or 4; and

[0529] p is 1 or 2.

[0530] 18. A method according to any one of items 15 to 17, wherein the ruthenium complex catalyst is Ru(Z) 2 D, wherein Z and D are as defined in item 17.

[0531] 19. A method according to any one of items 15 to 18, wherein the anionic ligand (Z) is independently selected from chloride, bromide, iodide, OAc and TFA.

[0532] 20. The method according to any one of items 15 to 19, wherein the anionic ligand (Z) is trifluoroacetate (TFA).

[0533] 21. A method according to any one of items 15 to 17, wherein the neutral ligand (L) is independently selected from benzene (C 6 H 6 ), p-cymene (pCym) and acetonitrile (AN).

[0534] 22. The method according to any one of items 15 to 17, wherein the neutral ligand (L) is benzene (C 6 H 6 ).

[0535] 23. The method according to any one of items 15 to 17, wherein the non-coordinating anion (Y) is selected from chloride, bromide, iodide and BF 4 - .

[0536] 24. The method according to any one of items 15 to 17, wherein the non-coordinating anion (Y) is BF 4 - .

[0537] 25. A method according to any one of items 15 to 17, wherein m is 1 or 4.

[0538] 26. A method according to any one of items 15 to 17, wherein E and E' are both chloride ions.

[0539] 27. The method according to any one of items 15 to 17, wherein the chiral diamine F is (1S,2S)-1,2-diphenylethylenediamine (S,S-DPEN).

[0540] 28. The method according to any one of items 15 to 17, wherein the chiral phosphine ligand D is selected from compounds of formula (D1) to (D12):

[0541]

[0542] in:

[0543] R 11 It is C 1-7 Alkyl, C 1-7 Alkoxy, hydroxyl or C 1-7 Alkyl-C(O)O-;

[0544] R 12 and R 13 are independently hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy or di(C 1-7 alkyl)amino; or

[0545] R connected to the same phenyl group 11 and R 12 or R connected to the same phenyl group 12 and R 13 Together is -X-(CH 2 ) r -Y-, wherein X is -O- or -C(O)O-, and Y is -O-, -N(lower alkyl)- or -CF 2 -, and r is an integer from 1 to 6; or

[0546] Two R's 11 Together is -O-(CH 2 )s -O- or O-CH(CH 3 )-(CH 2 ) s -CH(CH 3 )-O-, wherein s is an integer from 1 to 6; or

[0547] R 11 and R 12 or R 12 and R 13 Together with the carbon atoms to which they are attached, they form a naphthyl, tetrahydronaphthyl or dibenzofuran ring;

[0548] R 14 and R 15 Each is independently C 1-7 Alkyl, C 3-8 Cycloalkyl, phenyl, naphthyl or heteroaryl, optionally substituted with 1 to 7 substituents independently selected from the group consisting of: C 1-7 Alkyl, C 1-7 Alkoxy, di(C 1-7 alkyl)amino, morpholinyl, phenyl, tri(C 1-7 alkyl) silyl, C 1-7 Alkoxycarbonyl, hydroxycarbonyl, hydroxysulfonyl, (CH 2 ) t -OH and (CH 2 ) t -NH 2 , wherein t is an integer from 1 to 6;

[0549] R 16 It is C 1-7 alkyl;

[0550] R 17 It is C 1-7 Alkyl; and

[0551] R 18 are independently aryl, heteroaryl, C 3-8 Cycloalkyl or C 1-7 alkyl.

[0552] 29. The method according to any one of items 15 to 17, wherein the chiral phosphine ligand (D) is selected from the compound of formula (D1), wherein R 11 To R 15 As described in item 28.

[0553] 30. A method according to any one of items 15 to 17 and 28 to 29, wherein the chiral phosphine ligand (D) is selected from (R)-3,5-Xyl-BINAP, (R)-BINAP, (S)-2-furanyl-MeOBIPHEP, (S)-BINAP, (S)-BIPHEMP, (S)-MeOBIPHEP, (S)-pTol-BINAP), (S)-TMBTP and (S,S)-iPr-DUPHOS.

[0554] 31. A process according to any one of items 15 to 17 and 28 to 30, wherein the chiral phosphine ligand (D) is selected from (S)-BIPHEMP, (S)-BINAP and (S)-MeOBIPHEP.

[0555] 32. The method according to any one of items 15 to 17 and 28 to 31, wherein the chiral phosphine ligand (D) is (S)-BINAP.

[0556] 33. The process according to any one of items 15 to 17, wherein the ruthenium complex catalyst is selected from the group consisting of:

[0557] Ru(TFA) 2 ((R)-3,5-Xyl-BINAP),

[0558] Ru(OAc) 2 ((S)-2-Furyl-MeOBIPHEP),

[0559] Ru(OAc) 2 ((S)-BINAP),

[0560] [Ru(OAc) 2 ((S)-BINAP)]AlCl 3 ,

[0561] Ru(TFA) 2 ((S)-BINAP),

[0562] Ru(TFA) 2 ((S)-BINAPHANE),

[0563] Ru(TFA) 2 ((S)-BIPHEMP),

[0564] Ru(OAc) 2 ((S)-MeOBIPHEP),

[0565] Ru(TFA) 2 ((S)-TMBTP),

[0566] Ru(TFA) 2 ((S,S)-iPr-DUPHOS),

[0567] [Ru((R)-BINAP)(pCym)(AN)](BF 4 ) 2 ,

[0568] [RuBr((S)-BINAP)(C 6 H 6 )]Br、

[0569] [RuCl((S)-BINAP)(C 6 H 6 )]BF 4 ,

[0570] [RuI((S)-BINAP)(C 6 H 6 )]I.

[0571] [Ru((S)-BINAP)(AN) 4 ](BF 4 ) 2 and

[0572] RuCl 2 ((S)-pTol-BINAP)(S,S-DPEN).

[0573] 34. A method according to any one of items 15 to 17, wherein the ruthenium complex catalyst is Ru(TFA) 2 ((S)-BINAP).

[0574] 35. A process according to any one of items 15 to 34, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out in a solvent selected from alcohols, hydrocarbons, chlorinated hydrocarbons, fluorinated and polyfluorinated aliphatic or aromatic hydrocarbons, supercritical or liquid carbon dioxide, THF, water or mixtures thereof.

[0575] 36. A process according to any one of items 15 to 35, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out in a solvent selected from the list below: MeOH, EtOH, i-PrOH, EtOH / cyclopentyl methyl ether, EtOH / CH 2 Cl 2 , EtOH / EtOAc, EtOH / THF, EtOH / H 2 O、CH 2 Cl 2 and THF.

[0576] 37. A process according to any one of items 15 to 36, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out in ethanol (EtOH).

[0577] 38. The method according to any one of items 15 to 37, wherein the asymmetric hydrogenation of the compound of formula (IV) further comprises one or more selected from LiBF 4 、LiPF 6 、LiO 3 SCF 3 , NaCl, NaBr, NaI, KCl, KBr, KI, LiCl, LiBr, LiI, HBF 4 , HCl, HBr, H 2 SO 4 and CH 3 SO 3 H is a list of additives.

[0578] 39. A process according to any one of items 15 to 38, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a hydrogen pressure of 1 to 150 bar.

[0579] 40. The process according to any one of items 15 to 39, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a hydrogen pressure of 10 to 30 bar.

[0580] 41. The process according to any one of items 15 to 40, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a substrate / catalyst ratio (S / C) of 5 to 100'000.

[0581] 42. The process according to any one of items 15 to 41, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a substrate / catalyst ratio (S / C) of 100 to 15'000.

[0582] 43. A process according to any one of items 15 to 42, followed by adding to the hydrogenation reaction mixture a compound of formula C 1-7 Alkyl-OM metal alkoxide alcohol solution to form a salt, wherein R 1 and M are as defined in items 1 to 4.

[0583] 44. A method according to any item 43, wherein the metal alkoxide employed in the salt forming step is MeOM, EtOM, iPrOM, nPrOM, nBuOM, iBuOM or tBuOM.

[0584] 45. A method according to any one of items 43 or 44, wherein the metal alkoxide employed in the salt forming step is EtOM.

[0585] 46. ​​A process according to any one of items 43 to 45, wherein the alcohol used as solvent in the salt formation step is C 1-7 Alkyl-OH, more particularly MeOH, EtOH, iPrOH, nPrOH, nBuOH, iBuOH or tBuOH.

[0586] 47. A process according to any one of items 43 to 46, wherein the alcohol used as solvent in the salt formation step is EtOH.

[0587] 48. A method according to any one of items 1 to 14, which also includes a method for producing a compound of formula (III)

[0588]

[0589] It comprises the step of oxidoreductase-catalyzed reaction of a compound of formula (V)

[0590]

[0591] Asymmetric reduction, where R 2 As defined in any of items 1 and 3.

[0592] 49. A method for producing a compound of formula (III)

[0593]

[0594] It comprises the step of oxidoreductase-catalyzed reaction of a compound of formula (V)

[0595]

[0596] Asymmetric reduction, where R 2 As defined in any of items 1 and 3.

[0597] 50. A method according to any one of items 48 or 49, wherein the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with diastereoselectivity of at least 95% diastereomeric excess (de).

[0598] 51. A method according to any one of items 48 to 50, wherein the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereoselectivity of at least 98% de.

[0599] 52. A method according to any one of items 48 to 51, wherein the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is catalyzed by an oxidoreductase in the presence of a cofactor.

[0600] 53. The method according to any item 52, wherein the cofactor oxidized in the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is NADH or NADPH.

[0601] 54. A method according to any one of items 52 to 53, wherein the cofactor is regenerated in situ by enzyme-coupled cofactor regeneration using glucose and glucose dehydrogenase as co-substrates.

[0602] 55. A method according to any one of items 52 to 53, wherein the cofactor is regenerated in situ by substrate-coupled cofactor regeneration using a secondary alcohol as a co-substrate.

[0603] 56. A method according to item 55, wherein the secondary alcohol used as a co-substrate for substrate coupling regeneration is selected from 2-propanol, 2-butanol, butane-1,4-diol, 2-pentanol, pentane-1,5-diol, 4-methyl-2-pentanol, 2-hexanol, hexane-1,5-diol, 2-heptanol or 2-octanol.

[0604] 57. A method according to any one of items 55 to 56, wherein the secondary alcohol used as a co-substrate for the substrate-coupled cofactor regeneration is 2-propanol.

[0605] 58. A method according to any one of items 48 to 57, wherein the oxidoreductase 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.

[0606] 59. A method according to any one of items 48 to 58, wherein the oxidoreductase is a diastereoselective NADPH-dependent oxidoreductase selected from the list of: 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.

[0607] 60. A method according to any one of items 48 to 59, wherein the oxidoreductase 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.

[0608] 61. A method according to any one of items 48 to 60, wherein the oxidoreductase is a diastereoselective NADPH-dependent oxidoreductase selected from the list of: KRED-X1.1-P1C04 and KRED-X1.1-P1F01.

[0609] 62. A process according to any one of items 48 to 61, wherein the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is carried out in an aqueous medium in the presence of one or more organic co-solvents.

[0610] 63. A method according to item 62, wherein the organic co-solvent is present in a total concentration of 1 to 50 V%.

[0611] 64. According to the method of item 62, the organic co-solvent is present in a total concentration of 5 to 30 V%.

[0612] 65. A method according to any one of items 48 to 64, wherein the organic co-solvent is selected from the following list: glycerol, 2-propanol, diethyl ether, tert-butyl methyl ether, diisopropyl ether, dibutyl ether, methyltetrahydrofuran, ethyl acetate, butyl acetate, toluene, heptane, hexane, cyclohexene and mixtures thereof.

[0613] 66. A process according to any one of items 48 to 65, wherein the organic co-solvent is 2-propanol.

[0614] 67. A method according to any one of items 48 to 61, wherein the asymmetric reduction of the compound of formula (V) to the compound of formula (III) is carried out in an aqueous buffer solution.

[0615] 68. A method according to any item 67, wherein the buffer is 2-(N-morpholino)ethanesulfonic acid (MES) or potassium dihydrogen phosphate (PBS).

[0616] 69. The process according to any one of items 50 to 68, which is subsequently worked up by extraction or by filtration.

[0617] 70. A method according to any one of items 1 to 14, further comprising preparing a compound of formula (VI)

[0618]

[0619] or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I)

[0620]

[0621] Deprotection, where R 1 As defined in any one of items 1 to 2.

[0622] 71. The method according to claim 70, comprising the following reaction steps:

[0623] i) deprotecting the compound of formula (I) in a solvent under acidic conditions;

[0624] ii) adjusting the pH using a base in the solvent;

[0625] iii) optionally crystallizing the compound of formula (VI).

[0626] 72. A process according to any one of items 70 or 71, wherein the deprotection in step i) is carried out using hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid.

[0627] 73. A process according to any one of items 70 to 72, wherein the deprotection in step i) is carried out using hydrochloric acid.

[0628] 74. A process according to any one of items 70 to 73, wherein the solvent used for deprotection in step i) is selected from n-propanol, isopropanol and a 1:1 mixture of n-propanol / water.

[0629] 75. A process according to any one of items 70 to 74, wherein the base in step ii) is NaOH or ammonia.

[0630] 76. A process according to any one of items 70 to 75, wherein the solvent in step ii) is selected from n-propanol, isopropanol and a 1:1 mixture of n-propanol / water.

[0631] 77. The process according to any one of items 70 to 76, wherein the crystallization in step iii) is carried out by switching the solvent to a crystallization solvent suitable for crystallizing the compound of formula (VI).

[0632] 78. A method according to item 77, wherein the crystallization solvent in step iii) is selected from toluene, heptane, tetrahydrofuran, 2-acetone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

[0633] 79. A method according to claim 77, wherein the crystallization solvent in step iii) is ethyl acetate.

[0634] 80. Various compounds obtainable by a process according to any one of items 1 to 79.

[0635] 81. Various pharmaceutical compositions comprising a compound obtainable by a method according to any one of items 1 to 79.

[0636] 82. A compound of formula (II)

[0637]

[0638] Where R 1 and M is as defined in any one of items 1 to 5.

[0639] 83. A compound of formula (II) according to item 82, which is sodium (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate.

[0640] 84. A compound of formula (VI) according to item 70, comprising between 1 ppb and 100 ppm of the compound of formula (I), wherein R 1 As defined in any of items 1 or 2.

[0641] 85. A compound of formula (VI) according to item 70, comprising between 1 ppb and 1 ppm of the compound of formula (I), wherein R 1 As defined in any of items 1 or 2.

[0642] 86. A pharmaceutical composition comprising a compound of formula (VI) according to any one of items 84 or 85.

[0643] 87. A compound of formula (I) according to item 1, comprising between 1 ppb and 100 ppm of the compound of formula (II), wherein R 1 and M is as defined in any one of items 1 to 5.

[0644] 88. A compound of formula (I) according to item 1, comprising between 1 ppb and 1 ppm of the compound of formula (II), wherein R 1 and M is as defined in any one of items 1 to 5.

[0645] 89. A compound of formula (I) according to item 1, comprising between 1 ppb and 100 ppm of the compound of formula (III), wherein R 1 and R 2 As defined in any one of items 1 to 3.

[0646] 90. A compound of formula (I) according to item 1, comprising between 1 ppb and 1 ppm of the compound of formula (III), wherein R 1 and R 2 As defined in any one of items 1 to 3.

[0647] 91. A compound of formula (I) according to item 1, 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), wherein R 1 , R 2 and M is as defined in any one of items 1 to 5.

[0648] 92. A compound of formula (I) according to item 1, 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), wherein R 1 , R 2 and M is as defined in any one of items 1 to 5.

[0649] 93. The invention as herein before described. Example

[0650] The following Examples 1-15 are provided to illustrate the present invention. They should not be considered as limiting the scope of the invention, but merely as representative thereof.

[0651] Example 1

[0652] (E)-3-(tert-Butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic acid

[0653]

[0654] To a solution of ethyl formate (123.9 L, 1538.9 mol) in MTBE (189 L) was added ethyl 4-chlorophenylacetate (120 kg, 604.1 mol). The mixture was stirred at 15-30°C for 30 minutes, 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 between 0-10°C for 1.5 hours. The reaction mixture was added to an aqueous solution of hydrochloric acid (35%, 99.8 L in 560 L H 2 The mixture was stirred between 0-10°C for 30 minutes until a final pH = 2 was observed. The layers were separated and the organic layer was washed with 25% NaCl solution (496 L).

[0655] The mixture was cooled to -5°C, and then isopropylamine (107.2 L, 1251.9 mol) and AcOH (70.5 L, 1233.3 mol) were slowly added while maintaining the temperature at <10°C. The mixture was stirred at 0-10°C for 3 hours, and then H 2 O(760L), 15%Na 2 C0 3 The organic layer was washed with aqueous solution (424 L) and 25% NaCl aqueous solution (650 L). 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 60-65 ° C, and then (Boc) was slowly added over 24 hours. 2 O (951.6L, 4142mol), DMF (228.6L) and triethylamine (263.0L, 1821.8mol). After stirring for about 6 hours, the mixture was cooled to room temperature, and MTBE (1434L), water (1010L) and 10% citric acid aqueous solution (938L) were added. The aqueous layer was separated, and the mixture was washed with 25% NaCl aqueous solution (984L). The organic layer was then concentrated to a minimum working volume (about 240L) by distillation at a maintenance temperature lower than 50°C. The organic layer was then stirred at 0-5°C for 5 hours and filtered. The filter cake was washed with heptane (20.6L) and dried to provide (E)-3-((tert-butoxycarbonyl) (isopropyl) amino)-2-(4-chlorophenyl) ethyl acrylate (148.55kg, 63% yield, over three steps) as a white solid.

[0656] Add (E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (133.5 kg, 362.9 mol) to the stirred H 2O (252L), NaOH (58.25kg, 1456mol) and EtOH (383.5L). The mixture was warmed to 40-45°C for 2.5 hours until a clear solution was formed. The mixture was concentrated to a minimum working volume while maintaining a temperature below 50°C. The mixture was then cooled to 10-25°C, and a solution of HCl (842L 2N HCl and 11L 35% HCl) was added until a final pH = 2-4 was obtained. The aqueous layer was separated, and the organic layer was washed with a 25% NaCl aqueous solution (810L). n-heptane was added during distillation to form a suspension. The product was collected and washed with n-heptane, and dried at 40-45°C for about 10 hours to provide 110.7kg (90.5% yield) of (E)-3-(tert-butoxycarbonyl (isopropyl) amino)-2-(4-chlorophenyl) acrylic acid with a purity of 99.9% according to HPLC. The E configuration was confirmed using single crystal x-ray analysis.

[0657] Example 1a

[0658] (E)-3-((tert-Butoxycarbonyl)-(isopropyl)amino)-2-(4-chlorophenyl)acrylate

[0659]

[0660] To a concentrated solution of ethyl 2-(4-chlorophenyl)-3-(isopropylamino)acrylate (prepared as above in Example 1 from 120 kg of ethyl 2-(4-chlorophenyl)acetate, 0.604 kmol) was added DMF (354 kg) and the batch was concentrated to 3 volumes. DMAP (14.0 kg, 114.6 mol) and n-Bu 3 N (224.21 kg, 1.21 kmol) and heated the mixture to 70-75°C and added (BOC) at 70-75°C over 2 hours 2 O (330 kg, 1.51 kmol) in DMF (169 kg) solution. After the addition was complete, about 200 L of DMF was removed under vacuum at less than 75 ° C in 3 hours. Continue to add (BOC) at 70-75 ° C in 0.5 hours 2O (68.6kg, 0.314kmol) in DMF (32.4kg). After the addition is complete, the batch is concentrated at a temperature below 75°C and then cooled to about 23.5°C. MTBE (899.6kg) is charged and the mixture is then cooled to about 12.6°C. A solution of water (702kg) containing citric acid monohydrate (197.4kg) is added at 10-20°C. The layers are separated and the organic layer is washed with 5% aqueous NaCl (582kg). The layers are divided and the organic layer is concentrated to 240-360L at below 50°C. After n-heptane (77kg) is charged, the mixture is concentrated to 240-360L at below 50°C. After n-heptane (70kg) is charged, the suspension is stirred at 0-10°C for 4 hours and the product is collected by centrifugation. The cake was washed with n-heptane (28.2 kg) and (E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (170.6 kg, 77% yield, 99.8A% HPLC) was obtained, which was used to prepare (E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic acid as above in this Example 1.

[0661] Example 2

[0662] Sodium (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propionate

[0663]

[0664] In the glove box (O 2 A 50 ml autoclave was charged with 6.8 g (20.0 mmol) of (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid, 34 ml of ethanol and 4.81 mg (0.0051 mmol, S / C 4'000) [Ru(TFA) 2Asymmetric hydrogenation of ((S)-BINAP] was carried out at 60°C under 18 bar of hydrogen for 7 hours. 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 to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an S / R enantiomeric ratio of 99.3 to 0.7. The hydrogenated mixture was transferred to 1 4-nitropropionic acid solution under argon with the aid of 100 ml of tert-butyl methyl ether. 1 glass reactor, the mixture containing 6 similar hydrogenation experiments of the crude reaction mixture (a total of 47.9g (E) -2- (4-chlorophenyl) -3- [(2-methylprop-2-yl) oxycarbonyl -prop-2-ylamino] prop-2-enoic acid) was then added dropwise at 50 ° C. under stirring with a solution of sodium ethoxide in ethanol (52.3ml, 140mmol). A pale yellow precipitate was formed, which was stirred at the same temperature and then stirred at room temperature overnight. The precipitated product was filtered off, washed with a tert-butyl methyl ether / ethanol 4: 1 mixture (300ml) and tert-butyl methyl ether (200ml), and dried under vacuum until the weight was constant to produce (S) -3- (tert-butyloxycarbonyl (isopropyl) amino) -2- (4-chlorophenyl) propanoic acid sodium (49.03g) in 96.3% yield and S / R enantiomeric ratio> 99.9 to <0.1% as white crystals. 1 H-NMR (D 2 O): δ7.32 (d, 2H), 7.22 (d, 2H), 3.65-3.85 two broad singlets, aromatic- CH and N- CH (CH 3 ) 2 ),3.55(m,2H),1.29(s,9H),1.00(d,3H),0.80(bs,3H).

[0665] The enantiomeric ratio was determined by HPLC using a Chiralpak-AD-3 column of 150 mm*4.6 mm. Eluent: A) n-heptane containing 0.10% trifluoroacetic acid, B) ethanol, flow rate: 1.25 ml / min, 25°C, 5 μl injection volume, 220 nm. Retention time: (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid 2.48 minutes, (R)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid 2.77 minutes, (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid 3.16 minutes.

[0666] Example 3

[0667] Sodium (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propionate

[0668] In the glove box (O 2 A 185 ml autoclave was charged with 17.0 g (50.0 mmol) of (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid, 70 ml of ethanol and 4.74 mg (0.005 mmol, S / C 10'000) [Ru(TFA) 2 ((S)-BINAP] Asymmetric hydrogenation was carried out at 70°C under 18 bar of hydrogen for 22 hours. 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 to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an S / R enantiomeric ratio of 98.2 to 1.8. The hydrogenation mixture was transferred to a 400 ml glass reactor under argon with the aid of 200 ml of tert-butyl methyl ether, followed by dropwise addition of sodium ethoxide at 50°C with stirring. Ethanol solution (18.7 ml, 50 mmol). A light yellow precipitate is formed, which is stirred at the same temperature and then stirred at room temperature for a total of 3.5 hours. The precipitated product is filtered off, washed with tert-butyl methyl ether / ethanol 4:1 mixture (80 ml) and tert-butyl methyl ether (20 ml), and dried under vacuum until constant weight to produce (S)-3-(tert-butoxycarbonyl (isopropyl) amino)-2-(4-chlorophenyl) propionate sodium (17.35 g) in a 94.6% yield and an S / R enantiomeric ratio of 100 to 0% as white crystals.

[0669] Example 3a

[0670] Sodium (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propionate

[0671] In the glove box (O 2 A 185 ml autoclave was charged with 10.0 g (29.4 mmol) of (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid, 125 ml of ethanol, 0.118 mL of NaBr aqueous solution (1 M) and 5.77 mg (0.006 mmol, S / C 5'000) [Ru(TFA) 2((S)-BINAP] Asymmetric hydrogenation was carried out at 60°C under 18 bar of hydrogen for 22 hours. 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 to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an S / R enantiomeric ratio of 98 to 2. The hydrogenated mixture was transferred to a 0.5 L reactor with the aid of 10 mL of ethanol. The reaction mixture was evaporated in vacuo at 45°C to obtain a residual volume of 65 mL.

[0672] At 45 ° C, 70 ml of tert-butyl methyl ether was added. Then, at 45 ° C, an ethanol solution of sodium ethoxide (11.4 g, 35 mmol) was added dropwise under stirring. The funnel was rinsed with 1.3 g of ethanol. A light yellow precipitate was formed, which was stirred for 1 hour at the same temperature, then stirred for 1 hour at room temperature. The precipitated product was filtered off, washed with tert-butyl methyl ether / ethanol 1:1 mixture (13.6 g) and tert-butyl methyl ether (16 g), and dried under vacuum until constant weight to produce (S)-3-(tert-butoxycarbonyl (isopropyl) amino)-2-(4-chlorophenyl) sodium propionate (9.52 g) in a white crystalline shape with an S / R enantiomeric ratio of 100 to 0%.

[0673] Example 3b

[0674] Sodium (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propionate

[0675] In the glove box (O 2 A 185 ml autoclave was charged with 10.0 g (29.4 mmol) of (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid, 120 ml of ethanol (distilled under Ar), 0.118 mL of NaCl aqueous solution (1 M) and 5.8 mg (0.006 mmol, S / C 5'000) [Ru(TFA) 2 Asymmetric hydrogenation of ((S)-BINAP] was carried out at 60°C under 18 bar of hydrogen for 12 hours. 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 to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid with an S / R enantiomeric ratio of 99 to 1. The hydrogenated mixture was transferred to a 0.5 L reactor with the aid of 10 mL of ethanol. The reaction mixture was evaporated in vacuo at 45°C to obtain a residual volume of 65 mL.

[0676] At 20 ° C, 70 ml of tert-butyl methyl ether was added. Then, at 45 ° C, a solution of sodium ethoxide in ethanol (21% (m / m), 9.5 g, 29.4 mmol) was added dropwise under stirring. The funnel was rinsed with 1.3 g of ethanol. A precipitate was formed, which was stirred at the same temperature for 1 hour, then stirred at room temperature for 1 hour. The precipitated product was filtered off, washed with tert-butyl methyl ether / ethanol 1:1 mixture (13.6 g) and tert-butyl methyl ether (16 g), and dried under vacuum until constant weight to produce (S)-3-(tert-butoxycarbonyl (isopropyl) amino)-2-(4-chlorophenyl) propionate sodium (9.5 g) in a white crystal shape with an S / R enantiomeric ratio of 100 to 0%.

[0677] Example 3c

[0678] (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-propionic acid

[0679] In the glove box (O 2 content ≤ 2ppm), a 185ml autoclave was charged with 17.1g (50.0mmol) (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid and 75ml ethanol. In a separate flask, 4.79mg (0.005mmol, S / C10'000) [Ru(TFA) 2 A mixture of ((S)-BINAP] and 8.3 ml of ethanol was treated with 1.67 ml (0.10 mmol) of 60 millimolar aqueous HCl solution, the resulting suspension was stirred for 30 minutes and then added to the autoclave. After the autoclave had been sealed, asymmetric hydrogenation was carried out at 60° C. under 18 bar of hydrogen for 12 hours. 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 to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid, with an S / R enantiomeric ratio of 98.7 to 1.3.

[0680] Example 3d

[0681] (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-propionic acid

[0682] The procedure of Example 3c was repeated using HBr as additive. The hydrogenation was carried out at 99.8% conversion and the desired (S)-acid was isolated in quantitative yield with an S / R enantiomeric ratio of 98.7:1.3.

[0683] Example 3e

[0684] (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-propionic acid

[0685] In the glove box (O 2 content ≤2ppm), a 185ml autoclave was charged with 17.0g (50.0mmol) (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-2-ylamino]prop-2-enoic acid and 75ml ethanol. In a separate flask, 9.59mg (0.010mmol, S / C5'000) [Ru(TFA) 2 A mixture of ((S)-BINAP] and 9.8 ml of ethanol was treated with 0.20 ml (0.20 mmol) of 1 molar aqueous HCl solution, the resulting suspension was stirred for 30 minutes and then added to the autoclave. After the autoclave had been sealed, asymmetric hydrogenation was carried out at 60° C. under 18 bar of hydrogen for 12 hours. 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 to (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid, with an S / R enantiomeric ratio of 99.0 to 1.0.

[0686] Example 3f

[0687] (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-propionic acid

[0688] The procedure of Example 3f was repeated using LiBr as additive. The hydrogenation was carried out at 98.9% conversion and the desired (S)-acid was isolated in quantitative yield with an S / R enantiomeric ratio of 98.5:1.5.

[0689] Example 4

[0690] (S)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-propionic acid

[0691] In the glove box (O 2 A 35 ml autoclave equipped with a glass insert and a magnetic stirring bar was charged with 400 mg (1.18 mmol) of (E)-2-(4-chlorophenyl)-3-[(2-methylprop-2-yl)oxycarbonyl-prop-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 and asymmetric hydrogenation was carried out at 60° C. under stirring for 14 hours. After cooling to room temperature, the pressure was released from the autoclave and the ethanol solution was evaporated in vacuo to produce (S)-3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid in quantitative yield and with an S / R enantiomeric ratio of 99:1. The conversion rate was >=99.9%.

[0692] Examples 5.1 to 5.17 (S) or (R)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid

[0693] The procedure of Example 4 was repeated using different chiral ruthenium catalysts to produce the corresponding (R) and (S) isomers of 3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid. The results are shown in Table 1 together with the catalyst, conversion % and S / R enantiomeric ratio. In all experiments (unless explicitly indicated in the footnotes), the reaction scale was 400 mg, the temperature was 60° C., the hydrogen pressure was 20 bar, the reaction time was 14 hours at an S / C ratio of 200. The reactor was a 35 ml autoclave. The indicated additive amounts are intended to be relative to the amount of metal catalyst.

[0694] Table 1

[0695]

[0696]

[0697] 35 ml autoclave, 1.7 g scale; S / C 250, 22 hours. b) 1.7 g scale, S / C 250, 14 hours; c) 6.8 g substrate in 50 ml autoclave, S / C 1500, 5 hours. d) 2.56 mg [Ru(COD)(TFA)] was prepared by stirring in 3 ml ethanol at 50°C in a glove box. 2 ] 2 The catalyst was prepared in situ by adding 2.2 molar equivalents of a chiral diphosphine for 3 hours.

[0698] Examples 6.1 to 6.8

[0699] (S) or (R)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid

[0700] In a manner similar to Examples 5.1-5.16, the following hydrogenations were carried out using various substances as additives to provide the (R) and (S) isomers of 3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid in the purity and enantiomeric purity indicated in Table 2. In all experiments (unless explicitly indicated in a footnote), the reaction scale was 400 mg, the temperature was 60° C., the hydrogen pressure was 18-20 bar, during 4 hours, at an S / C ratio of 200. The reactor was a 35 ml autoclave. The indicated additive amounts are intended to be relative to the amount of metal catalyst.

[0701] Table 2

[0702]

[0703] For a) reaction time 14 h; b) S / C 4000, 18 h, 6.8 g scale, in 185 ml autoclave; c) S / C 200, 14 h, 1.18 g scale, 30 ml autoclave, 20 bar H 2 .

[0704] Examples 7.1 to 7.11

[0705] (S) or (R)-3-(tert-Butyloxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid

[0706] 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 the corresponding (R) and (S) isomers of 3-(tert-butoxycarbonyl-isopropyl-amino)-2-(4-chloro-phenyl)-propionic acid. The results are shown in Table 3. In all experiments (unless explicitly indicated in the footnotes), the reaction scale was 400 mg in 4 ml solvent, the temperature was 60° C., the reaction time was 14 hours at an S / C ratio of 200. The reactor was a 35 ml autoclave, the catalyst was Ru(TFA) 2 ((S)-BINAP).

[0707] Table 3

[0708]

[0709] For a) reaction time 4 hours; b) 200 mg substrate in 4 ml ethanol; c) 600 mg substrate in 2 ml ethanol; d) by stirring 2.56 mg [Ru(COD)(TFA) in 3 ml ethanol at 50°C in a glove box 2 ] 2 The catalyst was prepared in situ by adding 4.0 mg (S)-BINAP for 3 hours.

[0710] Example 8

[0711] (R)-tert-Butyl 4-(5-methyl-7-oxo-5,6-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

[0712]

[0713] (R)-3-(4,6-dichloropyrimidin-5-yl)butanoic acid methyl ester

[0714] Phosphorus oxychloride (0.960 L, 10.6 mol) was slowly added to a mixture of (R)-3-(4,6-dihydroxypyrimidin-5-yl)butanoic acid methyl ester (1.00 kg, 4.70 mol), toluene (4.00 L) and 2,6-lutidine (0.550 L, 4.70 mol) at 50°C. The mixture was stirred at 70°C for 24 hours. The solution was cooled to 0°C. While maintaining the internal temperature below 30°C, 20% aqueous sodium hydroxide solution (about 40.0 mol, 1.60 kg, in 8.00 L H 2 0 in) to obtain a final pH between 5 and 6. Ethyl acetate (2.50 L) was added, stirred for 0.5 hours, and then the layers were separated. The aqueous phase was extracted with ethyl acetate (3×1.00 L). The organics were combined and washed with 1N hydrochloric acid (2×2.50 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. This sequence was repeated twice to remove residual ethyl acetate and toluene (via 1 H NMR analysis confirmed). The remaining crude solution was used directly in the next step without further purification or isolation.

[0715] (R)-3-(4,6-diiodopyrimidin-5-yl)butanoic acid methyl ester

[0716] Sodium iodide (152 g, 1.02 mol) was added to a solution of (R)-3-(4,6-dichloropyrimidin-5-yl)butyric acid methyl ester (36.0 g, 145 mmol) in acetonitrile (540 mL). The mixture was stirred at 25 ° C for 30 minutes and then cooled to about 5 ° C. Methanesulfonic acid (9.41 mL, 1.00 equiv.) was added within 5 minutes. The mixture was stirred at about 5 ° C for 3 hours. 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 hour while the mixture was warmed 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 of less than 40 ° C to remove acetonitrile. The aqueous suspension was filtered to produce 48.8 g (78% yield) of off-white solid product.

[0717] (R)-tert-Butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate

[0718] To a solution of (R)-3-(4,6-diiodopyrimidin-5-yl)butanoic acid methyl ester (212 g, 491 mmol) and Boc-piperazine (101 g, 540 mmol) in methanol (424 mL) was added N,N-diisopropylethylamine (94.3 mL, 540 mmol). The mixture was heated at 60°C for 24 hours. Methanol was distilled off under reduced pressure at less than 40°C. 318 mL of tetrahydrofuran was added to the mixture. The above solvent exchange process was repeated twice. 424 mL of tetrahydrofuran, 212 mL of saturated aqueous ammonium chloride solution, and 21.2 mL of water were added to the mixture. The organic layer was washed with 212 mL (1.00 volume) of saturated aqueous ammonium chloride solution. This tetrahydrofuran solution was used in the next step without further purification (91% wt. yield).

[0719] (R)-3-(4-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-6-iodo-pyrimidin-5-yl)butanoic acid

[0720] 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) at 25°C was added a solution of lithium hydroxide monohydrate (56.2 g, 1.34 mol) in 329 mL of water. The mixture was stirred at 25°C for 5 hours. The bottom aqueous layer was discarded. The mixture was acidified with 1N hydrochloric acid at 5°C to produce a final pH value between about 1 and 2. The layers were separated. The top layer was then extracted with isopropyl acetate (440 mL×3), combined with the bottom layer, and washed with water (220 mL×2). The solvent was distilled off under reduced pressure at less than 50°C. The residual isopropyl acetate was removed azeotropically with heptane at less than 50°C under reduced pressure. The product gradually precipitated out and was filtered to yield an off-white to pale yellow powder (196 g, 84% yield).

[0721] (R)-4-(6-iodo-5-(4-(methoxy(methyl)amino)-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate Tert-butyl ester

[0722] 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) was added 1,1'-carbonyldiimidazole (40.9 g, 252 mmol) in portions. The reaction mixture was stirred at 20°C for 1 hour and cooled to 5°C. N,O-dimethylhydroxylamine 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 hour, slowly warmed to room temperature, and stirred for 24 hours. Saturated aqueous ammonium chloride solution (500 mL) and water (150 mL) were added to obtain a clear phase separation. The organic layer was washed with saturated aqueous ammonium chloride solution (500 mL) and brine (200 mL). Residual water was azeotropically removed by co-evaporation with tetrahydrofuran to less than 500 ppm. The product was used in the next step as a solution in tetrahydrofuran without further purification or isolation (gravimetric yield: >99%).

[0723] (R)-tert-Butyl 4-(5-methyl-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate

[0724] 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 minutes. Isopropylmagnesium 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 hour and slowly transferred to a 20 wt % cold aqueous ammonium chloride solution (600 mL) under stirring while maintaining the internal temperature below 10°C. The organic layer was then washed with a saturated aqueous ammonium chloride solution (500 mL). Tetrahydrofuran was distilled off under reduced pressure at 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 out during the process. The slurry was filtered and the filter cake was dried at 40°C under vacuum to yield a grey solid (52.3 g, 75% yield over two steps). 1 HNMR (300MHz, CDCl 3 )δ8.73(s,IH),3.92-3.83(m,2H),3.73-3.49(m,7H),2.96(dd,J=16.5,7. 2Hz, 1H), 2.33 (dd, J = 16.5, 1.8Hz, IH), 1.50 (s, 9H), 1.32 (d, J = 6.9Hz, 3H). C 17 H 25 N 4 0 3 HRMS calculated value: [M+H] + :333.1921, measured value: 333.1924.

[0725] Example 9

[0726] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0727]

[0728] Under vigorous stirring, a yellowish 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 the oxidation cofactor NADP [Roche] is formed. The reaction solution is heated to 40° C. and stirred for 5 minutes, and then the reduction is started by adding 30 mg of KRED-X1-P1B06. The pH is adjusted from 5.6 to 5.8. During the course of the reaction, which achieves almost complete conversion (IPC: 0.6 area % of educt) at 40° C. within 21.5 hours, the pH increases to 6.4. 30 ml of isopropyl acetate are added to the reaction and stirred vigorously for 15 minutes. Phase splitting occurs spontaneously. The separated aqueous phase was extracted twice with 50 ml of isopropyl acetate, a total of 100 ml of isopropyl acetate. The combined organic phases were purified by MgSO 4 Drying, filtration and evaporation under vacuum at 50° C. yielded 3.07 g (102%) of a reddish foam as 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) [254nm; Chiralpak IC-3; 150*4.6mm, 3μm, flow rate 0.8ml, 30℃, A: 60% n-heptane, B: 40% EtOH+0.1DEA, 0-15 minutes 100% B, 15-17 minutes 100% B, 17.1 minutes 40% B]; Chemical purity HPLC: 99.2 area% (containing 0.6 area% of the educt). 1 H NMR (600 MHz, CDCl 3 )δppm 1.17-1.22 (m, 3H) 1.45-1.51 (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 about 4% isopropyl acetate).

[0729] Examples 10.1-10.6

[0730] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0731] For Examples 9.1-9.6, the procedure of Example 9 was repeated, but the cofactor (NADP [Roche]) ratios were varied as indicated in the table below, and a different ketoreductase variant, namely KRED-X1, was applied.

[0732] Table 4

[0733]

[0734] Embodiment 11

[0735] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0736] Under vigorous stirring, a yellowish suspension of 6 g of tert-butyl 4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[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 the oxidation cofactor NADP [Roche] is formed. The reaction solution is heated to 40° C. and stirred for 5 minutes, and then the reduction is started by adding 60 mg of KRED-X1-P1B06. The pH is adjusted from 5.5 to 5.8. During the course of the reaction, which achieves almost complete conversion (IPC: 1 day 1.3 area % educt, 2 days 1.2 area % educt) at 40° C. within 2 days, the pH increases to 6.0. 30 ml of isopropyl acetate are added to the reaction and stirred vigorously for 15 minutes. Phase splitting occurs spontaneously. The separated aqueous phase was extracted twice with 50 ml of isopropyl acetate, a total of 100 ml of isopropyl acetate. The combined organic phases were purified by MgSO 4 Drying, filtration and evaporation under vacuum at 50° C. yielded 6.02 g (99.7%) of a reddish foam as 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) [254nm; Chirapakl IC-3; 150*4.6mm, 3μm, flow rate 0.8ml, 30℃, A: 60% n-heptane, B: 40% EtOH+0.1DEA, 0-15 minutes 100% B, 15-17 minutes 100% B, 17.1 minutes 40% B]; Chemical purity HPLC: 98.4 area% (containing 1.3 area% of the educt). 1 H NMR (600 MHz, CDCl 3)δppm 1.2 (d, J = 7.1 Hz 3H) 1.49 (s, 9H) 2.14-2.23 (m, 2H) 3.46-3.59 (m, 5H) 3.64 (ddd, J = 13.1, 6.9, 3.3 Hz, 2H) 3.78 (ddd J = 13.1, 7.2, 3.3 Hz, 2H) 5.12 (t, J = 7.2 Hz, 1H) 8.53 (s, 1H) (contains about 4% isopropyl acetate).

[0737] Example 12

[0738] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0739] Under vigorous stirring, a yellowish 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 potassium dihydrogen phosphate, pH 7.2; 2 mM magnesium chloride), 6 ml of 2-propanol and 3 mg of the oxidation cofactor NADP [Roche] is formed. The reaction solution is heated to 40° C. and stirred for 5 minutes, and then the reduction is started by adding 30 mg of KRED-X1-P1B06. The pH is adjusted from 7.5 to 7.2. During the course of the reaction, which achieves almost complete conversion (IPC: 0.8 area % educt) at 40° C. within 18.5 hours, the pH drops to 7.15. 30 ml of isopropyl acetate are added to the reaction and stirred vigorously for 15 minutes. Phase splitting occurs spontaneously. The separated aqueous phase was extracted twice with 50 ml of isopropyl acetate, a total of 100 ml of isopropyl acetate. The combined organic phases were purified by MgSO 4 Drying, filtration and evaporation under vacuum at 50° C. yielded 3.06 g (102%) of a reddish foam as 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) [254nm; Chirapakl IC-3; 150*4.6mm, 3μm, flow rate 0.8ml, 30℃, A: 60% n-heptane, B: 40% EtOH+0.1DEA, 0-15 minutes 100% B, 15-17 minutes 100% B, 17.1 minutes 40% B]; Chemical purity HPLC: 98.9 area% (containing 0.8 area% of the educt). 1 H NMR (600 MHz, CDCl 3)δppm 1.16-1.22 (m, 3H) 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=7.2Hz, 1H) 8.44–8.59 (m, 1H) (contains about 4% isopropyl acetate).

[0740] Examples 13.1–13.7

[0741] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0742] 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 2-propanol was added to a well of a deep-well plate containing 300 μl of buffer (100 mM MES, 2 mM MgCl 2 ; pH 5.8), 1 mg NADP and a variant of KRED-X1 were added to each well. After shaking at room temperature for 1.5 hours, 0.5 ml MeOH was added to each well and analyzed by HPLC. The results of the best variants are listed in the table below.

[0743] Table 5

[0744] Example Ketoreductase variants Product (R,S):(R,R) 13.1 KRED-X1.1-P1F01 0.00:85:96 13.2 KRED-X1.1-P1H10 0.00:81.87 13.3 KRED-X1.1-P1C08 0.00:78.20 13.4 KRED-X1.1-P1C04 0.03:94.83 13.5 KRED-X1.1-P1G11 0.03:94.06 13.6 KRED-X1.1-P1C11 0.04:86.69 13.7 KRED-X1-P1B06 0.08:79.80

[0745] Example 13a

[0746] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0747] A suspension of 50 g (150 mmol) of tert-butyl 4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[d]-pyrimidin-4-yl]piperazine-1-carboxylate in 100 ml of aqueous buffer (100 mM potassium dihydrogen phosphate, pH 7.2), 78 g of 2-propanol and 50 mg of NAD (75 μmol) was formed under vigorous stirring. The reduction was started by adding 500 mg of KRED-X1.1-P1F01. The reaction mixture was sparged with nitrogen and heated to 40° C. for 22 hours. After the reaction was complete, 174 g of isopropyl acetate was added, stirred, the phases were split and the aqueous phase was 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 to a final volume of 115 mL at 35° C. in vacuo. At the same temperature, 212 g of heptane were added within 1 hour, the suspension was aged for 1 hour and cooled to 10° C. within 6 hours. The suspension was filtered and washed with 68 g of heptane. After drying the filter cake at 50° C. for 4 hours, 41.1 g (82% yield, purity 100% area) of white crystals were obtained.

[0748] Example 13b

[0749] tert-Butyl 4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydrocyclopenta[d]pyrimidin-4-yl]piperazine-1-carboxylate

[0750] Under vigorous stirring, 40 g (150 mmol) of tert-butyl 4-[(5R)-5-methyl-7-oxo-5,6-dihydrocyclopenta[d]-pyrimidin-4-yl]piperazine-1-carboxylate was dissolved in 240 ml of a buffer solution (containing 3.3 g of KH 2 PO 4 and 8.4 g K 2 HPO 4), 26g glucose and 40mg NAD. The reduction was warmed to 35°C and started by adding 400mg KRED-X1.1-P1F01 and 400mg GDH-101. Over the course of the reaction (26 hours), 58.8mL KOH aqueous solution (10% (m / m)) was used to keep the pH at 7.0. After the reaction was complete, 290g isopropyl acetate and 117g NaSCN were added, stirred, each phase was split and the aqueous phase was removed. The organic phase was washed with 200g water and filtered using a filtrox filter plate, and the aqueous phase was washed with 175g isopropyl acetate. The combined organic phases were concentrated in vacuo to a final volume of 100mL at 25°C. At 25°C, 383g heptane was added within 1 hour. The suspension was cooled to 0°C in 30 minutes and aged for 30 minutes. The suspension was filtered and washed with 91g heptane. After drying the filter cake at 50° C. for 16 hours, 30.9 g (76% yield, purity 100% area) of white crystals were obtained.

[0751] Embodiment 14

[0752] 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

[0753]

[0754] A three-necked 500 mL reactor equipped with a mechanical stirrer, a nitrogen inlet, and a thermometer was charged with 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. 2-propanol (24.6 g, 140 mmol) containing 20.8% (m / m) HCl was then added at 55° C. over 10 minutes. 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 minutes. (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. Propanephosphonic anhydride (T3P) (50 w% (m / m) in toluene) (35 g, 57.3 mmol) was added at a rate to maintain the temperature at 5° C.

[0755] After the reaction is complete, 20g water is added. The solution is concentrated by distillation at 45 ℃ and 150 mbar until a final volume of 100mL. Toluene (260g) is added. The solution is concentrated again by distillation at 45 ℃ and 150 mbar until a final volume of 300mL. Water (150g) is added, and the suspension is stirred for 15 minutes. Each phase is separated for 15 minutes and the aqueous phase is removed. Water (100g) is added, and the suspension is stirred for 15 minutes. Each phase is separated for 15 minutes and the aqueous phase is removed. Water (100g) is added again, and the suspension is stirred for 15 minutes. Each phase is separated for 15 minutes and the aqueous phase is removed. The solution is concentrated by distillation at 45 ℃ and 150 mbar until a final volume of 100mL. n-Heptane (34 g) was added and 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. Further n-heptane (170 g) was added. The suspension was aged for 2 hours, filtered and washed with a mixture of toluene (6.4 g) and n-heptane (29.2 g), followed by two washes with heptane (68.4 g each). The filter cake was dried at ≤ 55 °C to yield 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, 23.9 g isolated, 86% yield. 1 H NMR (600 MHz, CDCl 3 )δppm 0.68(br.s.,3H)0.94-1.08(m,3H)1.14(d,J=7.0Hz,3H)1.47(s,10H)2.06-2.27(m,2H)3.30(br.s.,1H)3.38- 3.53(m,5H)3.56-3.73(m,4H)3.78(br.s.,3H)4.62(br.s.,1H)5.10(t,J=7.1Hz,1H)7.24(s,1H)8.49(s,1H).

[0756] Embodiment 15

[0757] (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

[0758]

[0759] To a 500 mL reactor equipped with a mechanical stirrer, nitrogen inlet, thermometer, and pH meter was added 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 wt % (m / m), 46.7 g) was added at 50° C. The solution was maintained at 50° C. until the reaction was complete, and the mixture was cooled to 25° C. A solution of ammonia in 2-propanol (2M, 66.6 g, 1.66 eq) was added over approximately 1 hour until pH 6.7 was reached. The suspension was cooled to 0° C. and filtered. The filter cake was washed with 2-propanol (39 g). The filtrate was concentrated by distillation at 50 ° C and 150 mbar until the final volume was 100 mL. Ethyl acetate (130 g) was added to the solution. The slurry was solvent-converted using ethyl acetate (670 g) at a constant volume (300 mL) at 40 ° C. The suspension was cooled to 5 ° C and the slurry was 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) piperazine-1-yl)-3-(isopropylamino) propan-1-one monohydrochloride as an off-white solid: 36.4 g (82% yield). ( 1 H NMR (600MHz, D 2 O)δppm0.92(d,J=7.1Hz,3H)1.23(t,J=6.4Hz,6H)1.89-2.15(m,2H)2.85-3.06(m,1H)3.17-3.59(m,10H)3.83(d,J=10.5Hz, 2H)4.33(dd,J=8.5,4.9Hz,1H)4.98(t,J=7.0Hz,1H)7.23(d,J=8.5Hz,2H)7.36(d,J=8.7Hz,2H)8.10-8.35(m,1H).LCMS[M+H] + 458.2).

[0760] Example 16

[0761] (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

[0762] To a 500 mL reactor equipped with a mechanical stirrer, nitrogen inlet, thermometer and pH meter was added 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. A solution of HCl in 1-propanol (22 wt % (m / m), 38.0 g) was added at 60° C. The solution was maintained at 50° C. until the reaction was complete, and the mixture was cooled to 25° C. Aqueous NaOH solution (28%) (16 g) was added until pH 6 was reached. The suspension was concentrated in vacuo at 60° C. until a final volume of 100 mL was reached. The suspension was cooled to 20°C, 90 g of ethyl acetate was added and filtered through a filtrox plate. The reactor and filter were washed with 41 g of 1-propanol / ethyl acetate. The solution was filtered through a charcoal filter pad at 20°C. The reactor and filter were rinsed with 82 g of 1-propanol / ethyl acetate. At 60°C, the solution was concentrated in vacuo to a final volume of 300 mL. The distillation was continued at 60°C and 1260 g of ethyl acetate was added while keeping the volume constant.

[0763] The suspension was cooled to 5° C. and the slurry was filtered. The filter cake was washed with EtOAc (105 mL) and dried under vacuum at 60° C. for 16 h 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: 36.5 g (81% yield, 91.4% (m / m) purity, 99.9% (area) assay).

Claims

1. A method for preparing a compound of formula (I) or a salt thereof, which comprises a compound of formula (II) With the compound of formula (III) The coupling reaction It also includes a process for producing a compound of formula (II) It comprises using a metal complex catalyst (C) to react a compound of formula (IV) Asymmetric hydrogenation; in R 1 is an amino protecting group selected from benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl; R 2 is an amino protecting group selected from benzyl, benzyloxycarbonyl (benzyloxycarbonyl, CBZ), 9-fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC) and trifluoroacetyl; and M is an alkali metal ion; and The metal complex catalyst is a ruthenium complex catalyst selected from the compounds 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) in: D is a chiral phosphine ligand; L is a neutral ligand selected from the following: C 2-7 Olefins, cyclooctene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol; Z is an anionic ligand selected from the group consisting of hydride, fluoride, chloride, bromide, 5 -2,4-pentadienyl, η 5 -2,4-dimethyl-pentadienyl or group A-COO - , provided that when two Zs are attached to the Ru atom, they are the same or different; A is for C 1-7 Alkyl, C 1-7 haloalkyl, aryl or haloaryl; Y is a non-coordinating anion selected from the group consisting of fluoride, chloride, bromide, BF4 - 、ClO4 - 、SbF6 - PF6 - 、B(phenyl)4 - 、B(3,5-di-trifluoromethyl-phenyl)4 - CF3SO3 - and C6H5SO3 - ; F is an optional chiral diamine; E and E' are both halogen ions, or E is a hydride ion and E' is BH4 - ; m is 1, 2, 3, or 4; and p is 1 or 2.

2. The method according to claim 1, wherein R 1 It is tert-butoxycarbonyl (BOC).

3. The method according to claim 1 or 2, wherein R 2 It is tert-butoxycarbonyl (BOC).

4. The method according to claim 2, wherein M is Na + .

5. The method according to claim 1 or 2, comprising the following reaction steps: a) deprotecting the compound of formula (III) in a solvent under acidic conditions; b) adjusting to 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.

6. The process according to claim 5, wherein the deprotection in step a) is carried out using hydrochloric acid.

7. The method according to claim 5, wherein the solvent used for deprotection in step a) is selected from n-propanol or isopropanol.

8. The method according to claim 5, wherein the base in step b) is selected from N-ethylmorpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), diisopropylethylamine (DIPEA), pyridine and lutidine.

9. The process according to claim 5, wherein the base in step b) is N-ethylmorpholine (NEM).

10. The method according to claim 5, wherein the solvent in step c) is selected from n-propanol or isopropanol.

11. The process according to claim 5, wherein the coupling agent used in step d) is propylphosphonic anhydride (T3P).

12. The process according to claim 5, wherein the solvent used in step d) is a mixture of n-propanol and toluene.

13. The process of claim 5, wherein after step d), the product is worked up by aqueous extraction.

14. A method for producing a compound of formula (II) It comprises using a metal complex catalyst (C) to react a compound of formula (IV) Asymmetric hydrogenation, where R 1 and M as defined in any one of claims 1 to 2; The metal complex catalyst is a ruthenium complex catalyst selected from the compounds 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) in: D is a chiral phosphine ligand; L is a neutral ligand selected from the following: C 2-7 Olefins, cyclooctene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol; Z is an anionic ligand selected from the group consisting of hydride, fluoride, chloride, bromide, 5 -2,4-pentadienyl, η 5 -2,4-dimethyl-pentadienyl or group A-COO - , provided that when two Zs are attached to the Ru atom, they are the same or different; A is for C 1-7 Alkyl, C 1-7 haloalkyl, aryl or haloaryl; Y is a non-coordinating anion selected from the group consisting of fluoride, chloride, bromide, BF4 - 、ClO4 - 、SbF6 - PF6 - 、B(phenyl)4 - 、B(3,5-di-trifluoromethyl-phenyl)4 - CF3SO3 - and C6H5SO3 - ; F is an optional chiral diamine; E and E' are both halogen ions, or E is a hydride ion and E' is BH4 - ; m is 1, 2, 3, or 4; and p is 1 or 2.

15. The method of claim 14, wherein the ruthenium complex catalyst is Ru(Z)2D.

16. The method of claim 14, wherein the anionic ligand (Z) is independently selected from chloride, bromide, OAc and TFA.

17. The method of claim 14, wherein the anionic ligand (Z) is trifluoroacetate (TFA).

18. The method of claim 14, wherein the neutral ligand (L) is independently selected from benzene (C6H6), p-cymene (pCym) and acetonitrile (AN).

19. The method of claim 14, wherein the neutral ligand (L) is benzene (C6H6).

20. The method according to claim 14, wherein the non-coordinating anion (Y) is selected from chloride, bromide and BF4 - .

21. The method of claim 14, wherein the non-coordinating anion (Y) is BF4 - .

22. The method of claim 14, wherein m is 1 or 4.

23. The method of claim 14, wherein E and E' are both chloride ions.

24. The method of claim 14, wherein the chiral diamine F is (1S,2S)-1,2-diphenylethylenediamine (S,S-DPEN).

25. The method according to claim 14, wherein the chiral phosphine ligand D is selected from the compounds of formula (D1) to (D12): in: R 11 It is C 1-7 Alkyl, C 1-7 Alkoxy, hydroxyl or C 1-7 Alkyl-C(O)O-; R 12 and R 13 are independently hydrogen, C 1-7 Alkyl, C 1-7 Alkoxy or di(C 1-7 alkyl)amino; or R connected to the same phenyl group 11 and R 12 or R connected to the same phenyl group 12 and R 13 Together they are -X-(CH2) r -Y-, wherein X is -O- or -C(O)O-, Y is -O- or -CF2-, and r is an integer from 1 to 6; or Two R's 11 Together they are -O-(CH2) s -O- or O-CH(CH3)-(CH2) s -CH(CH3)-O-, wherein s is an integer from 1 to 6; or R 11 and R 12 or R 12 and R 13 Together with the carbon atoms to which they are attached, they form a naphthyl, tetrahydronaphthyl or dibenzofuran ring; R 14 and R 15 Each independently is C 1-7 Alkyl, C 3-8 Cycloalkyl, phenyl, naphthyl or heteroaryl, optionally substituted with 1 to 7 substituents independently selected from the group consisting of: C 1-7 Alkyl, C 1-7 Alkoxy, di(C 1-7 alkyl)amino, morpholinyl, phenyl, tri(C 1-7 alkyl) silyl, C 1-7 Alkoxycarbonyl, hydroxycarbonyl, hydroxysulfonyl, (CH2) t -OH and (CH2) t -NH2, wherein t is an integer from 1 to 6; R 16 It is C 1-7 alkyl; R 17 It is C 1-7 Alkyl; and R 18 are independently aryl, heteroaryl, C 3-8 Cycloalkyl or C 1-7 alkyl.

26. The method according to claim 25, wherein the chiral phosphine ligand (D) is selected from the compounds of formula (D1).

27. The method according to claim 14, wherein the chiral phosphine ligand (D) is selected from (R)-3,5-Xyl-BINAP, (R)-BINAP, (S)-2-furyl-MeOBIPHEP, (S)-BINAP, (S)-BIPHEMP, (S)-MeOBIPHEP, (S)-pTol-BINAP), (S)-TMBTP and (S,S)-iPr-DUPHOS, wherein BINAP is 2,2'-bis(diphenylphosphino) )-1,1'-binaphthyl; BIPHEMP is (6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenyl-phosphine); iPr-DUPHOS is 1,2-bis(2,5-di-isopropylphospholyl)benzene; MeOBIPHEP is (6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenyl-phosphine); TMBTP is 2,2',5,5'-tetramethyl-4,4'-bis(diphenylphosphino)-3,3'-bithiophene; Xyl is 3,5-dimethylphenyl.

28. The method of claim 14, wherein the chiral phosphine ligand (D) is selected from (S)-BIPHEMP, (S)-BINAP and (S)-MeOBIPHEP, wherein BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; BIPHEMP is (6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenyl-phosphine); MeOBIPHEP is (6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenyl-phosphine).

29. The method of claim 14, wherein the chiral phosphine ligand (D) is (S)-BINAP, wherein BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

30. The method of claim 14, wherein the ruthenium complex catalyst is selected from the group consisting 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), Wherein AN is acetonitrile; BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; BINAPHANE is 1,2-bis[4,5-dihydro-3H-binaphtho(1,2-c:2',1'-e)phosphaheptaquinone]phenyl; BIPHEMP is (6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenyl-phosphine); DPEN is 1,2-diphenylethylenediamine; iPr-DUPHOS is 1,2-bis(2, 5-di-isopropylphospholyl)benzene; MeOBIPHEP is (6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenyl-phosphine); pCym is p-cymene; pTol-Binap is 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl; TMBTP is 2,2',5,5'-tetramethyl-4,4'-bis(diphenylphosphino)-3,3'-bithiophene; Xyl is 3,5-dimethylphenyl.

31. The method of claim 14, wherein the ruthenium complex catalyst is Ru(TFA)2((S)-BINAP), wherein BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

32. The process according to claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out in a solvent selected from alcohols, hydrocarbons, chlorinated hydrocarbons, fluorinated and polyfluorinated aliphatic or aromatic hydrocarbons, supercritical or liquid carbon dioxide, THF, water or mixtures thereof.

33. The method of claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out in a solvent selected from the group consisting of MeOH, EtOH, i-PrOH, EtOH / cyclopentyl methyl ether, EtOH / CH2Cl2, EtOH / EtOAc, EtOH / THF, EtOH / H2O, CH2Cl2 and THF.

34. The process of claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out in ethanol (EtOH).

35. The method of claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) further comprises one or more additives selected from LiBF4, LiPF6, LiO3SCF3, NaCl, NaBr, NaI, KCl, KBr, KI, LiCl, LiBr, LiI, HBF4, HCl, HBr, H2SO4 and CH3SO3H.

36. The process according to claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a hydrogen pressure of 1 to 150 bar.

37. The process according to claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a hydrogen pressure of 10 to 30 bar.

38. The process according to claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a substrate / catalyst ratio (S / C) of 5 to 100000.

39. The process according to claim 14, wherein the asymmetric hydrogenation of the compound of formula (IV) is carried out at a substrate / catalyst ratio (S / C) of 100 to 15000.

40. The process according to claim 14, wherein the hydrogenation reaction mixture is followed by adding a 1-7 The salt is formed by an alcoholic solution of an alkyl-OM metal alkoxide, wherein M is as defined in claims 1 to 2.

41. A method according to any claim 40, wherein the metal alkoxide employed in the salt forming step is MeOM, EtOM, iPrOM, nPrOM, nBuOM, iBuOM or tBuOM.

42. The method of claim 40, wherein the metal alkoxide employed in the salt forming step is EtOM.

43. The process of claim 40, wherein the alcohol used as solvent in the salt formation step is C 1-7 Alkyl-OH.

44. The process of claim 40, wherein the alcohol used as solvent in the salt formation step is MeOH, EtOH, iPrOH, nPrOH, nBuOH, iBuOH or tBuOH.

45. The method of claim 40, wherein the alcohol used as solvent in the salt formation step is EtOH.

46. ​​The method according to claim 14, further comprising the step of preparing a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) Deprotection, where R 1 As defined in any one of claims 1 to 2.

47. The method according to claim 46, comprising the following reaction steps: i) deprotecting the compound of formula (I) in a solvent under acidic conditions; ii) adjusting the pH using a base in the solvent; iii) optionally crystallizing the compound of formula (VI).

48. The process according to claim 47, wherein the deprotection in step i) is carried out using hydrochloric acid, sulfuric acid, trifluoroacetic acid or hydrobromic acid.

49. The process according to claim 47, wherein the deprotection in step i) is carried out using hydrochloric acid.

50. The method of claim 47, wherein the solvent used for deprotection in step i) is selected from n-propanol, isopropanol, and a 1:1 mixture of n-propanol / water.

51. The process of claim 47, wherein the base in step ii) is NaOH or ammonia.

52. The method of claim 47, wherein the solvent in step ii) is selected from n-propanol, isopropanol, and a 1:1 mixture of n-propanol / water.

53. The process of claim 47, wherein the crystallization in step iii) is carried out by switching the solvent to a crystallization solvent suitable for crystallizing the compound of formula (VI).

54. The process according to claim 53, wherein the crystallization solvent in step iii) is selected from the group consisting of toluene, heptane, tetrahydrofuran, 2-propanone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

55. The process of claim 53, wherein the crystallization solvent in step iii) is ethyl acetate.

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