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WO2025104679A1 - Procédés de production d'intermédiaires pour des inhibiteurs d'isoindolinone de l'interaction mdm2-p53 ayant une activité anticancéreuse - Google Patents

Procédés de production d'intermédiaires pour des inhibiteurs d'isoindolinone de l'interaction mdm2-p53 ayant une activité anticancéreuse Download PDF

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Publication number
WO2025104679A1
WO2025104679A1 PCT/IB2024/061378 IB2024061378W WO2025104679A1 WO 2025104679 A1 WO2025104679 A1 WO 2025104679A1 IB 2024061378 W IB2024061378 W IB 2024061378W WO 2025104679 A1 WO2025104679 A1 WO 2025104679A1
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compound
salt
solvent
acid
tert
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Sagar Shakya
Matt Johnson
Nicholas WONG
Prabhudas Bodhuri
Nipun Davar
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Otsuka Pharmaceutical Co Ltd
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Otsuka Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present disclosure relates to processes for preparing synthetic intermediates for the synthesis of isoindolinone inhibitors of the MDM2-p53 interaction having anticancer activity.
  • a process for preparing compound I-S, or a salt thereof: comprising contacting compound II-SA, or a salt thereof; with compound III, or a salt thereof: under conditions suitable to provide compound I-S; wherein R 1 is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(R a )(OR a ), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein R a is a C1-6 alkyl; and wherein when R 1 is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-S.
  • Also provided herein is a process for providing an enantiomerically enriched composition comprising compound II-S: or salt thereof, comprising contacting a compound of formula IV, or a salt thereof: iv, with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-S.
  • Also provided herein is a process for resolving a compound of formula IV: or salt thereof, to increase the proportion of the stereoisomer which is compound II-S: comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-S.
  • II-SC comprising contacting a compound of formula IV, or a salt thereof: under conditions suitable to provide compound II-SC.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 2.5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the term “contacting” refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
  • reaction conditions is intended to refer to the physical and/or environmental conditions under which a chemical reaction proceeds.
  • reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, mole ratio of reactants, the presence of a base or acid, one or more protecting groups, or catalyst, radiation, etc.
  • Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc.
  • Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical transformations provided herein can be found throughout, and in particular, the examples below. It is also contemplated that the reaction conditions can include reagents in addition to those listed in the specific reaction.
  • leaving group refers to an atom or a group capable of being displaced by a nucleophile.
  • halogen such as F, Cl
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional moiety.
  • “Deprotecting” or “deprotection” refers to a step removing the protecting group so as to restore the functional moiety to its original state.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See also Protective Groups in Organic Chemistry, Peter G. M. Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often utilized to mask the reactivity of certain functional moieties, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion.
  • a “carboxylic acid protecting group” refers to a protecting group useful for masking the carboxylic acid moiety, e.g., to render the carboxylic acid group unreactive during intermediate steps of a synthetic process.
  • exemplary carboxylic acid protecting groups include alkyl or benzyl protecting groups, such as methyl, ethyl, isopropyl, benzyl, or tert-butyl; silyl groups such as trimethylsilyl or 2- (trimethylsilyl)ethyl; and thioesters such as tert-butyl thioester.
  • the protecting group is tert-butyl.
  • Exemplary alcohol protecting groups include alkyl groups such as methyl, ethyl, isopropyl, or tert-butyl; optionally substituted benzyl groups such as benzyl, p-methoxybenzyl, or p- nitrobenzyl; an ester such as acetyl or benzoyl; or a silyl group such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.
  • alkyl groups such as methyl, ethyl, isopropyl, or tert-butyl
  • optionally substituted benzyl groups such as benzyl, p-methoxybenzyl, or p- nitrobenzyl
  • an ester such as acetyl or benzoyl
  • silyl group such as trimethylsilyl, tri
  • silylating reagent refers to a compound used to introduce silyl groups on a molecule, by replacing a proton on an alcohol, carboxylic acid, amine, thiol, or phosphate with a silyl ether. Silylating reagents are thus useful for installing silyl protecting groups.
  • Non-limiting examples of silylating reagents include trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, triethylsilyl chloride, triethylsilyl trifluoromethanesulfonate, tert-butyldimethylsilyl chloride, tert- butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl chloride, tert-butyldiphenylsilyl trifluoromethane sulfonate, triisopropylsilyl chloride, or triisopropylsilyl trifluoromethanesulfonate.
  • fluoride source refers to a compound which is capable of providing a fluoride ion. Fluoride sources may be employed in the removal of various silyl protecting groups. Non-limiting examples of fluoride sources include sodium fluoride, potassium fluoride, cesium fluoride, pyridinium fluoride, and tetrabutylammonium fluoride.
  • Coupled agent or an “activating agent” as defined herein refers to a chemical reactant that is capable of modifying an ester or carboxylic acid functional group to render it susceptible towards nucleophilic attack.
  • activating agents include, for example, 2-Pyod 1 -oxide (HOPG), carbonyl diimidazole (e.g., JV,N'-dicyclohexylcarbodiimide (DCC), . '-dicyclopcntylcarbodiimidc.
  • A'.N'-diisopropylcarbodiimidc (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), '-t-butyl- '-mcthylcarbodiimidc (BMC), JV-t-butyl-N- ethylcarbodiimide (BEC), l,3-bis(2,2-dimethyl-l,3-dioxolan-4-yhnethyl)carbodiimide (BDDC), etc.), anhydrides (e.g., symmetric, mixed, or cyclic anhydrides), activated ester forming agents (e.g., phenyl activated ester derivatives, p-hydroxamic activated ester, hexafluoroacetone (HF A), etc.), acylazole forming agents (acylimidazoles using CDI, acylbenzotriazoles, etc.),
  • Methods refers to a form of alkylation, with a methyl group replacing a hydrogen atom.
  • a “methylating agent” is a chemical substance capable of replacing a hydrogen atom with a methyl group.
  • Non-limiting examples of methylating agents include methyl iodide, methyl trifluoromethane sulfonate, methylfluorosulfonate, methyl methane sulfonate, and the like.
  • salt refers to a compound formed by the reaction of an acid and a base, resulting in the formation of a positively charged cation and a negatively charged anion.
  • a salt is defined as a compound that is formed by the combination of positively and negatively charged ions, where the charges of the ions result in a neutral compound. Salts can be either inorganic or organic.
  • salt includes partially or fully ionized salt forms. In some embodiments, the salt is fully ionized. In some embodiments, the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable.
  • “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt, particularly a pharmaceutically acceptable addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene-sulfonic acid, salicylic acid, benzenesulfonic acid and the like.
  • pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases.
  • Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines (i.e., NITfalkyl)). dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkylE).
  • alkyl amines i.e., NITfalkyl
  • dialkyl amines i.e., HN(alkyl)2
  • trialkyl amines i.e., N(alky
  • alkenyl amines i.e., NH2(alkenyl)
  • dialkenyl amines i.e., HN(alkenyl)2
  • trialkenyl amines i.e., N(alkenyl)3
  • substituted alkenyl amines i.e., NH2(substituted alkenyl)
  • di(substituted alkenyl) amines i.e., HN(substituted alkenyl ⁇
  • tri(substituted alkenyl) amines i.e., N(substituted alkenyl ⁇ , mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono
  • Suitable amines include, by way of example only, isopropylamine, trimethyl amine, tert-butylamine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, N, A'-dibcnzylcthanc-
  • 1.2-diamine (benzathine), tris(hydroxymethyl)aminomethane (tromethamine), l-(2- hydroxyethyl)pyrrolidine (epoloamine), meglumine, arginine, lysine, and the like.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 30 carbon atoms.
  • lower alkyl or “Ci-6-alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • C1-3- alkyl means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, w-propyl. iso -propyl, w-butyl. secbutyl, zso-butyl, tert-butyl, w-pcntyl.
  • Alkoxy refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
  • aryl refers to a phenyl group, or bicyclic aryl or tricyclic aryl fused ring systems.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a phenyl group.
  • Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups.
  • Representative examples of bicyclic aryls include, but are not limited to, naphthyl.
  • tricyclic aryls include, but are not limited to, anthracenyl.
  • the monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecular moiety through any carbon atom contained within the rings, and can be unsubstituted or substituted.
  • aryloxy refers to an oxygen atom substituted with any aryl group, such as phenoxy or naphthoxy, which may be optionally substituted.
  • benzyl refers to -C b-phcnyl. which may be unsubstituted or substituted, as defined herein.
  • Carboxyl ester or “ester” refer to both -OC(O)R X and -C(O)OR X , wherein R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein.
  • halogen or “halo” as used herein, means Cl, Br, I, or F.
  • Heteroaryl refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxid
  • fused-heteroaryl rings include, but are not limited to, benzo [d]thiazolyl, quinolinyl, isoquinolinyl, benzo [b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[l,5-a]pyridinyl, and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings).
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3- dithiolanyl, 1,3-dithianyl, l,3-dimethylpyrimidine-2,4(lH,3H)-dione, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3 -dihydrobenzofuranyl, 2,3- dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, azabicyclo [2.2. l]heptyl (including 2- azabicyclo [2.2.
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • tricyclic heterocycles include, but are not limited to, octahydro-2, 5-epoxypentalene, hexahydro-2H-2,5- mcthanocyclopcnta
  • the monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • substituted means any of the above groups wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, aryl, alkoxy, aryloxy, halo, heteroaryl, heterocyclyl, hydroxy, or -Si(R y )3, wherein each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.
  • Acid refers to a chemical species that donate protons.
  • Acidic compounds may be organic compounds such as carboxylic acids and sulfonic acids, inorganic compounds such as sulfuric acid, hydrochloric acid, nitric acids, and phosphoric acid, and may be classified as strong or weak.
  • Basic compounds refers to a chemical species that can accept protons.
  • Basic compounds may be organic compounds such as basic amines, inorganic compounds such as metal hydroxides and carbonates, and may be classified as strong or weak.
  • organic base generally refers to sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Non- limiting examples include phosphates such as potassium phosphate (mono-, di-, or tribasic), sodium phosphate (mono-, di-, or tribasic), ammonium phosphate (mono-, di-, or tribasic); acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; carbonates such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate; and alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide.
  • amine base generally refers to a primary, secondary, or tertiary amine, such as an alkyl amine, dialkyl amine, trialkyl amine, nitrogen-containing heterocycle, or nitrogencontaining heteroaryl, wherein each of which is optionally substituted, e.g., by alkyl.
  • the compounds of the disclosure, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (.S')- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (.S)-. or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and/or fractional crystallization.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • ‘ ‘Enantiomeric excess,” sometimes abbreviated to “ee,” is a measurement of the purity of a chiral chemical entity, and refers to the degree to which a particular enantiomer is present in greater amounts than the other enantiomer.
  • a racemic mixture has an ee of 0%, while a completely pure chiral enantiomer has an ee of 100%.
  • a chemical substance which has an ee of greater than 50% is sometimes referred to as “enantiomerically enriched”.
  • the enantiomerically enriched composition comprises an enantiomeric excess of an enantiomer greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of an enantiomer greater than 90%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of an enantiomer greater than 95%.
  • the enantiomeric excess of an enantiomer is greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. In some embodiments, the enantiomeric excess of an enantiomer is greater than 90%. In some embodiments, enantiomeric excess of an enantiomer is greater than 95%.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • a process for preparing compound I-S, or a salt thereof: comprising contacting compound II-SA, or a salt thereof: with compound III, or a salt thereof: under conditions suitable to provide compound I-S; wherein R 1 is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(R a )(0R a ), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein R a is a C1-6 alkyl; and wherein when R 1 is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-S.
  • a process for preparing compound I-R, or a salt thereof: comprising contacting compound II-RA, or a salt thereof: with compound III, or a salt thereof: under conditions suitable to provide compound I-R, wherein R 1 is H or a protecting group, and X is halo, Ci-6 alkoxy, Ce-io aryloxy, -N(R a )(OR a ), C4-10 heterocyclyl, C4-10 heteroaryl, or -O-C(O)-Ci-6 alkyl; wherein R a is a C1-6 alkyl; and wherein when R 1 is a protecting group, the process comprises a deprotection step after the contacting step to provide compound I-R.
  • X is halo. In some embodiments, X is F, Cl, Br, or I.
  • X is Cl.
  • X is C1-6 alkoxy. In some embodiments, X is methoxy. In some embodiments, X is ethoxy. In some embodiments, X is w-propoxy. In some embodiments, X is isopropoxy. In some embodiments, X is tert-butoxy.
  • X is Ce-io aryloxy. In some embodiments, X is phenoxy.
  • X is -N(R a )(OR a ), wherein R a is a C1-6 alkyl. In some embodiments, X is -
  • X is C4-10 heterocyclyl. In some embodiments, X is 2-pyrrolyl.
  • X is C4-10 heteroaryl. In some embodiments, X is 2-thiopyridine.
  • X is -O-C(O)-Ci-6 alkyl. In some embodiments, X is -O-C(O)CH 3 . In some embodiments, X is -O-C(O)C(CH 3 ) 3 .
  • R 1 is H. In some embodiments, R 1 is a protecting group.
  • R 1 when R 1 is a protecting group, the protecting group is a C1-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a C1-6 alkyl group or a phenyl.
  • R 1 when R 1 is a protecting group, the protecting group is a C1-6 alkyl group. In some embodiments, when R 1 is a protecting group, the protecting group is methyl. In some embodiments, when R 1 is a protecting group, the protecting group is ethyl. In some embodiments, the protecting group is isopropyl. In some embodiments, when R 1 is a protecting group, the protecting group is tert-butyl.
  • the protecting group when R 1 is a protecting group, is an optionally substituted benzyl. In some embodiments, when R 1 is a protecting group, the protecting group is benzyl. In some embodiments, when R 1 is a protecting group, the protecting group is p- methoxybenzyl. In some embodiments, when R 1 is a protecting group, the protecting group is p- nitrobenzyl.
  • R 1 when R 1 is a protecting group, the protecting group is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, when R 1 is a protecting group, the protecting group is -C(O)CH3. In some embodiments, when R 1 is a protecting group, the protecting group is -C(O)-phenyl.
  • R 1 when R 1 is a protecting group, the protecting group is a silyl group. In some embodiments, when R 1 is a protecting group, the protecting group is -SiR,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, when R 1 is a protecting group, the protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.
  • R 1 when R 1 is a protecting group, the protecting group is trimethylsilyl.
  • the conditions suitable to provide compound I-S or compound I-R comprise a base.
  • the base is an organolithium base.
  • the base is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide, methyllithium, isopropyllithium, w-butyllithium. scc-biityllithium. tert-butyllithium, w-hcxyllithium. or phenyllithium.
  • the base is w-butyllithium.
  • the conditions suitable to provide compound I-S or compound I-R further comprise a solvent. In some embodiments, the conditions suitable to provide compound I-S or compound I-R further comprise a solvent at a temperature of about -40 °C to about -100 °C. In some embodiments, the conditions suitable to provide compound I-S or compound I-R further comprise a solvent at a temperature of about -60 °C to about -80 °C.
  • the solvent is an ethereal solvent, a hydrocarbon, or a combination thereof.
  • the solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.
  • the solvent is an ethereal solvent. In some embodiments, the solvent is a combination of an ethereal solvent and a hydrocarbon.
  • the solvent is tetrahydrofuran. In some embodiments, the solvent is 2- methyltetrahydrofuran .
  • the conditions suitable to provide compound I-S or compound I-R, or a salt thereof comprise a base and a solvent. In some embodiments, the conditions comprise w-butyllithium and tetrahydrofuran. In some embodiments, the conditions suitable to provide compound I-S or compound I-R comprise w-butyllithium and tetrahydrofuran at a temperature of about -60 °C to about -80 °C. [0075] In some embodiments, the process for preparing compound I-S or compound I-R, or a salt thereof, further comprises isolation of compound I-S or compound I-R by slurry from a solvent. In some embodiments, the solvent is a hydrocarbon. In some embodiments, the hydrocarbon is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.
  • the solvent is heptane. In some embodiments, the solvent is toluene.
  • the process further comprises recrystallization of compound I-S or compound I-R from a solvent.
  • the solvent is a hydrocarbon, an ethereal solvent, a ketone, a nitrile, an ester, an amide, a sulfoxide, a halogenated solvent, or a combination thereof.
  • the solvent is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2- methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, A'.A'-dimcthylfonnamidc. N,N- dimethylacetamide, dimethylsulfoxide, dichloromethane, 1 ,2-dichloroethane, chlorobenzene, or a combination thereof.
  • the solvent is a hydrocarbon.
  • the hydrocarbon is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.
  • the solvent is an ethereal solvent.
  • the ethereal solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, or a combination thereof.
  • the solvent is a ketone. In some embodiments, the solvent is acetone or methyl ethyl ketone.
  • the solvent is a nitrile. In some embodiments, the solvent is acetonitrile.
  • the solvent is an ester. In some embodiments, the solvent is ethyl acetate or isopropyl acetate.
  • the solvent is an amide. In some embodiments, the solvent is N,N- dimethylformamide or N, '-dim ethyl acetamide.
  • the solvent is a sulfoxide. In some embodiments, the solvent is dimethylsulfoxide .
  • the solvent is a halogenated solvent.
  • the solvent is dichloromethane, 1,2-dichloroethane, or chlorobenzene.
  • the solvent is a hydrocarbon. In some embodiments, the solvent is an ethereal solvent. In some embodiments, the solvent is a combination of a hydrocarbon and an ethereal solvent.
  • the solvent is a combination of heptane and tetrahydrofuran.
  • the process for preparing compound I-S or compound I-R further comprises recrystallization of compound I-S or compound I-R from a combination of heptane and tetrahydrofuran.
  • a process for preparing compound I-S, or a salt thereof: comprising contacting compound II-SA, or a salt thereof: with compound III, or a salt thereof: in the presence of w-butyllithium in tetrahydrofuran at a temperature of about -60 °C to about -80 °C, to provide compound I-S; wherein R 1 is a protecting group, and X is Cl; optionally followed by recrystallization of compound I-S, or a salt thereof, from a combination of heptane and tetrahydrofuran.
  • a process for preparing compound I-R, or a salt thereof: comprising contacting compound II-RA, or a salt thereof: with compound III, or a salt thereof: in the presence of w-butyllithium in tetrahydrofuran at a temperature of about -60 °C to about -80 °C, to provide compound I-R; wherein R 1 is a protecting group, and X is Cl; optionally followed by recrystallization of compound I-R, or a salt thereof, from a combination of heptane and tetrahydrofuran.
  • the process further comprises a protection step comprising converting compound II-S: or a salt thereof, under conditions suitable to provide compound II-SA: or a salt thereof; wherein R 1 is a protecting group.
  • the process further comprises a protection step comprising converting compound II-R: or a salt thereof, under conditions suitable to provide compound II-RA: or a salt thereof; wherein R 1 is a protecting group.
  • the protecting group when R 1 is a protecting group, the protecting group is a Ci-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a Ci-6 alkyl group or a phenyl.
  • the protecting group when R 1 is a protecting group, the protecting group is a Ci-6 alkyl group.
  • the protecting group when R 1 is a protecting group, the protecting group is methyl.
  • the protecting group when R 1 is a protecting group, the protecting group is ethyl.
  • the protecting group when R 1 is a protecting group, the protecting group is is isopropyl. In some embodiments, when R 1 is a protecting group, the protecting group is tert-butyl.
  • the protecting group when R 1 is a protecting group, is an optionally substituted benzyl. In some embodiments, when R 1 is a protecting group, the protecting group is benzyl. In some embodiments, when R 1 is a protecting group, the protecting group is p- methoxybenzyl. In some embodiments, when R 1 is a protecting group, the protecting group is p- nitrobenzyl.
  • R 1 when R 1 is a protecting group, the protecting group is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, when R 1 is a protecting group, the protecting group is -C(O)CH3. In some embodiments, when R 1 is a protecting group, the protecting group is -C(O)-phenyl.
  • R 1 when R 1 is a protecting group, the protecting group is a silyl group. In some embodiments, when R 1 is a protecting group, the protecting group is -SiR ,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, when R 1 is a protecting group, the protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, /crt-biityldiphcnylsilyl chloride, or triisopropylsilyl.
  • R 1 when R 1 is a protecting group, the protecting group is trimethylsilyl.
  • the protection step comprises a silylating reagent.
  • the silylating reagent is trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate, triethylsilyl chloride, triethylsilyl trifluoromethanesulfonate, tertbutyldimethylsilyl chloride, tert-butyldimethylsilyl trifluoromethanesulfonate, tert-butyldiphenylsilyl chloride, tert-butyldiphenylsilyl trifluoromethanesulfonate, triisopropylsilyl chloride, triisopropylsilyl trifluoromethanesulfonate, trimethylsilylimidazole, l-(tert- butyldimethylsilyl)imidazole, hexamethyl
  • the silylating reagent is trimethylsilyl trifluoromethanesulfonate.
  • the protection step further comprise a base.
  • the base is an amine base.
  • the base is triethylamine, diisopropylethyl amine, tributyl amine, JV-methylmorpholine, pyridine, 4-dimethylaminopyridine, or JV-methylimidazole.
  • the base is triethylamine.
  • the protection step further comprise a solvent. In some embodiments, the protection step further comprise a solvent at a temperature of about -20 °C to about 20 °C. In some embodiments, the protection step further comprise a solvent at a temperature of about -10 °C to about 10 °C. In some embodiments, the protection step further comprise a solvent at a temperature of about -5 °C to about 5 °C.
  • the solvent is polar aprotic solvent or a halogenated solvent.
  • the solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, acetonitrile, ethyl acetate, isopropyl acetate, AA'-dimcthylformamidc. AA'-dimcthylacctamidc. A-mcthyl-2- pyrrolidone, dimethyl sulfoxide, or a combination thereof.
  • the solvent is a halogenated solvent.
  • the solvent is dichloromethane, 1,2-dichloroethane, or chlorobenzene, or a combination thereof.
  • the solvent is dichloromethane.
  • the protection step comprises a silylating reagent and a base, and a solvent.
  • the protection step comprises trimethylsilyl trifluoromethanesulfonate, triethylamine, and dichloromethane.
  • the protection step comprises trimethylsilyl trifluoromethanesulfonate, triethylamine, and dichloromethane at a temperature of about -10 °C to about 10 °C.
  • the protection step comprises trimethylsilyl trifluoromethanesulfonate, triethylamine, and dichloromethane at a temperature of about -5 °C to about 5 °C.
  • the process for preparing compound I-S further comprises a protection step comprising contacting compound II-S: or a salt thereof, with trimethylsilyl trifluoromethane sulfonate and triethylamine in dichloromethane at a temperature of about -5 °C to about 5 °C, to provide compound II-SA: or a salt thereof; wherein R 1 is trimethylsilyl.
  • the process for preparing compound I-R further comprises a protection step comprising contacting compound II-R: or a salt thereof, with trimethylsilyl trifluoromethane sulfonate and triethylamine in dichloromethane at a temperature of about -5 °C to about 5 °C, to provide compound II-RA: or a salt thereof; wherein R 1 is trimethylsilyl.
  • R 1 is a protecting group and the process for preparing compound I-S further comprise a deprotection step after the contacting step to provide compound I-S.
  • the deprotection step comprises converting a compound of formula I-SA, or a salt thereof: to compound I-S, or a salt thereof, under conditions suitable to provide compound I-S, wherein R 1 is a protecting group.
  • R 1 is a protecting group and the process for preparing compound I-R further comprise a deprotection step after the contacting step to provide compound I-R.
  • the deprotection step comprises converting a compound of formula I-RA, or a salt thereof: to compound I-R, or a salt thereof, under conditions suitable to provide compound I-R, wherein R 1 is a protecting group.
  • the protecting group R 1 is a Ci-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a Ci-6 alkyl group or a phenyl.
  • the protecting group R 1 is a Ci-6 alkyl group. In some embodiments, the protecting group is methyl. In some embodiments, the protecting group R 1 is ethyl. In some embodiments, the protecting group R 1 is isopropyl. In some embodiments, the protecting group R 1 is tert-butyl.
  • the protecting group R 1 is an optionally substituted benzyl. In some embodiments, the protecting group R 1 is benzyl. In some embodiments, the protecting group R 1 is p- methoxybenzyl. In some embodiments, the protecting group R 1 is -nitrobenzyl.
  • the protecting group R 1 is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, the protecting group R 1 is -C(O)CH3. In some embodiments, the protecting group R 1 is -C(O)-phenyl.
  • the protecting group R 1 is a silyl group. In some embodiments, the protecting group R 1 is -SiR ,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, the protecting group R 1 is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tertbutyldiphenylsilyl chloride, or triisopropylsilyl.
  • the protecting group R 1 is trimethylsilyl.
  • the deprotection step comprises an acid or a fluoride source.
  • the acid or fluoride source is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, -toluene sulfonic acid, tetrabutylammonium fluoride, cesium fluoride, or potassium fluoride.
  • the deprotection step comprises a fluoride source.
  • the fluoride source is tetrabutylammonium fluoride, pyridinium fluoride, sodium fluoride, potassium fluoride, or cesium fluoride.
  • the deprotection step comprises an acid.
  • the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, or -toluenesulfonic acid.
  • acid is phosphoric acid.
  • the deprotection step further comprises a solvent. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 20 °C to about 50 °C. In some embodiments, the deprotection step further comprises a solvent at a temperature of about 30 °C to about 50 °C, for example about 30 °C to about 40 °C.
  • the solvent is an ethereal solvent.
  • the solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, or a combination thereof.
  • the solvent is tetrahydrofuran.
  • the deprotection step comprises an acid and a solvent. In some embodiments, the deprotection step comprises phosphoric acid and tetrahydrofuran. In some embodiments, the deprotection step comprises phosphoric acid and tetrahydrofuran at a temperature of about 30 °C to about 50 °C, for example 30 °C to about 40 °C.
  • the deprotection step is followed by isolation of compound I-S or compound I-R by slurry in a solvent.
  • the solvent is a hydrocarbon.
  • the solvent is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, or xylene.
  • the solvent is heptane or toluene.
  • the process for preparing compound I-S further comprises a deprotection step comprising converting a compound of formula I-SA, or a salt thereof: to compound I-S, or a salt thereof, in the presence of phosphoric acid in tetrahydrofuran at a temperature of about 30 °C to about 50 °C, for example 30 °C to about 40 °C; wherein R 1 is trimethylsilyl, optionally followed by isolation of compound I-S by slurry in heptane or toluene.
  • the process for preparing compound I-R further comprises a deprotection step comprising converting a compound of formula I-RA, or a salt thereof: to compound I-R, or a salt thereof, in the presence of phosphoric acid in tetrahydrofuran at a temperature of about 30 °C to about 50 °C, for example 30 °C to about 40 °C; wherein R 1 is trimethylsilyl, optionally followed by isolation of compound I-R by slurry in heptane or toluene.
  • Also provided herein is a process for providing an enantiomerically enriched composition comprising compound II-S: or salt thereof, comprising contacting a compound of formula IV, or a salt thereof: with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-S.
  • Also provided herein is a process for providing an enantiomerically enriched composition comprising compound II-R: or salt thereof, comprising contacting a compound of formula IV, or a salt thereof: with a chiral base, or a salt thereof, under conditions suitable to provide the enantiomerically enriched composition comprising compound II-R.
  • Also provided herein is a process for resolving a compound of formula IV: iv, or salt thereof, to increase the proportion of the stereoisomer which is compound II-S: comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-S.
  • Also provided herein is a process for resolving a compound of formula IV: or salt thereof, to increase the proportion of the stereoisomer which is compound II-R: comprising contacting a compound of formula IV with a chiral base, or a salt thereof, under conditions suitable to increase the proportion of the stereoisomer which is compound II-R.
  • the chiral base is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the chiral base is ( l/?.2/?)-(+)- l .2-diphcnylcthylcncdiaminc. (lS,2R)-(+)- 2-amino-l,2-diphenylethanol, or ( I /?.2.S')-(-)-2-amino- 1 ,2-di phenyl ethanol. In some embodiments, the chiral base is ( l/?.2/?)-(+)- l .2-diphcnylcthylcncdiaminc.
  • the chiral base is ( l/?.2S)-(-)-2-amino- l .2-diphcnylcthanol. In some embodiments, the chiral base is (lS,2R)-(+)-2- amino- 1 ,2-diphenylethanol .
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%In some embodiments, the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 90%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 95%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (.S')-cnantiomcr of compound II-S greater than 98%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 90%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 95%.
  • the enantiomerically enriched composition comprises an enantiomeric excess of a (R)-enantiomer of compound II-R greater than 98%.
  • the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV is greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.
  • the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV step is greater than 90%.
  • the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV is greater than 95%.
  • the proportion of the stereoisomer which is compound II-S after resolving the compound of formula IV is greater than 98%.
  • the proportion of the stereoisomer which is compound II-R after resolving the compound of formula IV is greater than 50%, greater than 70%, greater than 80%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%. [0149] In some embodiments, the proportion of the stereoisomer which is compound II-R after resolving the compound of formula IV is greater than 90%.
  • the proportion of the stereoisomer which is compound II-R is after resolving the compound of formula IV greater than 95%.
  • the proportion of the stereoisomer which is compound II-R after resolving the compound of formula IV is greater than 98%.
  • conditions suitable to provide the enantiomerically enriched composition comprising compound II-S or compound II-R, or conditions suitable to resolve a compound of formula IV to increase the proportion of compound II-S or compound II-R further comprise a solvent.
  • the solvent is a ketone, an alcohol, a polar aprotic solvent, an ethereal solvent, a halogenated solvent, a hydrocarbon, water, or a combination thereof.
  • the solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, butanol, acetonitrile, ethyl acetate, isopropyl acetate, W-dimcthyl formamide, W-dimcthyl acetamide, dimethyl sulfoxide, V-methyl pyrrolidine, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane, 1,2-dichloroethane, chlorobenzene, water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene,
  • the solvent is a ketone.
  • the ketone is acetone, methyl ethyl ketone, methyl isobutyl ketone, or a combination thereof.
  • the solvent is an alcohol.
  • the alcohol is methanol, ethanol, isopropanol, butanol, or a combination thereof.
  • the solvent is a polar aprotic solvent.
  • the polar aprotic solvent is acetonitrile, ethyl acetate, isopropyl acetate, W-dimcthyl formamide, N,N- dimethyl acetamide, dimethyl sulfoxide, V-methyl pyrrolidine, or a combination thereof.
  • the solvent is an ethereal solvent.
  • the ethereal solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, or a combination thereof.
  • the solvent is a halogenated solvent.
  • the halogenated solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, or a combination thereof.
  • the solvent is a hydrocarbon.
  • the hydrocarbon is pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, or a combination thereof.
  • the solvent is a ketone, a polar aprotic solvent, a hydrocarbon, water, or a combination thereof.
  • the solvent is acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, heptane, water, or a combination thereof.
  • the solvent is isopropyl acetate, a combination of methyl ethyl ketone and heptane, or a combination of acetonitrile and water.
  • the solvent is isopropyl acetate. In some embodiments, the solvent is a combination of methyl ethyl ketone and heptane. In some embodiments, the solvent is a combination of acetonitrile and water. In some embodiments, the solvent is selected from isopropyl acetate and a combination of acetonitrile and water.
  • a process for providing an enantiomerically enriched composition comprising compound II-S: or salt thereof comprising contacting a compound of formula IV, or a salt thereof: with (17?,2S)-(-)-2-amino-l,2-diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone, and a combination of acetonitrile and water, to provide the enantiomerically enriched composition comprising compound II-S.
  • a process for providing an enantiomerically enriched composition comprising compound II-R: or salt thereof comprising contacting a compound of formula IV, or a salt thereof: iv, with ( IS, 2R)-(+)-2 -amino- 1,2-diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone, and a combination of acetonitrile and water, to provide the enantiomerically enriched composition comprising compound II-R.
  • a process for resolving a compound of formula IV: or salt thereof, to increase the proportion of the stereoisomer which is compound II-S: comprising contacting a compound of formula IV with ( l/?.2S)-(-)-2 -amino- 1,2-diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water.
  • the solvent is selected from isopropyl acetate and a combination of acetonitrile and water.
  • a process for resolving a compound of formula IV: or salt thereof, to increase the proportion of the stereoisomer which is compound II-R: or salt thereof comprising contacting a compound of formula IV with ( IS, 2R)-(+)-2 -amino- 1,2- diphenylethanol in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water.
  • II-SC comprising contacting a compound of formula IV, or a salt thereof: with a compound of formula V-S, or a salt thereof: under conditions suitable to provide compound II-SC.
  • II-RC comprising contacting a compound of formula IV, or a salt thereof: under conditions suitable to provide compound II-RC.
  • the conditions suitable to provide compound II-SC or compound II-RC further comprise a solvent.
  • the solvent is a ketone, an alcohol, a polar aprotic solvent, an ethereal solvent, a halogenated solvent, a hydrocarbon, water, or a combination thereof.
  • the solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, butanol, acetonitrile, ethyl acetate, isopropyl acetate, V '-dimcthyl formamide, N, '-dimcthyl acetamide, dimethyl sulfoxide, '-mcthyl pyrrolidine, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, dichloromethane, 1,2-dichloroethane, chlorobenzene, water, pentane, hexane, heptane, octane, petroleum ether, benzene,
  • the solvent is a ketone, a polar aprotic solvent, a hydrocarbon, water, or a combination thereof.
  • the solvent is acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, heptane, water, or a combination thereof.
  • the solvent is isopropyl acetate, a combination of methyl ethyl ketone and heptane, or a combination of acetonitrile and water.
  • the solvent is isopropyl acetate. In some embodiments, the solvent is a combination of methyl ethyl ketone and heptane. In some embodiments, the solvent is a combination of acetonitrile and water. In some embodiments, the solvent is selected from isopropyl acetate and a combination of acetonitrile and water.
  • the process for preparing compound II-SC or compound II-RC further comprises recrystallization from a solvent.
  • the solvent is water, a hydrocarbon, a polar aprotic solvent, or a combination thereof.
  • the solvent is water, pentane, hexane, heptane, octane, petroleum ether, benzene, toluene, xylene, acetonitrile, ethyl acetate, isopropyl acetate, N, '-dimcthyl formamide, N, '-dimcthyl acetamide, dimethyl sulfoxide, '-mcthyl pyrrolidine, or a combination thereof.
  • the solvent is a combination of water and a polar aprotic solvent. In some embodiments, the solvent is a combination of water and acetonitrile.
  • a process for preparing a salt of compound II-R, represented by formula II-RC: II-RC comprising contacting a compound of formula IV, or a salt thereof: in a solvent selected from isopropyl acetate, a combination of methyl ethyl ketone and heptane, and a combination of acetonitrile and water, to provide compound II-RC; optionally followed by recrystallization of compound II-RC in a combination of acetonitrile and water.
  • the process for preparing compound II-SC further comprises contacting compound II-SC with a base under conditions suitable to provide compound II-S, or a salt thereof:
  • the process for preparing compound II-RC further comprises contacting compound II-RC with a base under conditions suitable to provide compound II-R, or a salt thereof:
  • the process for resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-S comprises by contacting compound II-SC with a base under conditions suitable to provide compound II-S, or a salt thereof:
  • the process for resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-RC comprises by contacting compound II-RC with a base under conditions suitable to provide compound II-R, or a salt thereof:
  • the base is an inorganic base.
  • the base is sodium phosphate mono/di/tribasic, lithium phosphate mono/di/tribasic, potassium phosphate mono/di/tribasic, calcium phosphate mono/di/tribasic, magnesium phosphate mono/di/tribasic, tetramethylammonium phosphate mono/di/tribasic, or tetrabutylammonium phosphate mono/di/tribasic.
  • the base is potassium phosphate tribasic.
  • the conditions suitable to provide compound II-S or compound II-R further comprise a solvent.
  • the solvent is water, a halogenated solvent, or a combination thereof.
  • the solvent is water, dichloromethane, 1,2- dichloroethane, chlorobenzene, or a combination thereof.
  • the solvent is dichloromethane. In some embodiments, the solvent is a combination of dichloromethane and water.
  • the process for preparing compound II-S or compound II-R further comprises recrystallization from a solvent.
  • the solvent is water, a hydrocarbon, an ethereal solvent, or a combination thereof.
  • the solvent is water, pentane, hexane, heptane, petroleum ether, benzene, toluene, diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, tert-butyl methyl ether, or a combination thereof.
  • the solvent is 2-methyltetrahydrofuran, heptane, or a combination thereof. In some embodiments, the solvent is 2-methyltetrahydrofuran and heptane. In some embodiments, the solvent is 2-methyltetrahydrofuran.
  • the process for preparing compound II-S further comprises contacting compound II-SC with potassium triphosphate basic in dichloromethane to provide compound II-S, or a salt thereof: optionally followed by recrystallization of compound II-S in a combination of 2- methyltetrahydrofuran, heptane or a combination thereof.
  • the process for preparing compound II-R further comprises contacting compound II-RC with potassium triphosphate basic in dichloromethane to provide compound II-R, or a salt thereof: optionally followed by recrystallization of compound II-R in 2-methyltetrahydrofuran, heptane or a combination thereof.
  • resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-RC is followed by contacting compound II-SC with potassium triphosphate basic in dichloromethane to provide compound II-S, or a salt thereof: optionally followed by recrystallization of compound II-S in 2-methyltetrahydrofuran, heptane or a combination thereof.
  • resolving a compound of formula IV to increase the proportion of the stereoisomer which is compound II-RC is followed by contacting compound II-RC with potassium triphosphate basic in dichloromethane to provide compound II-R, or a salt thereof: optionally followed by recrystallization of compound II-R in 2-methyltetrahydrofuran, heptane or a combination thereof.
  • a process for preparing compound VI, or a salt thereof comprising the steps of:
  • step (b) comprises contacting compound I-S, or salt thereof: with a compound of formula VII, or a salt thereof: under conditions suitable to provide compound VIA, or a salt thereof: followed by a methylation step to provide compound VIB, or a salt thereof: followed by deprotection to provide compound VI, wherein R 2 is a protecting group.
  • the salt of the compound of formula VII is an acid salt.
  • the salt of the compound of formula VII is a hydrochloric acid salt, a toluenesulfonic acid salt, a benzenesulfonic acid salt, a methanesulfonic acid salt, a trifluoracetic acid salt, a trifluoromethanesulfonic acid salt, a phosphoric acid salt, or a sulfuric acid salt.
  • the salt of the compound of formula VII is a hydrochloride salt or a benzenesulfonic acid salt.
  • the salt of the compound of formula VI is a sodium, potassium, calcium, magnesium, ammonium, tert-butylamine, diethylamine, 2-dimethylaminoethanol (deanol), N,N- dibenzylethane-l,2-diamine (benzathine), tris(hydroxymethyl)aminomethane (tromethamine), l-(2- hydroxyethyl)pyrrolidine (epoloamine), meglumine, arginine, or lysine salt.
  • the salt of the compound of formula VI is a sodium salt. In some embodiments, the salt of the compound of formula VI is a tris(hydroxymethyl)aminomethane (tromethamine) salt. In some embodiments, the salt of the compound of formula VI is a l-(2- hydroxyethyl)pyrrolidine (epolamine) salt. In some embodiments, the salt of the compound of formula VI is a 2-dimethylaminoethanol (deanol) salt.
  • the protecting group R 2 is Ci-6 alkyl, benzyl, Si(Ci-6 alkyl)’,, or Si(Ci-6 alkyl)3-Ci-6 alkyl.
  • the protecting group R 2 is a Ci-6 alkyl group. In some embodiments, the protecting group R 2 is methyl. In some embodiments, the protecting group is R 2 ethyl. In some embodiments, the protecting group R 2 is isopropyl. In some embodiments, the protecting group R 2 is tert-butyl.
  • the protecting group R 2 is benzyl.
  • the protecting group R 2 is -Si(Ci-6 alkyl)3. In some embodiments, the protecting group R 2 is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, or triisopropylsilyl. In some embodiments, the protecting group R 2 is trimethylsilyl.
  • the protecting group R 2 is Si(Ci-6 alkyl)3-Ci-6 alkyl. In some embodiments, the protecting group R 2 is (trimethylsilyl)ethyl, (triethylsilyl)ethyl, or (tert-butyldimethylsilyl)ethyl. In some embodiments, the protecting group R 2 is (trimethylsilyl)ethyl.
  • the conditions suitable to provide compound VIA further comprise a coupling agent.
  • the coupling agent is W'-dicyclohcxylcarbodiimidc (DCC), W'-dicyclopcntylcarbodiimidc.
  • the coupling agent is a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO).
  • the conditions suitable to provide compound VIA further comprise a base.
  • the base is an amine base.
  • the base is triethylamine, diisopropylethyl amine, tributyl amine, '-mcthylmorpholinc. pyridine, 4-dimethylaminopyridine, or '-mcthy 1 imidazole.
  • the base is 4-dimethylaminopyridine or a combination of 4-dimethylaminopyridine and diisopropylethyl amine.
  • the base is a combination of 4-dimethylaminopyridine and diisopropylethyl amine
  • the conditions suitable to provide compound VIA further comprise a solvent.
  • the solvent is a halogenated solvent or a polar aprotic solvent.
  • the solvent is dichloromethane, 1,2-dichloroethane, chlorobenzene, or acetonitrile.
  • the solvent is dichloromethane.
  • the solvent is acetonitrile.
  • the conditions suitable to provide compound VIA comprise acetonitrile at a temperature of about 40 °C to about 60 °C.
  • the conditions suitable to provide compound VIA comprise a coupling agent, a base, and a solvent.
  • the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol- 1 -oxide (HOPO), a base, and a solvent.
  • the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4-dimethylaminopyridine, diisopropylethyl amine, and a solvent.
  • the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4- dimethylaminopyridine, diisopropylethyl amine, and dichloromethane.
  • the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4- dimethylaminopyridine, diisopropylethyl amine, and acetonitrile.
  • the conditions suitable to provide compound VIA comprise a combination of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and 2-pyridinol-l -oxide (HOPO), 4- dimethylaminopyridine, diisopropylethyl amine, and acetonitrile at a temperature of about 40 °C to about 60 °C.
  • the methylation step comprises a methylating agent.
  • the methylating agent is methyl iodide, methyl trifluoromethanesulfonate, methylfluorosulfonate, methyl methanesulfonate, dimethyl sulfate, trimethyloxonium tetrafluoroborate, or trimethylsilyldiazomethane .
  • the methylating agent is methyl trifluoromethanesulfonate.
  • the methylation step further comprises a base.
  • the base is an alkoxide base.
  • the alkoxide base is sodium methoxide, lithium methoxide, potassium methoxide, magnesium methoxide, calcium methoxide, sodium ethoxide, lithium ethoxide, potassium ethoxide, magnesium ethoxide, calcium ethoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, calcium tert-butoxide.
  • the base is sodium tert-butoxide, lithium tert-butoxide, or potassium tert- butoxide. In some embodiments, the base is lithium tert-butoxide.
  • the methylation step further comprises a solvent.
  • the solvent is an ethereal solvent.
  • the solvent is diethyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran, 2 -methyltetrahydrofuran, cyclopentyl methyl ether, or tert-butyl methyl ether, or a combination thereof.
  • the solvent is tetrahydrofuran.
  • the methylation step is carried out at a temperature of -60°C to -80 °C, for example -70 °C to - 80 °C.
  • the methylation step comprises methyl trifluoromethanesulfonate, lithium tert-butoxide, and tetrahydrofuran at a temperature of -60 °C to -80 °C.
  • the deprotection step comprises an acid or a fluoride source.
  • the acid or fluoride source is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, tetrabutylammonium fluoride, pyridinium fluoride, sodium fluoride, potassium fluoride, or cesium fluoride.
  • the deprotection step comprises a fluoride source.
  • the fluoride source is cesium fluoride.
  • the fluoride source is tetrabutylammonium fluoride.
  • the deprotection step further comprises a solvent.
  • the solvent is polar aprotic solvent.
  • the solvent is acetonitrile, ethyl acetate, isopropyl acetate, N, JV-dimethylformamide, N,N dimethylacetamide, JV-methyl-2-pyrrolidone, dimethyl sulfoxide, 2-methyl tetrahydrofuran or a combination thereof.
  • the solvent is W-dimcthylfonnamidc.
  • the solvent is acetonitrile or 2-methyl tetrahydrofuran.
  • the solvent is acetonitrile.
  • the solvent is 2-methyl tetrahydrofuran.
  • the deprotection step comprises a fluoride source that is tetrabutylammonium fluoride and a solvent that is acetonitrile or 2-methyl tetrahydrofuran. In some embodiments, the deprotection step comprises tetrabutylammonium fluoride and 2-methyl tetrahydrofuran. In some embodiments, the deprotection step comprises a fluoride source that is tetrabutylammonium fluoride and a solvent that is acetonitrile.
  • a process for preparing compound VI, or a salt thereof comprising the steps of:
  • a process for preparing compound VI, or a salt thereof comprising the steps of:
  • the disclosure provides for intermediate compounds that are useful in the processes described herein.
  • the straight bolded or dashed bond is used to indicate relative stereochemistry
  • the wedged bolded or dashed bond is used to indicate absolute stereochemistry.
  • the composition comprises more than 50% of a single enantiomer, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% ee.
  • the compound is identified as a single stereoisomer, it is intended that there is an enantiomeric excess of more than 50%, or at least about 55%, or at least about 60%, or at least about 65%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 97%, or about 99% ee.
  • R 1 is H. In some embodiments, R 1 is a protecting group.
  • R 1 when R 1 is a protecting group, the protecting group is a Ci-6 alkyl, an optionally substituted benzyl, a silyl group, or -C(O)R, wherein each R is a Ci-6 alkyl group or a phenyl.
  • the protecting group when R 1 is a protecting group, the protecting group is a Ci-6 alkyl group. In some embodiments, when R 1 is a protecting group, the protecting group is methyl. In some embodiments, when R 1 is a protecting group, the protecting group is ethyl. In some embodiments, when R 1 is a protecting group, the protecting group is isopropyl. In some embodiments, when R 1 is a protecting group, the protecting group is tert-butyl.
  • the protecting group when R 1 is a protecting group, the protecting group is an optionally substituted benzyl. In some embodiments, when R 1 is a protecting group, the protecting group is benzyl. In some embodiments, when R 1 is a protecting group, the protecting group is p- methoxybenzyl. In some embodiments, when R 1 is a protecting group, the protecting group is p- nitrobenzyl.
  • R 1 when R 1 is a protecting group, the protecting group is -C(O)R wherein each R is a Ci-6 alkyl group or a phenyl. In some embodiments, when R 1 is a protecting group, the protecting group is -C(O)CH3. In some embodiments, when R 1 is a protecting group, the protecting group is -C(O)-phenyl.
  • R 1 when R 1 is a protecting group, the protecting group is a silyl group. In some embodiments, when R 1 is a protecting group, the protecting group is -SiR,. wherein each R is independently a Ci-6 alkyl group or a phenyl. In some embodiments, when R 1 is a protecting group, the protecting group is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl chloride, or triisopropylsilyl.
  • R 1 when R 1 is a protecting group, the protecting group is trimethylsilyl.
  • the compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein.
  • the synthesis of compounds described herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers. Unless otherwise noted, the starting materials for the following reactions may be obtained from commercial sources.
  • Achiral HPLC was performed on an Agilent 1260 series LC system with a UV/Vis detector (210 nm, 220 nm or 230 nm) using the following conditions: i) Agilent ZORBAX Eclipse XDB C18, 4.6x50 mm, 1.8 pm column at a flow rate of 1.0 mL/min with 0.05% v/v trifluoroacetic acid in water (Mobile phase A) and 0.05% v/v trifluoroacetic acid in MeCN (Mobile phase B) at a gradient of 0.0 min: 10% Mobile phase B; 12.0 min: 95% Mobile phase B; 15.0 min: 95% Mobile phase B; and 15.1 min: 10% Mobile phase B; ii) Xbridge C18 4.6x150 mm, 3.5 pm column at a flow rate of 1.0 mL/min with 10 mM ammonium acetate in water (Mobile phase A) and MeCN (Mobile phase B) at a gradient of 0.0 min: 5% Mobile phase
  • a solution was obtained by mixing 3-fluoro-5-(l-hydroxy-l-(tetrahydro-2H-pyran-4- yl)propyl)benzoic acid (120 g, 1.0 equiv), (lR,2S)-2-amino-l,2-diphenylethan-l-ol (90.66 g, 1.0 equiv) and MEK (840 m , 7 Vol) at ambient temperature. w-Hcptanc was added to the solution and the resultant solution was stirred until the crystallization was deemed complete. The slurry was fdtered, and the fdter cake was washed with a mixture of MEK and w-hcptanc in three portions.
  • the crude salt can further be purified by dissolving it in IPAc (20 Vol) at about 65 °C, adding water (2 equiv) and seeds. The slurry was stirred at 20 °C for several hours and filtered. The cake was washed with IPAc and dried under vacuum to give 88% yield of (.S)-3-fluoro-5-( I -hydroxy- l-(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid ( 1R, 2S)-2 -amino- 1,2-diphenylethan-l-ol salt with 99% ee.
  • the aqueous phase was mixed with MeTHF (8.5 L, 5 Vol), adjusted the pH to ⁇ 2 by adding 3M HC1 aqueous solution and stirred. The layers were separated, and the organic phase was washed with 20% brine solution (8.5 L, 5 Vol). The organic layer was concentrated with addition of MeTHF to remove most of the water. w-Hcptanc (6.8 L, 4 Vol) was added slowly into the solution. The resultant slurry was stirred for at least 1 hour, seeds were added and the slurry was stirred for at least 1 hour. ⁇ -Heptane (10.2 L, 6 Vol) was slowly added, and the slurry was aged.
  • the mixture was stirred for at least 0.5 hours at 10 ⁇ 5 °C, and then the layers were separated.
  • the DCM phase was washed sequentially with the 0.5M KHSCL solution (8.3 L, 10 Vol) and water (8.3 L, 10 Vol).
  • the DCM layer was concentrated under reduced pressure until a final volume of 3.5-4.5 Vol (2.9 - 3.7 L) remained.
  • the solution was cooled to 20 ⁇ 5 °C and w-hcptanc (8.3 L, 10 Vol) was added followed by (.S)-3-fluoro-5-( l -(tctrahydro-2H-pyran-4-yl)- l - ((trimethylsilyl)oxy)propyl)benzoic acid seeds.
  • Toluene (9 L, 10 Vol) was added to the mixture and adjusted to 45 ⁇ 5 °C.
  • the solution was seeded with (.S')-2-(4-chlorobcnzoy I )-3 -fluoro-5 -( 1 -hydroxy- 1 -(tetrahydro-2H-pyran-4-yl)propyl)benzoic acid and aged at 45 ⁇ 5 °C.
  • the slurry was distilled under reduced pressure at 45 ⁇ 5 °C to a final volume near 9 ⁇ 0.5 Vol.
  • the slurry was aged at 45 ⁇ 5 °C, cooled to 20 ⁇ 5 °C over 1 hour, then stirred for 1 hour at 20 ⁇ 5 °C.

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Abstract

La présente invention concerne des procédés de préparation d'intermédiaires synthétiques pour la synthèse d'inhibiteurs d'isoindolinone de l'interaction MDM2-p53 ayant une activité anticancéreuse.
PCT/IB2024/061378 2023-11-16 2024-11-15 Procédés de production d'intermédiaires pour des inhibiteurs d'isoindolinone de l'interaction mdm2-p53 ayant une activité anticancéreuse Pending WO2025104679A1 (fr)

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US63/599,960 2023-11-16
GBGB2407356.1A GB202407356D0 (en) 2024-05-23 2024-05-23 Processes for making intermediates for isoindolinone inhibitors of the MDM2-P53 interaction having anticancer activity field
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017055860A1 (fr) 2015-09-29 2017-04-06 Astex Therapeutics Limited Inhibiteurs isoindolinone de l'interaction mdm2-p53 ayant une activité anticancéreuse
WO2018178691A1 (fr) * 2017-03-28 2018-10-04 Astex Therapeutics Limited Inhibiteurs isoindolinone de l'interaction mdm2-p53 et procédés de préparation de ces derniers
WO2022185260A1 (fr) * 2021-03-04 2022-09-09 Otsuka Pharmaceutical Co., Ltd. Biomarqueurs pour la thérapie anticancéreuse utilisant des antagonistes de mdm2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017055860A1 (fr) 2015-09-29 2017-04-06 Astex Therapeutics Limited Inhibiteurs isoindolinone de l'interaction mdm2-p53 ayant une activité anticancéreuse
WO2018178691A1 (fr) * 2017-03-28 2018-10-04 Astex Therapeutics Limited Inhibiteurs isoindolinone de l'interaction mdm2-p53 et procédés de préparation de ces derniers
WO2022185260A1 (fr) * 2021-03-04 2022-09-09 Otsuka Pharmaceutical Co., Ltd. Biomarqueurs pour la thérapie anticancéreuse utilisant des antagonistes de mdm2

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"Periodic Table of the Elements, CAS version", HANDBOOK OF CHEMISTRY AND PHYSICS
CARRUTHERS: "Some Modern Methods of Organic Synthesis", 1987, CAMBRIDGE UNIVERSITY PRESS
LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS, INC.
PETER G. M. WUTSTHEODORA W. GREENE, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, 2006
SMITHMARCH: "March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS, INC.
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