Methods and intermediates for preparing C5aR antagonists

Abstract

The present invention discloses intermediates and methods for preparing selected C5aR antagonist compounds.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of September 28, 2015, application number 201580052937.6, and invention name “Methods and intermediates for preparing C5aR antagonists”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application Serial No. 62 / 057,107, filed September 29, 2014, the entire contents of which are incorporated herein by reference.

[0004] STATEMENT REGARDING RIGHTS TO INventions Made Under Federally Sponsored Research and Development

[0005] not applicable.

[0006] Annex to a "Sequence Listing", table or computer program listing submitted on a CD-ROM

[0007] not applicable. Background of the Invention

[0008] The complement system plays a central role in the clearance of immune complexes and in the immune response to infectious agents, foreign antigens, virus-infected cells, and tumor cells. Inappropriate or excessive complement system activation can lead to harmful, even life-threatening, consequences due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested in a variety of diseases, including septic shock, myocardial failure, intestinal ischemia / reperfusion injury, transplant rejection, organ failure, nephritis, pathological inflammation, and autoimmune diseases.

[0009] Activation of the complement pathway generates biologically active fragments of complement proteins, such as C3a, C4a, and C5a anaphylatoxins and the C5b-9 membrane attack complex (MAC), all of which mediate inflammatory responses by affecting leukocyte chemotaxis and activating macrophages, neutrophils, platelets, mast cells, and endothelial cells, and increasing vascular permeability, cell lysis, and tissue damage.

[0010] Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The allergic C5a peptide is 100-fold more potent than C3a in initiating an inflammatory response on a molar basis.) C5a is the activated form of C5 (190 kD, molecular weight). C5a is present in human serum at approximately 80 μg / ml (Kohler, PF et al., J. Immunol. 99:1211-1216 (1967)). It consists of two polypeptide chains, a and β, with approximate molecular weights of 115 kD and 75 kD, respectively (Tack, BF et al., Biochemistry 18:1490-1497 (1979)). C5 is biosynthesized as a single-chain promolecule that is enzymatically cleaved into a double-chain structure during processing and secretion. After cleavage, the two chains are held together by at least one disulfide bond as well as non-covalent interactions (Ooi, YM et al., J. Immunol. 124:2494-2498 (1980)).

[0011] During complement pathway activation, C5 is cleaved into C5a and C5b fragments. The convertase responsible for C5 activation is a multi-subunit complex of C4b, C2a, and C3b for the classical pathway, and (C3b)2, Bb, and P for the alternative pathway (Goldlust, MB et al., J. Immunol. 113:998-1007 (1974); Schreiber, RD et al., Proc. Natl. Acad. Sci. 75:3948-3952 (1978)). C5 is activated by cleavage at positions 74-75 (Arg-Leu) in the α-chain. Following activation, the 11.2 kD, 74 amino acid peptide C5a is released from the amino-terminal portion of the α-chain. Both C5a and C3a are potent stimulators of neutrophils and monocytes (Schindler, R. et al., Blood 76:1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol. 138:794-700 (1987); Cavaillon, JM et al., Eur. J. Immunol. 20:253-257 (1990)).

[0012] In addition to its allergic properties, C5a induces chemotactic migration of neutrophils (Ward, PA et al., J. Immunol. 102:93-99 (1969)), eosinophils (Kay, AB et al., Immunol. 24:969-976 (1973)), basophils (Lett-Brown, MA et al., J. Immunol. 117:246-252 1976)), and monocytes (Snyderman, R. et al., Proc. Soc. Exp. Biol. Med. 138:387-390 1971)).

[0013] It is believed that the allergic and chemotactic effects of C5a are mediated by its interaction with the C5a receptor. The human C5a receptor (C5aR) is a 52 kD membrane-bound G protein-coupled receptor expressed on neutrophils, monocytes, basophils, eosinophils, hepatocytes, pulmonary smooth muscle and endothelial cells, and glomerular tissue (Van-Epps, DE et al., J. Immunol. 132: 2862-2867 (1984); Haviland, DL et al., J. Immunol. 154: 1861-1869 (1995); Wet (Wetsel, RA, Immunol. Leff. 44:183-187 (1995); Buchner, RR, et al., J. Immunol. 155:308-315 (1995); Chenoweth, DE, et al., Proc. Natl. Acad. Sci. 75:3943-3947 (1978); Zwirner, J., et al., Mol. Immunol. 36:877-884 (1999)). The ligand-binding site of C5aR is complex, consisting of at least two physically separable binding domains. One binds to the C5a amino terminus (amino acids 1-20) and the disulfide-linked core (amino acids 21-61), while the second binds to the C5a carboxyl terminus (amino acids 62-74) (Wetsel, RA, Curr. Opin. Immunol. 7:48-53 (1995)).

[0014] Only recently have non-peptide-based C5a receptor antagonists been described in the literature (e.g., Sumichika, H., et al., J. Biol. Chem. (2002), 277, 49403-49407). Non-peptide-based C5a receptor antagonists have been reported to be effective in treating endotoxic shock in rats (Stracham, AJ, et al., J. of Immunol. (2000), 164(12): 6560-6565) and for treating IBD in a rat model (Woodruff, TM, et al., J of Immunol., 2003, 171: 5514-5520). Non-peptide based C5a receptor modulators have also been described in the patent literature of Neuron Corporation (e.g., WO2004 / 043925, WO2004 / 018460, WO2005 / 007087, WO03 / 082826, WO03 / 08828, WO02 / 49993, WO03 / 084524), Dompe Corporation (WO02 / 029187) and the University of Queensland (WO2004 / 100975).

[0015] Recently, compounds having activity as C5aR antagonists have been identified and described in U.S. Patent No. 8,445,515 B2. Generally, the compounds are represented by Formula A, while selected embodiments are described as having Formula B:

[0016]

[0017] Selected compounds described therein are particularly active when resolved into their (2R, 3S) isomers and are provided as:

[0018]

[0019] Compound IA was prepared as Figure 4 , and involves a lengthy synthesis including classical resolution of isomers (see, for example, the conversion of 6 to 7).

[0020] There is a need in the art for more efficient methods of preparing compounds IA, IB, and IC. The present disclosure provides such methods, as well as intermediates in the synthetic pathways. Summary of the Invention

[0021] In one aspect, provided herein are compounds useful for preparing several C5aR antagonists having the formula (i-3):

[0022]

[0023] Wherein R is selected from H, C 1-8 Alkyl, aryl and aryl-C 1-4An alkyl group, or a salt thereof, which is substantially free of enantiomeric or diastereomeric impurities ((2R,3R), (2S,3R) and (2S,3S) isomers).

[0024] In another aspect, provided herein are compounds for preparing several C5aR antagonists, said compounds having the formula (ii-4):

[0025]

[0026] or a salt thereof, wherein R 1 is Cl or CF3, and wherein the compound is substantially free of enantiomeric or diastereomeric impurities (corresponding to (2R,3R), (2S,3R) and (2S,3S) isomers).

[0027] In yet another aspect, provided herein is a method for preparing a compound having formula (I) or a salt thereof:

[0028]

[0029] Among them, R 1 is Cl or CF3; R 2 is F or Cl; and R 3 is H or CH3; and wherein the compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities, the method comprising:

[0030] (a) reacting a compound of formula (i-3) under conditions sufficient to form a compound of formula (i-4),

[0031]

[0032] Where R is selected from C 1-8 Alkyl, aryl and aryl-C 1-4 An alkyl group, which is substantially free of enantiomeric or diastereomeric impurities, or a salt thereof, is contacted with a compound having the formula,

[0033]

[0034] Where LG is a leaving group;

[0035] and

[0036] (b) converting the compound of formula (i-4) into the compound of formula (I), wherein the compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities.

[0037] In yet another aspect, provided herein is another method of preparing a compound having formula (I) or a salt thereof:

[0038]

[0039] Among them, R 1 is Cl or CF3; R 2 is F or Cl; and R 3 is H or CH3; and wherein the compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities, the method comprising:

[0040] (a) reacting a compound of formula (ii-4) or a salt thereof under conditions sufficient to form a compound of formula (ii-5):

[0041]

[0042] The compound is substantially free of enantiomeric or diastereomeric impurities, contacted with cyclopentanone and a reducing agent,

[0043] and

[0044] (b) contacting the compound of formula (ii-5) with a compound having the formula, under conditions sufficient to form a compound of formula (I) substantially free of enantiomeric or diastereomeric impurities,

[0045]

[0046] Where LG is a leaving group.

[0047] Also provided are other methods as described below having two, three, or four or more synthetic transformations to prepare Compounds IA, IB, and / or IC or pharmaceutically acceptable salts thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The scheme provided generally illustrates the steps used to prepare compounds IA, IB, and IC, utilizing a hydrogenation step to set the (2R,3S) stereochemistry, followed by reductive amination of the cyclopentanone, benzoylation of the piperidine nitrogen, and addition of the aniline to form the C3 amide.

[0049] Figure 2 In the scheme provided, the formation of the C3 amide (the final step of Scheme 1) is carried out by converting the C3 ester to the C3 carboxylic acid, which upon treatment with the appropriate aniline can provide compounds such as IA, IB and IC.

[0050] Figure 3 In the scheme provided, the C3 amide is constructed early in the synthesis, and subsequent steps utilize hydrogenation to set the (2R,3S) stereochemistry, followed by reductive amination of the cyclopentanone, and finally benzoylation of the piperidine nitrogen to provide compounds such as IA, IB, and IC.

[0051] Figure 4 A protocol for the preparation of IA as described in US Patent 8,445,515 B2 is provided, which utilizes a classical resolution procedure to prepare compound 7 having (2R,3S) stereochemistry. DETAILED DESCRIPTION

[0052] definition

[0053] Unless otherwise stated, the term "alkyl" by itself or as part of another substituent refers to a group having the specified number of carbon atoms (i.e., C 1-8 " refers to a straight or branched hydrocarbon group having 1 to 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.

[0054] Unless otherwise indicated, the term "aryl" refers to a polyunsaturated, usually aromatic, hydrocarbon radical which can be a single ring or multiple rings (up to three) fused together or linked covalently. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl. Substituents for the above-mentioned aryl ring systems are selected from the group of acceptable substituents described below.

[0055] The term "arylalkyl" or "aryl-C 1-4 "Alkyl" is intended to include those groups in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, etc.).

[0056] In some embodiments, the above terms (eg, "alkyl" and "aryl") will refer to both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0057] Substituents used on alkyl groups (including those groups commonly referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from the group consisting of -halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"' , -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -CN and -NO2, in a number ranging from 0 to (2m'+1), where m' is the total number of carbon atoms in the group. R', R" and R"' are each independently hydrogen, unsubstituted C 1-8 Alkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 Alkyl, C 1-8 Alkoxy or C 1-8 Thioalkoxy or unsubstituted aryl-C 1-4 Alkyl. When R' and R" are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1-pyrrolidinyl and 4-morpholinyl.

[0058] Similarly, the substituents used on the aryl group are various and are generally selected from the group consisting of -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R"', -NH -C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, numbered from 0 to the total number of open valences on the aromatic ring system, and wherein R', R" and R'" are independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 3-6 Cycloalkyl, C 2-8 Alkenyl and C 2-8 Other suitable substituents include the above aryl substituents each connected to a ring atom via an alkylene chain of 1 to 4 carbon atoms.

[0059] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -TC(O)-(CH2) q -U-substituent, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a -U-substituent of the formula -A-(CH2) r -B-substituent substitution, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a double bond of the formula -(CH2) s -X-(CH2) t -substituent substitution, wherein s and t are independently integers of 0-3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted C 1-6 alkyl.

[0060] As used herein, a wavy line that intersects a single, double, or triple bond in any chemical structure described herein Indicates the point of attachment of this single, double, or triple bond to the rest of the molecule.

[0061] Unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 The term "haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0062] "Contacting" refers to the process of bringing at least two different substances into contact so that they can react. However, it should be understood that the resulting reaction product can be directly produced by a reaction between the added reagents or by an intermediate of one or more added reagents produced in the reaction mixture.

[0063] The term "under conditions sufficient to..." refers to the selection of reaction conditions (including solvent or solvent mixture, temperature selection including variations in temperature as the reaction proceeds, reactant concentrations, order of addition of reagents and reactants to the reaction mixture, length of reaction time, etc.) that can result in the desired reaction or conversion of one molecule to another.

[0064] "Transformation" refers to the transformation of a compound to change the compound into a different compound, for example by modifying one functional group to another, joining two molecules to form a new molecule, or in some cases forming a salt. However, "transformation" can also involve more than one transformation.

[0065] "Solvent" refers to a substance, such as a liquid, that can dissolve a solute. Solvents can be polar or non-polar, protic or aprotic. Polar solvents generally have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, and non-polar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having protons that can be removed, such as by having hydroxyl or carboxyl groups. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.) and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, dimethylformamide, acetonitrile and dimethyl sulfoxide. Representative non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, toluene and 1,4-dioxane.

[0066] "Reducing agent" refers to a reagent that can reduce an atom from a higher oxidation state to a lower oxidation state. Reducing agents can include, but are not limited to, zinc, iron, Raney nickel, platinum, iridium, rhodium, palladium, sodium sulfide, sodium bisulfite, ammonium sulfide, and hydrogen donors such as lithium aluminum hydride, sodium borohydride, and sodium triacetoxyborohydride.

[0067] "Leaving group" refers to a group that maintains a bonded electron pair during heterolytic bond cleavage. For example, during a nucleophilic displacement reaction, a leaving group is easily displaced. Suitable leaving groups include, but are not limited to, chloro, bromo, iodo, hydroxyl, mesylate (or mesylate), trifluoromethanesulfonate (triflate), benzenesulfonate, 4-methylbenzenesulfonate (toluenesulfonate), 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, and the carboxylate component of a mixed or symmetrical anhydride. Those skilled in the art will recognize other leaving groups that can be used in the present invention.

[0068] "Substantially free of enantiomeric or diastereomeric impurities" refers to a compound having at least one chiral center that is present as a single enantiomer or diastereomer in an amount of at least 80% relative to the other enantiomers or diastereomers of the compound. In some embodiments, the term will refer to a compound that is present as a single enantiomer or diastereomer in an amount of at least 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% relative to the other enantiomers or diastereomers of the compound.

[0069] "Nitrating agent" refers to a reagent capable of adding a nitro group -NO2 to a compound. Representative nitrating agents include, but are not limited to, nitric acid.

[0070] "Chlorinating agent" refers to a reagent that is capable of adding a chloro group -Cl to a compound. Representative chlorinating agents include, but are not limited to, phosphorus oxychloride, thionyl chloride, oxalyl chloride, and sulfuryl chloride.

[0071] The term "pharmaceutically acceptable salt" or "salt" is intended to include salts of the compounds, which are prepared with relatively nontoxic acids or bases, depending on the particular substituents on the compounds described herein. When the compound contains a relatively acidic functional group, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al., "Pharmaceutically Acceptable Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, allowing the compounds to be converted into base or acid addition salts.

[0072] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, other salts are equivalent to the parent form of the compound.

[0073] In addition to salt forms, the present invention provides compounds in the form of co-crystals. Co-crystals are those complexes of the compounds described herein wherein the compound crystallizes in the presence of a second compound, such as an amino acid, ethylene glycol, or a lower alcohol.

[0074] Certain compounds of the present invention may exist in unsolvated forms and solvated forms, including hydrated forms. Generally, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polymorphic or amorphous forms. Generally, for the intended uses of the present invention, all physical forms are equivalent and are encompassed within the scope of the present invention.

[0075] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., different enantiomers) are encompassed within the scope of the present invention unless otherwise specified. The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. An unnatural proportion of an isotope can be defined as the amount from that found in nature to that consisting of 100% of said atoms. For example, a compound may contain a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C). Such isotopic variants may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may find additional utility, including but not limited to, as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, which may help to enhance safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of this invention.

[0076] "Kilogram scale" refers to a reaction in which at least one of the reagents is used in an amount of at least 1 kilogram.

[0077] Overview

[0078] As noted above, provided herein are intermediates and methods useful for preparing C5aR antagonist compounds for use in treating diseases or disorders, generally characterized as inflammatory diseases or disorders, cardiovascular or cerebrovascular diseases or disorders, and autoimmune diseases or disorders.

[0079] Specific intermediates having a (2R,3S) configuration can be prepared according to the methods herein and subsequently converted to C5aR antagonist compounds.

[0080] Modes for Carrying Out the Invention

[0081] C5aR antagonist intermediate

[0082] In one aspect, provided herein are compounds for preparing several C5aR antagonists, said compounds having the formula (i-3):

[0083]

[0084] Wherein R is selected from H, C 1-8 Alkyl, aryl and aryl-C 1-4 alkyl, or a salt thereof. In one set of embodiments, the compound is substantially free of enantiomeric or diastereomeric impurities. In another set of embodiments, compound (i-3) is provided as an L-DTTA salt ((-)-O,O'-di-p-toluoyl-L-tartrate); and in some embodiments, compound (i-3) is provided as a bis-L-DTTA salt.

[0085] The compound of formula (i-3), which is substantially free of enantiomeric or diastereomeric impurities, refers to a compound (or any salt form thereof) that is substantially free of one or more of the following isomers:

[0086]

[0087] As provided herein, the total amount of any one of (ia), (ib) or (ic) relative to the total weight of (i-3), (ia), (ib) and (ic) is typically less than about 5 wt %. More typically, the amount of any combination of (ia), (ib) and / or (ic) relative to (i-3) is less than about 5 wt %, less than about 4 wt %, less than about 3 wt %, and in some embodiments, less than about 2.5, 2.0, 1.5 or 1.0 wt %.

[0088] In another aspect, provided herein are compounds for preparing several C5aR antagonists, said compounds having the formula (ii-4):

[0089]

[0090] or a salt thereof, wherein R1 is Cl or CF3. In one set of embodiments, the compound is substantially free of enantiomeric or diastereomeric impurities. In another set of embodiments, compound (ii-4) is provided as an L-DTTA salt ((-)-O,O'-di-p-toluoyl-L-tartrate); and in some embodiments, compound (ii-4) is provided as a bis-L-DTTA salt.

[0091] The compound of formula (ii-4), which is substantially free of enantiomeric or diastereomeric impurities, refers to a compound (or any salt form thereof) that is substantially free of one or more of the following isomers:

[0092]

[0093] As provided herein, the total amount of any one of (ii-a), (ii-b) or (ii-c) relative to the total weight of (ii-4), (ii-a), (ii-b) and (ii-c) is typically less than about 5 wt %. More typically, the amount of any combination of (ii-a), (ii-b) and / or (ii-c) relative to (ii-4) is less than about 5 wt %, less than about 4 wt %, less than about 3 wt %, and in some embodiments, less than about 2.5, 2.0, 1.5 or 1.0 wt %.

[0094] Preparation method of C5aR antagonist

[0095] In another aspect, provided herein are methods of preparing a compound having formula (I) or a salt thereof:

[0096]

[0097] Among them, R 1 is Cl or CF3; R 2 is F or Cl; and R 3 is H or CH3; and wherein the compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities, the method comprising:

[0098] (a) reacting a compound of formula (i-3) or a salt thereof under conditions sufficient to form a compound of formula (i-4)

[0099]

[0100] Where R is selected from C 1-8 Alkyl, aryl and aryl-C 1-4 An alkyl group, which is substantially free of enantiomeric or diastereomeric impurities, is contacted with a compound having the formula,

[0101]

[0102] Where LG is a leaving group;

[0103] and

[0104] (b) converting the compound of formula (i-4) into the compound of formula (I), wherein the compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities.

[0105] Turning first to step (a), in one set of embodiments, a compound of formula (i-3) is provided that is substantially free of isomers (ia), (ib), and (ic). In certain preferred embodiments, compound (i-3) is provided and is at least 95% pure, more preferably at least 96%, 97%, or at least 98% pure, relative to the other isomers. In even further preferred embodiments, compound (i-3) is provided and is at least 99% or 99.5% pure relative to the other isomers.

[0106] In step (a), compound (i-3) is contacted with a compound having the formula:

[0107] wherein LG is a leaving group. One skilled in the art will appreciate that a suitable leaving group is one that promotes the compound to participate in the desired amide bond formation. More specifically, LG is a leaving group that promotes the reaction at the carbonyl center bearing LG. In one set of embodiments, LG is a halogen. In another set of embodiments, LG is Cl. In another set of embodiments, -LG is selected from -OH, -OAc, -OS(O)2-(4-methylphenyl) and -OS(O)2methyl. In another set of embodiments, -LG is -OC(O)Ph(R 2 )(R 3)-, forming a symmetrical anhydride with the rest of the molecule. In some embodiments, the contacting is carried out in an organic solvent or solvent mixture or an aqueous solvent mixture, for example a mixture of water and an ether such as methyl tert-butyl ether (MTBE). In other embodiments, the solvent mixture is an aqueous THF, dioxane or acetonitrile solvent mixture. In still other embodiments, the contacting is carried out in the presence of a base. Suitable bases include triethylamine, N,N-diisopropylethylamine, DBU and N-methylmorpholine, as well as potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3) or sodium bicarbonate (NaHCO3). In one set of embodiments, the contacting is carried out at a temperature of -20°C to about 50°C. In another set of embodiments, the contacting is carried out at ambient temperature (about 25°C ± 5°C). After the initial contact, the reaction can be monitored until completion, which may involve a period of about 20 minutes to about 3 days depending on the specific conditions (and solvents) used. Typically, the production of compound (i-4) is completed within about 1-2 hours. In some embodiments, compound (i-4) is isolated according to standard protocols, such as those provided in the Examples below.

[0108] Compounds of formula (I-4) can then be converted to compounds of formula (I) by direct amidation of the ester (present in (i-4)) or by first converting the ester to the carboxylic acid and then forming the amide using a suitable aniline. As provided herein, suitable anilines are selected from the group consisting of 4-methyl-3-(trifluoromethyl)aniline and 3-chloro-4-methylaniline.

[0109] For direct amidation, aniline is combined with compound (i-4) in the presence of a metal reagent such as an organoaluminum reagent or aluminum compound (salt), an alkyllithium compound, a Grignard reagent, an organozinc reagent or zinc compound (salt), sodium hydride, or sodium, potassium or lithium HMDS salt. In some embodiments, the metal reagent is an organoaluminum reagent such as Al(Me) 3 or a metal reagent in DABAL-Me 3 (trimethylaluminum complex with DABCO). In some selected embodiments, the metal reagent is Al(Me) 3.

[0110] For those embodiments in which the ester form of compound (i-4) is converted to a carboxylic acid, hydrolysis can be performed using an aqueous acid solution such as sulfuric acid. In some embodiments, temperatures above ambient temperature, for example, up to 100° C., can be used. Coupling of the carboxylic acid form of (i-4) with an aniline, such as 4-methyl-3-(trifluoromethyl)aniline or 3-chloro-4-methylaniline can be performed by an activated ester method (using methanesulfonyl chloride with a base such as N,N-diisopropylethylamine) or another coupling reagent such as HATU with a base such as N-methylmorpholine.

[0111] In another aspect, provided herein is another method for preparing a compound having formula (I) or a salt thereof:

[0112]

[0113] Among them, R 1 Cl or CF 3 ; R 2 is F or Cl; and R 3 H or CH 3 ; and wherein the compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities, the method comprising:

[0114] (a) reacting a compound of formula (ii-4) or a salt thereof under conditions sufficient to form a compound of formula (ii-5):

[0115]

[0116] said compound being substantially free of enantiomeric or diastereomeric impurities,

[0117] Contact with cyclopentanone and reducing agent,

[0118] and

[0119] (b) contacting the compound of formula (ii-5) with a compound having the formula, under conditions sufficient to form a compound of formula (I) substantially free of enantiomeric or diastereomeric impurities,

[0120]

[0121] Where LG is a leaving group.

[0122] In one set of embodiments, R 1 CF3; R 2 is F; and R 3 In another embodiment, R 1 CF3; R 2 is Cl; and R 3 is H. In yet another group of embodiments, R 1 is Cl; R 2 is F; and R 3 For CH3.

[0123] Turning first to step (a), in one set of embodiments, a compound of formula (ii-4) is provided that is substantially free of isomers (ii-a), (ii-b), and (ii-c). In some preferred embodiments, compound (ii-4) is provided and is at least 95% pure, more preferably at least 96%, 97%, or at least 98% pure relative to the other isomers. In even further preferred embodiments, compound (ii-4) is provided and is at least 99% or 99.5% pure relative to the other isomers.

[0124] Compound (ii-4) is usually first contacted with cyclopentanone and acid to promote the formation of the intermediate imine, and then reduced to the corresponding amine using a suitable reducing agent. Examples of suitable reducing agents include hydrogen (and palladium or other metal catalysts), borohydride reagents and aluminum hydride reagents. In one group of embodiments, the reducing agent is a borohydride reagent, such as sodium borohydride or lithium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The conditions for imine formation and subsequent reduction can be changed according to conventional methods. For example, imine formation can be completed in a single solvent or solvent mixture (such as dichloromethane and p-dioxane). Similarly, the temperature of the reaction will be selected to reduce the amount of by-products and maintain a good yield. Typically, such a reaction can be carried out at ambient temperature for 1-2 hours up to 18 hours or longer.

[0125] Formula (ii-5) compound can be separated using standard post-treatment conditions for the reductive amination step. These conditions may include, for example, any acid in the neutralization reaction (or contact) mixture, and by extracting the mixture with an organic solvent, then removing the solvent from the organic portion to separate compound (ii-5). Typically, further purification of compound (ii-5) is not required before starting step (b).

[0126] In step (b), the product of step (a) is contacted with a compound having the formula,

[0127] wherein LG is a leaving group. As with the earlier methods described, one skilled in the art will appreciate that a suitable leaving group is one that promotes the compound to participate in the desired amide bond formation. More specifically, LG is a leaving group that promotes the reaction at the carbonyl center bearing LG. In one set of embodiments, LG is a halogen. In another set of embodiments, LG is Cl. In another set of embodiments, -LG is selected from -OH, -OAc, -OS(O)2-(4-methylphenyl) and -OS(O)2methyl. In another set of embodiments, -LG is -OC(O)Ph(R 2 )(R 3)-, forming a symmetrical anhydride with the rest of the molecule. In some embodiments, the contact is carried out in an organic solvent or a solvent mixture or an aqueous solvent mixture, for example a mixture of water and an ether such as methyl tert-butyl ether (MTBE). In selected embodiments, the solvent is an organic solvent, such as THF or another ether solvent. In other embodiments, the contact is carried out in the presence of a base. Suitable bases include triethylamine, diisopropylethylamine, DBU and N-methylmorpholine, as well as potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3) or sodium bicarbonate (NaHCO3). In one group of embodiments, the contact is carried out at a temperature of -20°C to about 50°C. In another group of embodiments, the contact is carried out at ambient temperature (about 25°C ± 5°C). After the initial contact, the reaction can be monitored until completion, which may involve a period of about 20 minutes to about 3 days depending on the specific conditions (and solvents) used. Typically, the preparation of compound (I) is completed in about 1-2 hours. In some embodiments, compounds of Formula (I) are isolated according to standard protocols, such as those provided in the Examples below.

[0128] In yet another aspect, provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, comprising any two, three or four of steps (a), (b), (c), (d), (d1) and (d2), which steps may be sequential or discontinuous in the synthetic scheme:

[0129] (a) ester of 3-(4-nitrophenyl)-3-oxo-propionate (i-1) (R is an alkyl group, preferably C 1-8 Alkyl or aryl or aryl-C 1-4 alkyl) with (R)-(-)-2-phenylglycinol and acrolein diethyl acetal or its equivalent to produce compound (i-2);

[0130]

[0131] (b) hydrogenating or reducing (i-2) to produce an intermediate amine, and converting the intermediate to (i-3) using cyclopentanone and a reducing agent;

[0132]

[0133] (c) reacting (i-3) with 2-fluoro-6-methylbenzoyl chloride or 2-chlorobenzoyl chloride to obtain (i-4);

[0134]

[0135] (d) reacting (i-4) with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline under conditions sufficient to provide a compound of formula (I).

[0136]

[0137] Optionally, in some embodiments, the conversion provided in step (d) can be performed in a two-step process, comprising:

[0138] (d)(1) Converting the ester (i-4) into the carboxylic acid (i-5):

[0139]

[0140] (d)(2) Compound (i-5) is reacted with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline under conditions sufficient to provide a compound of formula (I).

[0141]

[0142] In some embodiments, the method for preparing a compound of formula (I) comprises steps (a) and (b). In other embodiments, the method for preparing a compound of formula (I) comprises steps (b) and (c). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (c) and (d). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (c) and (d)(1). In other embodiments, the method for preparing a compound of formula (I) comprises steps (c) and (d)(2). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (b) and (d). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (b) and (d1). In other embodiments, the method for preparing a compound of formula (I) comprises steps (b) and (d2).

[0143] In some embodiments, the method for preparing a compound of formula (I) comprises steps (a) and (c). In other embodiments, the method for preparing a compound of formula (I) comprises steps (a) and (d). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (a) and (d1). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (a) and (d)(2).

[0144] In other embodiments, the method for preparing a compound of formula (I) comprises steps (a), (b), (c) and (d), or optionally at least three of (d)(1) and (d)(2). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (a), (b) and (c). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (a), (b) and (d). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (a), (b) and (d1). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (a), (b) and (d2). In another group of embodiments, the method for preparing a compound of formula (I) comprises steps (b), (c) and (d). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (b), (c) and (d1). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (b), (c) and (d2).

[0145] In another related aspect, provided herein is a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, comprising any two, three or four of steps (a'), (b'), (c'), (d') and (e'), which steps may be sequential or discontinuous in the overall synthetic pathway:

[0146] (a') esters of 3-(4-nitrophenyl)-3-oxo-propionate (i-1 or ii-1, wherein R is an alkyl group, preferably C 1-8 Alkyl, aryl or aryl-C 1-4 alkyl), with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline under conditions sufficient to provide a compound of formula (ii-2);

[0147]

[0148] (b') (ii-2), (R)-(-)-2-phenylglycinol and acrolein diethyl acetal or its equivalent to obtain compound (ii-3);

[0149]

[0150] (c') reducing (ii-3) under conditions sufficient to produce the intermediate diamine (ii-4) substantially free of enantiomeric or diastereomeric impurities;

[0151]

[0152] (d') converting (ii-4) to (ii-5) using cyclopentanone and a reducing agent; and

[0153]

[0154] (e') reacting (ii-5) with 2-fluoro-6-methylbenzoyl chloride or 2-chlorobenzoyl chloride to obtain (I);

[0155]

[0156] In the above methods using steps (a), (b), (c), (d), (d1), (d2), (a'), (b'), (c'), (d') or (e'), those skilled in the art will understand that the indicated compounds can be used as salts, hydrates or solvates in some cases; and conditions can be selected that are favorable to the indicated reactions and improve the yield and / or purity of the step products.

[0157] In some embodiments, the method for preparing a compound of formula (I) comprises steps (a') and (b'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (b') and (c'). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (c') and (d'). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (d') and (e').

[0158] In some embodiments, the method for preparing a compound of formula (I) comprises steps (a') and (c'). In yet other embodiments, the method for preparing a compound of formula (I) comprises steps (a') and (d'). In yet other embodiments, the method for preparing a compound of formula (I) comprises steps (a') and (e').

[0159] In other embodiments, the method for preparing a compound of formula (I) comprises steps (b') and (d'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (b') and (e'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (c') and (e').

[0160] In some embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), and (c'). In some embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), and (d'). In some embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), and (e'). In some embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (c'), and (d'). In some embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (c'), and (e'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (d'), and (e'). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (b'), (c'), and (d'). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (b'), (c'), and (e'). In still other embodiments, the method for preparing a compound of formula (I) comprises steps (c'), (d'), and (e').

[0161] In other embodiments, the method for preparing a compound of formula (I) comprises at least four steps of steps (a'), (b'), (c'), (d'), and (e'). In selected embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), (c'), and (d'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), (c'), and (e'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), (d'), and (e'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (c'), (d'), and (e'). In another group of embodiments, the method for preparing a compound of formula (I) comprises steps (b'), (c'), (d'), and (e'). In other embodiments, the method for preparing a compound of formula (I) comprises steps (a'), (b'), (c'), (d'), and (e').

[0162] The methods provided above and herein provide cost-effective, safe, efficient and / or readily scalable methods for the large-scale or commercial production of each of IA, IB and IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof.

[0163] In one embodiment, provided herein are methods for preparing substantially pure compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or rotamers thereof. In one embodiment, provided herein are methods for preparing substantially chemically pure compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or rotamers thereof. In one embodiment, provided herein are methods for preparing compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or rotamers thereof that are suitable for use in humans, such as for the treatment, prevention and / or management of diseases or conditions, including but not limited to diseases mediated by C5a receptor antagonists.

[0164] In one embodiment, provided herein is a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof on a scale greater than 1 gram, greater than 10 grams, greater than 100 grams, greater than 1,000 grams, greater than 10,000 grams or greater than 100,000 grams.

[0165] In one embodiment, provided herein is a method for preparing a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or rotamer thereof, in an overall yield of greater than about 10%, greater than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or greater than about 95%, wherein the yield is calculated based on the limiting starting material.

[0166] In one embodiment, provided herein is a method for preparing a substantially pure compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or rotamer thereof. In one embodiment, the purity of the compound of Formula IA, IB, and IC, or a pharmaceutically acceptable salt, solvate, hydrate, or rotamer thereof, is greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, greater than about 99.8%, greater than about 99.9%, greater than about 99.95%, greater than about 99.98%, or greater than about 99.99% by weight of the total batch.

[0167] In one embodiment, the total impurities in the compound of Formula IA, IB and / or IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, prepared by the methods provided herein, are less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, less than about 0.1%, less than about 0.05%, less than about 0.02%, less than about 0.01%, less than about 0.005% or less than about 0.001% by weight of the total batch.

[0168] In one embodiment, each impurity in a compound of Formula (I) prepared by a method provided herein, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, is less than about 5%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, less than about 0.01%, less than about 0.005%, less than about 0.001%, less than about 0.0005% or less than about 0.0001% by weight of the total batch.

[0169] In one embodiment, the methods herein provide substantially chemically pure compounds of Formula (I), or pharmaceutically acceptable salts, solvates, hydrates, or rotamers thereof. In one embodiment, the chemical purity of the compounds of Formula IA, IB, or IC, or pharmaceutically acceptable salts, solvates, hydrates, or rotamers thereof, is greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, greater than about 99.5%, greater than about 99.8%, greater than about 99.9%, greater than about 99.95%, greater than about 99.98%, or greater than about 99.99% by weight of the total batch.

[0170] In one embodiment, the purity of the isolated product or reaction mixture provided herein is analyzed by one or more analytical methods, e.g., HPLC (high performance liquid chromatography), GC (gas chromatography), and TLC (thin layer chromatography). In one embodiment, impurities are detected by analytical methods, e.g., HPLC, GC, or TLC. In one embodiment, impurities or expected impurities in the isolated product or reaction mixture provided herein include, but are not limited to, the starting materials used for the reaction or any starting materials used in the preceding steps.

[0171] In some cases, the impurity in the isolated product of the methods provided herein can be a volatile organic compound, such as methanol, dimethylformamide, dichloromethane, toluene, acetone, methyl tert-butyl ether, ethanol, or tetrahydrofuran.

[0172] In some cases, the methods provided herein produce a compound of Formula IA, IB or IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, that has a loss on drying (LOD) of less than about 5 wt%, less than about 2 wt%, less than about 1 wt%, less than about 0.9 wt%, less than about 0.8 wt%, less than about 0.7 wt%, less than about 0.6 wt%, less than about 0.5 wt%, less than about 0.4 wt%, less than about 0.3 wt%, less than about 0.2 wt%, less than about 0.1 wt%, less than about 0.05 wt%, or less than about 0.01 wt% of the total batch.

[0173] In one embodiment, the methods provided herein produce a compound of Formula IA, IB or IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, having a residue on ignition of less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05% or less than about 0.01% by weight of the total batch.

[0174] In one embodiment, the methods provided herein produce a compound of Formula IA, IB or IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, having a total heavy metal-based impurity level of less than about 500 ppm (parts per million) w / w, less than about 200 ppm w / w, less than about 100 ppm w / w, less than about 50 ppm w / w, less than about 20 ppm w / w, less than about 10 ppm w / w, less than about 5 ppm w / w, less than about 2 ppm w / w, less than about 1 ppm w / w, less than about 0.5 ppm w / w, less than about 0.2 ppm w / w, or less than about 0.1 ppm w / w for the total batch.

[0175] In one embodiment, provided herein are methods for preparing the compounds of Formula IA, IB or IC, or pharmaceutically acceptable salts, solvates, hydrates or rotamers thereof, which are substantially free of one or more residual solvents, including but not limited to methanol, ethanol, dimethylformamide, toluene, dichloromethane, acetone, methyl tert-butyl ether and tetrahydrofuran. In one embodiment, the residual solvent or expected residual solvent is less than about 5,000 ppm w / w, less than about 2,000 ppm w / w, less than about 1,000 ppm w / w, less than about 500 ppm w / w, less than about 200 ppm w / w, less than about 100 ppm w / w, less than about 50 ppm w / w, less than about 20 ppm w / w, less than about 10 ppm w / w, less than about 5 ppm w / w, less than about 2 ppm w / w, less than about 1 ppm w / w, less than about 0.5 ppm w / w, less than about 0.2 ppm w / w or less than about 0.1 ppm w / w for the total batch. In one embodiment, expected residual solvents such as methanol, ethanol, dimethylformamide, toluene, dichloromethane, acetone, methyl tert-butyl ether, and tetrahydrofuran are not detected.

[0176] In one embodiment, provided herein are methods for preparing a compound of Formula IA, IB or IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, wherein the water content is less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2% or less than about 0.1% by weight of the total batch.

[0177] In one embodiment, provided herein are methods for preparing the compound of Formula IA, IB or IC, or a pharmaceutically acceptable salt, solvate, hydrate or rotamer thereof, that has the appearance of a white or off-white solid.

[0178] In one embodiment, one or more steps of the methods provided herein are performed under GMP (Good Manufacturing Practice) conditions. In one embodiment, one or more steps of the methods provided herein are performed under non-GMP conditions.

[0179] Example

[0180] The abbreviations used in the following examples have the following meanings:

[0181] aq: aqueous; BBr3: boron tribromide; CH2Cl2 or DCM: dichloromethane; CH3CN: acetonitrile; CH3OH or MeOH: methanol; DIEA: N,N-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; equiv. or eq.: equivalent; Et3N: triethylamine; Et2O: triethylamine; EtOH: ethanol; h: hour; HATU, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HCl: hydrogen chloride; H2O: water; K2CO3: potassium carbonate;

[0182] KHSO4: potassium bisulfate; MgSO4: magnesium sulfate; mL: milliliter; NaCl: sodium chloride; NaH: sodium hydride; NaHCO3: sodium bicarbonate; NaOEt: sodium ethoxide; NaOH: sodium hydroxide; NaOMe: sodium methoxide; Na2SO4: sodium sulfate; NH4Cl: ammonium chloride; NMP: N-methylpyrrolidone

[0183] pH: -log[H + ]; POCl3: phosphorus trichloride; PPTS: pyridinium p-toluenesulfonate; RP-HPLC: reversed-phase high-pressure liquid chromatography; RT: room temperature; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin-layer chromatography

[0184] Example 1

[0185] This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide using the following reagents: Figure 1 (Scheme 1) provides a more general approach.

[0186] Route 1:

[0187]

[0188] Step 1: A 12 L oven-dried three-necked flask equipped with a mechanical stirrer, condenser, and thermometer was charged with acrolein diethyl acetal (1127 g, 8.666 mol, 1.05 eq) and heated to 40° C. A mixture of ethyl 3-(4-nitrophenyl)-3-oxopropionate (1956 g, 8.253 mol) and (R)-(-)-2-phenylglycinol (>99.5% ee, 1187 g, 8.666 mol, 1.05 eq) was added portionwise over 40 minutes to maintain a stirrable mixture at an internal temperature of approximately 40° C. After all solids were added, the mixture was stirred at 40° C. for 10 minutes. A 4 M solution of HCl in dioxane (206.2 mL, 0.825 mol, 10 mol%) was then added via the condenser over 2 minutes, raising the internal temperature to 70° C. The reaction was stirred for 22 hours, at which point LC-MS indicated consumption of the starting material and enamine intermediate. The heat was turned off and ethanol (6.6 L) was added. The solution was then seeded with 4 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-3-carboxylate and stirred at room temperature for 18 hours. The solid was then filtered off and the flask and filter apparatus were rinsed with 0.1 L of ethanol. The isolated solid was then washed three times with ethanol on the filter (250 mL each) and dried under vacuum to afford 1253 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate as a bright yellow solid (38% yield, 98.5 w / w % HPLC purity, 0.15 wt % EtOH).

[0189] Step 2: 260 g of ethyl (3R,8aR)-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxylate (0.659 mol), 0.66 L of ethanol and 56 g of palladium catalyst (10% Pd / C, Degussa type E101 NE / W, 50% wet, 21.5 wt% powder, 4.0 mol% Pd) were placed in a 2.2 L Parr bottle and purged with nitrogen. The bottle was mounted on a Parr shaker apparatus and hydrogen was added at a rate that maintained the external temperature of the bottle below 30°C. After 4 hours, the consumption of hydrogen slowed down. The bottle was then shaken under 50 psi of hydrogen for 2 hours. Subsequently, 94 ml of glacial acetic acid (1.65 mol, 2.5 eq) was added to the bottle and the bottle was purged with hydrogen three times at 50 psi. The bottle is then shaken under 35-55psi hydrogen for 48 hours, keeping the temperature below 30°C. Remove the bottle from the device, add 55 milliliters of 12M HCl aqueous solution (0.659 mole, 1 equivalent), then add 87mL cyclopentanone (0.989 mole, 1.5 equivalents). Purge the bottle three times with hydrogen at 50psi, then vibrate under 50psi hydrogen for 16-20 hours. The mixture is removed from the device and filtered through a sintered funnel containing diatomaceous earth (80 grams), then washed three times with 0.125L ethanol. Add 54.1 grams of anhydrous sodium acetate (0.659 mole, 1 equivalent), and the mixture is concentrated in vacuo at 40-55°C to remove 0.9 liters of volatile components. Add 2.0 liters of acetonitrile and remove 2.0L of volatile components in vacuo. The crude material is diluted with 1.0 liters of acetonitrile and mechanically stirred at room temperature for 30 minutes. The mixture was filtered through celite (40 g) and the filter cake was washed with 0.28 L of acetonitrile. The combined filtrates gave a crude ammonium acetate solution (solution A, ee=78%). The two independently obtained solutions A were combined for further processing.

[0190] In a 12-liter three-necked flask equipped with a mechanical stirrer, an internal thermometer, and a reflux condenser, (-)-O,O'-di-p-toluoyl-L-tartaric acid (1.019 kg, 2.64 mol, 2 equivalents) was dissolved in 5.8 L of acetonitrile. The mixture was heated to 60°C with stirring, and then 1 L of Solution A was quickly added. The resulting solution was seeded with 4 g of crystalline (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylic acid ethyl ester (-)-O,O'-di-p-toluoyl-L-tartaric acid salt (1:2) and stirred at 60°C for 15 minutes. A seed bed formed after 15 minutes at 60°C. The remainder of Solution A was added over 2.5 hours, maintaining an internal temperature of 60°C. After the addition was complete, the heat was turned off, and the mixture was stirred for 17 hours, reaching a final temperature of 22.5°C. The suspension was filtered, and the solids were washed with 0.50 L of acetonitrile to rinse the equipment and transfer all the solids to the filter. The resulting wet solids were washed on the funnel with 3.0 L of acetonitrile and dried in a vacuum oven at 45°C for 48 hours to yield 1.005 kg of (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylic acid ethyl ester (-)-O,O'-di-p-toluoyl-L-tartrate (1:2) as an off-white solid (70% yield, containing 1% by weight of acetonitrile). The enantiomeric ratio of the product was 99.4:0.6.

[0191] Step 3: In a 5-L three-necked flask equipped with a mechanical stirrer and addition funnel, solid anhydrous potassium carbonate (KCO, 226 g, 1.64 mol, 4.1 eq) was dissolved in water (0.82 L) and cooled to ambient temperature. MTBE (0.82 L) was added, followed by solid (2R,3S)-2-[4-(cyclopentylamino)phenyl]piperidine-3-carboxylic acid ethyl ester (-)-O,O′-di-p-toluoyl-L-tartrate (1:2) (436 g, 0.400 mol). The mixture was stirred vigorously at room temperature for 1 hour, followed by the addition of 2-fluoro-6-methylbenzoyl chloride (72.5 g, 0.420 mmol, 1.05 eq) in MTBE (0.14 L) dropwise over 1 hour. The product began to precipitate from the reaction before the addition of the acid chloride was complete. The reaction was stirred vigorously at room temperature for 30 minutes and monitored by LC-MS for the disappearance of the starting material. The mixture was then transferred to a 5L evaporating flask using 0.3L MTBE to rinse the equipment and remove all solids. The mixture was concentrated in vacuo to remove the MTBE, and then 0.3L of heptane was added and the mixture was evaporated again, leaving only the product suspended in the aqueous solution. The flask was removed from the rotary evaporator and water (0.82L) and heptane (0.82L) were added. The suspension was stirred vigorously with a mechanical stirrer for 16 hours. The contents were then filtered and the solid was washed with water (2×0.42L) and heptane (0.42L). The solid was dried in a vacuum oven at 45°C to give 172g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid ethyl ester as an off-white powder (95% yield).

[0192] Step 4: A 0.5-liter, three-necked round-bottom flask was dried overnight in an oven at 200°C and then cooled under a stream of nitrogen. The flask was equipped with a magnetic stir bar, a nitrogen inlet, and a thermometer. Under nitrogen, 30.2 g of ethyl (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylate (66.7 mmol), 11.5 mL of 4-methyl-5-trifluoromethylaniline (80 mmol, 1.2 eq), and 141 mL of dry toluene were added to the flask. Nitrogen was bubbled through the resulting solution for 10 minutes, after which the solution was warmed to 30°C. The oil bath was removed, and 100 mL of a 2 M AlMe3 solution in toluene (Aldrich, 200 mmol, 3 eq) was added to the reaction mixture over approximately 45 minutes at a rate that maintained the reaction temperature between 35-40°C. The temperature of the reaction mixture was then raised to 55°C over 1 hour, and the reaction mixture was stirred at 55°C for 8 hours, thereby consuming all the starting ester (monitored by LC-MS). The reactants were then cooled overnight to ambient temperature, and the solution was then added to a mechanically stirred 1-liter flask containing a solution of 67.8 g of potassium sodium tartrate tetrahydrate (240 mmol, 3.6 equivalents) in 237 ml of water, pre-cooled to 10°C in an ice bath. The addition process took approximately 30 minutes, during which the reaction mixture self-heated to 57°C. The empty reaction flask was then rinsed with 20 ml of dry toluene, and the solution was mixed with the quenched mixture. The mixture was then cooled to room temperature under stirring, 91 ml of ethyl acetate was added, and the mixture was stirred for an additional 15 minutes. The mixture was then filtered through a pad of celite, and the filtrate was separated into two layers. The organic layer was then separated and washed with a solution of 5.7 g of potassium sodium tartrate tetrahydrate (20 mmol) in 120 ml of water, followed by two 120 ml portions of water. The wet organic solution was concentrated in vacuo to approximately 150 g weight and solvent exchanged with ethanol, maintaining a total volume of 0.2-0.3 L, until the 1H NMR observed <1 mol% toluene relative to ethanol. The solution was then evaporated at elevated temperature to a weight of 223 g and heated to reflux. Mechanical stirring was initiated and 41 ml of water was added. The resulting solution was seeded with crystals of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide at 60°C and then slowly cooled to room temperature over 2 hours. The slurry was then stirred for 18 hours and the solid was filtered off. The solid was then washed with two 30 mL portions of 7:3 ethanol / water and dried in a vacuum oven at 50° C. for 24 h to afford 31.0 g of ((2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as off-white crystals (80% yield). Analytical data: HPLC purity: 99.59%; >99.8% HPLC de and ee; ICP-OES Pd: <1 ppm; Al: 6 ppm; residual toluene by headspace GC-MS analysis: 15 ppm; trace <0.1%; KF 0.1%. 1 H NMR(400MHz,TFA-d)δ7.91(d,J=8.6Hz,1H),7.84(d,J=8.6Hz,1H),7.58-6.82(m,8H),6.75(t,J=8.6Hz,1H),4.10-4.00(m,1H) ,3.60-3.47(m,1H),3.45-3.41(m,1H),3.33-3.25(m,1H),2.44-2.22(m,7H),2.04-1.92(m,4H),1.82-1.69(m,7H),MS:(ES)m / z 582(M+H + ).

[0193] Example 2

[0194] This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide using the reagents shown in Scheme 2 by Figure 2 (Scheme 2) provides a general method.

[0195] Route 2:

[0196]

[0197] Step 1: Solid (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid ethyl ester (316 g, 0.698 mol) was added portionwise to a 12-L flask containing 2.80 L of 0.44 M H2SO4 mechanically stirred in water heated to 70°C. 0.36 L of an additional 0.44 M H2SO4 was used to wash the solid down from the funnel. The suspension was raised to 95°C and stirred at this temperature for 21 hours, after which complete dissolution occurred with no more than 4% of the starting material remaining. The reaction was cooled to ambient temperature. To the mixture was added 2.80 L of 1 M aqueous NaOH solution over 30 minutes, maintaining the temperature at approximately 20°C, followed by 1.58 L of MTBE and then 1.40 L of 1 M NaOH. The mixture was stirred vigorously for 1 hour until all the solids dissolved (final pH was 13.1). The layers were separated and the organic layer discarded. The aqueous layer was extracted again with 1.58 L of MTBE. The aqueous layer was concentrated in vacuo to remove excess MTBE. The solution was transferred back to the mechanically stirred flask and acidified with 1 M H2SO4 over 25 minutes until the pH reached 4.8 (approximately 0.71 L of 1 M H2SO4), and the resulting mixture was stirred at ambient temperature for 1 hour. The slurry was filtered and the solid was washed with two 2.0 L / portions of water, followed by 1.0 L of heptane. The solid was dried in a vacuum oven at 45°C to give 279 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid as a white solid (94% yield).

[0198] Step 2, Condition 1: To a 12 L flask containing (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid in 1.66 L of dichloromethane was added 4-methyl-3-(trifluoromethyl)aniline (112 mL, 137 g, 0.782 mol, 1.2 eq) followed by N,N-diisopropylethylamine (204 mL, 152 g, 1.17 mol, 1.8 eq). The solution was cooled to 0°C and methanesulfonyl chloride (65.6 mL, 97.1 g, 0.848 mol, 1.3 eq) was added dropwise. After stirring at ambient temperature for 18 hours, N,N-diisopropylethylamine (114 mL, 84.2 g, 0.652 mol, 1.0 eq) was added. The reaction mixture was stirred at ambient temperature for 15 minutes, and 2.22 L of isopropyl acetate and 0.55 L of DCM were added to the flask. The solution was washed with 2.22 L of water and then with 1.11 L of water. The organic layer was washed twice with 2.22 L of 0.1 M aqueous sodium hydroxide solution. 139 g of anhydrous sodium sulfate was added to the organic layer and stirred for 15 minutes. 544 g of silica gel (230-400 mesh) was added to the suspension, and the mixture was stirred for 30 minutes. The suspension was filtered using a high-sintered funnel, and the silica gel bed on the funnel was washed with 2.50 L of isopropyl acetate / DCM (1:1). The combined solution was concentrated under vacuum at 40°C to a weight of approximately 760 g. The flask was equipped with a mechanical stirrer, at which point spontaneous crystallization began. After stirring for 15 minutes, 1.14 L of heptane was added to the suspension over a period of 20 minutes. Stirring at ambient temperature for 16 hours gave colorless crystals, which were filtered off and washed on the funnel with two portions of heptane (0.76 L and 0.38 L). The solid was dried in a vacuum oven at 45° C. for 16 hours to give 289 g of ((2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as colorless crystals (76% yield, ee 98.6%, 1.4% by weight of isopropyl acetate ( 1 H NMR); 98.1% HPLC purity, 220 nm). 1 H NMR(400MHz,TFA-d)δ7.91(d,J=8.6Hz,1H),7.84(d,J=8.6Hz,1H),7.58-6.82(m,8H),6.75(t,J=8.6Hz,1H),4.10-4.00(m,1H) ,3.60-3.47(m,1H),3.45-3.41(m,1H),3.33-3.25(m,1H),2.44-2.22(m,7H),2.04-1.92(m,4H),1.82-1.69(m,7H),MS:(ES)m / z 582(M+H+ ).

[0199] Step 2, Condition 2: To a 250 mL flask containing (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid (8.01 g, 18.8 mmol) in 40 mL of isopropyl acetate was added 4-methyl-3-(trifluoromethyl)aniline (2.97 mL, 3.62 g, 20.7 mmol, 1.1 eq) followed by N-methylmorpholine (3.10 mL, 2.85 g, 28.2 mmol, 1.5 eq) and HATU (9.29 g, 24.4 mol, 1.3 eq). After stirring at ambient temperature for 44 hours, the reaction mixture was diluted with 100 mL of isopropyl acetate and 60 mL of water and stirred for 15 minutes. Undissolved solids were filtered off and the aqueous layer discarded. The organic phase was washed twice with 60 mL of water and then concentrated in vacuo to a weight of 58 g. The solvent was then exchanged with ethanol by co-distillation, and the solution was concentrated in vacuo to a weight of 74 g (0.6 wt% residual isopropyl acetate). The mixture was heated to reflux, and 14 ml of water was added. The resulting solution was seeded with crystals of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide at 60°C and then slowly cooled to room temperature over 2 hours. The slurry was then stirred for 18 hours, and the solid was filtered off. The solid was then washed with two 8-ml portions of 7:3 ethanol / water and dried in a vacuum oven at 50°C for 24 hours to afford 7.91 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as colorless crystals (72% yield). Analytical data: HPLC purity: 99.26%; >99.8% HPLC de and ee. 1 H NMR(400MHz,TFA-d)δ7.91(d,J=8.6Hz,1H),7.84(d,J=8.6Hz,1H),7.58-6.82(m,8H),6.75(t,J=8.6Hz,1 H),4.10-4.00(m,1H),3.60-3.47(m,1H),3.45-3.41(m,1H),3.33-3.25(m ,1H),2.44-2.22(m,7H),2.04-1.92(m,4H),1.82-1.69(m,7H),MS:(ES)m / z 582(M+H + ).

[0200] Example 3

[0201] This example illustrates the preparation of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide using the reagents shown in Scheme 3 by Figure 3 (Scheme 3) provides a general method.

[0202] Route 3:

[0203]

[0204] Step 1: To a 500 mL three-necked round-bottom flask equipped with a thermometer was added ethyl 3-(4-nitrophenyl)-3-oxo-propionate (50 g, 211 mmol), o-xylene (100 mL), and then 4-methyl-3-(trifluoromethyl)aniline (33.25 mL, 232 mmol). The resulting reaction mixture was stirred at 130°C for 6 hours (a distillation condenser was used to remove ethanol produced during the reaction, as it formed). The reaction mixture was cooled to room temperature and aged overnight. The resulting crystals were collected by filtration, washed with diethyl ether (500 mL), and dried under high vacuum to provide N-[4-methyl-3-(trifluoromethyl)phenyl]-3-(4-nitrophenyl)-3-oxo-propionamide (74.4 g) in a 96% yield as a bright yellow crystalline solid. 1 H NMR showed a ~2:1 mixture of keto-enol tautomers. 1 H NMR (400MHz, DMSO-d6) δ10.61(bs,1H),10.48(s,1H),8.37-8.31(m,2H),8.21(d,J=9Hz,1H),8.0-7.95(m,2H),7.6 5(dd,J=21.2,8.2Hz,1H),7.37(dd,J=13.3,8.2Hz,1H),6.06(s,1H),4.25(s,2H),2.37,2.36(2s,3H);MS:(ES)m / z 367(M+H + ).

[0205] Step 2: A mixture of (R)-(-)-2-phenylglycinol (3.02 g, 22 mmol), N-[4-methyl-3-(trifluoromethyl)phenyl]-3-(4-nitrophenyl)-3-oxo-propionamide (7.32 g, 20 mmol), acrolein diethyl acetal (4 ml, 28.6 mmol) and formic acid (0.8 ml, 20 mmol) in p-dioxane (10 ml) was stirred at 90°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (20 mL), adsorbed onto silica gel, and purified by column chromatography (the product was eluted with 30% ethyl acetate in hexanes) to give (3R)-N-[4-methyl-3-(trifluoromethyl)phenyl]-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxamide (8.4 g) in 80% yield as a yellow foam with a diastereomeric ratio of ~3:2. 1 H NMR (400MHz, CDCl3) δ7.96-786(bs,1H),7.20-7.15(m,3H),7.15-7.0(m,6H),6.9(dd,J=7.81,1.57Hz,1H) ,6.7(d,J=8.6Hz,1H),6.44(d,J=29.7Hz,1H),5.26(dd,J=8.6,3.5Hz,0.6H),5.06(dd,J=9.77,2.73Hz,0. 4H),4.48(d,J=6.25Hz,0.5H),4.36-4.28(m,1H),4.22-4.17(m,0.5H),4.02(dd,J=8.99,1.56Hz,0.5H),3 .8(dd,J=8.6,5.08Hz,0.5H),3.2-2.8(m,1H),2.7-2.4(m,2H),2.14(s,3H),1.95-1.85(m,1H); MS:(ES)m / z 524(M+H + ). .

[0206] Step 3: (3R)-N-[4-methyl-3-(trifluoromethyl)phenyl]-5-(4-nitrophenyl)-3-phenyl-3,7,8,8a-tetrahydro-2H-oxazolo[3,2-a]pyridine-6-carboxamide (2.1 g, 4 mmol), DMF (12 mL), palladium catalyst (10% Pd / C, Degussa type E101 NE / W, 50% wet, 800 mg, 45 wt% powder, 0.36 mmol) and acetic acid (0.6 mL, 10 mmol) were placed in a Parr bottle and stirred under hydrogen (60 psi) at ambient temperature for 20 hours. The reaction mixture was passed through a glass frit to remove the palladium catalyst, washed with methanol (2×20 mL), and evaporated to dryness in vacuo on a rotary evaporator to give the crude product. To this crude product were added ethyl acetate (30 mL), dichloromethane (60 mL), and (-)-O,O'-di-p-toluoyl-L-tartaric acid (L-DTTA, 1.55 g, 4 mmol), and the resulting mixture was aged at room temperature overnight. The resulting crystals were collected by filtration, washed with cold ethyl acetate (2 x 10 mL), and dried under high vacuum to afford (2R,3S)-2-(4-aminophenyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide as a 1:1 L-DTTA salt (1.32 g) in 43% yield with an enantiomeric ratio of 98:2 (chiral column: Regis Cell, HPLC system: Agilent 1200 Series Model G1312A, solvent: 0.1% diethylamine in MeOH, isocratic, flow rate: 1 mL / min, ambient temperature, retention time of the major isomer: 6.86 minutes). 1 H NMR (400MHz, CD3OD) δ8.01(d,J=6.6Hz,4H),7.88(d,J=2.35Hz,1H),7.5(dd,J=8.4 ,2.34Hz,1H),7.28(d,J=7.8Hz,2H),7.26(d,J=8.99Hz,2H),7.14(d,J=8.6Hz,2H), 6.68(d,J=8.6Hz,2H),5.87(s,2H),4.35(d,J=3.12Hz,1H),3.52-3.58(m,1H),3.06 -3.23(m,2H),2.40(s,9H),2.18-2.12(m,2H),1.84(d,J=14.46Hz,1H);MS:(ES)m / z 378(M+H + ).

[0207] Step 4: To (2R,3S)-2-(4-aminophenyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (-)-O,O′-di-p-toluoyl-L-tartrate (1:1) (15.17 g, 19.85 mmol) in dichloromethane (100 mL) at room temperature were added cyclopentanone (1.93 mL, 21.84 mmol), 4N HCl in p-dioxane (6.31 mL, 25.24 mmol) and acetic acid (3.57 mL, 59.55 mmol), followed by sodium triacetoxyborohydride (6.31 g, 29.78 mmol), and the resulting reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution (100 mL) was slowly added and the organic layer was separated. The aqueous layer was further extracted with dichloromethane (2×100 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give crude (2R,3S)-2-[4-(cyclopentylamino)phenyl]-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (9.5 g), which was used directly in the next step without further purification. 1 HNMR(400MHz,CD3OD)δ7.71(d,J=1.96Hz,1H),7.43(dd,J=8.2,1.95Hz,1H),7. 22(d,J=8.6Hz,1H),7.08(d,J=8.6Hz,2H),6.58(d,J=8.6Hz,2H),3.88(d,J=3. 52Hz,1H),3.69(q,J=12.1,6.3Hz,1H),3.33-3.35(m,1H),2.88-2.78(m,2H),2 .39(s,3H),2.16-1.85(m,5H),1.75-1.5(m,5H),1.45-1.35(m,2H); MS:(ES)m / z 446(M+H + ).

[0208] Step 5: To a flask containing a solution of sodium bicarbonate (1.9 g, 22.62 mmol) in 45 mL of water was added a solution of crude (2R,3S)-2-[4-(cyclopentylamino)phenyl]-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (5.0 g, 11.23 mmol) in 90 mL of tetrahydrofuran over a period of 10 minutes. The resulting mixture was stirred at ambient temperature for 1 hour. A solution of 2-fluoro-6-methylbenzoyl chloride (1.73 g, 8.98 mmol) in 5 mL of tetrahydrofuran was added dropwise over 10 minutes. After the reaction was complete, the undissolved solids were filtered off and the filtrate was concentrated in vacuo. Heptane (50 mL) was added to the remaining aqueous layer, and the mixture was stirred vigorously at room temperature for 16 hours. The contents were filtered, and the solids were washed with water (2 x 30 mL) and then with heptane (30 mL). The solid was dried under high vacuum to give the crude product (3.68 g) which was dissolved in ethanol (22 mL), heated gently, and then water (4 mL) was added. The resulting clear brown solution was cooled to room temperature and stirred overnight. The crystals were collected by filtration, washed with cold ethanol (5 mL), and dried under high vacuum to give (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide (1.66 g) in 28% yield with an enantiomeric ratio of 98:2 over the two steps (chiral column: Pirkle Covalent, (S,S) Whelk-O1, 5 / 100, 25 cm x 4.6 mm Kromasil, S / N 50404, HPLC system: Agilent 1200 Series Model G1312A, solvent: 15% hexane in isopropanol, isocratic, flow rate: 1 mL / min, column temperature: 75°C, retention time of the major isomer: 9.9 min). 1 H NMR(400MHz,TFA-d)δ7.91(d,J=8.6Hz,1H),7.84(d,J=8.6Hz,1H),7.58-6.82(m,8H),6.75(t,J=8.6Hz,1H),4.10-4.00(m,1H) ,3.60-3.47(m,1H),3.45-3.41(m,1H),3.33-3.25(m,1H),2.44-2.22(m,7H),2.04-1.92(m,4H),1.82-.169(m,7H),MS:(ES)m / z 582(M+H + ).

[0209] Example 4

[0210] This example illustrates the synthesis of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-chlorophenyl]piperidine-3-carboxamide.

[0211]

[0212] To a 100 mL flask containing (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid (2.71 g, 6.38 mmol) in 20 mL of dichloromethane was added 3-chloro-4-methylaniline (0.85 mL, 7.01 mmol, 1.1 eq), followed by N-methylmorpholine (1.05 mL, 968 mg, 9.57 mmol, 1.5 eq) and HATU (2.91 g, 7.66 mol, 1.2 eq). After stirring at ambient temperature for 24 hours, the reaction mixture was concentrated in vacuo, diluted with 50 mL of isopropyl acetate and 20 mL of water, and stirred for 15 minutes. Undissolved solids were filtered off and the aqueous layer discarded. The organic phase was washed twice with 20 mL of water and then concentrated in vacuo to dryness. The solid was evaporated twice with 30 mL of ethanol. The resulting residue was then dissolved in 22 ml of refluxing ethanol and 4 ml of water was added. The resulting solution was then refluxed for 15 minutes (until an initial seed bed formed) and then slowly cooled to room temperature. The slurry was then stirred for 3 hours and the solid was filtered off. The solid was then washed with 10 ml of 7:3 ethanol / water and dried in a vacuum oven at 50°C for 24 hours to yield 2.95 g of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)-N-[4-methyl-3-chlorophenyl]piperidine-3-carboxamide as colorless crystals (84% yield).

[0213] It should be understood that the embodiments and implementations described herein are for illustrative purposes only and that various modifications or changes therefrom will be suggested to those skilled in the art and that such modifications or changes are included within the spirit and purview of this application and the scope of the appended claims.

[0214] All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.

Claims

1. A compound of formula (ii-4) or a salt thereof: Where R 1 is Cl or CF3, said compound being at least 95% free of enantiomeric or diastereomeric impurities.

2. The compound according to claim 1, wherein The compound is in the salt form of L-DTTA salt ((-)-O,O'-di-p-methylbenzoyl-L-tartrate).

3. The compound according to claim 1, wherein R 1 It is CF3.

4. The compound according to claim 1, wherein R 1 For Cl.

5. The compound according to claim 1, wherein The compound is in the salt form of bis-L-DTTA salt ((-)-O,O'-di-p-methylbenzoyl-L-tartrate).

6. A method for preparing a compound of formula (I) or a salt thereof, Where R 1 is Cl or CF3; R 2 is F or Cl; and R 3 is H or CH3; And among them, The compound of formula (I) is at least 95% free of enantiomeric or diastereomeric impurities, and the method comprises: (a) a compound having the formula (ii-4) or a salt thereof: Where R 1 is Cl or CF3; said compound is at least 95% free of enantiomeric or diastereomeric impurities, contacting with cyclopentanone and a reducing agent to form a compound having formula (ii-5), (b) contacting the compound of formula (ii-5) with a compound having the formula: Where LG is a leaving group; R 2 is F or Cl; and R 3 is H or CH3.

7. The method according to claim 6, wherein R 1 CF3, R 2 is F, and R 3 For CH3.

8. The method according to claim 6, wherein R 1 CF3, R 2 is Cl, and R 3 For H.

9. The method according to claim 6, wherein R 1 Cl, R 2 is F, and R 3 For CH3.

10. The method according to any one of claims 6 to 9, characterized in that The reducing agent is selected from the group consisting of hydrogen gas plus a metal catalyst, sodium sulfide, sodium bisulfite, ammonium sulfide, lithium aluminum hydride, lithium borohydride, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.

11. The method according to claim 6, wherein LG is selected from the group consisting of halogen, hydroxy, methanesulfonate (or mesylate), trifluoromethanesulfonate (triflate), benzenesulfonate, 4-methylbenzenesulfonate (toluenesulfonate), 4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate and carboxylic acid ester components of mixed or symmetrical anhydrides.

12. The method according to claim 6, wherein LG stands for halogen.

13. The method according to claim 6, wherein The base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, DBU, N-methylmorpholine, potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), sodium carbonate and sodium bicarbonate (NaHCO3).

14. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of: (a') 3-(4-nitrophenyl)-3-oxo-propionate (i-1 or ii-1, wherein R is C 1-8 reacting an alkyl ester with 3-chloro-4-methylaniline or 3-trifluoromethyl-4-methylaniline under conditions sufficient to provide a compound of formula (ii-2); (b') (ii-2), (R)-(-)-2-phenylglycinol and acrolein diethyl acetal to obtain compound (ii-3); (c') reducing (ii-3) under conditions sufficient to produce the intermediate diamine (ii-4) that is at least 95% free of enantiomeric or diastereomeric impurities; (d') converting (ii-4) to (ii-5) using cyclopentanone and a reducing agent; and (e') reacting (ii-5) with 2-fluoro-6-methylbenzoyl chloride or 2-chlorobenzoyl chloride to provide (I); in, R 1 Cl or CF 3 ; R 2 is F or Cl; and R 3 is H or CH3.

15. A compound of formula (ii-5) or a salt thereof: Where R 1 is Cl or CF3, said compound being at least 95% free of enantiomeric or diastereomeric impurities.

Images