Process for the preparation of benzoxazepine oxazolidinone compounds

Abstract

Methods for preparing benzoxazepine oxazolidinone compounds and synthetic intermediates, including compound (10-2) and compound 18, are described. [Case 1] TIFF2024520479000264.tif37170 and [Case 2] TIFF2024520479000265.tif40170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 194,382, filed May 28, 2021, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to methods for preparing benzoxazepine oxazolidinone compounds and useful intermediates. [Background technology]

[0003] 2. Background of the Invention The PI3 kinase / Akt / PTEN pathway is an attractive target for cancer drug development, as such agents are expected to inhibit cell proliferation, suppress signals from stromal cells that lead to cancer cell survival and chemoresistance, reverse the inhibition of apoptosis, and overcome the intrinsic resistance of cancer cells to cytotoxic agents. PI3K is activated through receptor tyrosine kinase signaling as well as through activating mutations in the p110 catalytic subunit of PI3K, loss of function of the tumor suppressor PTEN, or through rare activating mutations in AKT.

[0004] Benzoxazepine compounds have potent and selective activity as inhibitors of the PI3K alpha isoform. Taselisib, designated 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (GDC-0032, Roche RG7604, CAS Registry Number 1282512-48-4, Genentech Inc.), has potent PI3K activity (Ndubaku, CO et al. (2013) J. Med. Chem. 56:4597-4610; WO 2011 / 036280; U.S. Patent No. 8,242,104; U.S. Patent No. 8,343,955) and has been studied in patients with locally advanced or metastatic solid tumors. Taselisib (GDC-0032) is a beta isoform sparring inhibitor of the PI3K catalytic subunit that is 31-fold more selective for the alpha subunit compared to the beta. Taselisib shows greater selectivity for mutant PI3Kα isoforms over wild-type PI3Kα (Olivero AG et al., AACR 2013. Abstract DDT02-01). Taselisib is currently in development as a treatment for patients with estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (mBC) and non-small cell lung cancer (NSCLC). Novel selective inhibitors of mutant PI3Kα isoforms are needed.

[0005] Inavolisib, also known as GDC-0077 or IUPAC name: (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide, has potent PI3K activity (WO 2017 / 001645, U.S. Patent Application 2017 / 0015678; Edgar K. et al., #156, ''Preclinical characterization of GDC-0077, a specific PI3K alpha inhibitor in early clinical development'', and Staben. S., #DDT02-0, ''Discovery of GDC-0077, a highly isoform selective inhibitor of PI3K alpha that promotes selective loss of mutant-p110alpha'', American Assoc. for Cancer Research, 2014). Res. (AACR) annual meeting, April 2, 2017, Washington DC), has been studied in patients with locally advanced or metastatic solid tumors. There remains a need for novel methods for producing benzoxazepine oxazolidinone compounds such as inavolisib. Summary of the Invention

[0006] Summary of the Invention The present invention relates to a method for producing benzoxazepine oxazolidinone compounds and intermediates thereof.

[0007] In one embodiment, the compound of formula (8A): [ka] (8A)(in the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C6-14 is aryl; R 11 is a hydrogen or a hydroxyl protecting group), or a salt thereof.

[0008] In some embodiments, R 1 is optionally substituted C 1-12 In some embodiments, R 1 is an optionally substituted tertiary C 4-12 In some embodiments, R 1 are tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl and naphthyl.

[0009] In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is benzyl.

[0010] In some embodiments, the compound of formula (8A) has formula (8B): [ka] (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 aryl, R 11 is hydrogen or a hydroxyl protecting group), or a salt thereof.

[0011] In some embodiments, the compound of formula (8A) has the formula (8-1): [ka] (8-1), or a salt thereof, or a compound of the formula (8-2): [ka] (8-2), or a salt thereof.

[0012] In another embodiment, the compound of formula (7A): [ka] (7A)(in the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 2 is optionally substituted C 1-12 Alkyl or optionally substituted C 6-14 is aryl; Each R 3 is independently an optionally substituted C 1-12 Alkyl, optionally substituted C 6-14 Aryl, or OR 2 or a salt thereof.

[0013] In some embodiments, the compound of formula (7A) has the formula (7): [ka] (7) or a salt thereof.

[0014] In yet another embodiment, the compound of formula (8C): [ka] (8C)(in the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 aryl), or a salt thereof, comprising the steps of: (iii) Formula (4A): [ka] (4A)(in the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 4 is optionally substituted C 1-6 or a salt thereof, Formula (5A): [ka] (5A)(in the formula, R 2 is optionally substituted C 1-12 Alkyl or optionally substituted C 6-14 is aryl; Each R 3 is independently an optionally substituted C 1-12 Alkyl, optionally substituted C 6-14 Aryl, or OR 2 and; Grignard Reagent (X is a halide) thereby reacting with a compound of formula (7A): [ka] forming a compound of formula (7A), or a salt thereof; and (iv) reacting said compound of formula (7A) with a fluoride salt, a base and an oxidizing agent to form said compound of formula (8C).

[0015] In some embodiments, the method comprises: (i) Formula (1A): [ka] (1A) (In the formula, R 4 is optionally substituted C 1-6or a salt thereof to obtain a compound of formula (2A): [ka] (2A) or a salt thereof; and (ii) reacting a compound of formula (2A) with a compound of formula (3A): [ka] (3A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 aryl) in the presence of a dehydrating reagent to obtain a compound of formula (4A): [ka] The method further comprises forming a compound of formula (4A), or a salt thereof.

[0016] In some of these embodiments, the method further comprises: (v) Formula (8C): [ka] (8C) (In the formula, R 1 is as defined in claim 11), or a salt thereof, with an acid to thereby produce a compound of formula (9-1): [ka] The method further includes the step of obtaining an amine compound of formula (9-1) or an acid addition salt thereof.

[0017] In some of these embodiments, the method further comprises: (vi) reacting a compound of formula (9-1), or an acid addition salt thereof, with an acylating agent to obtain a compound of formula (10-1): [ka] The method further comprises forming a compound of formula (10-1), or a salt thereof.

[0018] In some embodiments, the compound of formula (7A) has formula (7B): [ka] or a salt thereof, and the compound of formula (8C) has the formula (8D): [ka] or a salt thereof, 1 , R 2 , and R 3 is as defined above).

[0019] In some embodiments, the compound of formula (3A) has formula (3B): [ka] and the compound of formula (4A) is represented by formula (4B): [ka] or a salt thereof, 1 and R 4 is as defined above).

[0020] In some embodiments, the compound of formula (9-1) has the formula (9-3): [ka] It is.

[0021] In some of these embodiments, the compound of formula (10-1) has formula (10-2): [ka] It is.

[0022] In some embodiments, R 1 In some of these embodiments, R 2 is 2-propyl, and each R 3 is methyl and X is chloride. In some of these embodiments, R 4 is ethyl.

[0023] In some of these embodiments, the acid for step (v) is HCl and the acid addition salt of the compound of formula (9-1) has the structure (9-2): [ka] It is the hydrochloride salt having the formula:

[0024] In one embodiment, the method of preparing a compound of formula (8C) comprises: (iii) Formula (4): [ka] A compound of formula (4) or a salt thereof Formula (5): [ka] (5) Compound (5), By reacting in a solvent (e.g., THF), a compound of formula (7): [ka] forming a compound of formula (7), or a salt thereof; and (iv) reacting the compound of formula (7) with potassium fluoride, potassium bicarbonate and hydrogen peroxide in a solvent (e.g., methanol) to give the compound of formula (8-2): [ka] The method includes forming a compound of formula (8-2).

[0025] In yet another embodiment, the compound of formula (8A): [ka] (8A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 11 is a hydroxyl protecting group), or a salt thereof, comprising the steps of: (b) Formula (12A): [ka] (12A) of formula (13A): [ka] (13A) (In the formula, R 12 is optionally substituted C 6-14 aryl) and a base at a temperature below 0° C. to give a compound of formula (14A): [ka] forming a compound of formula (14A); and (c) reacting a compound of formula (14A) with magnesium in the presence of an acetate buffer, thereby forming a compound of formula (8A).

[0026] In some of these embodiments, the method comprises reacting a compound of formula (11A): [ka] With a compound of formula (3A): [ka] in the presence of a dehydrating reagent to obtain a sulfonamide compound of formula (12A): [ka] (In the formula, R 1 and R 11 is as defined above. In some embodiments, the method further comprises (d) forming a compound of formula (8A): [ka] or a salt thereof with an acid to obtain a compound of formula (9A): [ka] (In the formula, 1 and R 11 is as defined above), or an acid addition salt thereof. In some embodiments, the method further comprises (e) removing the hydroxyl protecting group of a compound of formula (9A) to obtain a compound of formula (9-1): [ka] or an acid addition salt thereof; and (f) reacting the compound of formula (9-1), or an acid addition salt thereof, with an acylating agent to form a compound of formula (10-1): [ka] The method further comprises forming a compound of formula (I).

[0027] In some of these embodiments, the compound of formula (12A) has formula (12B): [ka] and the compound of formula (14A) is represented by formula (14B): [ka] and the compound of formula (8A) is represented by formula (8B): [ka] (wherein R1 , R 11 , and R 12 is as defined above).

[0028] In some embodiments, the compound of formula (3A) has formula (3B): [ka] (In the formula, R 1 In some embodiments, the compound of formula (9A) has formula (9B): [ka] (In the formula, R 11 is as defined above. In some embodiments, where applicable, the acid in step (d) is HCl, and the acid addition salt of the compound of formula (9A) or (9B) has the structure (9C): [ka] It is the hydrochloride salt having the formula:

[0029] In some embodiments, where applicable, the compound of formula (9-1) has formula (9-3): [ka] or an acid addition salt thereof; the compound of formula (10-1) is a compound of formula (10-2): [ka] In some embodiments, R 1 is tert-butyl. In some embodiments, R 11 is benzyl. In some embodiments, R 12 is phenyl, and the compound of formula (13A) has the structure (13): [ka] In some embodiments, the base in step (b) is NaHMDS and step (b) is carried out at a temperature of about -70°C. In some embodiments, the acetate buffer in step (c) comprises HOAc and NaOAc. In some embodiments, the dehydrating reagent in step (a) is CuSO 4 Includes.

[0030] In some of these embodiments, the method comprises the step of: [ka] or a compound of formula (10-2) (having the structure: [ka] ) with compound 15 (having the structure: [ka] ), a copper salt, and a ligand to give compound 16 (structure: [ka] In some of these embodiments, the copper salt is copper(II) acetate. In some of these embodiments, the copper salt is copper(I) iodide. In some embodiments, the ligand is trans-N,N-dimethylcyclohexane-1,2-diamine.

[0031] In some of these embodiments, the method includes reacting compound 16 with (S)-2-aminopropanoic acid and a copper(I) catalyst to produce compound 17, structure: [ka] In some embodiments, the copper(I) catalyst is copper(I) oxide. In some of these embodiments, the method further comprises reacting compound 17 with ammonia (or an ammonia equivalent) and a peptide coupling reagent to form compound 18, which has the structure: [ka] The method further includes forming a film having

[0032] In yet another embodiment, the compound of formula (8A): [ka] (8A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 11 is a hydroxyl protecting group), or a salt thereof, comprising the steps of: (ii) Formula (4A): [ka] (4A) (In the formula, R 4 is optionally substituted C 1-6 or a salt thereof, With a Grignard reagent, thereby preparing a compound having formula (8-A). In some of these embodiments, the Grignard reagent is prepared by reacting iodomethyl pivalate with sec-butyl magnesium chloride. In some embodiments, the method includes (iii) hydrolyzing the compound having formula (8-A) with an acid to obtain a compound having formula (9-1): [ka] or a salt thereof.

[0033] In another embodiment, the compound of formula (9-1): [ka] A process for preparing a compound of formula (9-1), or an acid addition salt thereof, comprising the steps of: The method comprises: (i) Formula (2A): [ka] (2A) (In the formula, R 4 is optionally substituted C 1-6 or a salt thereof, (S)-2-methylpropane-2-sulfinamide, thereby producing (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (structure: [ka] preparing a compound having the formula: (ii) (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide is reacted with trimethylsilyl-cyanide to give the aminonitrile (S)-N-((S)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (structure: [ka] obtaining a compound having the formula: (iii) Hydrolysis of (S)-N-((S)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide in acid to produce the product (S)-2-(chloro-λ 5 -Azanil)-3,3-difluoropropanoic acid; [ka] obtaining; and (iv) (S)-2-(chloro-λ 5 The method includes the step of reducing (-azaneyl)-3,3-difluoropropanoic acid to obtain a compound of formula (9-1), or an intermediate compound of an acid addition salt thereof.

[0034] The compounds of formula (7A) and (8A) are useful intermediates of 4-(difluoromethyl)oxazolidin-2-one, which is a key building block in the synthesis of various compounds such as (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (inavolisib). The method of producing 4-(difluoromethyl)oxazolidin-2-one is very complicated since it is a small chiral molecule with a difficult difluoromethyl group. Provided herein is an efficient method for producing (S)-4-(difluoromethyl)oxazolidin-2-one with high stereospecificity and optical purity. Also provided is a method of making inavolisib using the (S)-4-(difluoromethyl)oxazolidin-2-one product as a key intermediate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description of the Invention definition As used in this disclosure, the articles "a" and "an" are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "element" means one element or more than one element.

[0036] The term "and / or" in this disclosure is used to mean either "and" or "or" unless otherwise specified. The use of the term "or" means "and / or" even though the present disclosure supports a definition that refers to alternatives only and "and / or" unless expressly indicated to refer to alternatives only or that the alternatives are mutually exclusive.

[0037] As used herein, the term "about" is used to indicate that a value includes the standard deviation of error of the device or method used to determine the value. In certain embodiments, the term "about" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the stated value, unless otherwise specified or clear from the context (e.g., when such a number exceeds 100% of possible values).

[0038] "Optionally" or "may" means that the subsequently described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined herein. With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and / or inherently unstable.

[0039] Unless otherwise specified, the term "optionally substituted" means that a group may be unsubstituted or may be substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any of these range variables) of the substituents recited for that group, which may be the same or different. In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In another embodiment, the optionally substituted group has five substituents. For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have a substituent other than hydrogen. For example, an alkyl group may be bonded at any point along the chain to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may include other functional groups, but does not necessarily have more functional groups.

[0040] As used herein, "alkyl" can mean a straight or branched saturated chain having 1 to 12 carbon atoms, including primary, secondary, and tertiary alkyl groups. Representative saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, and longer alkyl groups such as heptyl, and octyl. Alkyl groups may be unsubstituted or substituted. Alkyl groups containing 3 or more carbon atoms may be straight or branched. As used herein, "lower alkyl" refers to an alkyl having 1 to 6 carbon atoms.

[0041] "Cycloalkyl" refers to a monocyclic ring having 3 to 20 cyclic carbon atoms, e.g., 3 to 15 ring atoms, e.g., 3 to 12 ring atoms, all of which are saturated (i.e., C 3 ~C 20In certain embodiments, the cycloalkyl group is either monocyclic ("monocyclic cycloalkyl") or contains fused, bridged, or spiro ring systems, such as bicyclic rings ("bicyclic cycloalkyl"), and may be saturated. "Cycloalkyl" includes ring systems in which a cycloalkyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl groups, and the point of attachment is on the cycloalkyl ring, and in such cases the number of carbon atoms recited continues to represent the number of carbons in the cycloalkyl ring containing the point of attachment. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 2-adamantyl, and the like. [ka] 2-(2,3-dihydro-1H-indene) [ka] and 9-fluorenyl [ka] As noted above, cycloalkyl rings can be further identified by the number of ring atoms. For example, a cyclohexyl ring is C , which has 6 ring atoms. 6 Cycloalkyl ring, 2-(2,3-dihydro-1H-indene) is a C 5 Also, for example, 9-fluorenyl is a C cycloalkyl ring with 13 ring atoms. 5 2-adamantyl is a cycloalkyl ring having 10 ring atoms. 6 It is cycloalkyl.

[0042] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a multiple condensed all-carbon ring system, where at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 5-20 annular carbon atoms, 5-14 annular carbon atoms, or 5-12 annular carbon atoms. Aryl also includes multiple condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having about 9-20 carbon atoms, where at least one ring is aromatic and the other rings may or may not be aromatic (i.e., cycloalkyl). "Aryl" includes ring systems in which an aryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl groups, where the point of attachment is on the aryl ring, and in such cases the number of carbon atoms recited continues to represent the number of carbon atoms in the aryl ring containing the point of attachment. Examples of aryl groups include phenyl, naphthyl, anthracenyl, azulenyl, and 5-(2,3-dihydro-1H-indene): [ka] As noted above, aryl rings can be further identified by the number of ring atoms. For example, phenyl is C, which has 6 ring atoms. 6 While aryl, 5-(2,3-dihydro-1H-indene) is a C 6 It is aryl.

[0043] A "hydroxyl protecting group" is a chemical moiety that is introduced into a molecule by chemical modification of a hydroxyl group, thereby providing chemoselectivity in a subsequent chemical reaction. Examples of hydroxyl protecting groups include, but are not limited to, acetyl, trimethylacetyl, benzyl: [ka] and silyl ethers, including trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and di-tert-butylmethylsilyl.

[0044] The term "chiral" refers to molecules that have the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0045] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0046] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0047] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0048] The definitions and conventions of stereochemistry used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers (stereocenters) and therefore may exist in various stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane polarized light by a compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically isomeric species that is devoid of optical activity.

[0049] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0050] As used herein, the phrase "pharmaceutical acceptable salt" refers to the pharmaceutical acceptable organic or inorganic salt of the compound of the present invention.Representative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as acetate, succinate or other counter ions. Counter ions can be any organic or inorganic moiety that stabilizes the charge of the parent compound. In addition, pharmaceutically acceptable salts can have multiple charged atoms in their structure. When multiple charged atoms are part of the pharmaceutically acceptable salt, they can have multiple counter ions. Thus, pharmaceutically acceptable salts can have one or more charged atoms and / or one or more counter ions.

[0051] Where the compound of the invention is a base, the desired pharma- ceutically acceptable salt may be prepared by any suitable method available in the art, for example by reacting the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, or with an acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, benzoic acid or cinnamic acid, a sulfonic acid, for example p - They may be prepared by treatment with an aromatic acid such as toluenesulfonic acid or ethanesulfonic acid.

[0052] If the compound of the present invention is an acid, the desired pharma- ceutically acceptable salt can be prepared by any suitable method, for example, by treating the free base with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines (such as piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0053] "Solvate" refers to the association or complex of one or more solvent molecules with the compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0054] All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof, such as racemic mixtures, are intended to form part of the present invention.Furthermore, the present invention encompasses all geometric and positional isomers.In the structures shown herein, when the stereochemistry of any specific chiral atom is not specified, all stereoisomers are contemplated and included as compounds of the present invention.When stereochemistry is specified by a solid wedge or a dashed line representing a specific configuration, that stereoisomer is so specified and defined.

[0055] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the present invention is meant to encompass both solvated and unsolvated forms.

[0056] The compounds of the present invention may also exist in various tautomeric forms, and all such forms are encompassed within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via rearrangement of some of the bond electrons.

[0057] The compounds of the present invention also include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms are replaced by an atom that has a different atomic mass or mass number than the atomic mass or mass number that is usually found in nature.All isotopes of any particular atom or element specified are contemplated within the scope of the compounds of the present invention and their applications.Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g. 2 H, 3 H, 11 C. 13C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of the present invention, such as 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. 15 O. 13 N, 11 C, and 18 Positron emitting isotopes such as F are useful for positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotopically labeled compounds of the present invention may generally be prepared by following procedures similar to those described in the Examples set forth herein below, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0058] Intermediates useful in the preparation of benzoxazepine oxazolidinone compounds In some embodiments, the present invention relates to intermediates suitable for use in the preparation of benzoxazepine oxazolidinone compounds.

[0059] In some embodiments, the compound has formula (8A): [ka] (8A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 11 is a hydrogen or a hydroxyl protecting group), or a salt thereof.

[0060] In some embodiments, R 1 is optionally substituted C 1-12 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, as well as longer alkyl groups such as heptyl, and octyl. In some embodiments, R 1 is an optionally substituted tertiary C 4-12 In some embodiments, the tertiary C 4-12 Alkyl may be selected from tert-butyl, tert-pentyl, 2,3-dimethylbutyl, 3-ethylpentan-3-yl, 3-ethylpentan-2-yl, and the like. In some embodiments, R 1 is tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl, and naphthyl. 1 is tert-butyl.

[0061] In some embodiments, R 11is hydrogen. In some embodiments, R 11 is a hydroxyl protecting group selected from the group consisting of optionally substituted acetyl, trimethylacetyl, benzyl, and silyl ethers, including trimethylsilyl, triethylsilyl, triiso-propylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and di-tert-butylmethylsilyl. In some embodiments, R 11 is benzyl.

[0062] In some embodiments, the intermediate has formula (8B): [ka] (8B) (In the formula, R 1 and R 11 is as defined above for compounds of formula (8A), or a salt thereof.

[0063] In some embodiments, the intermediate has formula (8C): [ka] (8C) (In the formula, R 1 is as defined above for compounds of formula (8A), or a salt thereof.

[0064] In some embodiments, the intermediate has formula (8D): [ka] (8D) (In the formula, R 1 is as defined above for compounds of formula (8A), or a salt thereof.

[0065] In some embodiments, the intermediate has formula (8-1) or formula (8-2): [ka] (8-1), or a salt thereof, [ka] (8-2) or a salt thereof.

[0066] In some embodiments, the intermediate has formula (7A): [ka] (7A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 2 is optionally substituted C 1-12 Alkyl or optionally substituted C 6-14 is aryl; R 3 is optionally substituted C 1-12 Alkyl, optionally substituted C 6-14 Aryl, or OR 2 or a salt thereof.

[0067] In some embodiments, R 1 is optionally substituted C 1-12 In some embodiments, R 1 is tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl, and naphthyl. 1 is tert-butyl.

[0068] In some embodiments, R 2 is unsubstituted C 1-12Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, as well as longer alkyl groups such as heptyl, and octyl. In some embodiments, R 2 is an optionally substituted secondary C 3-12 In some embodiments, R 2 is an optionally substituted tertiary C 4-12 In some embodiments, R 2 is selected from among methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. 2 is isopropyl.

[0069] In some embodiments, R 3 is independently an optionally substituted C 1-12Alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, as well as longer alkyl groups such as heptyl, and octyl. In some embodiments, R 3 is an optionally substituted secondary C 3-12 In some embodiments, R 3 is an optionally substituted tertiary C 4-12 In some embodiments, R 3 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. 3 is methyl.

[0070] In some embodiments, the intermediate has formula (7B): [ka] (7B) (In the formula, R 1 , R 2 and R 3 is as defined above for compounds of formula (7A), or a salt thereof.

[0071] In some embodiments, the intermediate has formula (7): [ka] (7) or a salt thereof.

[0072] Preparation of intermediates useful for the preparation of benzoxazepine oxazolidinone compounds In some embodiments, the present invention relates to methods for preparing intermediates suitable for use in the preparation of benzoxazepine oxazolidinone compounds.

[0073] Intermediates prepared according to the methods disclosed herein have the structures (10-1) and (10-2): [ka] (10-1) and [ka] It is useful for the preparation of compounds having the formula (10-2).

[0074] Compounds having structures (10-1) and (10-2) are useful intermediates in the preparation of benzoxazepine oxazolidinone compounds.

[0075] 1. Grignard-Tamao Path In some embodiments, the method comprises: Formula (8C): [ka] (8C) (In the formula, R 1 is the preparation of an intermediate compound of formula (8A), or a salt thereof, which is defined above for the compound of formula (8A).

[0076] In some embodiments, the method comprises: Formula (8D): [ka] (8D) (In the formula, R 1 is the preparation of an intermediate compound of formula (8A), or a salt thereof, which is defined above for the compound of formula (8A).

[0077] In some embodiments, the method comprises: Formula (8-2): [ka] Preparation of the intermediate compound (8-2) or a salt thereof.

[0078] The method comprises: (i) reacting a compound represented by the formula (1A): [ka] (1A) (In the formula, R 4 is optionally substituted C 1-6 or a salt thereof, to give a compound of formula (2A) [ka] (2A), or a salt thereof.

[0079] In some embodiments, R 4 is optionally substituted C 1-6 Alkyl. Optionally substituted C 1-6 Alkyl is selected from among methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. 4 is ethyl.

[0080] In some embodiments, the compound of formula (1A) is a compound of formula (1) and the compound of formula (2A) is a compound of formula (2): [ka] (1) or a salt thereof, and [ka] (2) or its salt.

[0081] The reducing agent may be selected from among Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride), lithium aluminum hydride (LAH), lithium tri-tert-butoxyaluminum hydride, and diisobutylaluminum hydride (DIBAL). The reaction may take place in a suitable solvent, such as methyl tert-butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane (glyme), 1-methoxy-2-(2-methoxyethoxy)ethane (diglyme), diethoxyethane, toluene, anisole, dichloromethane, dichloroethane, hexane, heptane, and the like. The reduction reaction preferably takes place at lower temperatures, for example below about 20° C., or for example from about 0° C. to about 10° C. The hemiacetal of formula (2A) may be obtained in solution in an organic solvent. Isolation of the hemiacetal is optional and not necessary.

[0082] The method comprises (ii) reacting a compound of formula (2A) with a compound of formula (3A): [ka] (3A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 aryl) in the presence of a dehydrating reagent to obtain a compound of formula (4A): [ka] (4A), or a salt thereof.

[0083] In some embodiments, R 1 is optionally substituted C 1-12 In some embodiments, R 1 is tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl, and naphthyl. 1 is tert-butyl.

[0084] In some embodiments, R 4 is an optionally substituted C selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. 1-6 In some embodiments, R 4 is ethyl.

[0085] In some embodiments, the compound of formula (3A) has formula (3B): [ka] (3B).

[0086] In some embodiments, the compound of formula (3A) has the formula (3): [ka] (3)

[0087] In some embodiments, the compound of formula (4A) has formula (4B): [ka] (4B), or a salt thereof.

[0088] In some embodiments, the compound of formula (4A) has the formula (4): [ka] (4) or a salt thereof.

[0089] The dehydrating agent has the general formula Ti(OR) 4 (Wherein, R is C 1-6 In some embodiments, R is ethyl and the dehydrating agent is Ti(OCH 2 CH 3 ) 4 Further suitable dehydrating agents include magnesium sulfate, copper sulfate, molecular sieves, triisopropyl borate, tetramethyl orthosilicate, tetraethyl orthosilicate, and bis(trimethylsilyl)acetamide. The reaction can be carried out by adding the sulfonamide compound of formula (3A) and the dehydrating agent to a solution containing the hemiacetal of formula (2A). The reaction occurs at an elevated temperature, for example at least about 50°C, or at least about 70°C, for example between about 80°C and about 90°C, or about 85°C.

[0090] The method comprises: (iii) reacting a compound represented by formula (4A): [ka] A compound of formula (4A) or a salt thereof Formula (5A): [ka] React with Griyard reagent (5A), This results in equation (7A): [ka] (7A), or a salt thereof.

[0091] In some embodiments, R 2 is optionally substituted C 1-12 Alkyl or optionally substituted C 6-14 In some embodiments, R 2 is unsubstituted C 1-12 In some embodiments, R2 is an optionally substituted secondary C 3-12 In some embodiments, R 2 is an optionally substituted tertiary C 4-12 In some embodiments, R 2 is selected from among methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. 2 is isopropyl.

[0092] In some embodiments, R 3 is optionally substituted C 1-12 Alkyl, optionally substituted C 6-14 Aryl, or OR 2 In some embodiments, R 3 is optionally substituted C 1-12 In some embodiments, R 3 is an optionally substituted secondary C 3-12 In some embodiments, R 3 is an optionally substituted tertiary C 4-12 In some embodiments, R 3 is selected from among methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. 3 is methyl.

[0093] In some embodiments, X is a halide, such as chloride, bromide, or iodide. In some embodiments, X is chloride.

[0094] The Grignard reagent of formula (5A) has the formula (5'A): [ka] The corresponding alkyl halide of (5'A) It can be prepared in situ by reacting with magnesium The reaction can be started by adding a small amount of an initiator, such as 1,2-dibromoethane.

[0095] In some embodiments, the compound of formula (5A) is a compound of formula (5) and the compound of formula (5'A) is a compound of formula (5'): [ka] (5); [ka] (5').

[0096] In some embodiments, the compound of formula (7A) has formula (7B): [ka] (7B) or a salt thereof.

[0097] In some embodiments, the compound of formula (7A) has the formula (7): [ka] (7) or a salt thereof.

[0098] The Grignard reaction can be carried out in a suitable solvent such as methyl tert-butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane (glyme), 1-methoxy-2-(2-methoxyethoxy)ethane (diglyme), diethoxyethane, toluene, anisole, hexane, and n-heptane. The reaction occurs at a lower temperature, such as below about 20° C., or below 10° C., for example, from about −40° C. to about 0° C., or for example, about −25° C. The first equivalent of the Grignard reagent removes ethanol from the compound of formula (4A) to release the corresponding imine. Without being bound to any particular theory, according to Ellman and coworkers (J. Am. Chem. Soc. 1997, 119, 9913-9914.), the reaction proceeds through a six-membered transition state 6, which induces high stereocontrol: [ka] .

[0099] The reaction proceeds by adding a molar excess of Grignard reagent relative to the compound of formula (4A), for example a molar ratio of Grignard reagent of at least about 1.1:1, at least about 1.2:1, or at least about 1.5:1, or at least about 2:1, for example about 2.2:1, to prepare a compound of formula (7A) having high stereocontrol, such as at least about 80:20, or at least about 90:10, or even at least about 75:5, for example about 97:3 or about 94:6, in favor of the (R),(S) configuration.

[0100] The method further includes (iv) reacting the compound of formula (7A) or a salt thereof with a fluoride salt, a base, and an oxidizing agent to form a compound of formula (8C) or a salt thereof. The reaction proceeds by Fleming-Tamao oxidation. (See, e.g., Org. Process Res. Dev. 2014, 18, 66-81.) Suitable fluoride salts include sodium fluoride, potassium fluoride, and potassium difluoride. Suitable bases include sodium bicarbonate, potassium bicarbonate, disodium phosphate, and potassium hydroxide. Suitable oxidizing agents include hydrogen peroxide and meta-chloroperoxybenzoic acid (mCPBA). The reaction may be carried out in a suitable solvent, such as tetrahydrofuran, dimethylformamide, methanol, ethanol, and 1-propanol. In some embodiments, the solvent is methanol. In some embodiments, the reaction occurs at elevated temperatures, such as at least about 30° C., such as about 40° C. to about 50° C. or about 45° C.

[0101] In some embodiments of the method, in step (iv), the compound of formula (7A) is reacted with a compound of formula (7′A): [ka] (7'A)(wherein, R 1 and R 3 is as defined above in formula (7A), It is then contacted with a fluoride salt, a base, and an oxidizing agent to form a compound of formula (8C) or a salt thereof. The reaction may take place in a biphasic system in which an organic phase (e.g., in THF) is mixed with an aqueous phase. In such cases, a biphasic catalyst (such as tetrabutylammonium hydrogen sulfate) may be used.

[0102] The method comprises (v) reacting a compound of formula (8C): [ka] (8C), or a salt thereof, By reacting with an acid, the compound of formula (9-1) [ka] The method further includes the step of obtaining an amine compound of formula (9-1) or an acid addition salt thereof.

[0103] Suitable acids include hydrogen halides, such as hydrogen bromide, hydrogen chloride, and hydrogen iodide. Further suitable acids include trifluoroacetic acid, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. In some embodiments, the acid in step (v) is HCl, and the acid addition salt of the compound of formula (9-1) has the structure (9-2): [ka] (9-2) is the hydrochloride salt.

[0104] In some embodiments, the compound of formula (9-1) has the formula (9-3): [ka] The compound is (9-3).

[0105] The reaction can take place in a suitable solvent such as methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxanemethanol, methanol, ethanol, 1-propanol, and 2-propanol. The reaction can take place at a temperature of about 15° C. to about 25° C.

[0106] The method includes (vi) reacting a compound of formula (9-1), or an acid addition salt thereof having the structure (9-3), with an acylating agent to obtain a compound of formula (10-1): [ka] The method further comprises forming a compound of formula (10-1).

[0107] In some embodiments, the compound of formula (10-1) has the formula (10-2): [ka] (10-2).

[0108] The reaction may occur in the presence of a base to release a free amine, followed by the addition of an acylating agent. The acylating agent may be selected from among 1,1'-carbonyldiimidazole (CDI), phosgene, diphosgene, triphosgene, bis(2,2,2-trifluoroethyl)carbonate, bis(2,5-dioxopyrrolidin-1-yl)carbonate, 4-nitrophenyl chloroformate, di(pyridin-2-yl)carbonate, and diphenyl carbonate. The base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, tripotassium phosphate, dipotassium hydrogen phosphate, diisopropylethylamine (DIPEA), triethylamine, N-methylmorpholine, and pyridine. The reaction may occur at a temperature of about 10°C to about 35°C. The reaction may take place in a suitable solvent such as methyl tert-butyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, dichloromethane, methanol, ethanol, trifluoroethanol and 1-propanol.

[0109] In some embodiments, the method of making a compound of formula (10-2) follows the following sequence of steps: [ka] .

[0110] In some embodiments, the method of making a compound of formula (10-2) follows the following sequence of steps: [ka] .

[0111] The Grignard-Tamao route offers a safe, short, highly robust and cost-effective method with increased yields, reduced injectable / hazardous reactants / solvents, ease of workup and easy scale-up.

[0112] 2. Grignard-Nockel pathway In some embodiments, the method comprises reacting a compound of formula (8A): [ka] (8A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 11 is a hydrogen or hydroxyl protecting group), or a salt thereof.

[0113] In some embodiments, R 1 is optionally substituted C 1-12 In some embodiments, R 1 is an optionally substituted tertiary C 4-12 In some embodiments, the tertiary C 4-12 Alkyl may be selected from tert-butyl, tert-pentyl, 2,3-dimethylbutyl, 3-ethylpentan-3-yl, 3-ethylpentan-2-yl, and the like. In some embodiments, R 1 is tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl, and naphthyl. 1 is tert-butyl.

[0114] In some embodiments, R 11 is a hydroxyl protecting group selected from the group consisting of optionally substituted acetyl, trimethylacetyl, benzyl, and silyl ethers including trimethylsilyl, triethylsilyl, triiso-propylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and di-tert-butylmethylsilyl. In some embodiments, R11 is an optionally substituted acetyl (eg, pivalyl).

[0115] In some embodiments, the method comprises reacting a compound of formula (8B): [ka] (8B) (In the formula, R 1 and R 11 is as defined above for compounds of formula (8A), or a salt thereof.

[0116] In some embodiments, the method comprises reacting a compound of formula (8-3): [ka] A method for producing an intermediate compound of formula (8-3) or a salt thereof.

[0117] In some embodiments, the method comprises reacting a compound of formula (4A): [ka] (4A)(in the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 4 is optionally substituted C 1-6 The method includes step (i) of preparing a compound of formula (I) wherein R is an alkyl or hydrogen, or a salt thereof.

[0118] In some embodiments, R 1 is optionally substituted C 1-12Alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, as well as longer alkyl groups such as heptyl, and octyl. In some embodiments, R 1 is an optionally substituted tertiary C 4-12 In some embodiments, the tertiary C 4-12 Alkyl may be selected from tert-butyl, tert-pentyl, 2,3-dimethylbutyl, 3-ethylpentan-3-yl, 3-ethylpentan-2-yl, and the like. In some embodiments, R 1 is tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl, and naphthyl. 1 is tert-butyl.

[0119] In some embodiments, R 4 is optionally substituted C 1-6 Alkyl. Optionally substituted C 1-6Alkyl is selected from among methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. 4 is ethyl.

[0120] In some embodiments, step (i) comprises reacting a compound of formula (2A): [ka] (2A), or a salt thereof, is reacted with a sulfonamide compound of formula (3A): [ka] (3A), or a salt thereof, in the presence of a dehydrating reagent to form a compound of formula (4A).

[0121] In some embodiments, the compound of formula (2A) has the formula (2): [ka] (2), or a salt thereof.

[0122] In some embodiments, the compound of formula (3A) has formula (3B): [ka] (3B).

[0123] In some embodiments, the compound of formula (3A) has the formula (3): [ka] (3)

[0124] In some embodiments, the compound of formula (4A) has formula (4B): [ka] (4B), or a salt thereof.

[0125] In some embodiments, the compound of formula (4A) has the formula (4): [ka] (4) or a salt thereof.

[0126] The dehydrating agent has the general formula Ti(OR) 4 (Wherein, R is C 1-6 In some embodiments, R is ethyl and the dehydrating agent is Ti(OCH 2 CH 3 ) 4 Further suitable dehydrating agents include magnesium sulfate, copper sulfate, molecular sieves, triisopropyl borate, tetramethyl orthosilicate, tetraethyl orthosilicate, and bis(trimethylsilyl)acetamide. The reaction can be carried out by adding the sulfonamide compound of formula (3A) and the dehydrating agent to a solution containing the hemiacetal of formula (2A). The reaction occurs at an elevated temperature, for example at least about 50°C, or at least about 70°C, for example from about 80°C to about 90°C.

[0127] In some embodiments, the method comprises reacting a compound represented by formula (4A): [ka] A compound of formula (4A) or a salt thereof The method includes step (ii) of reacting with a Grignard reagent. The Grignard reaction can be prepared in situ. The reaction can take place in a suitable solvent such as methyl tert-butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane (glyme), 1-methoxy-2-(2-methoxyethoxy)ethane (diglyme), diethoxyethane, toluene, anisole, hexane and n-heptane. The Grignard reagent can be prepared by reacting iodomethyl pivalate and sec-butylmagnesium chloride, each of which has the structure shown below. [ka]

[0128] The reaction occurs by adding iodomethyl pivalate together with sec-butyl magnesium chloride to a solution containing the compound of formula (4A). Iodomethyl pivalate and sec-butyl magnesium chloride are added in molar excess relative to the compound of formula (4A), for example at least about 1.1:1, at least about 1.2:1, or at least about 1.5:1, or at least about 2:1, for example about 2.2:1. The reaction occurs at low temperatures, such as less than about -25°C, or less than about -35°C, or less than about -45°C, or less than about -55°C, for example about -65°C. The preparation of the Grignard reagent is carried out according to the protocol reported by Knochel (Synlett, (11), 1820-1822; 1999).

[0129] The product of the reaction is a compound of formula (8-3), which is hydrolyzed with an acid in step (iii) to give a compound of formula (9-1): [ka] The amine compound (9-1) or an acid addition salt thereof is obtained.

[0130] Suitable acids include hydrogen halides, such as hydrogen bromide, hydrogen chloride, and hydrogen iodide. Further suitable acids include trifluoroacetic acid, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. In some embodiments, the acid in step (v) is HCl, and the acid addition salt of the compound of formula (9-1) has the structure (9-2): [ka] (9-2) is the hydrochloride salt.

[0131] The reaction can take place in a suitable solvent such as 1,4-dioxane, methanol, ethanol, 1-propanol, and 2-propanol. The reaction can take place at a temperature of about 15° C. to about 25° C.

[0132] The method comprises reacting a compound of formula (9-1) or an acid addition salt thereof having the structure (9-2) with an acylating agent to form a compound of formula (10-1): [ka] The method includes the step (IV) of forming a compound of formula (10-1).

[0133] In some embodiments, the compound of formula (10-1) has the formula (10-2): [ka] (10-2).

[0134] The reaction may occur in the presence of a base to release a free amine, followed by the addition of an acylating agent. The acylating agent may be selected from among 1,1'-carbonyldiimidazole (CDI), phosgene, diphosgene, triphosgene, bis(2,2,2-trifluoroethyl)carbonate, bis(2,5-dioxopyrrolidin-1-yl)carbonate, 4-nitrophenyl chloroformate, di(pyridin-2-yl)carbonate, and diphenyl carbonate. The base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, tripotassium phosphate, dipotassium hydrogen phosphate, diisopropylethylamine (DIPEA), triethylamine, N-methylmorpholine, and pyridine. The reaction may occur at a temperature of about 10°C to about 35°C. The reaction may take place in a suitable solvent such as methyl tert-butyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, dichloromethane, methanol, ethanol, trifluoroethanol and 1-propanol.

[0135] 3. Strecker pathway In some embodiments, the method comprises reacting a compound of formula (9-1): [ka] A method for preparing an amine compound of formula (9-1) or an acid addition salt thereof.

[0136] In some embodiments, the method comprises reacting a compound of formula (9-3): [ka] (9-3), or a salt thereof.

[0137] In some embodiments, the method comprises reacting a compound of formula (2A): [ka] A compound of formula (2A) or a salt thereof and (S)-2-methylpropane-2-sulfinamide (Ellman's auxiliary), thereby preparing (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide having the structure: [ka]

[0138] In some embodiments, R 4 is an optionally substituted C selected from methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. 1-6 In some embodiments, R 4 is ethyl. The reaction may be carried out in a suitable solvent such as methyl tert-butyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and dichloromethane. The reaction may be refluxed in a Dean-Stark distillation apparatus.

[0139] In some embodiments, the reaction comprises step Strecker reaction (ii) of (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide with trimethylsilyl-cyanide to give the aminonitrile (S)-N-((S)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide having the following structure: [ka] .

[0140] The reaction occurs in the presence of a Lewis acid, suitably scandium triflate, yttrium triflate and trimethylsilyl triflate. The reaction can occur in a suitable solvent, such as methyl tert-butyl ether, toluene, tetrahydrofuran, acetonitrile and dichloromethane. The reaction proceeds with high stereocontrol, such as at least about 80:20, or at least about 85:15, for example about 89:11, in favor of the (S) configuration.

[0141] In some embodiments, in step (iii), (S)-N-((S)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide is hydrolyzed in acid to produce the product (S)-2-(chloro-λ 5 -Azanil)-3,3-difluoropropanoic acid; [ka] is obtained.

[0142] Suitable acids include hydrogen halides, such as hydrogen bromide, hydrogen chloride and hydrogen iodide. Further suitable acids include trifluoroacetic acid, sulfonic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. In some embodiments, the acid is HCl.

[0143] In step (iv), (S)-2-(chloro-λ 5 -azaneyl)-3,3-difluoropropanoic acid is reduced to give the compound of formula (9-1): [ka] Compound (9-3), or a salt thereof is provided.

[0144] The reducing agent may be selected from among Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride), lithium aluminum hydride (LAH), lithium tri-tert-butoxyaluminum hydride, and diisobutylaluminum hydride (DIBAL). A suitable reducing agent is borane (BH 3 ). The reaction can take place in a suitable solvent such as methyl tert-butyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane (glyme), 1-methoxy-2-(2-methoxyethoxy)ethane (diglyme), diethoxyethane, toluene, anisole, dichloromethane, dichloroethane, hexane, heptane, etc. The reaction can take place at temperatures between 0 and 45 °C.

[0145] In step (v), the method comprises reacting a compound of formula (9-3) with an acylating reagent to produce a compound of formula (10-1): [ka] The method includes forming a compound of formula (10-1).

[0146] In some embodiments, the compound of formula (10-1) has the formula (10-2): [ka] (10-2).

[0147] The reaction may occur in the presence of a base to release a free amine, followed by the addition of an acylating agent. The acylating agent may be selected from among 1,1'-carbonyldiimidazole (CDI), phosgene, diphosgene, triphosgene, bis(2,2,2-trifluoroethyl)carbonate, bis(2,5-dioxopyrrolidin-1-yl)carbonate, 4-nitrophenyl chloroformate, di(pyridin-2-yl)carbonate, and diphenyl carbonate. The base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, tripotassium phosphate, dipotassium hydrogen phosphate, diisopropylethylamine (DIPEA), triethylamine, N-methylmorpholine, and pyridine. The reaction may occur at a temperature of about 10°C to about 35°C. The reaction may take place in a suitable solvent such as methyl tert-butyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, dichloromethane, methanol, ethanol, trifluoroethanol and 1-propanol.

[0148] 4. Sulfone Pathway In some embodiments, the method comprises reacting a compound of formula (8A): [ka] (8A) (In the formula, R 1 is optionally substituted C 1-12 Alkyl, optionally substituted C 3-14 Cycloalkyl or optionally substituted C 6-14 is aryl; R 11 is a hydroxyl protecting group.

[0149] In some embodiments, R 1 is optionally substituted C 1-12 In some embodiments, R 1 is an optionally substituted tertiary C 4-12In some embodiments, the tertiary C 4-12 Alkyl may be selected from tert-butyl, tert-pentyl, 2,3-dimethylbutyl, 3-ethylpentan-3-yl, 3-ethylpentan-2-yl, and the like. In some embodiments, R 1 is tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl, and naphthyl. 1 is tert-butyl.

[0150] In some embodiments, R 11 is a hydroxyl protecting group selected from the group consisting of optionally substituted silyl ethers, including acetyl, trimethylacetyl, benzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and di-tert-butylmethylsilyl. In some embodiments, R 11 is benzyl.

[0151] In some embodiments, the method comprises reacting a compound of formula (8B): [ka] (8B) (In the formula, R 1 and R 11 is as defined above in formula (8A).

[0152] In some embodiments, the method comprises reacting a compound of formula (8-1): [ka] The method for preparing an intermediate compound of formula (8-1) or a salt thereof is as follows:

[0153] In some embodiments, the method comprises: (a) reacting a compound of formula (11A): [ka] Compound (11A) Formula (3A) [ka] A sulfonamide compound of formula (3A), By reacting in the presence of a dehydrating reagent, a compound of formula (12A): [ka] (12A): (In the formula, R 1 and R 11 is as defined above in formula (8A).

[0154] In some embodiments, R 11 is benzyl, and the compound of formula (11A) has the formula (11): [ka] (11), or a salt thereof.

[0155] In some embodiments, the compound of formula (3A) has formula (3B): [ka] The compound is (3B). In some embodiments, R 1 is tert-butyl, and the compound of formula (3A) is a compound of formula (3): [ka] (3) is the compound.

[0156] In some embodiments, the compound of formula (12A) has formula (12B): [ka] (12B) (In the formula, R 1 and R 11is as defined above in formula (8A).

[0157] In some embodiments, the compound of formula (12A) has the formula (12): [ka] (12) is the compound.

[0158] Suitable dehydrating agents have the general formula Ti(OR) 4 (Wherein, R is C 1-6 The titanium alkoxide may have an alkyl group. 1-6 Alkyl is selected from among methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like. In some embodiments, R is ethyl and the dehydrating agent is Ti(OCH 2 CH 3 ) 4 Further suitable dehydrating agents include magnesium sulfate, copper sulfate, molecular sieves, triisopropyl borate, tetramethyl orthosilicate, tetraethyl orthosilicate, and bis(trimethylsilyl)acetamide. In some embodiments, the dehydrating agent is copper sulfate. The reaction can occur in a suitable solvent, such as methyl tert-butyl ether, toluene, tetrahydrofuran, and dichloromethylene. The reaction can occur at room temperature, for example, at a temperature of about 20 to about 30° C.

[0159] In some embodiments, the method comprises (b) reacting a compound represented by formula (12A): [ka] (12A) (In the formula, R 1 and R 11 is as defined above in formula (8A), Formula (13A): [ka] (13A); (In the formula, R 12 is optionally substituted C 6-14 aryl) and a base at a temperature below 0° C. to give a compound of formula (14A): [ka] The method includes forming a compound of formula (14A).

[0160] In some embodiments, R 12 is phenyl, and the compound of formula (13A) has the structure (13): [ka] (13)

[0161] In some embodiments, the compound of formula (14A) has formula (14B): [ka] The compound is (14B).

[0162] In some embodiments, the compound of formula (14A) has the formula (14): [ka] The compound is (14).

[0163] In some embodiments, the base in step (b) is sodium bis(trimethylsilyl)amide (NaHMDS). In some embodiments, step (b) is carried out at a temperature below about −20° C., such as below about −30° C., such as below about −50° C., such as about −70° C. to about −80° C. The reaction may be carried out in a suitable solvent, such as methyl tert-butyl ether, toluene, tetrahydrofuran, N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, and dichloromethane.

[0164] In some embodiments, the method includes (c) reacting the compound of formula (14A) with magnesium in the presence of an acetate buffer, thereby forming a compound of formula (8A). The magnesium is elemental magnesium and is obtained as substantially pure (e.g., greater than 98%) turnings. An acetate buffer containing acetic acid and sodium acetate is suitable for controlling the pH at about 4 to about 6. The reaction can occur in a suitable solvent, such as methyl tert-butyl ether, toluene, and tetrahydrofuran. The reaction can occur at room temperature, for example, about 20 to about 30° C.

[0165] This method involves (d) formula (8A): [ka] Compound (8A) By reacting with an acid, [ka] The method includes a step of obtaining an amine compound of formula (9A) or an acid addition salt thereof.

[0166] In some embodiments, the compound of formula (9A) has the formula (9B): [ka] (9B) or an acid addition salt thereof.

[0167] In some embodiments, the acid in step (d) is HCl and the acid addition salt of the compound of Formula (9A) or (9B) has the structure (9C): [ka] (9C) is the hydrochloride salt.

[0168] In some embodiments, the compound of formula (9A) has the formula (9-4): [ka] (9-4), Compound or structure (9-5) [ka] (9-5) is an acid addition salt.

[0169] Suitable acids include hydrogen halides, such as hydrogen bromide, hydrogen chloride, and hydrogen iodide. Further suitable acids include trifluoroacetic acid, sulfonic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. The reaction can take place in a suitable solvent, such as methyl tert-butyl ether, toluene, tetrahydrofuran, n-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, dichloromethylene, methanol, and 1-propanol. The reaction can take place at room temperature, for example, about 20 to about 30°C.

[0170] In some embodiments, the method includes (e) removing the hydroxyl protecting group of a compound of formula (9A) to provide a compound of formula (9-1): [ka] The method includes a step of obtaining an amine compound of formula (9-1) or an acid addition salt thereof.

[0171] In some embodiments, the compound of formula (9-1) has the structure (9-2): [ka] (9-2) is the hydrochloride salt.

[0172] In some embodiments, the compound of formula (9-1) has the formula (9-3): [ka] (9-3) or an acid addition salt thereof.

[0173] The hydroxyl protecting group may be removed by hydrogenation over palladium on carbon (Pd / C) in the presence of hydrogen gas. The reaction may occur at room temperature, for example, from about 20 to about 30° C.

[0174] In some embodiments, the method includes (f) reacting a compound of formula (9-1), or an acid addition salt thereof, with an acylating reagent to produce a compound of formula (10-1): [ka] The method includes forming a compound of formula (10-1).

[0175] In some embodiments, the compound of formula (10-1) has the formula (10-2): [ka] (10-2).

[0176] The reaction may occur in the presence of a base to release a free amine, followed by the addition of an acylating agent. The acylating agent may be selected from among 1,1'-carbonyldiimidazole (CDI), phosgene, diphosgene, triphosgene, bis(2,2,2-trifluoroethyl)carbonate, bis(2,5-dioxopyrrolidin-1-yl)carbonate, 4-nitrophenyl chloroformate, di(pyridin-2-yl)carbonate, and diphenyl carbonate. The base may be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, tripotassium phosphate, dipotassium hydrogen phosphate, diisopropylethylamine (DIPEA), triethylamine, N-methylmorpholine, and pyridine. The reaction may occur at a temperature of about 10°C to about 35°C. The reaction may take place in a suitable solvent such as methyl tert-butyl ether, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone, acetonitrile, dimethylformamide, dichloromethane, methanol, ethanol, trifluoroethanol and 1-propanol.

[0177] Preparation of benzoxazepine oxazolidinone compounds In some embodiments, the present invention includes processes, methods, reagents, and intermediates for the synthesis of benzoxazepine oxazolidinone compounds, including (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide 18, having the following structure: [ka] .

[0178] In one embodiment, compound 18 has the structure: [ka] A method for preparing Compound 17, having the following structure: [ka] Methods of preparation are provided that include reacting with ammonia or an ammonia equivalent via an amide bond forming reaction (ie, in the presence of or by contact with one or more peptide coupling reagents).

[0179] The amide bond forming reaction of compound 17 with ammonia or an ammonia equivalent to form compound 18 can be facilitated using peptide coupling reagents such as N-hydroxysuccinimide (HOSu) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and EDC, 1-hydroxy-7-azabenzotriazole (HOAt) and EDC, 2-hydroxypyridine-1-oxide and EDC, ethyl(hydroxyimino)cyanoacetate (Oxyma) and EDC, 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazole-1-oxide hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and 1,1'-carbonyldiimidazole (CDI). The dehydrating reagent EDC may be replaced by other carbodiimides such as N,N'-diisopropylcarbodiimide (DIC) or N,N'-dicyclohexylcarbodiimide (DCC).

[0180] Examples of ammonia equivalents include, but are not limited to, ammonium acetate, ammonium bicarbonate, ammonium carbamate, ammonium carbonate, ammonium chloride, ammonium hydroxide, and ammonium phosphate.

[0181] In some embodiments, the method for preparing compound 18 includes reacting compound 17 with ammonia or an ammonia equivalent and a peptide coupling reagent. In some embodiments, the peptide coupling reagent includes a carbodiimide (e.g., DIC or EDC) and an auxiliary reagent (e.g., HOSu or HOBt). In some embodiments, the peptide coupling reagent includes CDI. Coupling reagents such as DIC / HOSu, EDC / HOSu, EDC / HOBt or CDI provide a method with higher efficiency and lower cost, especially for synthesis at kilogram or larger scale, as well as easier to remove environmentally friendly by-products, compared to methods using coupling reagents such as HATU and HBTU. In some embodiments, the method for preparing compound 18 includes reacting compound 17 with ammonia or an ammonia equivalent and a peptide coupling reagent selected from the group consisting of DIC / HOSu, EDC / HOSu, EDC / HOBt and CDI. In one embodiment, the method for preparing compound 18 includes reacting compound 17 with ammonia, HOSu and EDC. In one embodiment, the method for preparing compound 18 includes reacting compound 17 with ammonium bicarbonate, HOSu and DIC.

[0182] In some embodiments, compound 17 is prepared by reacting compound 16, which has the following structure: [ka] It is prepared by a process which comprises reacting with (S)-2-aminopropanoic acid via copper-catalyzed (i.e., in the presence of or by contact with a copper catalyst) C-N coupling.

[0183] In some embodiments, the CN coupling between compound 16 and (S)-2-aminopropanoic acid to form compound 17 may be carried out using a copper catalyst, a base, and a solvent. Examples of copper catalysts include, but are not limited to, copper(I) oxide, copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(I) trifluoromethanesulfonate, copper(II) oxide, and the like. Examples of bases include, but are not limited to, for example, potassium phosphate, cesium carbonate, and potassium carbonate, and the like. The solvent may be selected from, but is not limited to, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and N-methyl-2-pyrrolidinone (NMP). In some embodiments, compound 17 is prepared by a method comprising reacting compound 16 with a copper(I) catalyst (e.g., copper(I) oxide). In some embodiments, compound 17 is prepared by a method comprising reacting compound 16 with (S)-2-aminopropanoic acid in a solvent (e.g., DMSO) in the presence of a copper(I) catalyst (e.g., copper(I) oxide) and a base (e.g., tripotassium phosphate).

[0184] The carboxylic acid formed from the coupling of compound 16 with (S)-2-aminopropanoic acid is unstable, difficult to isolate, and subject to decomposition. Conversion of the acid to the ammonium salt (compound 17) provides a stable intermediate compound that can be isolated from unreacted starting materials and by-products.

[0185] In some embodiments, compound 16 is prepared by reacting compound 15 having the following structure: [ka] Compound (10-2) having the following structure: [ka] (10-2) and It is prepared by a process comprising reacting via a copper catalyzed C-N coupling reaction.

[0186] In one embodiment, the CN coupling reaction of compound 15 with compound (10-2) to form compound 16 may be carried out using a copper salt, a ligand, a base, and a solvent. Examples of suitable copper salts include, but are not limited to, copper(I) oxide, copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(I) trifluoromethanesulfonate, copper(II) acetate, copper(II) chloride, copper(II) bromide, copper(II) iodide, copper(II) oxide, and copper(II) trifluoromethanesulfonate. Examples of suitable ligands include, but are not limited to, 1,2-diamines (e.g., trans-N,N-dimethylcyclohexane-1,2-diamine, trans-1,2-diaminocyclohexane, and N,N'-dimethylethylenediamine, 1,10-phenanthroline or derivatives (e.g., 3,4,7,8-tetramethyl-1,10-phenanthroline), glycine, N,N-dimethylglycine, 2,2,6-trimethylheptane-3,5-dione, and 2-isobutyrylcyclohexane-1-one. Examples of suitable bases include, but are not limited to, potassium phosphate, cesium carbonate, and potassium carbonate. Suitable solvents Examples of suitable solvents include, but are not limited to, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidinone (NMP), acetonitrile, 2-methyltetrahydrofuran, toluene, and 1,4-dioxane. In some embodiments, compound 16 is prepared by a method comprising reacting compound 15, compound (10-2), a copper salt (e.g., copper(II) acetate or copper(I) iodide), and a ligand (e.g., trans-N,N-dimethylcyclohexane-1,2-diamine or 3,4,7,8-tetramethyl-1,10 phenanthroline).In some embodiments, compound 16 is prepared by a method comprising reacting compound 15, compound (10-2), a copper salt (e.g., copper(II) acetate or copper(I) iodide) and a ligand (e.g., trans-N,N-dimethylcyclohexane-1,2-diamine or 3,4,7,8-tetramethyl-1,10 phenanthroline) in a solvent (e.g., 2-methyltetrahydrofuran or acetonitrile) in the presence of a base (e.g., cesium carbonate or potassium tribasic phosphate). In one embodiment, compound 16 is prepared by a method comprising reacting compound 15, compound (10-2), copper(II) acetate and trans-N,N-dimethylcyclohexane-1,2-diamine in 2-methyltetrahydrofuran in the presence of cesium carbonate. In another embodiment, compound 16 is prepared by a method comprising reacting compound 15, compound (10-2), copper(II) acetate, and 3,4,7,8-tetramethyl-1,10-phenanthroline in acetonitrile in the presence of tribasic potassium phosphate. In one embodiment, compound 16 is prepared by a method comprising reacting compound 15, compound (10-2), copper(I) iodide, and trans-N,N-dimethylcyclohexane-1,2-diamine in 2-methyltetrahydrofuran in the presence of cesium carbonate.

[0187] In some embodiments, compound 15 is prepared by the method disclosed in International Application PCT / EP2017 / 083143 (WO 2018 / 109204), the entire disclosure of which is incorporated by reference as if set forth in its entirety. Briefly, WO 2018 / 109204 discloses a method for preparing compound 15, comprising the steps of:

[0188] (a) 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (compound 13′), having the following structure: [ka] with an iodination reagent (e.g., N-iodosuccinimide (NIS), iodine, or iodine monochloride) to form 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (compound 14') having the following structure: [ka] ; and (b) reacting 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (compound 14′) with a Grignard reagent (e.g., ethylmagnesium bromide or isopropylmagnesium chloride) to form compound 15.

[0189] In some embodiments, the iodination reagent used to convert compound 13' to compound 14' is iodine and sodium periodate. The reaction can take place in acetonitrile in the presence of an acid (such as aqueous sulfuric acid).

[0190] In some embodiments, reacting compound 14' with a Grignard reagent comprises a batch process in which the reactants are added in batches to a reaction vessel to form compound 15. In some embodiments, reacting compound 14' with a Grignard reagent and then quenching the reaction mixture (e.g., with acetic acid) comprises a flow process in which the reactants are continuously fed into a pipe reactor to form compound 15.

[0191] In some embodiments, 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (compound 13′) is compound 12′ having the following structure: [ka] with chloroacetaldehyde to form 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine.

[0192] In one embodiment, the condensation reaction can be carried out in a solvent in the presence of a base.Suitable bases include, but are not limited to, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.Suitable solvents include, but are not limited to, isopropyl alcohol and 2-methyltetrahydrofuran.

[0193] The process of the present invention is very economical and robust, and ensures a reliable, high quality product.

[0194] 14 C-labeled inavolisib In addition, it is useful to study the absorption, distribution, metabolism and excretion of inavolisib in humans. 14 C-labeled inavolisib, (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-keto-oxazolidin-3-yl]-5,6-dihydro[2- 14 C]imidazolo[1,2-d][1,4]benzoxazepin-9-yl]amino]propionamide is provided.

[0195] (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-keto-oxazolidin-3-yl]-5,6-dihydro[2- 14 C]imidazolo[1,2-d][1,4]benzoxazepin-9-yl]amino]propionamide may be synthesized according to the procedure described in International Application PCT / EP2017 / 083143 (WO 2018 / 109204) for the preparation of inavolisib from 4-bromo-2-fluoro-benzo[14C]nitrile, for example as shown in Scheme 6.

[0196] 4-Bromo-2-fluoro-benzo[ 14 C] nitrile to (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-keto-oxazolidin-3-yl]-5,6-dihydro[2- 14 C]imidazolo[1,2-d][1,4]benzoxazepin-9-yl]amino]propionamide,14 A method for preparing C-labeled inavolisib is provided. In some embodiments, the method includes the steps shown in Scheme 6. The detailed reaction conditions in Scheme 6 are intended to be examples of reagents, solvents and reaction conditions, and should not be construed as limiting. Other equivalents may apply.

[0197] Scheme 6: 14 Synthesis of C-labeled inavolisib [ka]

[0198] The starting materials and reagents for preparing the compounds disclosed herein are generally available from commercial sources or are readily prepared using methods well known to those of skill in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, NY (eds. 1967-1999), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. eds. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0199] The following schemes and examples depict chemical reactions, processes, and methods for synthesizing benzoxazepine oxazolidinone compounds as well as certain intermediates and reagents.

[0200] Scheme 1: Synthesis of compound (10-2) via Grignard-Tamao route [ka]

[0201] (i)Red-Al,TBME,0℃,40-50% o.th.in TBME;(ii)Ti(OEt) 4, oily solid 55-60% o.th.; (iii) THF, 10°C, 75% o.th.dr: 93:7; (iv) KF, KHCO 3 ,H 2 O 2 , MeOH, 45°C, white solid, 61% o.th.; (v) HCl, MeOH, room temperature, white solid, 2.8 g, 92% o.th., and (vi) CDI, DIPEA, DMF, 49% o.th.

[0202] Scheme 1 shows the synthesis of (S)-4-(difluoromethyl)oxazolidin-2-one (10-2). The hemiacetal, 1-ethoxy-2,2-difluoroethan-1-ol 2, was obtained by partial reduction of ethyl 2,2-difluoroacetate 1 with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) at 0 °C. The hemiacetal, 1-ethoxy-2,2-difluoroethan-1-ol 2, was obtained in solution in tert-butyl methyl ether (TBME). The hemiacetal, 1-ethoxy-2,2-difluoroethan-1-ol 2, and (S)-tert-butylsulfinamide 3 were reacted in the presence of titanium ethoxide. The N,O-acetal, (S)-N-(1-ethoxy-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide 4, was obtained in 60% yield as a mixture of diastereomers. An excess of the Grignard reagent (((isopropoxydimethylsilyl)methyl)magnesium chloride 5 was reacted with 4 in tetrahydrofuran (THF). The first equivalent of the Grignard reagent 5 removes ethanol from 4 to release the corresponding imine. According to Ellman et al. (J. Am. Chem. Soc. 1997, 119, 9913-9914.), the reaction proceeds via a six-membered transition state that induces high stereocontrol. The reaction was carried out at -25°C, which gave (S)-N-((R)-1,1-difluoro-3-(isopropoxydimethylsilyl)propan-2-yl)-2-methylpropane-2-sulfinamide 7 with a diastereomeric ratio of 97:3. The reaction was repeated at 10°C to give 7 at 75% o.th. with a diastereomeric ratio of 93:7.

[0203] The crude (S)-N-((R)-1,1-difluoro-3-(isopropoxydimethylsilyl)propan-2-yl)-2-methylpropane-2-sulfinamide 7 was directly subjected to Tamao oxidation conditions using potassium fluoride, potassium bicarbonate and hydrogen peroxide in methanol. The alcohol (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 8-2 could be obtained in 61% yield as a white solid (Org. Process Res. Dev. 2014, 18, 66-81 describes the Tamao oxidation of the related isopropyloxydimethylsilane, but does not include the sulfinamide part).

[0204] Hydrolysis of tert-butylsulfinamide 8-2 with hydrochloric acid in methanol afforded 9-2 in good yield. The latter was treated with N,N-diisopropylethylamine (DIPEA) to release the free amine, followed by the addition of carbonyldiimidazole (CDI). (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) was isolated in 48% o.th. with an enantiomeric ratio of 97:3.

[0205] Scheme 1A: Alternative synthesis of compound (10-2) via Grignard-Tamao route [ka]

[0206] Scheme 1A shows another synthesis of (S)-4-(difluoromethyl)oxazolidin-2-one (10-2). Further details of the method are provided in the Examples below.

[0207] Scheme 2: Synthesis of compound 10-2 via Grignard-Knochel route [ka]

[0208] (i) Ti(OEt) 4, neat, 60°C, 42% o.th., (ii) iodomethyl pivalate, iPrMgCl, THF / NMP, -65°C, 75% o.th.; (iii) HCl, 22%, 80°C, 2 h, 97%, o.th.; and (iv) Et 3 N,CDI,ACN,room temperature,55%,o.th.

[0209] Scheme 2 shows the synthesis of intermediate 9-3. Magnesation of iodomethyl pivalate was carried out at -78 °C following the protocol reported by Knochel (Synlett, (11), 1820-1822; 1999). 2.2 equivalents of iodomethyl pivalate and isopropylmagnesium chloride were used to remove ethanol from N,O-acetal 4 to generate the imine in situ which was further reacted to 8-3. The reaction worked very well on a small scale and 8-3 was isolated by column chromatography at 75% o.th. with no detectable minor isomers (crude, 1 H-NMR). The reaction was repeated on a 20 g scale. In this case, rubber balls formed after magnesiumation of iodomethyl pivalate at -60 to 78 °C. Knochel states that Grignard reagents are stable for only a few hours. Ester 8-3 was hydrolyzed with HCl at 80 °C to give the amino alcohol hydrochloride 9-3 in quantitative yield. The amino alcohol hydrochloride 9-3 was mixed with triethylamine and ACN at room temperature. CDI was added in one portion at room temperature. After 2 h 9-3 was completely converted. The volatiles were evaporated and the crude product was purified by column chromatography. (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) was obtained as a pale yellow oil (308 mg, 55% o.th single enantiomer).

[0210] Scheme 3: Synthesis of compound (10-2) via the Strecker route [ka]

[0211] (i) (S) Ellmans aux, toluene reflux 18% o.th.; (ii) TMSCN (2.0 equiv), cat. Y (OTf 3 ),10 V DCM,room temperature,73% o.th.,dr=5:1,isol.dr=89:11;(iii)HCl,33%,80℃;(iv)BH 3 , THF, 0-45°C, 30% o.th.; and (v) Et 3 N,CDI,IPAc,room temperature,45-50% o.th.

[0212] Scheme 3 shows the synthesis of (S)-4-(difluoromethyl)oxazolidin-2-one (10-2). Hemiacetal 2 and (S)-tert-butylsulfinamide in toluene were refluxed under Dean-Stark conditions. The desired imine was obtained by vacuum distillation with low yield. Severe corrosion was observed on our laboratory glass equipment, indicating the formation of hydrofluoric acid due to decomposition. Strecker reaction of (S)-tert-butylsulfinamide with TMS-CN and Lewis acid gave the desired aminonitrile. The diastereoselectivity of the Strecker reaction was found to be strongly dependent on Lewis (scandium triflate, yttrium triflate and trimethylsilyl triflate). The reaction was carried out on a larger scale using yttrium triflate. The crude product was purified by column chromatography to give the aminonitrile in 73% o.th. and 89:11 dr. The aminonitrile was hydrolyzed and the auxiliary was cleaved using aqueous solution. The alanine hydrochloride derivative 9-2 was obtained with HCl. The carboxylic acid 9-2 was reduced with borane THF complex to give the amino alcohol 9-3 in low yield. The sequence was completed with CDI to give the oxazolidinone 10-2. Based on chiral GC analysis, we obtained the enantiomers of 10-2 with a de of 89:11.

[0213] Scheme 4: Synthesis of compound (10-2) via the sulfone route [ka]

[0214] (a)CuSO 4 , DCM; (b) NaHMDS, THF, -78 ° C, quantitative yield dr> 99:1 (NMR); (c) Mg, AcOH / NaOAc, DMF, room temperature 48% o.th.; (d) HCl, 37%, MeOH, room temperature, 79% o.th.; (e) H2, Pd / C, MeOH, room temperature, 78% o.th.; (f) DIPEA, CDI, THF, room temperature, 44% o.th.

[0215] Scheme 4 shows the synthesis of (S)-4-(difluoromethyl)oxazolidin-2-one (10-2). The aldehyde 2-(benzyloxy)acetaldehyde 11 and (S)-tert-butylsulfinamide 3 were stirred in dichloromethane (DCM) in the presence of copper sulfate. Complete and clean conversion to the imine (R,E)-N-(2-(benzyloxy)ethylidene)-2-methylpropane-2-sulfinamide 12 was obtained overnight. Refluxing the reaction in toluene significantly reduced the yield (less than 50% o.th.). Treatment of the imine 12 and difluoromethylphenylsulfone 13 as a solution in tetrahydrofuran (THF) with sodium bis(trimethylsilyl)amide (NaHMDS) at 70 °C gave the desired product 14. The reaction profile was very clean (only one spot by TLC) and no minor diastereomers were detected by NMR. The phenylsulfone (R)-N-((S)-3-(benzyloxy)-1,1-difluoro-1-(phenylsulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide 14 was deprotected using elemental magnesium turnings in dimethylformamide (DMF) / acetate buffer to give the key intermediate (S)-N-((S)-3-(benzyloxy)-1,1-difluoropropan-2-yl)-2-methylpropane-2-sulfinamide 8-1 as a single product in 48% o.th. (not optimized). Alternative methods to remove the sulfone, such as hydrogenation with Raney nickel, did not afford conversion to 8-1. The auxiliary was cleaved using aqueous HCl in methanol to give the ammonium hydrochloride salt of 3-(benzyloxy)-1,1-difluoropropan-2-amine 9-5 as a white crystalline solid in good yield. The benzyl group of 9-5 was removed by hydrogenation over Pd / C to give the ammonium hydrochloride salt of 2-amino-3,3-difluoropropan-1-ol 9-2 as a white solid. The free amine was released by treatment of 9-2 with N,N-diisopropylethylamine (DIPEA), followed by addition of carbonyldiimidazole (CDI) to give (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) in moderate yield.Based on chiral GC analysis, we obtained the enantiomer of (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) in >99.9% ee.

[0216] Scheme 5: Synthesis of compound 18 [ka]

[0217] a:i) Mg(OEt) 2 ,MeOH,MeTHF,ii)HCl,n-PrOH;b:ClCHCHO,KHCO 3 ,MeTHF,H 2 O,c:NIS,DMF;d:EtMgBr,THF;e:(10-2),Cu(OAc) 2 ,trans-N,N'-dimethylcyclohexane-1,2-diamine,Cs 2 CO 3 ,MeTHF;f:i)(S)-2-aminopropanoic acid,Cu 2 OK 3 PO 4 , DMSO, ii) NH 3 ,MeOH,THF;g:i)NH 3 ,HOSu,EDC,THF, i PrOH, ii) EtOH, H 2 O.

[0218] Scheme 5 shows the preparation of (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide 18. Magnesium ethoxide, Mg(OEt) in methanol. 22-(5-Bromo-2-cyanophenoxy)ethane-1-aminium chloride 11', cyclized with and acidified with n-propanol solution of hydrogen chloride, gave 8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine hydrochloride 12'. 12' was cyclized to form the imidazole ring using aqueous chloroacetaldehyde in the presence of potassium bicarbonate as a base to give 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 13'. Imidazole 13' was bis-iodinated with N-iodosuccinimide (NIS) or other iodination reagents such as iodine or iodine monochloride to give 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 14'. Selective reduction of 14′ via iodo-metal exchange using Grignard reagents such as ethylmagnesium bromide or isopropylmagnesium chloride afforded 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 15. In the presence of a copper catalyst such as copper(II) acetate or copper(I) iodide, a ligand such as trans-N,N'-dimethylcyclohexane-1,2-diamine, 1,10-phenanthroline, or 3,4,7,8-tetramethyl-1,10-phenanthroline, an inorganic base such as cesium carbonate or tripotassium phosphate, and 2-methyltetrahydrofuran or acetonitrile as solvent, the iodide from 15 was chemoselectively displaced by (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) to give (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one 16.Displacement of the bromide from 16 with (S)-2-aminopropanoic acid in the presence of a copper catalyst such as copper(I) oxide, an inorganic base such as tripotassium phosphate, and DMSO as the solvent, followed by formation of the ammonium salt in THF using a solution of ammonia in methanol as the ammonia source, gave ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate 17. Conversion of the carboxylate salt 17 to the carboxamide was achieved using a solution of ammonia in 2-propanol, additives such as N-hydroxysuccinimide (HOSu) or 1-hydroxybenzotriazole (HOBt), and a dehydrating reagent such as N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) or N,N'-diisopropylcarbodiimide (DIC) in THF to give 18. EXAMPLES

[0219] Scheme 1 Scheme 1, step (i): [ka]

[0220] The hemiacetal 1-ethoxy-2,2-difluoroethan-1-ol 2 was obtained by partial reduction of ethyl 2,2-difluoroacetate 1 with sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) at 0 °C. The hemiacetal 1-ethoxy-2,2-difluoroethan-1-ol 2 was obtained in solution in tert-butyl methyl ether (TBME).

[0221] Scheme 1, step (ii): [ka]

[0222] Difluoroacetaldehyde ethyl hemiacetal 2 (60.7 g; 90% w / w:10% w / w ethanol) was placed in a 500 mL double-walled packed glass reactor equipped with a mechanical stirrer, thermometer, funnel and nitrogen supply. (S)-tert-butylsulfinamide 3 (50.0 g) and titanium(IV) ethoxide (99.0 g) were added at a temperature below 20 °C. The suspension was heated at 80-90 °C for at least 3 h. The reaction mixture was stirred at this temperature for 4 h until an orange solution was formed. The solution was cooled to 70-80 °C and the amount of (S)-tert-butylsulfinamide 3 was determined. The reaction mixture was cooled to 15-25 °C and aged for at least 2 h.

[0223] In another 100 mL double-glazed packed reactor equipped with a mechanical stirrer, thermometer, funnel and nitrogen supply, 200 mL of pharmaceutical grade water and citric acid (79.4 g) were added at a temperature of 50 °C. Potassium hydroxide (58.9 g, 50%) was added and the temperature was lowered to 15-20 °C. The reaction mixture prepared above (204 g, 190 mL) was added adiabatically at a temperature below 45 °C. The orange solution was stirred for at least 60 minutes at a temperature of 30-40 °C. The phases were separated into an aqueous phase and an organic phase. tert-Butyl methyl ether was added to the aqueous phase and the mixture was stirred for at least 5 minutes at 30-40 °C, followed by another phase separation. The two organic phases were combined at a temperature below 30 °C. Pharmaceutical grade toluene (100 mL) was added and the mixture was stirred for at least 5 minutes at a temperature of 15-25 °C. The phases were separated for at least 10 minutes.

[0224] Magnesium sulfate (anhydrous, 35 g) was suspended in pharmaceutical grade toluene (80 mL) and added to the organic phase and stirred for at least 30 min at a temperature below 30 °C. The suspension was filtered. The filtrate contains the desired product (443 mL; 398 g). The filtrate is heated to a temperature of 35-45 °C and distilled under reduced pressure (90-22 mBar) to collect distillate 1 (312 mL, 253 g). Distillation is continued by the addition of pharmaceutical grade toluene (150 mL) to collect distillate 2 (160 mL, 136 g). The combined distillates were filtered with pharmaceutical grade toluene (50 mL) to give -,(S)-N-(1-ethoxy-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide 4 (170 mL, 171.2 g) as a pale yellow solution in toluene. The yield was 89.2% and the purity was 98.1%.

[0225] Scheme 1, step (iii): [ka]

[0226] Tetrahydrofuran (stabilized, 700 mL) was placed in a 1500 mL double-glazed packed reactor equipped with a mechanical stirrer, thermometer, addition funnel and nitrogen supply at below 30 °C. Magnesium turnings (23.9 g) were added at below 30 °C. The suspension was warmed to 55-65 °C. 1,2-dibromoethane (6.4 g) was added over 15 minutes, maintaining the temperature at 55-65 °C. (Chloromethyl)dimethylisopropyloxysilane (5.7 g) was added over at least 20 minutes while maintaining the temperature at 55-65 °C. The suspension was stirred for at least 15 minutes. (Chloromethyl)dimethylisopropyloxysilane (164.0 g) was added over at least 120 minutes while maintaining the temperature at 55-65 °C. The black mixture was stirred at a temperature of 55-65 °C for at least 60 minutes and then cooled to 45-55 °C. The mixture was cooled to 0-10 °C. ((isopropoxydimethylsilyl)methyl)magnesium chloride 5 was obtained in solution with a purity of 85-90%. (S)-N-(1-ethoxy-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide 4 (160 g) in toluene was added over 2 h.

[0227] A solution was prepared by combining pharmaceutical grade water (168 g), citric acid (117.3 g) and ammonia solution (122.4 g, 25%) and mixing at a temperature of 15-20 °C. A mixture of ((isopropoxydimethylsilyl)methyl)magnesium chloride 5 and (S)-N-(1-ethoxy-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide 4 (1050 mL) was added to the ammonium citrate solution over 5 min. The biphasic mixture was stirred at a temperature of 35-45 °C for at least 10 min and the phases were allowed to separate over at least 15 min. The lower aqueous phase (350 mL, 438 g) was drained, leaving a light brown clear organic phase (1050 mL, 940 g). Potassium bicarbonate (1.7 g) and pharmaceutical grade water (34 mL) were added to the organic phase. The organic phase was distilled under reduced pressure (90-300 mBar) at temperatures between 35-50 °C. The collected distillate (420-450 mL) was combined with pharmaceutical grade water (600 mL) and distilled again until 1000-1050 mL of distillate was collected. The distillate contained (S)-N-((R)-1,1-difluoro-3-(isopropoxydimethylsilyl)propan-2-yl)-2-methylpropane-2-sulfinamide 7 (887 g). The pH of the distillate was adjusted to pH 5.2-5.7 using citric acid (10% solution) and distilled again at temperatures between 35-55 °C and reduced pressure between 80-120 mBar to collect 480-520 mL of distillate. The distillate contained 492 g of (S)-N-((R)-1,1-difluoro-3-(isopropoxydimethylsilyl)propan-2-yl)-2-methylpropane-2-sulfinamide 7.

[0228] Scheme 1, step (iv): [ka]

[0229] The distillate of step (iii) (196 g) containing (S)-N-((R)-1,1-difluoro-3-(isopropoxydimethylsilyl)propan-2-yl)-2-methylpropane-2-sulfinamide 7 was placed in a 1000 mL double-glazed packed reactor equipped with a mechanical stirrer, thermometer, funnel and nitrogen supply. The distillate was heated to 40-50 °C and potassium bicarbonate (33.9 g), potassium fluoride (39.4 g) and tert-butylammonium hydrogen sulfate (5.9 g) were added. Hydrogen peroxide (49.58 g, 35%) was charged over a period of at least 180 min. The pale yellow emulsion was aged at a temperature of 40-55 °C for at least 30 min.

[0230] The biphasic mixture was cooled to 15-25°C and sodium sulfite (4.27 g) was added over 30 min at a temperature of 15-30°C. The reaction vessel was flushed with nitrogen to purge oxygen and Celite 545 AW (15 g) was added in anhydrous acetonitrile (150 mL). The suspension was stirred for at least 30 min. The suspension was filtered. The filtrate was washed twice with anhydrous acetonitrile (35 mL).

[0231] The resulting triphasic mixture was allowed to separate for at least 15 minutes at 20-30 °C. The lowest aqueous phase was drained and the biphasic mixture was allowed to separate for 15 minutes. The oily middle phase was drained. The upper organic phase (290 mL, 271 g) was distilled at 40-50 °C and a reduced pressure of 90-240 mBar. Toluene (300 mL) was added during the distillation. The collected distillate was 390 mL and weighed 324 g. Anhydrous acetonitrile (40 mL) was added to the distillate and the mixture was warmed to 60-70 °C. The product was cooled to 35-40 °C and allowed to crystallize. The solution was filtered and the solid was rinsed with anhydrous acetonitrile. Toluene (100 mL) was added and the mixture was distilled at 40-50 °C under a reduced pressure of 120-240 mBar. The collected distillate was 90-110 mL and weighed 127 g. Toluene (50 mL) was added and the distillation was continued. The distillate was cooled to 0-10 °C for at least 120 min. The distillate was filtered. The solid filter cake was washed twice with toluene (50 mL, 25 mL) to give crude (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 8-2 (49.06 g) which was dried at 20 mBar and 40-50 °C. Pure (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 8-2 (46.0 g) was obtained in 63% yield. 1H NMR(400MHz,DMSO-d6)δ6.04(td,J=55.6,3.3Hz,1H),5.53(d,J=9.1Hz,1H),4.96 (s,1H),3.54(dd,J=6.3,3.6Hz,2H),3.43(ddqd,J=18.6,9.4,6.0,3.0Hz,1H).13C NMR(101MHz,DMSO-d6)δ115.90(t,J=242.5Hz),60.44,59.02(t,J=20.5Hz),56.34,22.86.

[0232] Scheme 1, step (v): [ka]

[0233] 1-Propanol (32.7 g) was placed in a 200 ml double-glazed packed reactor equipped with a mechanical stirrer, thermometer, addition funnel and nitrogen supply at below 20 °C. Hydrochloric acid (gas, 9.0 g) was charged at 20 °C below the solvent niveau. Dry (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 8-2 (45.0 g) was added in portions over 90 min and the suspension was stirred at 15-25 °C for 30 min. Crystallization occurred spontaneously. Toluene (20 mL) was added over 30 min and the suspension was stirred for at least 30 min. The suspension was filtered. The filter cake was washed three times with toluene (total 60 mL). The hydrochloride salt of (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 9-2 was obtained with a mass of 31.6 g, which was then dried under reduced pressure (20 mBar) at 45° C. The dried hydrochloride salt of (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 9-2 was obtained with a mass of 29.5 g, with a purity of 99.7% and a yield of 96%. 1H NMR(400MHz,DMSO-d6)δ8.78(s,3H),6.31(td,J=54.3,3.9Hz,1H),5.63(s,1H),3.88-3.66(m,2H),3.57(ddq,J=14.6,9.4,4.8Hz,1H).13C NMR(101MHz,DMSO-d6)δ114.20(t,J=238.9Hz),63.56(t,J=4.6Hz),53.2(dd,J=24.2,23.6Hz).

[0234] Scheme 1, step (vi): [ka]

[0235] 2,2,2-Trifluoroethanol (850 g) was charged to a 3500 ml double-glazed packed reactor equipped with a mechanical stirrer, thermometer, addition funnel and nitrogen supply at below 30 °C. 1,1'-carbonyldiimidazole (652 g) was charged in portions at a temperature of 10-35 °C over at least 60 min. The light brown suspension was warmed to 80-140 °C (start: 90 °C, end: 130 °C) and distilled at 200-270 mbar. 919 g, 620 ml of distillate 1 are collected. The distillate was cooled to 80-100 °C and pharmaceutical grade water (15 g) was added over 60 min, followed by another 480 g over 15 min, followed by cooling the distillate to below 30 °C. The solution is distillate 1.

[0236] 2,2,2-Trifluoroethanol (911 g) was placed in a 3500 ml double-glazed packed reactor equipped with a mechanical stirrer, thermometer, addition funnel and nitrogen supply at <30 °C. (S)-N-((S)-1,1-difluoro-3-hydroxypropan-2-yl)-2-methylpropane-2-sulfinamide 9-2 dry hydrochloride (330 g) was added and the suspension was warmed to 40-55 °C. Potassium carbonate (401 g) was added over 30 min and the addition funnel was rinsed with 2,2,2-trifluoroethanol (137 g).

[0237] Distillate 1 (833 g) was added over 60 min at 40-55 °C, followed by stirring for at least 60 min. The suspension was cooled to 15-25 °C, pharmaceutical grade water (990 g), hydrochloric acid (382 g, 33%) were added and the pH was adjusted to 5.8-6.2 with additional hydrochloric acid. The suspension was warmed to 40-55 °C and distilled at 220-270 mBar. 1400-1600 mL of distillate was collected. The solution was cooled to 15-30 °C (target: 25 °C) and the pH was adjusted with hydrochloric acid. Water (150 g) and isopropyl acetate (990 mL) were added and the biphasic colorless mixture was stirred for at least 15 min. The phases were separated for at least 5 min. The aqueous phase was extracted 11 times with isopropyl acetate (330 ml each) at 15-30 °C. The mixture was stirred for at least 15 min for each extraction. The phases were separated for at least 5 min. When the salt had precipitated, purified water (20 mL) was added. All organic extracts (4442 g, 4940 mL) were collected and combined. The organic layer was distilled at 35-55 °C and 170-250 mBar pressure. The distillate was filtered and washed with isopropyl acetate (200 mL). Seed crystals (100 mg) were added if necessary. The suspension was cooled to 0-10 °C and methylcyclohexane (1815 mL) was added over 60 min. The suspension was aged for at least 30 min and then filtered twice with methylcyclohexane (660 mL total). The wet (S)-4-(difluoromethyl)oxazolidin-2-one 10-2 (291 g) was dried at 25-35 °C and 10 mBar pressure. The dried product weighed 283 g, with a purity of nearly 100% and a yield of 92%. 1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),6.09(td,J=55.3,3.3Hz,1H),4.41(tt,J=9.3,1.1Hz,1H),4.25(dd,J=9.3,4.2Hz,1H),4.22-4.08(m,1H).13C NMR(101 MHz,DMSO-d6)δ159.07,115.45(t,J=251.5 Hz),63.56(t,J=4.7 Hz),53.2(t,J=24.3 Hz).

[0238] Scheme 1A Scheme 1A Step 1: Difluoroacetaldehyde-ethyl hemiacetal (72.8 kg, 1.05 equiv.), ethanol (2 kg) and (S)-tert-butylsulfinamide (60.0 kg, 1.0 equiv.) were charged and the temperature was set below 25°C. Titanium(IV) ethoxide (119 kg, 1.0 equiv.) and ethanol (5 kg) were added and the temperature was raised to 80-90°C over at least 90 min. The reaction mixture was stirred at 80-90°C for at least 4 h and the conversion was checked by LC. When the IPC limit was met ((S)-tert-butylsulfinamide was ≤1.0%-a / a), the reaction mixture was cooled to 15-25°C and aged for at least 2 h. The disappearance of the hydrate impurity was checked by LC. When the IPC limits were met (hydrate step 1 1.0% ≤ 1.0%-a / a), the reaction mixture was quenched under adiabatic conditions at 30-40 °C with potassium citrate solution (95 kg, 1.0 equiv. citric acid; 71 kg, 1.27 equiv. KOH 50%; 240 kg water). The reaction vessel was rinsed with TBME (60 L). The quenched mixture was stirred for 60 min and the phases were separated. The upper organic phase was kept in a separate vessel and the lower aqueous phase was extracted once with TBME (60 L). The lower aqueous phase was drained and the two organic phases were combined. Toluene (120 L) was added to the combined organic phase and the mixture was stirred for 15 min. The newly formed aqueous layer was separated for 15 min and drained. Magnesium sulfate (42 kg, 0.71 equiv.) was added as a suspension in toluene (72 L). Residual water was controlled by Karl Fischer titration. When the IPC limits were met (water less than 2.0%-w / w), the suspension was filtered off and the filter cake was washed with toluene (2 x 36 L). The solvent was partially distilled off under reduced pressure at 30-45 °C. A feed distillation was performed with toluene (180 L) to remove ethanol. The ethanol content was confirmed by GC-HS (ethanol ≤ 1.0%-w / w). The solution from step 1 was diluted with toluene (60 L), discharged onto a filter cartridge and telescoped directly to the next step.

[0239] Scheme 1A Step 2: Magnesium turnings (9.8 kg, 2.9 equiv.) and THF (255 kg) were charged and the suspension was warmed to 50-65 °C. 1,2-Dibromoethane (0.8 kg, 0.1 equiv.) was added and the mixture was stirred for at least 10 min with formation of ethylene gas. (Chloromethyl)dimethylisopropyloxysilane (3.6 kg, 0.1 equiv.) was added over at least 20 min at 50-65 °C (target: 60 °C). The start of the reaction was confirmed by observation of heat formation. If no clear temperature increase was observed, the start of the reaction could be confirmed by GC ((chloromethyl)dimethylisopropyloxysilane ≤ 5.0%-a / a). When IPC limits were met (internal temperature ≥ 3 C or increasing in case of conversion), the dosage of the remaining (chloromethyl)dimethylisopropyloxysilane (4 x 16.5 kg, 2.9 equiv.) was complete over at least 4 h. The reaction mixture was aged at 50-65 °C for at least 60 min. Complete consumption of magnesium turnings was confirmed by GC ((chloromethyl)dimethylisopropyloxysilane ≥ 3.0%-a / a). Once IPC criteria was reached, the reaction mixture was cooled to 0-10 °C. The toluene solution from step 1 (74 kg, 1.0 equiv.) was added over at least 120 min at 0-10 °C. A useful IPC was measured to confirm the reaction profile. In a second reactor, an ammonium citrate solution (48 kg, 1.8 equiv. citric acid; 50 kg, 5.3 equiv. ammonia, 25%, 69 kg water) was prepared and pre-cooled to 10-20 °C. The reaction mixture from the first reactor was poured into the ammonium citrate solution under adiabatic conditions. The temperature of the quench mixture reaches 34-45 °C. THF was added (10 L). The lower aqueous layer was separated and drained. A solution of potassium bicarbonate 5% (0.7 kg, 0.05 equiv.) in water (14 kg) was added. The bulk of the solvent was removed at 35-45°C and 100-250 mbar, followed by a feed distillation with water (250 kg) to remove THF and volatile siloxane residues. Removal of THF was confirmed by GC-HS (THF ≤ 0.50%-w / w). Citric acid solution (10 L, 10% in water) was added to adjust the pH to 5.5 at 35-45°C. Distillation was continued at 40-55°C and 50-150 mbar to remove isopropanol / water.The conversion of step 2 intermediates and removal of solvent were confirmed by LC and GC-HS (THF≦0.50%-w / w, isopropanol≦0.50%-w / w, step 2 intermediates≦10%-a / a). If the IPC criteria were met, the mixture was discharged onto a filter cartridge to obtain step 2 as a two-phase mixture with water. This mixture was telescoped directly to the next step.

[0240] Scheme 1A, Step 3: Step 2 (12.14 kg, 1.0 equiv.) as a biphasic mixture with water was charged along with potassium bicarbonate (2.17 kg, 1.0 equiv.), potassium fluoride (2.52 kg, 2.0 equiv.) and tetrabutylammonium hydrogen sulfate (0.37 kg, 0.05 equiv.). The mixture was warmed to 40-50 °C and hydrogen peroxide 35% (3.16 kg, 1.5 equiv.) was added over at least 180 min. The mixture was aged for at least 60 min. Conversion was checked by LC. Once IPC limits were met (step 2 and step 2 dimers <5.0%-a / a), the reaction mixture was quenched with sodium sulfite (0.27 kg, 0.1 equiv.) at 40-50 °C. The mixture was diluted with toluene (7.8 kg, 0.7 V) at 40-50 °C. The biphasic cloudy emulsion was cooled to 35-45°C (target: 40°C) and the mixture was aged for at least 60 min to allow spontaneous crystallization to begin. The suspension was cooled to 0-10°C over at least 180 min and stirred for at least 30 min. The product was isolated by filtration and the filter cake was washed with toluene (10 L, 0.6 V). Step 3, crude wet, was dried under reduced pressure at 40-50°C until the water content was <1.0%-w / w. Step 3, crude dry, was obtained as an off-white to orange solid containing off-white inorganic salts (4.75 kg, 56% o.th, 99.2%-a / a and 62%-w / w).

[0241] Scheme 1A, Step 4: Step 3, A mixture of crude dry matter (4.75 kg, 1.0 equiv, 62%-w / w) with acetonitrile (11.7 kg, 2.8 V) and toluene (1.3 kg, 0.27 V) was charged and the mixture was warmed to 40-50 °C. The suspension was filtered against a second reactor and the filter cake was washed with acetonitrile (3.9 kg, 0.53 V). The solution was concentrated under reduced pressure at 40-50 °C (2 V distillate). Distillation was continued under reduced pressure at 40-50 °C by feeding toluene (15.5 kg, 3.3 V) at a constant reactor level while forming a suspension. The suspension was cooled to 15-25 °C and 1-propanol (2.47 kg, 3.0 equiv) was added. Hydrogen chloride gas (0.55 kg, 1.1 equiv) was passed at 15-25 °C for at least 1 h and the suspension was aged for at least 30 min. The conversion was confirmed by GC. Once the IPC limits were met (step 3 0.5%-a / a), the product was isolated by filtration and the filter cake was washed with toluene (5.7 kg, 1.2 V displacement). Step 4, the pure wet was dried at 40-50 °C under reduced pressure until LOD < 0.40%-w / w and 1-propanol < 500 ppm were reached. Step 4, the pure wet was obtained as a white to off-white solid (1.88 kg, 94% ot and 99.9%-a / a purity).

[0242] Scheme 1A, Step 5: The reagent (bis(2,2,2 trifluoroethyl)carbonate) was prepared according to the following procedure: 2,2,2-trifluoroethanol (104 kg, 2.1 equiv.) was charged at a JT below 30 °C. 1,1'-carbonyldiimidazole (80 kg, 1.0 equiv.) was charged portionwise at IT = 10-55 °C over at least 60 min. The thick suspension was heated to IT = 80-130 °C and bis(2,2,2 trifluoroethyl)carbonate (BTFEC) was added under reduced pressure (150-3 The distillation residue was quenched with a small amount of water (1.8 kg, 1.8 L). The complete hydrolysis of the remaining bis(2,2,2-trifluoroethyl)carbonate in the distillation residue was controlled by GC (IPC bis(2,2,2-trifluoroethyl)carbonate ≤ 0.1%-a / a). When the IPC criteria were met, the quench residue was diluted with water (57 kg, 57 L) and discarded.

[0243] The process for oxazolidinone formation was carried out according to the following procedure: Step 4 (pure dry material) (15.0 kg, 1.0 equiv.) was suspended in 2,2,2-trifluoroethanol (45 kg, 32 L) at an IT below 30 °C. The suspension was warmed to IT = 40-55 °C. Potassium carbonate powder (18.2 kg, 1.3 equiv.) was added portionwise over at least 30 min at IT = 40-55 °C. The addition funnel was rinsed with a small amount of 2,2,2-trifluoroethanol (2 L). Bis(2,2,2 trifluoroethyl)carbonate (34.4 kg, 1.5 equiv.) was charged over at least 60 min at IT = 40-55 °C. The suspension was further aged for at least 60 min. The conversion was checked by GC (Step 4, a / a below 0.5%). Once the IPC limits were met, the mixture was cooled to IT = 15-30 °C and the reaction mixture was quenched by adding water (44 kg, 44 L) at an IT below 30 °C. The pH was adjusted to 5.5-6.5 with 33% hydrochloric acid (19.4 kg, ca. 1.6 equiv.). The solvent fraction was distilled off under reduced pressure at IT = 40-55 °C. The mixture was cooled to IT = 15-30 °C and the pH was checked and readjusted to 5.5-6.5 with small amounts of 33% hydrochloric acid. The aqueous product solution was extracted 12 times with isopropyl acetate (170 kg, 195 L). The combined organic layers were concentrated under reduced pressure at IT = 40-55 °C. The concentrate was transferred to a second reactor on a filter cartridge. The filter cartridge was rinsed with a small amount of isopropyl acetate (8 L). The product was further concentrated under reduced pressure at IT = 40-55 °C. The product solution was cooled to IT = 35-40 °C. If crystallization did not start spontaneously, the mixture was seeded. The onset of crystallization was controlled by visual inspection. After crystallization started, the suspension was cooled to IT0-10°C over at least 120 min. Methylcyclohexane (69 kg, 89 L) was then added over at least 60 min. The suspension was aged for at least 30 min to complete the crystallization process. The product was isolated by centrifugation. The pure wet material was dried under reduced pressure at 25-35°C to obtain the pure dry material as a white to off-white solid (23.4 kg, 89% o.th., 100%-a / a purity).

[0244] Scheme 2 Scheme 2, step (i): [ka]

[0245] (i) Ti(OEt) 4 , undiluted, 60°C, 42% o.th. (S)-tert-Butylsulfinamide 2 (10 g, 82 mmol, 1.0 equiv), hemiacetal 3 (14.8 g, 116 mmol, 1.4 equiv) and titanium ethoxide (26.3 g, 116 mmol, 1.4 equiv) were mixed and heated to 60 °C. Complete conversion of 3 was obtained after 16 h (TLC). The solution was quenched with saturated brine (50 ml) and EtOAc (200 ml). The slurry was filtered through Celite (10 g). The phases were separated and the organic layer was washed with MgSO 4 The mixture was dried at rt. The solvent was evaporated and the crude product was purified by column chromatography (EtOAc cyclohexane 2:1). N,O-acetal 4 was obtained as a colorless solid (7.2 g, 42% o.th.). 1 H NMR (300 MHz, DMSO-d 6 )δ 6.45(d,J=10.0 Hz,1H),5.83(td,J=55.4,4.4 Hz,1H),4.65-4.41(m,1H),3.88(dq,J=9.5,7.1 Hz,1H),3.50(dq,J=9.5,6.9 Hz,1H),1.17-1.10(m,12H tBu).

[0246] Scheme 2, step (ii): [ka]

[0247] Iodomethyl pivalate (8.0 g, 33 mmol, 3.0 equiv) was dissolved in a mixture of THF (50 ml) and NMP (10 ml). The solution was cooled to -65°C. A 2.0 M solution of iPrMgCl in THF (19.0 ml, 38 mmol, 3.5 equiv) was added over 30 min at IT = -65°C. Then N,O-acetal 4 (2.5 g, 11 mmol, 1.0 equiv) dissolved in THF (5 ml) was added over 30 min at -65°C. The diastereoselectivity was 94:6 (NMR). The mixture was washed with saturated NH 4 The mixture was quenched with aqueous Cl (50 ml). The aqueous layer was extracted with TBME. The organic layers were combined and diluted with MgSO 4 The crude product was purified by column chromatography to give pivalate 8-3 as a grey solid (2.46 g, 75% o.th.). 1 H NMR (300 MHz, DMSO-d 6 )δ 6.09(td,J=55.1,3.6 Hz,1H),5.81(d,J=9.3 Hz,1H),4.18(dd,J=11.5,5.1 Hz,1H),4.08(ddd,J=11.5,6.4,1.1 Hz,1H),3.88-3.62(m,1H),1.15(s,9H),1.14(s,9H).

[0248] Scheme 2, step (iii): [ka]

[0249] Pivalate 8-3 (1.0 g, 4.4 mmol, 1.0 equiv) was mixed in 33% HCl (4 ml). The reaction mixture was heated to 80° C. After 2 h, pivalate 8-3 was completely converted (TLC: EtOAc). The mixture was concentrated and coevaporated with MeOH, ACN and toluene. The remaining solid was suspended in TBME (5 ml) and filtered off. Amino alcohol hydrochloride 9-3 was obtained as a grey solid (0.64 g, 97% o.th.). 1 H NMR (300 MHz, DMSO-d 6)δ 8.78(s,3H),6.31(td,1H,J=54.3 Hz,J=3.9 Hz,H3),5.63(s,1H,OH),3.88-3.66(m,2H,H1),3.65-3.50(m,1H,H2).

[0250] Scheme 2, step (iv): [ka]

[0251] The amino alcohol hydrochloride 9-3 (0.60 g, 4.1 mmol, 1.0 equiv) was mixed with triethylamine (1.2 ml, 8.2 mmol, 2.0 equiv) and ACN (5 ml, 8V) at room temperature. CDI (725 mg 4.5 mmol, 1.1 equiv) was added in one portion at room temperature. After 2 h 9-3 was completely converted (IPC:TLC BuOH, AcOH, water 5:1:1). The volatiles were evaporated and the crude product was purified by column chromatography. (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) was obtained as a pale yellow oil (308 mg, 55% o.th single enantiomer). 1 H NMR (300 MHz, DMSO-d 6 )δ=8.26(s,1H),6.09(td,1H,J=55.3 Hz,J=3.3 Hz,H4),4.41(tt,J=9.3 Hz,J=1.1 Hz,1H),4.25(dd,J=9.3 Hz,J=4.2 Hz,H3),4.22-4.08(m,1H,H2).

[0252] Scheme 3 Scheme 3, step (i): [ka]

[0253] Hemiacetal 2 (5.0 g, 40 mmol, 1.0 equiv.) and (S)-tert-butylsulfinamide (4.8 g, 40 mmol, 1.0 equiv.) were dissolved in toluene (25 ml, 5V). The mixture was refluxed for 5 h with a Dean-Stark trap. The solvent was evaporated. The crude product was purified by distillation under reduced pressure at 100° C. (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide was obtained as a colorless liquid (1.1 g, 18% o.th yield). 1 H NMR (300 MHz, chloroform-d) δ 8.07 (dt, J = 4.7, 3.1 Hz, 1H), 6.28 (td, J = 54.6, 4.7 Hz, 1H), 1.27 (s, 9H).

[0254] Scheme 3, step (ii): [ka]

[0255] (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (13 g, 71 mmol, 1.0 equiv.) was dissolved in DCM (130 ml, 10 V). Y(OTf) 3 (3.8 g, 7.1 mmol, 10 mol%) was added and the suspension was stirred for 15 min. TMSCN (18 ml, 142 mmol, 2.0 equiv) was added over 30 min at room temperature. The reaction mixture was stirred for 4 h until complete conversion of (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (TLC: EtOAc). The reaction was quenched by addition of water (50 mL). The organic layer was washed twice with 50 ml water and the solvent was evaporated. The diastereomeric ratio of the crude product was 5:1 (NMR). The crude product was purified by column chromatography (1:3 to 1:1 EtOAc cyclohexane). Diastereomerically pure (S)-N-((R)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide was obtained as a light brown solid (11 g, 73% o.th). 1H NMR (300 MHz, chloroform-d) δ 5.95 (ddd, J = 55.0, 54.3, 3.2 Hz, 1H), 4.61 (dddd, J = 14.2, 9.2, 8.4, 3.2 Hz, 1H), 1.29 (s, 9H).

[0256] Scheme 3, step (iii): [ka]

[0257] (S)-N-((R)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (6.0 g, 29 mmol, 1.0 equiv) was dissolved in 33% HCl (30 ml, 5 V). The mixture was gently heated to 80° C. and stirred for 4 h until complete conversion of (S)-N-((R)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (TLC: EtOAc). Volatiles were removed under reduced pressure. Methanol (10 V) was added and the suspension was stirred at room temperature for 30 min. The solid (NH 4 The toluene (HCl) was filtered off and the filter cake was washed with methanol (1.0 V). Methanol was removed and the residue was suspended in TBME (10 V) and stirred at room temperature for 30 min. The suspension was filtered off and the wet product was dried under reduced pressure. The amino acid hydrochloride salt 9-2 was obtained as a light brown solid (4.3 g, 93% o.th.). 1 H NMR (300 MHz, heavy water) δ 6.46(td,J=52.8,1.9 Hz,1H),4.70(s,4H),4.40(dt,J=25.8,1.9 Hz,1H).

[0258] Scheme 3, step (iv): [ka]

[0259] The amino acid hydrochloride 9-2 (1.0 g, 6.6 mmol, 1.0 equiv.) was suspended in THF (5 ml, 5 V). 3(20 ml, 3.0 equiv) was added at 0° C. over 30 min. Vigorous gas evolution was observed. The suspension was heated to 45° C. for 2 h. After 2 h the starting material was completely converted (IPC:TLC BuOH, AcOH, water 5:1:1). The mixture was quenched with methanol (5 ml, 5 V) and acetic acid (5 ml, 5 V) at room temperature. The volatiles were evaporated and the residue was dissolved in 33% HCl (1.5 ml, 1.5 V). The volatiles were evaporated and the solid was dried under reduced pressure. The crude amino alcohol hydrochloride salt 9-3 was used directly in the next step. 1 H NMR (300 MHz, DMSO-d 6 )δ 8.78(s,3H),6.31(td,1H,J=54.3 Hz,J=3.9 Hz,H3),5.63(s,1H,OH),3.88-3.66(m,2H,H1),3.65-3.50(m,1H,H2).

[0260] Scheme 3, step (v): [ka]

[0261] The crude mixture from amino alcohol hydrochloride 9-3 was mixed with triethylamine (0.92 ml, 18 mmol, 3.0 equiv.) and IPAc (5 ml, 5V) at room temperature. CDI (1.24 g, 2.0 equiv.) was added in one portion at room temperature. After 2 h the amino alcohol 9-3 was completely converted (IPC:TLC 1-BuOH, AcOH, water 5:1:1). The volatiles were evaporated and the crude product was purified by column chromatography. (S)-4-(difluoromethyl)oxazolidin-2-one 10-2 was obtained as a pale yellow oil (450 mg, 50% o.th. over two steps). The ratio of the enantiomers was 89:11. 1 H NMR (300 MHz, chloroform-d) δ 6.33 (s, 1H), 5.71 (td, J = 55.3, 4.5 Hz, 1H), 4.46 (td, J = 9.2, 1.3 Hz, 1H), 4.35 (dd, J = 9.6, 4.5 Hz, 1H), 4.04 (ddq, J = 13.9, 9.3, 4.5 Hz, 1H).

[0262] Scheme 4 Scheme 4, step (a): [ka]

[0263] Benzyloxyacetaldehyde 11 (2.50 g, 16.7 mmol, 1.0 equiv.) and (R)-tert-butylsulfinamide 3 (2.15 g, 18.3 mmol, 1.1 equiv.) were dissolved in DCM (25 ml, 10 V). Copper sulfate (6.44 g, 41.8 mmol, 2.5 equiv.) was added and the suspension was stirred at 25° C. for 16 h until complete conversion of 11 was reached (TLC: EtOAc heptane 1:1). Celite (10 g) was added and the suspension was filtered through silica (10 g). The filter cake was rinsed with DCM (50 ml, 20 V) and the solvent was evaporated. Sulfinimide 12 was obtained as a yellow oil (4.05 g, quantitative yield). 1 H NMR (300 MHz, chloroform-d) δ 8.06 (t, J = 3.3 Hz, 1H), 7.34-7.20 (m, 5H), 4.56 (s, 2H), 4.33 (dd, J = 3.2, 1.0 Hz, 2H), 1.14 (s, 9H).

[0264] Scheme 4, step (b): [ka]

[0265] Sulfinimide 12 (600 mg, 2.4 mmol, 1.0 equiv) and difluoromethylphenyl sulfone 13 (500 mg, 2.6 mmol, 1.1 equiv) were dissolved in THF (12 ml, 20V). The solution was cooled to -78°C. NaHMDS 40% in THF (1.3 g, 2.8 mmol, 1.2 equiv) was added over 5 min at -78°C. The purple solution was stirred for 15 min. Complete conversion was reached (TLC, EtOAc / heptane 1:1). The reaction mixture was washed with saturated NaHCO 3The mixture was quenched with 20 ml of EtOAc. The aqueous layer was extracted with 50 ml of EtOAc. The organic layer was washed with MgSO 4 After drying at 40° C. and evaporating the solvent, sulfone 14 was obtained as a light brown oil (1.05 g, quantitative yield). 1 H NMR(300 MHz,chloroform-d)δ 7.81(d,J=7.4 Hz,2H),7.65-7.55(m,1H),7.46(t,J=7.7 Hz,2H),7.25-7.11(m,5H),4.49(d,J=11.8 Hz,1H),4.41(d,J=11.8 Hz,1H),4.25(ddddd,J=15.2,10.8,9.2,4.4,3.3 Hz,1H),4.06(d,J=9.2 Hz,1H),3.90(ddd,J=10.5,3.3,1.4 Hz,1H),3.81(dd,J=10.5,4.4 Hz,1H),1.12(s,9H).

[0266] Scheme 4, step (c): [ka]

[0267] Sulfone 14 (7.03 g, 15.7 mmol, 1.0 equiv) was dissolved in DMF (105 ml, 15 V) and acetate buffer (5.0 g acetic acid, 6.4 g NaOAc, 13 g water). Magnesium modifier (5.67 g, 23.5 mmol, 15 equiv) was added in one portion and the suspension was stirred at 30 °C for 3 h until complete conversion of sulfone 14 was reached (TLC: EtOAc). The remaining magnesium modifier was filtered off and the reaction mixture was quenched with MTBE / water (2.0 V). The aqueous layer was extracted three times with MTBE (150 ml). The organic layers were combined and washed with water (50 ml). The volatiles were evaporated and the crude product was purified by column chromatography (1:1 to 2:1 EtOAc-heptane). Sulfinamide 8-1 was obtained as a single diastereomer (2.3 g, 48% ot). 1H NMR(300 MHz,chloroform-d)δ 7.40-7.14(m,5H),5.75(ddd,J=56.4,55.5,4.7 Hz,1H),4.51(d,J=11.7 Hz,1H),4.43(d,J=11.8 Hz,1H),3.76(ddd,J=9.7,3.6,2.2 Hz,2H),3.69-3.61(m,1H),3.55(dddd,J=11.9,8.3,4.9,2.6 Hz,1H),1.16(s,9H).

[0268] Scheme 4, step (d): [ka]

[0269] Sulfinamide 8-1 (2.00 g, 6.6 mmol, 1.0 equiv) was dissolved in methanol (10 ml, 5.0 V). 37% hydrochloric acid (0.65 ml, 7.9 mmol, 1.2 equiv) was added at room temperature and the reaction mixture was stirred for 3 h until complete conversion was reached (TLC: EtOAc heptane 1:1). Volatiles were evaporated. The residue was suspended in MTBE (20 ml, 10 V). The solid was filtered off and dried under reduced pressure. Benzyl ether 9-5 was obtained as a white solid (1.23 g, 79% ot). 1 H NMR (300 MHz, DMSO-d 6 )δ 8.93(s,3H),7.45-7.27(m,5H),6.37(td,J=54.1,3.7 Hz,1H),4.57(d,J=2.7 Hz,2H),3.96-3.82(m,1H),3.82-3.65(m,2H).

[0270] Scheme 4, step (e): [ka]

[0271] Benzyl ether 9-5 (1.1 g, 4.6 mmol, 1.0 equiv) was dissolved in methanol (10 ml, 5.0 V) and Pd / C 5.0% (200 mg) was added. The tube was purged with hydrogen three times. The reaction mixture was stirred at room temperature under 20 bar of hydrogen for 5 h until complete conversion of benzyl ether 9-5 was obtained (TLC: DCM MeOH 20:1). The catalyst was filtered off and the solvent was evaporated. The residue was suspended in MTBE (20 ml, V). The solid was filtered off and dried under reduced pressure. The amino alcohol hydrochloride salt 9-2 was obtained as a white solid (0.53 g, 78% o.th. yield). 1 H NMR (300 MHz, DMSO-d 6 )δ 8.78(s,3H),6.31(td,1H,J=54.3 Hz,J=3.9 Hz,H3),5.63(s,1H,OH),3.88-3.66(m,2H,H1),3.65-3.50(m,1H,H2).

[0272] Scheme 4, step (f): [ka]

[0273] The amino alcohol hydrochloride 9-2 (0.44 g, 3.0 mmol, 1.0 equiv) was suspended in THF (5 ml, 11 V). DIPEA (1.15 ml, 9.0 mmol, 2.0 equiv) was added and the suspension was stirred at room temperature for 30 min. CDI (0.72 g, 4.4 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 16 h until complete conversion of 8 was reached. The reaction mixture was absorbed onto silica and purified by column chromatography. The enantiomer of (S)-4-(difluoromethyl)oxazolidin-2-one 10-2 was obtained as a colorless oil (180 mg, 44% o.th., single enantiomer). 1 H NMR (300 MHz, chloroform-d) δ 6.33 (s, 1H), 5.71 (td, J = 55.3, 4.5 Hz, 1H), 4.46 (td, J = 9.2, 1.3 Hz, 1H), 4.35 (dd, J = 9.6, 4.5 Hz, 1H), 4.04 (ddq, J = 13.9, 9.3, 4.5 Hz, 1H).

[0274] Scheme 5 Scheme 5, step a: A suspension of 2-(5-bromo-2-cyanophenoxy)ethane-1-aminium chloride 11' (20.4 kg, 97.8 wt%, 71.9 mol, 100 mol%) in MeOH (64.0 kg) was treated with solid magnesium ethoxide, Mg(OEt) 2 (17.9 kg, 219 mol%) was charged. The mixture was stirred at 25° C. for 30 min, after which 2-methyltetrahydrofuran, 2-MeTHF (140 kg) was added and the reaction mixture was heated to reflux and stirred for 40 h. After the reaction was complete, the batch was concentrated to about 50 L under reduced pressure below 40° C. Subsequently, 2-MeTHF (172 kg) was added and a solution of hydrogen chloride in n-propanol (83.0 kg, 5.00 M) was added below 15° C. The suspension was stirred at 15° C. for 4 h and filtered. The resulting solid was washed with 2-MeTHF (10 kg) and dried under reduced pressure at 50° C. to give 8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine hydrochloride 12′ (17.6 kg, 88% yield) as a hygroscopic solid, which was used directly in the next step. 1 H NMR (500 MHz, DMSO-d 6 )δ 8.32(s,3H),7.74(d,J=8.3 Hz,1H),7.61(d,J=1.5 Hz,1H),7.38(dd,J=8.3,1.5 Hz,1H),4.44(t,J=5.2 Hz,2H),3.24(t,J=5.2 Hz,2H).

[0275] Scheme 5, step b: A mixture of 8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine hydrochloride 12' (17.6 kg, 63.4 mol, 100 mol%) and 2-MeTHF (122 kg) was charged with 40% aqueous chloroacetaldehyde (16.4 kg, 132 mol%) and water (10 kg). The mixture was heated to 40°C and aqueous potassium bicarbonate was charged. The reaction mixture was stirred at 45°C for 21 hours. After the reaction was complete, the reaction mixture was cooled to 20°C, stirred for 30 minutes, and filtered. The resulting cake was rinsed with 2-MeTHF (33.0 kg) and the combined filtrate was allowed to settle. The resulting organic layer was washed with aqueous sodium bisulfite (30 kg) and concentrated under reduced pressure at less than 45°C to about 26 L. DMF (25 kg) was added and the mixture was then concentrated under reduced pressure at less than 45°C to about 26 L. Water (154 kg) was charged at 40° C., followed by seed crystals of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 13′ (1.20 kg). The mixture was stirred at 40° C. for another 1.5 h and cooled to 20° C. After stirring at 20° C. for 10 h, the suspension was filtered. The resulting solid was washed twice with water (25 kg×2) and dried under reduced pressure at 45° C. to give 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 13′ (16.3 kg, 97.5 wt %, 95% yield). 1 H NMR (500 MHz, DMSO-d 6 )δ 8.33(d,J=8.6 Hz,1H),7.35(s,1H),7.31-7.22(m,2H),7.06(s,1H),4.45(q,J=5.3 Hz,4 H);HRMS calculated value C 11 H 10 BrN 2 O [M+H] + About: 264.9971, actual value is 264.9976.

[0276] Scheme 5, step c: To a solution of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 13' (16.3 kg, 97.5 wt%, 59.9 mol, 100 mol%) in DMF (78.0 kg) was added N-iodosuccinimide (NIS) (29.0 kg, 215 mol%) at 40°C. The reaction mixture was slowly heated to 70°C and stirred for 6 hours. After the reaction was complete, 10% aqueous sodium sulfite (78.0 kg) was charged at 45°C, followed by water (154 kg). The resulting suspension was stirred at 45°C for 1 hour and cooled to 20°C. After stirring at 20°C for 8 hours, the suspension was filtered. The resulting solid was washed with water (160 kg) and dried under reduced pressure at 45° C. to give 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 14′ (29.7 kg, 100% by weight, 96% yield) as an off-white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ 8.21(d,J=8.6 Hz,1H),7.32-7.24(m,2H),4.51-4.45(m,2H),4.39-4.34(m,2H);HRMS calculated value C 11 H 8 BrI 2 N 2 O [M+H] + About: 516.7904, actual value is 516.7911.

[0277] Scheme 5, step d: To a solution of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 14' (39.4 kg, 76.2 mol, 100 mol%) in tetrahydrofuran was added THF (180 kg), 2.0 M solution of ethylmagnesium bromide in 2-methyltetrahydrofuran (44.0 kg, 120 mol%) at 10° C. The reaction mixture was stirred at 10° C. for 2 hours. After the reaction was complete, 5% acetic acid (133 kg) was charged while maintaining the batch temperature below 30° C. Ethyl acetate (168 kg) was charged and the resulting mixture was stirred at 20° C. for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl acetate (77.8 kg). The combined organic layers were washed with water (76.0 kg) and filtered through a silica gel pad (19.8 kg). The silica gel pad was rinsed with ethyl acetate (69.6 kg). The combined filtrate was concentrated to about 100 L under reduced pressure below 50° C. and THF (146 kg) was added. The resulting mixture was heated to 60° C. until a clear solution was obtained, then concentrated to about 100 L under reduced pressure below 50° C. and then cooled to 30° C. n-heptane (86.8 kg) was charged and the resulting mixture was stirred at 30° C. for 2 hours. The batch was solvent switched to n-heptane by 3 cycles of batch concentration to about 180 L and n-heptane addition (47.6 kg×3) under reduced pressure below 35° C. The resulting suspension was cooled to 20° C., stirred for 12 hours and filtered. The resulting solid was washed with n-heptane (64.0 kg) and dried under reduced pressure at 45 °C to give 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 15 (25.3 kg, 98.7 wt%, 84% yield) as a light brown solid. 1 H NMR (500 MHz, DMSO-d 6 )δ 8.23(d,J=8.6 Hz,1H),7.55(s,1H),7.32-7.24(m,2H),4.44(q,J=5.4 Hz,4H);HRMS calculated value C 11 H 9 N 2 O [M+H] + About: 390.8937, actual value is 390.8949.

[0278] Scheme 5, Step e: 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 15 (6.90 kg, 98.7 wt%, 17.4 mol, 100 mol%) was charged to the reactor followed by (S)-4-(difluoromethyl)oxazolidin-2-one (10-2) (2.68 kg, 112 mol%), copper(II) acetate (0.653 kg, 20.6 mol%) and Cs 2 CO 3 (11.7 kg, 206 mol%) was charged to the reactor. The reactor was evacuated and backfilled with nitrogen three times. Then, 2-methyltetrahydrofuran (36.0 kg) and trans-N,N-dimethylcyclohexane-1,2-diamine (0.764 kg, 30 mol%) were charged to the reactor. The reactor was evacuated and backfilled with nitrogen three times. The reaction mixture was heated to 78 °C and stirred for 22 h. After the reaction was complete, 20 wt% NaHSO was added while maintaining the internal temperature at 60-70 °C. 4 Aqueous solution (42.0 kg) was added slowly. The layers were separated at 65 °C and the aqueous layer was removed. The batch was solvent exchanged into acetonitrile by constant volume distillation under reduced pressure at 60-70 °C by adding acetonitrile (62.3 kg). Water (14.1 kg) was added to the reactor while maintaining the batch temperature at 60-70 °C. The suspension was cooled to 20 °C at a rate of 0.5 °C / min, stirred for 18 h, and filtered. The resulting solid was washed with a mixture of acetonitrile and water (50 kg, 44:56, w / w) and dried under reduced pressure at 90 °C to give (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one 16 as a tan solid (5.85 kg, 91.9 wt%, 77% yield). 1 H NMR (500 MHz, CDCl 3)δ 8.22(d,J=8.8 Hz,1H),7.31(s,1H),7.28-7.19(m,2H),6.71-6.62(m,1H),4.90(ddd,J=24.0,9.3,3.8 Hz,1H),4.75(dd,J=9.4,3.9 Hz,1H),4.56(t,J=9.3 Hz,1H),4.51-4.44(m,2H),4.41-4.35(m,2H);HRMS calcd.C 15 H 13 BrF 2 N 3 O 3 [M+H] + The calculated value is 400.0103 and the actual value is 400.0134.

[0279] Scheme 5, step f: (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one 16 (3.96 kg, 91.9 wt%, 9.19 mol, 100 mol%) was charged to the reactor, followed by (S)-2-aminopropanoic acid (L-alanine) (2.49 kg, 307 mol%), K 3 PO 4(5.84 kg, 303 mol%), and DMSO (19.9 kg). The mixture was flushed with nitrogen for 1 hour and heated to 95° C. Then a slurry of copper(I) oxide (67.1 g, 5.16 mol%) in DMSO (2.21 kg) was pre-stirred for 30 minutes and then transferred to the reactor. The reaction mixture was stirred at 95° C. for 4 hours. After the reaction was complete, the reaction mixture was cooled to 20° C. DCM (37.3 kg) was added to the reactor followed by water (24.2 kg). The layers were separated and the organic layer was removed. The aqueous layer was washed once more with dichloromethane, DCM (26.6 kg). THF (35.2 kg) and aqueous sodium bisulfate (19 wt%, 20.7 kg) were charged sequentially to the reactor. The layers were separated and the aqueous layer was removed. The organic layer was washed with 15 wt% brine (2×12 kg). SiliaMetS® DMT (Silicycle Inc., 1.60 kg) was charged and the batch was stirred at 25° C. for 15 hours and filtered to remove residual metals. SiliaMetS® DMT is a silica-bound equivalent of 2,4,6-trimercaptotriazine (trithiocyanuric acid, TMT) and is a versatile metal scavenger for a variety of metals, including ruthenium catalysts and hindered Pd complexes. Tetrahydrofuran, THF (24.8 kg) was used to rinse the filter. The combined filtrates were heated to 50° C. A 7N solution of ammonia in methanol (1.02 kg, 100 mol%) was added, followed by a slurry of seed crystals (ammonium S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate 17, 19.5 g) in THF (0.395 kg). The resulting suspension was stirred at 50 °C for 2 h and residual water was removed by constant volume distillation under reduced pressure at 40-60 °C and addition of anhydrous THF (60.1 kg). A 7N solution of ammonia in methanol (1.02 kg, 100 mol%) was added. The suspension was stirred at 50 °C for 15 h and filtered.The resulting solid was washed with THF (21.8 kg) and dried under reduced pressure at 25 °C to give ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate 17 as a beige solid (3.19 kg, 98.0 wt%, 81% yield). 1 H NMR (DMSO-d 6 )δ 7.97(d,J=8.8Hz,1H),7.16(s,1H),6.74-6.69(m,1H),6.38(dd,J=9.0,2.2 HRMS Calculated value C 18 H 19 F 2 N 4 O 5 [M+H] + About: 409.1318, actual value is 409.1318.

[0280] Scheme 5, step g: Ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate 17 (5.60 kg, 13.2 mol, 100 mol%) was charged to the reactor followed by N-hydroxysuccinimide, HOSu (1.52 kg, 102 mol%) and THF (49.6 kg). The batch was flushed with nitrogen for 40 minutes and cooled to 10° C. A 2N solution of ammonia in 2-propanol (5.05 kg, 101 mol%) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, EDC (5.20 kg, 210 mol%) were charged sequentially to the reactor. The reaction mixture was stirred at 10° C. for 20 hours. After the reaction was complete, the mixture was warmed to 20°C and 15 wt% brine (33.7 kg) was added. The layers were separated at 35°C and the aqueous layer was removed. The organic layer was washed sequentially with 15 wt% brine (2 x 16.9 kg) and a mixture of 15 wt% brine (8.97 kg) and 28.0-30.0 wt% ammonium hydroxide (7.55 kg), then filtered through a polishing filter unit. The filter unit was rinsed with THF (5.05 kg). The combined filtrate was distilled under reduced pressure at 50°C to approximately half its original volume. Ethanol (8.90 kg) was charged at 50° C., followed by a slurry of seed crystals ((S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide 18, 27.1 g) in ethanol (0.340 kg). The resulting suspension was stirred at 50° C. for 30 min and the solvent was switched to ethanol by constant volume distillation under reduced pressure at 40-60° C. by adding ethanol (39.9 kg). Water (0.379 kg) was added at 50° C. The suspension was cooled to 20° C., stirred for 23 h and filtered.The resulting solid was washed with a 90:10 (w / w) mixture of ethanol and water (27.9 kg) and dried under reduced pressure at 80° C. to give (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide 18 as a pale pink solid (4.37 kg, 99.7 wt %, 83% yield). 1 H NMR (600 MHz, CD 3 CN) δ 8.08(d,J=8.8 Hz,1H), 7.11(s,1H), 6.86-6.50(m,1H), 6.41(dd,J=8.8,2.3 Hz,1H), 6.12(d,J=2.4 Hz,1H), 4.87(dd,J=23.8,8.8 Hz,1H), 4.67-4.50(m,2H), 4.43-4.33(m,2H), 4.33-4.26(m,2H), 3.82(q,J=7.0 Hz,1H), 1.41(d,J=7.0 Hz,3H)(Note: NH protons omitted for clarity); 13 C NMR (151 MHz, CD 3 CN)δ 178.2,157.0,155.1,149.1,141.6,135.4,130.8,113.3,108.9,108.1,107.7,102.1,68.5,61.7,56.1,53.1,49.6,18.2;HRMS calculation value C 18 H 20 F 2 N 5 O 4 [M+H] + About: 408.1478, actual value is 408.1473.

[0281] Scheme 5 (alternative method) Scheme 5, step b (alternative method) A mixture of 8-bromo-2,3-dihydrobenzo[f][1,4]oxazepin-5-amine hydrochloride (40.00 g, 144 mmol) and 2-MeTHF (444 g, 520 mL) was charged with 46% aqueous chloroacetaldehyde (39.27 g, 231 mmol, 1.6 equiv) and water (20 mL). The mixture was heated to 65° C. and an aqueous solution (161 mL) of potassium bicarbonate (45.45 g, 454 mmol, 3.15 equiv) was added over 2 h. The reaction mixture was stirred at 65° C. for 0.5 h. The aqueous layer was separated and the resulting organic layer was concentrated under reduced pressure to about 200 mL. Ethanol (200 mL, 156 g) was added and the resulting mixture was concentrated under reduced pressure to about 200 mL. Ethanol (200 mL, 156 g) was added and the resulting mixture was concentrated under reduced pressure to about 200 mL. Ethanol (200 mL, 156 g) was added and the resulting mixture was concentrated under reduced pressure to approximately 200 mL and warmed to 50° C. Water (200 g, 200 mL) was added to the resulting solution over 1.5 h, after which the mixture was seeded with 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (200 mg) and stirred at 50° C. for an additional 1.0 h and cooled to 0° C. for 6 h. After stirring at 0° C. for 1 min, the suspension was filtered. The resulting solid was washed three times with water (3×50 mL) and dried under reduced pressure at 50° C. to give 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (33.9 g, 100.0 wt %, 89% yield).

[0282] Scheme 5, Step C (Alternative Method) To a solution of 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (20 g, 75.4 mmol) in MeCN (139 g, 177 mL) was added iodine (19.15 g, 75.4 mmol, 1.0 equiv), sodium periodate (9.68 g, 45.3 mmol, 0.6 equiv) and MeCN (10 g, 17.2 mL) at 25° C. 10% aqueous sulfuric acid (37.00 g, 75.4 mmol, 1.0 equiv) was added over 0.5 h. The reaction mixture was heated to 60° C. for 0.5 h, stirred for 13 h and then cooled to 30° C. for 0.5 h. A solution of sodium sulfite (18.54 g, 147 mmol, 1.95 equiv) in water (210 g, 210 mL) was added over 2 h. The resulting suspension was stirred at 30° C. for 1 h and filtered. The resulting solid was washed twice with water (2×40 g) and dried under reduced pressure at 50° C. to give 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (36.8 g, 100.0 wt %, 94.4% yield).

[0283] Scheme 5, step d (alternative method) To a mixture of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.30 kg, 2.51 mol, 1.0 equiv.) and toluene (11.3 kg) was added a solution of 24% ethylmagnesium bromide (2.00 kg, 3.60 mmol, 1.4 equiv.) in 2-methyltetrahydrofuran at -10 °C over 1.5 h. The reaction mixture was stirred at -10 °C for 1 h and then transferred to an aqueous solution (7.2 kg) of 80% acetic acid (1.04 kg, 13.9 mmol, 5.5 equiv.) at 15-20 °C over 1 h. The mixture was heated to 60 °C, after which the aqueous phase was separated and the organic phase was washed twice with water (2 × 7.2 kg). The resulting organic layer was concentrated under reduced pressure to approximately 6.5 L. The solution was heated to 85° C., after which heptane (14.3 kg) was added over 1.5 h. The mixture was cooled to 10° C. over 8 h. After stirring at 0° C. for 1 min, the suspension was filtered. The resulting solid was washed twice with heptane (2×2.7 kg) and dried under reduced pressure at 50° C. to give 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 15 (0.94 kg, 98.9 wt %, 95.8% yield).

[0284] Scheme 5, step e (alternative method) 9-Bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (15.00 g, 38.34 mmol, 1.0 equiv.), (S)-4-(difluoromethyl)oxazolidin-2-one (5.78 g, 42.2 mmol, 1.1 equiv.), trans-N,N-dimethylcyclohexane-1,2-diamine (0.818 g, 5.75 mmol, 0.15 equiv.) and Cs 2 CO 3 A suspension of (31.2 g, 95.9 mmol, 2.5 equiv) in 2-methyltetrahydrofuran (120 mL, 102 g) was thoroughly purged with argon. Copper(I) iodide (0.365 g, 1.92 mmol, 0.05 equiv) was then added and the reaction mixture was heated to 70° C. and stirred for 46 h. The mixture was cooled to 60° C. and diluted with THF (120 mL) before being diluted with NH 4A 5% aqueous solution of OH (44 mL) was added. The phases were separated and the organic phase was diluted with NH 4 The resulting organic layer was concentrated under reduced pressure to approximately 90 mL. Distillation was continued with successive addition of constant volumes of acetonitrile (200 mL). The resulting suspension was heated to 60° C. and water (35 g) was added over 20 min. The mixture was cooled to 20° C. over 1.5 h. After stirring at 20° C. for 1 min, the suspension was filtered. The resulting solid was washed with three portions of a mixture of acetonitrile (39 g) and water (18 g) and dried under reduced pressure at 50° C. to give (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (13.79 g, 100.5 wt %, 90% yield).

[0285] Scheme 5, step f (alternative method) (S)-3-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-4-(difluoromethyl)oxazolidin-2-one (33 g, 81.1 mmol, 1.0 equiv.) was charged to the reactor, followed by (S)-2-aminopropanoic acid (L-alanine) (21.69 g, 243.4 mmol, 3.0 equiv.), Cu(I) oxide (0.290 g, 2.0 mmol, 0.025 equiv.) and K 3 PO 4(51.67 g, 243.4 mmol, 3.0 equiv.). The flask was carefully evacuated and backfilled with nitrogen three times. DMSO (167 mL, 183 g) was added and the reactor was evacuated and backfilled with nitrogen three times. The mixture was heated to 95 C. A slurry of copper(I) oxide (67.1 g, 5.16 mol%) in DMSO (2.21 kg) was then pre-stirred for 30 minutes and then transferred to the reactor. The reaction mixture was stirred at 95 C for 6 hours. After the reaction was complete, the reaction mixture was cooled to 20 C. A solution of ammonium pyrrolidine dithiocarbamate (12 mmol, 0.15 equiv.) dissolved in water (212 mL) and 2-MeTHF (232 mL) was added and the mixture was stirred for 2 hours. The lowest of the three liquid phases was separated and the mixture was filtered. The upper organic phase was discarded and the lower aqueous phase was washed with 2-MeTHF (132 mL). To the aqueous phase was added 2-MeTHF (660 mL) and 20% aqueous sodium hydrogen sulfate (171.5 g). The mixture was stirred for 20 minutes, filtered, and the filter was rinsed with 2-MeTHF (99 mL). The aqueous phase was separated. To the resulting organic phase was added acetonitrile (99 mL), a solution of ammonia in methanol (7N, 3.4 mL, 24 mmol, 0.3 equiv.) and seeds of ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate (10 mg). The mixture was stirred for 2 hours, after which additional ammonia in methanol solution (7N, 14.0 mL, 98 mmol, 1.2 equiv.) was added over 2 hours. The resulting suspension was stirred for 12 hours and filtered. The resulting solid was washed twice with 2-MeTHF (2×200 mL) and dried under reduced pressure at 50° C. to give ammonium (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate (29.9 g, 87% yield).

[0286] Scheme 5, step g (alternative method) To a suspension of ammonium (S)-2-((2-((S)-4(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propionate (25.0 g, 58.8 mmol, 1.0 equiv)) in THF (250 mL) was added N-hydroxysuccinimide (1.35 g, 11.8 mmol, 0.2 equiv), ammonium bicarbonate (2.32 g, 29.4 mmol, 0.5 equiv), N,N-diisopropylcarbodiimide (8.90 g, 10.99 mL, 70.5 mmol, 1.2 equiv) and N-methylmorpholine (4.16 g, 4.57 mL, 41.1 mmol, 0.7 equiv). The mixture was stirred at 25° C. for 16 h. 10% aqueous sodium chloride solution (150 mL) was added and the mixture was heated to 40° C. The aqueous phase was separated and the organic layer was washed twice with a mixture of 10% aqueous sodium chloride solution (80 mL) and 5% aqueous sodium bicarbonate solution (40 mL). The organic solution was washed with 10% aqueous sodium chloride solution (80 mL), heated to 50° C. and concentrated under reduced pressure to approximately 125 mL. 1-propanol (125 mL) was added and the resulting mixture was concentrated under reduced pressure to approximately 125 mL. 1-propanol (125 mL) was added and the resulting mixture was concentrated under reduced pressure to approximately 125 mL and warmed to 50° C. The suspension was cooled to 20° C. over 2 h, stirred for 4 h and filtered. The resulting solid was washed with 1-propanol (75 mL), water (75 mL) and 1-propanol (75 mL) and dried under reduced pressure at 60° C. to give (S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)amino)propanamide (20.18 g, 97.8 wt %, 82% yield).

[0287] Scheme 5 Step d-Continuous flow process The continuous flow process was carried out in pipe reactor 1 (JT 10 °C, T res30 s) followed by simultaneous addition of 9-bromo-2,3-diiodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (compound 14') (1.00 equiv., 0.223 M in THF) and EtMgBr (1.45 equiv., 40.0 wt % in MeTHF), followed by addition of 1000 mL ... res The reaction mixture was collected over a specific period of time and the yield was calculated based on the flow rate (mmol / min) and run time of compound 14'. The biphasic reaction mixture from the continuous process was diluted with toluene and diluted with NaHCO 3 The organic phase was concentrated, anti-solvent heptane was added, and the product 9-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (compound 15) was filtered and dried under reduced pressure to give compound 15 as a pink powder in 92–96% yield.

[0288] 1 4 Analysis of C-labeled inavolisib (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-keto-oxazolidin-3-yl]-5,6-dihydro[2- 14 C]Imidazolo[1,2-d][1,4]benzoxazepin-9-yl]amino]propionamide (14.4 mCi, 107.7 mg of a tan, beige solid) was made according to Scheme 6 and analyzed by HPLC.

[0289] HPLC method: Column: XBridge C18; 3.5 μm (3.0 × 100 mm). Mobile phase A: Water / acetonitrile 95:5 + 0.1% phosphoric acid. Mobile phase B: Acetonitrile Conditions: 0% B, 0-2 min; 0-15% B, 2-18 min; 15-90% B, 18-26 min; 90% B 26-28 min. Flow rate: 0.8 mL / min Temperature: 35 °C

[0290] The UV purity (λ: 330 nm) was 98.8% (retention time: 13.4 min), and the radiochemical purity (β-Ram detector) was 98.5% [1.5% of diastereoisomers were detected (retention time: 14.60 min)].

[0291] The identity and purity of the materials was verified by HPLC analysis by co-injection with unlabeled reference standards.

[0292] Flow injection mass spectrometry was performed. MS(ESI)m / z [ 14 C-M+H] + 410.15,[ 12 C-M+H] + 408.15

[0293] The compounds were found to be 89% (by MS) and 87.48% (by gravimetric analysis). 14 C isotope enrichment is shown. Specific activity was measured gravimetrically and determined to be 133.35 μCi / mg (4933.95 kBq / mg), 54.6 mCi / mmol.

[0294] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, these descriptions and examples should not be construed as limiting the scope of the invention. Accordingly, all suitable modifications and equivalents may be deemed to be within the scope of the invention as defined by the following claims. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

1. Compound of formula (8A): 【Chemical 1】 (8A) (In the formula, R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl; R １１ is a hydrogen or hydroxyl protecting group) or a salt thereof.

2. R １ is optionally substituted C １－１２ alkyl, the compound according to claim 1.

3. R １ is an optionally substituted tertiary C ４－１２ alkyl, the compound according to claim 1.

4. R １ The compound according to claim 1, wherein R is selected from the group consisting of tert-butyl, tert-pentyl, 3-ethylpentan-3-yl, 1-methylcyclohexyl, 1-adamantyl, phenyl and naphthyl.

5. R １１ The compound according to claim 1, wherein R is hydrogen.

6. R １１ The compound according to claim 1, wherein R is benzyl.

7. The compound according to claim 1, wherein the compound is a compound of formula (8B): 【Chemical 2】 (8B) (In the formula, R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl; R １１ is a hydrogen or hydroxyl protecting group) or a salt thereof.

8. The compound according to claim 1, wherein the compound is a compound of formula (8-1): 【Chemical Formula 3】 （８－１）、 or a salt thereof, or a compound of formula (8-2): [Chemical Formula 4] （８－２） or a salt thereof.

9. Compound of formula (7A): 【Chemical Formula 5】 (7A) (wherein R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl; R ２ is optionally substituted C １－１２ alkyl, or optionally substituted C ６－１４ aryl; Each R ３ is, independently, optionally substituted C １－１２ alkyl, optionally substituted C ６－１４ aryl, or OR ２ wherein) or a salt thereof.

10. The compound according to claim 9, wherein the compound is a compound of formula (7): 【Chemical Formula 6】 （７） or a salt thereof.

11. Compound of formula (8C): 【Chemical Formula 7】 (8C) (wherein R １ is a method for preparing a compound of (optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl), or a salt thereof; The method comprises (iii) reacting with a Grignard reagent of formula (4A): 【Chemical Formula 8】 (4A) (wherein R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl; R ４ is a compound which may be substituted C １－６ alkyl or hydrogen), or a salt thereof, Compound of formula (5A): 【Chemical Formula 9】 (5A) (wherein R ２ is optionally substituted C １－１２ alkyl, or optionally substituted C ６－１４ aryl; Each R ３ is independently optionally substituted C １－１２ alkyl, optionally substituted C ６－１４ aryl, or OR ２ ; X is a halide) to form a compound of formula (7A): (7A) 【Chemical 10】 or a salt thereof, and (iv) reacting the compound of formula (7A) with a fluoride salt, a base and an oxidizing agent to form the compound of formula (8C). A method comprising the above steps.

12. The method according to claim 11, further comprising (i) forming a compound of formula (1A): (1A) 【Chemical 11】 (2A) (wherein R ４ is optionally substituted C １－６ alkyl or hydrogen), or a salt thereof, is partially reduced to give the formula (2A): 【Chemical 12】 or a salt thereof, and (ii) reacting the compound of formula (2A) with a compound of formula (3A): (3A) 【Chemical 13】 (4A) (wherein R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl), and reacting in the presence of a dehydrating reagent to give formula (4A): 【Chemical Formula 14】 to form a compound or a salt thereof.

13. The method according to claim 11, further comprising (v) obtaining an amine compound of formula (8C): (8C) 【Chemical Formula 15】 or an acid addition salt thereof. (wherein R １ is as defined in claim 11), or a salt thereof, is reacted with an acid, whereby the formula (9-1): 【Chemical 16】 （９－１）

14. The method according to claim 13, further comprising (vi) reacting the compound of formula (9-1) or an acid addition salt thereof with an acylating reagent to form a compound of formula (10-1): or a salt thereof. 【Chemical 17】 （１０－１）

15. The method according to claim 11, wherein the compound of formula (7A) is a compound of formula (7B): (7B) 【Chemical Formula 18】 or a salt thereof, and the compound of formula (8C) is a compound of formula (8D): (8D) 【Chemical 19】 or a salt thereof. (wherein, R １ , R ２ , and R ３ are as defined in claim 11)

16. The method according to claim 12, wherein the compound of formula (3A) is a compound of formula (3B): (3B) 【Chemical 20】 and the compound of formula (4A) is a compound of formula (4B): (4B) 【Chemical 21】 or a salt thereof. (wherein R １ and R ４ are as defined in claim 12)

17. The method according to claim 13, wherein the compound of formula (9-1) is a compound of formula (9-3):

18. 【Chemical 22】 （９－３） ​ ​ The method according to claim 14, wherein the compound of formula (10-1) is a compound of formula (10-2): 【Chemical 23】 （１０－２） A method, which is a compound of

19. R １ The method according to claim 11, wherein R is tert-butyl.

20. R ２ is 2-propyl, each R ３ is methyl, and X is chloride, the method according to claim 11.

21. R ４ The method according to claim 11, wherein R is ethyl.

22. The method according to claim 11, wherein (iii) A compound of formula (4): 【Chemical 24】 （４） or a salt thereof is reacted with A compound of formula (5): 【Chemical 25】 （５） to form a compound of formula (7): or a salt thereof, and 【Chemical 26】 （７） and (iv) Reacting the compound of formula (7) with potassium fluoride, potassium bicarbonate and hydrogen peroxide to form a compound of formula (8-2): A method comprising the step of forming a compound of 【Chemical 27】 （８－２）

23. The method according to claim 11, wherein in step (iv), the fluoride salt is potassium fluoride and the base is potassium bicarbonate.

24. The method according to claim 13, wherein the acid in step (v) is HCl, and the acid addition salt of the compound of formula (9-1) is a hydrochloride salt having the structure (9-2): A method, which is a hydrochloride salt having ​ （９－２）

25. The following series of steps: A method for producing a compound of formula (10-2) according to 【Chemical formula 29】

26. Formula (8A): (8A) 【Chemical Formula 30】 (wherein (b) A compound of formula (12A): R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl; R １１ is a hydroxyl protecting group), or a salt thereof, which is a method for preparing a compound, (12A) 【Chemical Formula 31】 is reacted with A compound of formula (13A): (13A) 【Chemical 32】 (14A) (wherein R １２ is an optionally substituted C ６－１４ aryl), and reacting with a base at a temperature below 0 ° C to give a compound of formula (14A): 【Chemical 33】 to form a compound of and (c) Reacting the compound of formula (14A) with magnesium in the presence of an acetate buffer to thereby form the compound of formula (8A). A method comprising

27. The method according to claim 26, wherein (a) A compound of formula (11A): (11A) 【Chemical 34】 is reacted with A sulfonamide compound of formula (3A): (3A) 【Chemical 35】 in the presence of a dehydrating reagent to form the compound of formula (12A): (12A) (12A) 【Chemical 36】

28. (wherein R １ and R １１ are as defined in claim 26), further comprising the step of forming a compound of the formula, a method. The method according to claim 26, wherein (d) A compound of formula (8A): (8A) 【Chemical 37】 or a salt thereof is reacted with an acid to form a compound of formula (9A): (9A) 【Chemical Formula 38】

29. (wherein R １ and R １１ are as defined in claim 26), or an acid addition salt thereof, and a method further comprising the step of obtaining the same. The method according to claim 28, wherein (e) Removing the hydroxyl protecting group of the compound of formula (9A) to form a compound of formula (9-1): or an acid addition salt thereof, and 【Chemical Formula 39】 （９－１） and (f) Reacting the compound of formula (9-1) or an acid addition salt thereof with an acylating reagent to form a compound of formula (10-1): A method further comprising the step of forming a compound of 【Chemical 40】 （１０－１）

30. The method according to claim 26, wherein the compound of formula (12A) is a compound of formula (12B): (12B) 【Chemical 41】 and the compound of formula (14A) is a compound of formula (14B): (14B) (14B) 【Chemical Formula 42】 and the compound of formula (8A) is a compound of formula (8B): (8B) (8B) 【Chemical 43】 ​ (wherein R １ , R １１ and R １２ are as defined in claim 26), or a salt thereof, method.

31. The method according to claim 27, wherein the compound of formula (3A) is a compound of formula (3B): 【Chemical 44】 (3B) (wherein R １ is as defined in claim 27) of the compound, method.

32. The method according to claim 28, wherein the compound of formula (9A) is a compound of formula (9B): 【Chemical 45】 (9B) (wherein R １１ is as defined in claim 28), or a salt thereof, a method.

33. The method according to claim 29, wherein the acid in step (d) is HCl, and the acid addition salt of the compound of formula (9A) or (9B) is a hydrochloride salt having the structure (9C): 【Chemical 46】 (9C) A method which is a hydrochloride salt having.

34. The method according to claim 29, wherein the compound of formula (9-1) is a compound of formula (9-3): 【Chemical 47】 （９－３） Or an acid addition salt thereof, The compound of formula (10-1) is a compound of formula (10-2): 【Chemical 48】 （１０－２） A method which is a compound of.

35. The method according to claim 18 or 29, having the structure: 【Chemical 49】 （１０－１）、 【Chemical Formula 50】 （１０－２） A compound of formula (10-1) or a compound of formula (10-2) having, Structure: 【Chemical Formula 51】 Compound 15 having, Reacting with a copper salt and a ligand to form a compound 16 having the structure: 【Chemical 52】 A method further comprising the step of forming.

36. The method according to claim 35, wherein the copper salt is copper (II) acetate or copper (I) iodide, and the ligand is trans-N,N-dimethylcyclohexane-1,2-diamine.

37. The method according to claim 35, further comprising reacting compound 16 with (S)-2-aminopropanoic acid and a copper (I) catalyst to form a compound 17 having the structure: A method further comprising. ​

38. The method according to claim 37, wherein the copper (I) catalyst is copper (I) oxide.

39. The method according to claim 37, further comprising reacting compound 17 with ammonia or an ammonia equivalent and a peptide coupling reagent to form a compound 18 having the structure: A method further comprising. 【Chemical 54】

40. Formula (8A): (8A) 【Chemical Formula 55】 (Wherein, (ii)Formula (4A): R １ is optionally substituted C １－１２ alkyl, optionally substituted C ３－１４ cycloalkyl, or optionally substituted C ６－１４ aryl; R １１ is a hydroxyl protecting group), or a salt thereof, which comprises a method for preparing (4A) 【Chemical 56】 Reacting with a Grignard reagent, thereby preparing a compound having formula (8-A). A method comprising the step of. (wherein R ４ is optionally substituted C １－６ alkyl or hydrogen), or a salt thereof,

41. The method according to claim 40, wherein the Grignard reagent is prepared by reacting iodomethyl pivalate with sec-butylmagnesium chloride.

42. The method according to claim 40, wherein

43. (iii)Hydrolyzing the compound having formula (8-A) with an acid, thereby obtaining an amine compound of formula (9-1): 【Chemical 57】 （９－１） Or an acid addition salt thereof. A method further comprising the step of.

44. Formula (9-1): 【Chemical 58】 （９－１） A method for preparing a compound of formula (1) or an acid addition salt thereof, comprising: (i) reacting with (S)-2-methylpropane-2-sulfinamide of formula (2A): 【Chemical Formula 59】 (2A) (wherein R ４ is optionally substituted C １－６ alkyl or hydrogen), or a salt thereof, to thereby prepare (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide having the structure: 【Chemical Formula 60】 A step of preparing (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide having; (ii) reacting (S,E)-N-(2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide with trimethylsilyl cyanide to obtain an aminonitrile having the structure: 【Chemical Formula 61】 A step of obtaining (S)-N-((S)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide; (iii) Hydrolyzing (S)-N-((S)-1-cyano-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide in acid to give the product (S)-2-(chloro-λ ５ -azaniumyl)-3,3-difluoropropanoic acid; 【Chemical Formula 62】 A step of obtaining; and (iv) Reducing (S)-2-(chloro-λ ５ -azanidyl)-3,3-difluoropropanoic acid to obtain a compound of formula (9-1) or an acid addition salt thereof; A method comprising.

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