Synthesis of Ras inhibitor

Abstract

The invention relates to a Ras inhibitor and a method for preparing the Ras inhibitor.

Description

Background Technology

[0001] Most small molecule drugs work by binding to a functionally important pocket on a target protein, thereby modulating its activity. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, preventing the enzyme from binding to its substrate. In fact, many such drug / target interactions are known, which might mislead one into believing that, given a reasonable amount of time, effort, and resources, small molecule regulators targeting most (if not all) proteins could be discovered. But this is far from the truth. Currently, it is estimated that only about 10% of all human proteins are suitable targets for small molecules. (Bojadzic and Buchwald, Curr Top Med Chem 18: 674-699 (2019)). The remaining 90% are currently considered difficult to treat or manage with the aforementioned small molecule drugs. These targets are often referred to as “undruggable.” These undruggable targets comprise a large and largely unexplored library of medically important human proteins. Therefore, there is great interest in discovering novel molecular modalities that can modulate the function of such druggable targets.

[0002] The literature has well established that Ras proteins (K-Ras, H-Ras, and N-Ras) play crucial roles in various human cancers, thus making them suitable targets for anticancer therapies. In fact, approximately 30% of all human cancers in the United States are caused by Ras protein mutations, many of which are fatal. Dysregulation of Ras proteins caused by activating mutations, overexpression, or upstream activation is common in human tumors, and activating mutations of Ras are frequently found in human cancers. For example, an activating mutation at codon 12 in the Ras protein significantly biases the Ras mutant protein population towards the "on" (GTP-binding) state (Ras(ON)) by inhibiting GTPase activator protein (GAP) dependence and intrinsic GTP hydrolysis rate, leading to the action of oncogenic MAPK signaling. Notably, Ras exhibits a picomolar affinity for GTP, allowing it to be activated even in the presence of low concentrations of this nucleotide. Mutations at codons 13 (e.g., G13C) and 61 (e.g., Q61K) in Ras also cause oncogenic activity in some cancers.

[0003] Despite extensive drug discovery efforts targeting Ras over the past decades, only two agents targeting the K-Ras G12C mutant have been approved in the United States (sotorasib and adagrasib). Further efforts are needed to discover other drugs for cancers driven by various Ras mutations, and convenient, scalable synthetic methods remain essential. Summary of the Invention

[0004] The present invention is characterized by a method for preparing compound A, an intermediate that can be used to synthesize compound A, and a method for preparing said intermediate. Compound A is a RAS inhibitor having the following structure: Compound A In a first aspect, this disclosure provides a method for preparing compound 1: Compound 1 The method includes: a) React compound 1a and compound 1b to form compound 1c: ; b) Oxidate and hydrolyze compound 1c to form compound 1d: ;as well as c) Cyclate compound 1d to form compound 1: .

[0005] In some embodiments, reaction step (a) includes contacting compounds 1a and 1b with a base. In some embodiments, the base is sodium hydroxide. In some embodiments, reaction step (a) is carried out in the presence of hydroquinone.

[0006] In some embodiments, the oxidation and hydrolysis step (b) is carried out in the presence of sulfuric acid and nitric acid. In some embodiments, the oxidation and hydrolysis step (b) includes a first step of oxidizing compound 1c to compound 1e and a second step of hydrolyzing compound 1e to compound 1d. .

[0007] In some embodiments, the oxidation step includes contacting NaClO2 with compound 1c. In some embodiments, the hydrolysis step includes contacting potassium hydroxide with compound 1e. In some embodiments, the second step further includes protonating compound 1d by contacting the reactants with hydrochloric acid.

[0008] In some embodiments of the method for preparing compound 1, the cyclization step (c) includes contacting acetic anhydride and compound 1d.

[0009] In some embodiments, the method further includes purifying compound 1 by decolorization with activated carbon. In some embodiments, compound 1 is purified by recrystallization. In some embodiments, recrystallization is repeated more than once. In some embodiments, recrystallization is carried out in methyl tert-butyl ether and n-heptane.

[0010] On the other hand, this disclosure provides a compound of formula II: Formula II or its salt, wherein R 1 The substituted C1-C6 alkyl, the substituted 3- to 10-membered cycloalkyl, or the substituted C6-C 10 Aryl. In some implementations, R 1 The C1-C6 alkyl group (e.g., methyl) may be substituted.

[0011] In some embodiments, the compound has the structure of formula IIa: Formula IIa or its salt, wherein R 1 The substituted C1-C6 alkyl, the substituted 3- to 10-membered cycloalkyl, or the substituted C6-C 10 Aryl. In some implementations, R 1 The C1-C6 alkyl group (e.g., methyl) may be substituted.

[0012] In another aspect, this disclosure provides a method for preparing compound 2a. The method includes: a) Esterify compound 2b to form compound 2c: ; b) Protecting and toluenesulfonating compound 2c to form compound 2d: ;as well as c) Iodize compound 2d to form compound 2a: .

[0013] In some embodiments of the method for preparing compound 2a, the esterification step (a) includes contacting a protonated solution of thionyl chloride (e.g., a methanol solution) with compound 2b.

[0014] In some embodiments, the protection and toluenesulfonation step (b) includes a first step of protecting compound 2c to form compound 2e and a second step of toluenesulfonating compound 2e to form compound 2d: .

[0015] In some embodiments, the first protection step includes contacting di-tert-butyl dicarbonate with compound 2c, and the second toluenesulfonation step includes contacting toluenesulfonyl chloride with compound 2e.

[0016] In some embodiments, the iodination step (c) includes contacting compound 2d with sodium iodide.

[0017] In one aspect, this disclosure provides a method for preparing compound 3: Compound 3 The method includes: a) Contacting compounds 3a and 3b in the presence of a base to form compound 3c: ;as well as b) Hydrolyze compound 3c to form compound 3: .

[0018] In some embodiments, the base in step (a) is n-butyllithium. In some embodiments, the contact step (a) is carried out using a flow process.

[0019] On the other hand, this disclosure provides a compound having the structure of compound 4: Compound 4 Or its salt, wherein R is H or In some implementations, R is H. In some implementations, R is... .

[0020] In some embodiments, the compound has the structure of formula IIIa: Formula IIIa Or its salt, wherein R is H or In some implementations, R is H. In some implementations, R is... .

[0021] In another aspect, this disclosure provides a compound having the structure of compound 5: Compound 5 Or its salt.

[0022] In some embodiments, the compound has the structure of compound 5a: Compound 5a Or its salt.

[0023] On the other hand, this disclosure provides a compound having the structure of compound 6: Compound 6 Or its salt.

[0024] In some embodiments, the compound has the structure of compound 6a: Compound 6a Or its salt.

[0025] In another aspect, this disclosure provides a method for preparing compound 6a. The method includes: a) Boronize compound 7 to form compound 4a: ; b) Couple compound 4a and compound 6b to form compound 5a: ;as well as c) Boridate compound 5a to form compound 6a: .

[0026] In some embodiments, the method for preparing compound 6a includes: a) Boronize compound 7 to form compound 4a: ; b) Couple compound 4a and compound 6b to form compound 5a: ;as well as c) Boridate compound 5a to form compound 6a: .

[0027] In some embodiments, the borylation step (a) includes contacting compound 7 with an iridium catalyst. In some embodiments, the coupling step (b) includes contacting compounds 4a and 5a with a copper source. In some embodiments, the copper source is Cu(OAc)₂. In some embodiments, the coupling step (b) includes a batch reaction. In some embodiments, the coupling step (b) includes a flow reaction. In some embodiments, the borylation step (c) includes contacting compound 5a with a palladium catalyst and a boron source.

[0028] On the other hand, this disclosure provides a compound having the structure of Formula I: Formula I or its salt, wherein R 1 It is H or C1-C6 alkyl.

[0029] In some embodiments, the compound has the structure of formula Ia: Formula Ia Or its salt.

[0030] In some implementation schemes, R 1 For H. In some implementations, R 1 It is CH3.

[0031] In one aspect, this disclosure provides a method for preparing compound 9: .

[0032] Compound 9 The method includes: a) Couple compound 2a with compound 9a to form compound 9b: ; b) Hydrolyze compound 9b to form compound 9c: ; c) Couple compound 9c and compound 9d to form compound 9e: ; d) Deprotecting compound 9e to form compound 9f: ; e) Couple compound 9f with compound 3 to form compound 9g: ;as well as f) Hydrolyze compound 9g to form compound 9: .

[0033] In some embodiments, the coupling step (a) includes contacting compound 2a with a zinc source to form compound 2a-Zn: .

[0034] In some embodiments, the coupling step (a) includes contacting compound 2a-Zn and compound 9a with a palladium catalyst.

[0035] In some implementations, the coupling step (c) includes contacting compounds 9c and 9d with EDCI.

[0036] In some implementations, the coupling step (e) includes contacting compounds 9f and 3 with EDCI.

[0037] In another aspect, this disclosure provides a method for preparing compound A. The method includes: a) Contacting compound 6a with pinacol to form compound 10: ; b) Esterification of compound 9 with compound 10 to form compound 11: ;as well as c) Cyclate compound 11 to form compound A: .

[0038] In some embodiments, the esterification step (b) includes contacting compounds 9 and 10 with EDCI. In some embodiments, the cyclization step (c) includes contacting compound 11 with a palladium catalyst.

[0039] In another aspect, this disclosure provides a method for preparing compound A, the method comprising: a) Couple compound 6a and compound 9 to form compound 12: ;as well as b) Lactolation of compound 12 to form compound A: .

[0040] In some embodiments, the coupling step (a) includes contacting compounds 6a and 9 with a palladium catalyst.

[0041] In some embodiments, the lactoneation step (b) includes contacting compound 12 with EDCI.

[0042] In some embodiments of the method for preparing compound A, the method further includes purifying compound A. In some embodiments, purification includes forming a salt of compound A. In some embodiments, the salt of compound A is a hydrochloride salt of compound A. In some embodiments, the salt of compound A is a lactate salt of compound A.

[0043] In some embodiments, purification includes converting a salt of compound A into a free basic form of compound A. In some embodiments, converting a salt of compound A into a free basic form of compound A includes contacting the salt of compound A with a base. In some embodiments, the base is sodium carbonate. In some embodiments, the method further includes precipitating the free basic form of compound A from the solution. In some embodiments, precipitation includes adding heptane to the solution of the free basic form of compound A. In some embodiments, the free basic form of compound A is dried under humidity and nitrogen.

[0044] In some embodiments, purification includes recrystallizing compound A. In some embodiments, recrystallization includes adding a first solvent followed by the addition of a second solvent. In some embodiments, the first solvent is a protic solvent. In some embodiments, the first solvent is methanol. In some embodiments, the second solvent is water.

[0045] On the other hand, this disclosure provides a compound having the structure of compound 10: Or its salt.

[0046] In some embodiments, this disclosure provides a compound having the structure of formula IV: Where X is boric acid, borate ester or halogen.

[0047] On the other hand, this disclosure provides a compound having the structure of compound 11: Or its salt.

[0048] On the other hand, this disclosure provides a compound having the structure of compound 12: Or its salt.

[0049] Definitions and chemical terms In this application, unless the context clearly indicates otherwise, (i) the term “a (a)” means “one or more”; (ii) the term “or” is used to mean “and / or” unless explicitly indicated that the term refers to an alternative that is unique or that the alternatives are mutually exclusive, however, the definition supported by this disclosure refers to a unique alternative and “and / or”; (iii) the terms “comprising” and “including” should be understood to encompass the listed components or steps, whether presented alone or in combination with one or more additional components or steps; and (iv) when providing a scope, endpoints are included.

[0050] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the error of the apparatus or method used to determine that value. In some embodiments, the term "about" refers to a range of values ​​in any direction (greater or less than) within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or lower percentages of the value, unless otherwise specified or otherwise apparent from the context (e.g., when the figure would exceed 100% of the possible value).

[0051] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to divalent atoms directly connected by covalent bonds.

[0052] As used herein, “compounds of the present invention” and similar terms, whether explicitly indicated or not, refer to the Ras inhibitors described herein (e.g., compound A) and intermediates in their synthesis, as well as their salts (e.g., pharmaceutically acceptable salts), solvates, hydrates, stereoisomers (including transisomers) and tautomers.

[0053] Those skilled in the art will understand that some of the compounds described herein may exist in one or more different isomeric forms (e.g., stereoisomers, geometric isomers, transisomers, tautomers) or isotopic forms (e.g., one or more atoms are substituted with different isotopes of that atom, such as hydrogen substituted with deuterium). Unless otherwise indicated or clearly apparent from the context, the described structures are to be understood as representing any such isomeric or isotopic forms, individually or in combination.

[0054] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are covered. Compounds of this disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolving racemic mixtures or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc., may also be present in the compounds described herein, and all such stable isomers are covered in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and can be isolated in mixtures of isomers or in separate isomeric forms.

[0055] In some embodiments, one or more compounds illustrated herein may exist in different tautomer forms. As will be clear from the context, unless explicitly excluded, references to such compounds encompass all such tautomer forms. In some embodiments, the tautomer form is obtained by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. In some embodiments, the tautomer form may be a proton-transfer tautomer, which is an isomer protonated state having the same empirical formula and total charge as the reference form. Examples of portions having a proton-transfer tautomer form include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, amide-imine pairs, enamine-imine pairs, and cyclic forms where the proton can occupy two or more positions in the heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. In some embodiments, the tautomer form may be in equilibrium or spatially locked into one form through appropriate substitution. In some embodiments, the tautomer form is obtained by the interconversion of acetals.

[0056] Unless otherwise specified, the structures described herein also mean compounds that differ solely due to the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example... 2 H, 3 H, 11 C 13 C 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 I. Isotope-labeled compounds (e.g.) 3 H and 14 C-labeled compounds can be used in the determination of compound or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are available because they are easy to prepare and detect. Alternatively, heavier isotopes, such as deuterium (i.e.,...), can be used. 2 H) substitution can provide certain therapeutic benefits due to increased metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In some embodiments, one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being... 13 C or 14 Carbon-enriched carbon substitution. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following a procedure similar to that disclosed for the compounds of the invention described herein, by replacing unlabeled reagents with isotopically labeled reagents.

[0057] As is known in the art, many chemical entities can be in a variety of different solid forms, such as amorphous or crystalline forms (e.g., polymorphs, hydrates, solvates). In some embodiments, the compounds of the present invention can be utilized in any of these forms, including any solid form. In some embodiments, the compounds described or depicted herein can be provided or utilized in hydrate or solvate form.

[0058] Throughout this specification, substituents of the compounds disclosed herein are disclosed by group or by range. Specifically, this disclosure is intended to include every individual combination of members of such groups and ranges. For example, specifically, the term "C1-C6 alkyl" is intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound comprises multiple positions, and where substituents are disclosed by group or by range at said positions, unless otherwise indicated, this disclosure is intended to cover the individual compounds and groups of compounds (e.g., species and subclasses) containing every individual combination of members at each position.

[0059] The intended term “optionally substituted X” (e.g., “optionally substituted alkyl”) is equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended that the characteristic “X” (e.g., alkyl) itself is optional. As described herein, certain compounds of interest may contain one or more “optionally substituted” moieties. Generally, the term “substituted”, whether or not preceded by the term “optionally”, means that one or more hydrogens of the specified moiety are substituted by a suitable substituent, such as any of the substituents or groups described herein. Unless otherwise indicated, the “optionally substituted” group may have a suitable substituent at each substituted position of the group, and the substituents at each position may be the same or different when more than one position in any given structure can be substituted by more than one substituent selected from the specified group. For example, in the term “optionally substituted C1-C6 alkyl-C2-C9 heteroaryl,” the alkyl moiety, the heteroaryl moiety, or both may be optionally substituted. The combinations of substituents contemplated in this disclosure are preferably combinations of substituents that form stable or chemically viable compounds. As used herein, the term "stable" means that a compound remains substantially unchanged when subjected to conditions that allow it to be generated, detected, and, in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0060] The suitable monovalent substituent on the substituted carbon atom of the "optionally substituted" group can be independently deuterium; halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°; -O-(CH2)0-4C(O)OR°; -(CH2)0-4CH(OR°)2; -(CH2)0-4SR°; -(CH2)0-4Ph, which can be substituted by R°; -(CH2)0-4O(CH2)0-1Ph, which can be substituted by R°; -CH=CHPh, which can be substituted by R°; -(CH2)0-4O(CH2)0-1-pyridyl, which can be substituted by R°; 4-8 member saturated or unsaturated heterocyclic alkyl groups (e.g., pyridyl); 3-8 member saturated Or unsaturated cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, or cyclopentyl); -NO2; -CN; -N3; ​​-(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2) 0-4-C(O)-N(R°)2;-(CH2)0-4-C(O)-N(R°)-S(O)2-R°;-C(NCN)NR°2;-(CH2)0-4C(O)SR°;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0- 4SR°; -SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O )R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NOR°)NR°2; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -P(O)(OR°)2; -OP(O)R°2; -OP(O)(OR°)2; -OP(O)(OR°)R°, -SiR°3; -(C.1-4 (linear or branched alkylene)ON(R°)2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R°)2, wherein each R° may be substituted as defined below and independently be hydrogen, -C 1-6 Aliphatic group, -CH2Ph, -O(CH2)0-1Ph, -CH2- (5-6 membered heteroaryl ring), or 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, despite the above definitions, two independently occurring R° together with their inserted atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0061] Suitable monovalent substituents on R° (or a ring formed by two independently occurring R°s together with their inserted atoms) can be independently halogens, -(CH2)O-2R ● -(halogenated R) ● -(CH2)O-2OH, -(CH2)O-2OR ● -(CH2)0-2CH(OR) ● )2、-O(halogenated R ● ), -CN, -N3, -(CH2)0-2C(O)R ● , -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR ● -(CH2)O-2SR ● , -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR ● -(CH2)0-2NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● -(C1-4 straight-chain or branched alkylene)C(O)OR ● or -SSR ● , where each R ● It is either unsubstituted or, in the case of being preceded by "halogenated," substituted with only one or more halogens, and independently selected from C. 1-4 Aliphatic groups, -CH2Ph, -O(CH2)0-1Ph, or 5-6 member saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

[0062] Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR.* 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * -O(C(R) * 2))2-3O-or-S(C(R) * 2))2-3S-, where R * Each time it appears independently, it is selected from hydrogen, and C can be substituted as defined below. 1-6 An aliphatic group or an unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to the adjacent substituted carbon of the "optionally substituted" group include: -O(CR * 2)2-3O-, where R * Each time it appears independently, it is selected from hydrogen, and C can be substituted as defined below. 1-6 Aliphatic group or unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0063] R * Suitable substituents on aliphatic groups include halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of being preceded by "halogenated," substituted with only one or more halogens, and independently C. 1-4 Aliphatic group, -CH2Ph, -O(CH2)0-1Ph or a 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0064] Suitable substituents on the substituted nitrogen of the "optionally substituted" group include -R † -NR † 2. -C(O)R † -C(O)OR † -C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR †2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R) † )S(O)2R † ; where each R † Independently hydrogen; can be substituted C as defined below. 1-6 Aliphatic group; unsubstituted -OPh; or unsubstituted 3-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur; or, despite the above definitions, two independently occurring R groups. † Together with their inserted atoms, they form unsubstituted 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings with 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur.

[0065] R † Suitable substituents on the aliphatic group are independently halogens, -R ● -(halogenated R) ● -OH, -OR ● -O (halogenated R) ● -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● -NR ● 2 or -NO2, where each R ● It is either unsubstituted or, in the case of being preceded by "halogenated," substituted with only one or more halogens, and independently C. 1-4 Aliphatic group, -CH2Ph, -O(CH2)0-1Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R † Suitable divalent substituents on saturated carbon atoms include =O and =S.

[0066] As used herein, the term "acetyl" refers to the group -C(O)CH3.

[0067] As used herein, the term "alkoxy" refers to -O-Cl-C 20 Alkyl group, wherein the alkoxy group is attached to the remainder of the compound via an oxygen atom.

[0068] As used herein, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms (e.g., 1 to 10 or 1 to 6). In some embodiments, the alkyl group is unbranched (i.e., straight-chain); in other embodiments, the alkyl group is branched. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and neopentyl.

[0069] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight-chain or branched saturated hydrocarbon by removing two hydrogen atoms, and examples include methylene, ethylene, isopropylene, etc. The term "C" x -C y "Alkylene" refers to an alkylene group having x to y carbons. Indicative values ​​of x are 1, 2, 3, 4, 5, and 6, and indicative values ​​of y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C...). 10 C2-C 20 C2-C6, C2-C 10 Or C2-C 20 Alkylene). In some embodiments, the alkylene may be further substituted with one, two, three or four substituents as defined herein.

[0070] Unless otherwise specified, as used herein, the term "alkenyl" refers to a monovalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds, and examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. Alkenyl groups include both cis and trans isomers. Unless otherwise specified, as used herein, the term "alkenylene" refers to a divalent straight-chain or branched group having 2 to 20 carbons (e.g., 2 to 6 or 2 to 10 carbons) containing one or more carbon-carbon double bonds.

[0071] As used herein, the term "alkynyl" refers to a monovalent straight-chain or branched group containing a carbon-carbon triple bond and having 2 to 20 carbons (e.g., 2 to 4, 2 to 6, or 2 to 10 carbons), and examples of such groups are ethynyl and 1-propynyl.

[0072] As used herein, the term "amino" signifies -N(R) † )2, for example -NH2 and -N(CH3)2.

[0073] As used herein, the term "aminoalkyl" refers to an alkyl moiety that is substituted with one or more amino groups on one or more carbon atoms.

[0074] As used herein, the term "aryl" refers to a monovalent monocyclic, bicyclic, or polycyclic system formed of carbon atoms, wherein the ring attached to a side group is an aromatic ring. Examples of aryl groups are phenyl, naphthyl, phenanthryl, and anthracene. An aromatic ring may be attached to its side group at any heteroatom or carbocyclic atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0075] As used herein, the term “C0” signifies a bond. For example, a portion of the term -N(C(O)-(C0-C5 alkylene-H)- includes -N(C(O)-(C0 alkylene-H)-, which is also represented as -N(C(O)-H)-.

[0076] As used herein, the terms "carbocyclic" and "carbocyclic group" refer to a monovalent, optionally substituted C3-C group. 12 A monocyclic, bicyclic, or tricyclic structure, which can be bridged, fused, or spirocyclic, wherein all rings are formed of carbon atoms and at least one ring is a non-aromatic ring. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloynyl groups. Examples of carbocyclic groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indenyl, decahydronaphthyl, etc. The carbocyclic ring can be attached to its side group at any ring atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0077] As used herein, the term "carbonyl" refers to a C(O) group, which can also be represented as C=O.

[0078] As used herein, the term "carboxyl" refers to -CO2H, (C=O)(OH), COOH, or C(O)OH, or its unprotonated counterpart.

[0079] As used herein, the term "cyano" refers to the -CN group.

[0080] Unless otherwise specified, as used herein, the term "cycloalkyl" means a monovalent saturated cyclic hydrocarbon group having three to eight ring carbons, which may be bridged, fused or spirocyclic, and examples of which are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloheptyl.

[0081] Unless otherwise specified, as used herein, the term "cycloalkenyl" means a monovalent, non-aromatic, saturated cyclic hydrocarbon group having three to eight cyclic carbons and containing one or more carbon-carbon double bonds, which may be bridged, fused, or spirocyclic.

[0082] As used in this article, the term "diastereomer" refers to stereoisomers that are not mirror images of each other and cannot be superimposed on each other.

[0083] As used herein, the term "enantiomer" means each individual optically active form of the compound of the invention having at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98% optical purity or enantiomer excess (as determined by standard methods in the art).

[0084] As used herein, the term "haloacetyl" refers to an acetyl group in which at least one hydrogen atom is replaced by a halogen.

[0085] As used herein, the term "haloalkyl" refers to an alkyl moiety substituted with one or more identical or different halogen moieties on one or more carbon atoms.

[0086] As used herein, the term "halogen" refers to a halogen selected from bromine, chlorine, iodine, or fluorine.

[0087] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein, in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). The heteroatom may be present in the middle or at the end of the group.

[0088] As used herein, the term "heteroaryl" refers to a monovalent monocyclic or polycyclic structure containing at least one fully aromatic ring: that is, it contains 4-hydroxyl groups within the monocyclic or polycyclic system. n +2 π electrons and containing at least one cyclic heteroatom selected from N, O, or S in the aromatic ring. An illustrative unsubstituted heteroaryl group has 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heteroaryl" includes bicyclic, tricyclic, and tetracyclic groups fused to any of the aforementioned heteroaromatic rings with one or more aromatic or carbocyclic rings, such as benzene or cyclohexane rings. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl. The heteroaryl ring may be attached to its side groups at any ring atom that produces a stable structure, and any ring atom may optionally be substituted unless otherwise specifically stated. In some embodiments, the heteroaryl group is substituted with one, two, three, or four substituents.

[0089] As used herein, the term "heterocyclic alkyl" refers to a monovalent monocyclic, bicyclic, or polycyclic system in which at least one ring is a non-aromatic ring and said non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. It can be bridged, fused, or spirocyclic. Five-membered rings have zero to two double bonds, and six- and seven-membered rings have zero to three double bonds. Illustrative unsubstituted heterocyclic alkyl groups have 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. The term "heterocyclic alkyl" also refers to a heterocyclic compound having a bridged polycyclic structure, wherein one or more carbons or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as a quinine cycloyl group. The term "heterocyclic alkyl" includes bicyclic, tricyclic, and tetracyclic groups fused with any of the aforementioned heterocycles and one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, such as aromatic, cyclohexane, cyclohexene, cyclopentane, cyclopentene, pyridine, or pyrrolidine rings. Examples of heterocyclic alkyl groups are pyrrolidinyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridinyl, and decahydronaphthidyl. Heterocyclic alkyl rings may be attached to their side groups at any ring atom that produces a stable structure, and unless otherwise specified, any ring atom may optionally be substituted.

[0090] As used herein, the term "hydroxyl group" refers to the -OH group.

[0091] As used herein, the term "hydroxyalkyl" refers to an alkyl moiety that is substituted with one or more -OH moieties on one or more carbon atoms.

[0092] As used herein, the term "isomer" means any tautomer, stereoisomer, transisomer, enantiomer, or diastereomer of any compound of the present invention. It should be understood that the compounds of the present invention may have one or more chiral centers or double bonds, and thus exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the present invention, the chemical structures described herein and therefore the compounds of the present invention cover all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms and mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of the present invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, recrystallization of the compound in the form of a chiral salt complex, or recrystallization of the compound in a chiral solvent. The enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts via well-known asymmetric synthetic methods.

[0093] As used herein, the term "stereoisomer" refers to all possible different isomers and conformations that a compound (e.g., any compound of the formula described herein) may have, particularly all possible stereochemical and conformational isomers of the basic molecular structure, all diastereomers, enantiomers, or conformational isomers, including transisomers. Some compounds of the present invention may exist in different tautomer forms, all of which are included within the scope of the present invention.

[0094] As used herein, the term "sulfonyl" refers to the -S(O)2- group.

[0095] As used herein, the term "thiocarbonyl" refers to the -C(S)- group.

[0096] The term "Boc" refers to a structure The tert-butoxycarbonyl or tert-butoxycarbonyl protecting group.

[0097] The term "BPin" refers to a structure The pinnatol boron alkyl group.

[0098] Those skilled in the art who have read this disclosure will understand that certain compounds described herein may be provided or utilized in any of a variety of forms, such as salt forms, protective forms, prodrug forms, ester forms, isomer forms (e.g., optical or structural isomers), isotopic forms, etc. In some embodiments, reference to a specific compound may refer to a specific form of the compound. In some embodiments, reference to a specific compound may refer to the compound in any form. In some embodiments, for example, a formulation of a single stereoisomer of a compound may be considered as a form of the compound different from a racemic mixture of the compound; a specific salt of a compound may be considered as a form different from another salt form of the compound; a formulation of a conformational isomer ((Z) or (E)) containing a double bond may be considered as a form different from a formulation of another conformational isomer ((E) or (Z)) containing that double bond; a formulation in which one or more atoms are isotopes different from atoms present in a reference formulation may be considered as a different form. Detailed Implementation

[0099] This document provides synthetic methods and intermediates for the production of Ras inhibitor compound A or its salts. These methods and intermediates can be used to achieve higher yields, higher chemical purity and / or higher stereoisomer purity, and lower costs in preparing compound A. Further synthetic details are provided in the examples. The structure of compound A is shown below.

[0100] Compound A The compounds described herein can be prepared using the methods described herein and / or using known organic, inorganic, or enzymatic processes. Synthetic methods may employ commercially available starting materials or starting materials prepared by processes known to those skilled in the art of organic synthesis. These methods include (but are not limited to) the methods described in the following schemes and in WO 2021 / 091967 and WO 2022 / 060836, the disclosure of each of which is incorporated herein by reference.

[0101] In one aspect, this disclosure provides a method for preparing compound 1: .

[0102] Compound 1 The preparation method may include: a) React compound 1a and compound 1b to form compound 1c: ; b) Oxidate and hydrolyze compound 1c to form compound 1d: ;as well as c) Cyclate compound 1d to form compound 1: .

[0103] In some embodiments, reaction step (a) includes contacting compounds 1a and 1b with a base. In some embodiments, the base is sodium hydroxide. In some embodiments, an excess of compound 1b is used relative to the amount of compound 1a. In some embodiments, 1.25 equivalents of compound 1b are used relative to compound 1a. In some embodiments, reaction step (a) is carried out in the presence of hydroquinone. In some embodiments, less than 1 equivalent (e.g., less than 0.9 equivalents, less than 0.5 equivalents, less than 0.25 equivalents, less than 0.1 equivalents, or less than 0.01 equivalents) of hydroquinone is used relative to the amount of compound 1a. In some embodiments, less than 0.01 equivalents of hydroquinone are used relative to the amount of compound 1a. In some embodiments, reaction step (a) is carried out in a solvent. In some embodiments, the solvent is an ether solvent. In some embodiments, the solvent is dioxane. In some embodiments, the solvent is 1,4-dioxane. In some embodiments, reaction step (a) is carried out at temperatures above room temperature (e.g., above 20°C, above 30°C, above 40°C, above 50°C, above 60°C, or above 70°C). In some embodiments, reaction step (a) is carried out at 65°C. In some embodiments, reaction step (a) is carried out between 70 and 75°C.

[0104] In some implementations, reaction step (a) is carried out according to the following scheme: .

[0105] In some implementations, reaction step (a) is carried out according to the following scheme: .

[0106] In some embodiments, the oxidation and hydrolysis step (b) is carried out in the presence of sulfuric acid and nitric acid. In some embodiments, the reaction in the presence of sulfuric acid and nitric acid is carried out at temperatures above room temperature (e.g., above 20°C, above 30°C, above 40°C, above 50°C, above 60°C, or above 70°C). In some embodiments, the reaction in the presence of sulfuric acid and nitric acid is carried out between 70 and 75°C.

[0107] In some implementations, the oxidation and hydrolysis step (b) is carried out according to the following scheme: In some embodiments, the oxidation and hydrolysis step (b) includes a first step of oxidizing compound 1c to compound 1e and a second step of hydrolyzing compound 1e to compound 1d: .

[0108] In some embodiments, the oxidation step includes contacting NaClO2 with compound 1c. In some embodiments, the oxidation step includes contacting compound 1c with NaClO2 and KH2PO4. In some embodiments, the oxidation step includes contacting compound 1c with NaClO2, KH2PO4, and DMSO. In some embodiments, the oxidation step is carried out in a solvent. In some embodiments, the solvent is water.

[0109] In some embodiments, the hydrolysis step includes contacting potassium hydroxide and compound 1e. In some embodiments, compound 1e is contacted with more than one equivalent (e.g., more than three equivalents) of potassium hydroxide. In some embodiments, compound 1e is contacted with potassium hydroxide at temperatures above 30°C (e.g., above 40°C, above 50°C, above 60°C, above 70°C, above 80°C, or above 90°C). In some embodiments, compound 1e is contacted with potassium hydroxide between 90 and 100°C. In some embodiments, the second step further includes protonating compound 1d by contacting the reactants with hydrochloric acid.

[0110] In some embodiments of the method for preparing compound 1, the cyclization step (c) includes contacting acetic anhydride and compound 1d. In some embodiments, the cyclization step (c) includes contacting compound 1d with acetic anhydride for at least one hour. In some embodiments, the cyclization step (c) includes contacting compound 1d with acetic anhydride at a temperature above 80°C (e.g., between 80 and 85°C or at 110°C).

[0111] In some implementations, the oxidation and hydrolysis step (b) and the cyclization step (c) are carried out according to the following scheme: In some embodiments, the method further includes purifying compound 1 by decolorization with activated carbon. In some embodiments, compound 1 is purified by recrystallization. In some embodiments, recrystallization is repeated more than once. In some embodiments, recrystallization is carried out in methyl tert-butyl ether and n-hexane.

[0112] In another aspect, this disclosure provides a method for preparing compound 2a. The method includes: a) Esterify compound 2b to form compound 2c: ; b) Protecting and toluenesulfonating compound 2c to form compound 2d: ;as well as c) Iodize compound 2d to form compound 2a: .

[0113] In some embodiments of the method for preparing compound 2a, the esterification step (a) includes contacting a methanol solution of thionyl chloride with compound 2b. In some embodiments, compound 2b is contacted with the methanol solution of thionyl chloride at room temperature (e.g., between 15°C and 25°C, at 20°C, or at 25°C).

[0114] In some embodiments, the protection and toluenesulfonation step (b) includes a first step of protecting compound 2c to form compound 2e and a second step of toluenesulfonating compound 2e to form compound 2d: .

[0115] In some embodiments, the first protecting step includes contacting di-tert-butyl dicarbonate and compound 2c, and the second toluenesulfonation step includes contacting toluenesulfonyl chloride and compound 2e. In some embodiments, the first protecting step further includes contacting compound 2c with a base. In some embodiments, the base is sodium bicarbonate. In some embodiments, the second toluenesulfonation step further includes contacting compound 2e with a base. In some embodiments, the base is pyridine.

[0116] In some embodiments, the iodination step (c) includes contacting compound 2d with sodium iodide. In some embodiments, the iodination step (c) further includes contacting compound 2d with an acid. In some embodiments, the acid is citric acid.

[0117] In some embodiments, the method for preparing compound 2a is carried out according to the following scheme: In one aspect, this disclosure provides a method for preparing compound 3: Compound 3 The method includes: a) Contacting compounds 3a and 3b in the presence of a base to form compound 3c: ;as well as b) Hydrolyze compound 3c to form compound 3: .

[0118] In some embodiments, the base in step (a) is n-butyllithium. In some embodiments, the contacting step (a) is carried out using a flow process. In some embodiments, the hydrolysis step (b) includes contacting compound 3c with a hydroxide base. In some embodiments, the hydroxide base is sodium hydroxide. In some embodiments, the hydrolysis step (b) further includes contacting compound 3c with dicyclohexylamine. In some embodiments, the hydrolysis step (b) first forms a dicyclohexylamine salt of compound 3. In some embodiments, the hydrolysis step (b) further includes contacting the dicyclohexylamine salt of compound 3 with (R)-(+)-N-benzyl-1-phenylethylamine.

[0119] In some implementations, contact step (a) is performed according to the following scheme: In some implementations, the hydrolysis step (b) is carried out according to the following scheme: In some embodiments, this disclosure provides a method for preparing compound 6a. The method includes: a) Boronize compound 7 to form compound 4a: ; b) Couple compound 4a and compound 6b to form compound 5a: ; as well as c) Boridate compound 5a to form compound 6a: .

[0120] In some embodiments, the borylation step (a) includes contacting compound 7 with an iridium catalyst. In some embodiments, the borylation step (a) further includes contacting compound 7 with bis(pinacolyl)diboron. In some embodiments, the borylation step (b) is performed according to the following scheme: In some embodiments, coupling step (b) includes contacting compounds 4a and 6b with a copper source. In some embodiments, the copper source is Cu(OAc)₂. In some embodiments, coupling step (b) includes a batch reaction. In some embodiments, coupling step (b) includes a flow reaction. In some embodiments, coupling step (b) further includes contacting compounds 4a and 6b with oxygen.

[0121] In some implementations, the coupling step (b) is performed according to the following scheme: In some embodiments, the boration step (c) includes contacting compound 5a with a palladium catalyst and a boron source. In some embodiments, the boron source is B2(OH)4. In some embodiments, the boration step (c) is performed according to the following scheme: In some embodiments of the above reaction, 1.5 equivalents of B2(OH)4 are used. In some embodiments of the above reaction, 2.1 equivalents of KOPiv are used.

[0122] In some embodiments, this disclosure provides a method for preparing compound 9: .

[0123] Compound 9 The method includes: a) Couple compound 2a with compound 9a to form compound 9b: ; b) Hydrolyze compound 9b to form compound 9c: ; c) Couple compound 9c and compound 9d to form compound 9e: ; d) Deprotecting compound 9e to form compound 9f: ; e) Couple compound 9f with compound 3 to form compound 9g: ;as well as f) Hydrolyze compound 9g to form compound 9: .

[0124] In some embodiments, this disclosure includes a method for preparing compound 9c or a salt thereof: .

[0125] The method includes: a) Formylating compound 9c-1 to form compound 9c-2: ; b) Condensate compound 9c with malonic acid to form compound 9c-3: ; c) Amination of compound 9c-3 to form compound 9c-4 H2O: ;as well as d) Protecting compound 9c-4 to form compound 9c: .

[0126] In some embodiments, the amination step c) is performed using an enzyme. In some embodiments, the enzyme is phenylalanine ammonia-lyase (PAL). PAL is well known in the art and is available from multiple suppliers, such as Pharmaron (e.g., PH-AML-18), Hande, Apeloa, and WuXi STA. In some embodiments, compound 9c prepared by this method can be used in the method for preparing compound 9.

[0127] In some embodiments, compound 9c is synthesized according to the following scheme: In some embodiments, the coupling step (a) includes contacting compound 2a with a zinc source to form compound 2a-Zn: .

[0128] In some embodiments, contacting compound 2a with a zinc source further includes contacting 2a with 1,2-dibromoethane. In some embodiments, contacting 2a with a zinc source further includes contacting compound 2a with trimethylchlorosilane.

[0129] In some embodiments, the coupling step (a) includes contacting compounds 2a-Zn and 9a with a palladium catalyst. In some embodiments, the coupling step (a) is performed according to the following scheme: In some implementations, the hydrolysis step (b) is carried out according to the following scheme: In some embodiments, coupling step (c) includes contacting compounds 9c and 9d with EDCI. In some embodiments, coupling step (c) further includes contacting compounds 9c and 9d with HOBt. In some embodiments, coupling step (c) is performed according to the following scheme: In some embodiments, the deprotection step (d) includes contacting compound 9e with thionyl chloride. In some embodiments, the deprotection step (d) is performed according to the following scheme: In some embodiments, the coupling step (e) includes contacting compounds 9f and 3 with EDCI. In some embodiments, the coupling step (e) further includes contacting compounds 9f and 3 with NMM. In some embodiments, the coupling step (e) further includes contacting compounds 9f and 3 with HOBt.

[0130] In some implementations, the coupling step (e) is performed according to the following scheme: In some implementations, the hydrolysis step (f) is carried out according to the following scheme: In another aspect, this disclosure provides a method for preparing compound A. The method includes: a) Contacting compound 6a with pinacol to form compound 10: ; b) Esterification of compound 9 with compound 10 to form compound 11: ;as well as c) Cyclate compound 11 to form compound A: .

[0131] In some embodiments, the esterification step (b) includes contacting compounds 9 and 10 with EDCI. In some embodiments, the esterification step (b) further includes contacting compounds 9 and 10 with a base (e.g., DMAP).

[0132] In some implementations, the esterification step (e) is performed according to the following scheme: .

[0133] In some embodiments, the cyclization step (c) includes contacting compound 11 with a palladium catalyst. In some embodiments, the cyclization step (c) is performed according to the following scheme: .

[0134] In another aspect, this disclosure provides a method for preparing compound A, the method comprising: a) Couple compound 6a and compound 9 to form compound 12: ;as well as b) Lactolation of compound 12 to form compound A: .

[0135] In some embodiments, coupling step (a) includes contacting compounds 6a and 9 with a palladium catalyst. In some embodiments, the palladium catalyst is Pd(dtbpf)Cl2. In some embodiments, coupling step (a) further includes contacting compounds 6a and 12 with a base (e.g., potassium carbonate). In some embodiments, coupling step (a) is performed at temperatures above room temperature (e.g., above 20°C, above 30°C, above 40°C, above 50°C, above 60°C, or above 70°C). In some embodiments, coupling step (a) is performed between 70°C and 80°C.

[0136] In some implementations, the coupling step (a) is performed according to the following scheme: .

[0137] In some embodiments, the lactone formation step (b) includes contacting compound 12 with EDCI. In some embodiments, the lactone formation step (b) further includes contacting compound 12 with one or more bases (e.g., DMAP and / or DIPEA). In some embodiments, the lactone formation step (b) further includes contacting compound 12 with HOBt. In some embodiments, the lactone formation step (b) is performed according to the following scheme: .

[0138] In some embodiments of the method for preparing compound A, the method further includes purifying compound A. In some embodiments, purification includes forming a salt of compound A. In some embodiments, the salt of compound A is a hydrochloride salt of compound A. In some embodiments, the salt of compound A is a lactate salt of compound A. In some embodiments, the lactate salt of compound A is formed by contacting compound A with lactic acid (e.g., with 1 equivalent of lactic acid, 2 equivalents of lactic acid, 3 equivalents of lactic acid, or 4 equivalents of lactic acid). In some embodiments, the contacting of compound A with lactic acid is carried out in a solvent (e.g., acetonitrile).

[0139] In some embodiments, purification includes converting a salt of compound A into a free base form of compound A. In some embodiments, converting a salt of compound A into a free base form of compound A includes contacting the salt of compound A with a base. In some embodiments, the base is sodium carbonate. In some embodiments, contacting the salt of compound A with a base is carried out in an organic solvent (e.g., an ether solvent, such as 2-methyltetrahydrofuran). In some embodiments, the method further includes precipitating the free base form of compound A from the solution. In some embodiments, precipitation includes adding heptane to the solution of the free base form of compound A.

[0140] In some embodiments, purification includes recrystallizing compound A. In some embodiments, recrystallization includes adding a first solvent followed by the addition of a second solvent. In some embodiments, the first solvent is a protic solvent. In some embodiments, the first solvent is methanol. In some embodiments, the second solvent is water.

[0141] Compounds and intermediates This disclosure provides compounds and intermediates that can be used to prepare compound A. For example, in some embodiments, this disclosure provides a compound having the structure of compound 2: Compound 2 Or its salt.

[0142] In some embodiments, the compound has the structure of compound 2a: Compound 2a Or its salt.

[0143] On the other hand, this disclosure provides a compound having the structure of compound 4: Compound 4 Or its salt.

[0144] In some embodiments, the compound has the structure of compound 4a: Compound 4a Or its salt.

[0145] In another aspect, this disclosure provides a compound having the structure of compound 5: Compound 5 Or its salt.

[0146] In some embodiments, the compound has the structure of compound 5a: Compound 5a Or its salt.

[0147] On the other hand, this disclosure provides a compound having the structure of compound 6: Compound 6 Or its salt.

[0148] In some embodiments, the compound has the structure of compound 6a: Compound 6a Or its salt.

[0149] On the other hand, this disclosure provides a compound having the structure of Formula I: Formula I or its salt, wherein R 1 It is H or C1-C6 alkyl.

[0150] In some embodiments, the compound has the structure of formula Ia: Formula Ia Or its salt.

[0151] In some implementation schemes, R 1 For H. In some implementations, R 1 It is CH3.

[0152] In some embodiments, this disclosure provides a compound having the structure of compound 9c: , Or its salt.

[0153] In some embodiments, this disclosure provides a compound having the structure of compound 10: Or its salt.

[0154] In some embodiments, this disclosure provides a compound having the structure of compound 11: Or its salts. In some embodiments, Br may be replaced by a halogen (e.g., iodine or chlorine) suitable for the Suzuki reaction. In some embodiments, BPi may be replaced by a borate ester (e.g., neopentyl borate and catechol borate) suitable for the Suzuki reaction.

[0155] In some embodiments, this disclosure provides a compound having the structure of compound 12: Or its salt.

[0156] Example This disclosure will be further illustrated by the following examples and composite examples, which should not be construed as limiting the scope or spirit of this disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain implementations and are not intended to limit the scope of this disclosure. It should be further understood that various other implementations, modifications, and equivalents that may be conceived by those skilled in the art may be employed without departing from the spirit of this disclosure or the scope of the appended claims.

[0157] Example 1. Synthetic procedure for compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine.

[0158] The general synthetic procedure for compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine is described in detail below.

[0159] Synthesis of compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine.

[0160] Synthesis of part 1 - compound 13 - 1-(3-bromopyridin-2-yl)ethyl-1-one.

[0161] Toluene (2,100 L, 7 V) and 3-bromopyridinecarboxylon (300 kg, 1,639 mol, 1 equivalent) were charged into the reactor. The resulting mixture was cooled to and maintained at -20 °C. MeMgCl (3 M solution in THF, 601 L, 1,803 mol, 1.1 equivalent) was then charged into the reactor. The resulting mixture was heated to and maintained at 10-20 °C for 16 hours, at which point HPLC analysis indicated that the reaction was complete.

[0162] The reaction mixture was loaded into a pre-cooled (-10 to 0°C) 4 M HCl aqueous solution (1,070 L, 2.6 equivalents) at -10 to 10°C, and the resulting mixture was maintained at 15–25°C for 30 minutes. The phases were separated, and the aqueous phase was extracted with toluene (600 L × 5, 2 V × 5). The combined organic layers were washed with a saturated NaHCO3 aqueous solution (100 L, 0.3 V) and then concentrated (50–60°C, -0.08 MPa) to about 200 L (0.7 V) to give crude 1-(3-bromopyridin-2-yl)ethyl-1-one (compound 13) (346 kg, 93.7% a / a purity, 83.4% w / w determination, 88% yield, Table 1) as a brown oil, which was used directly in the next step.

[0163] Table 1. HPLC method used for part 1 of Example 1

[0164] LRMS (ESI+)

[0165] 1 H NMR (400 MHz, DMSO- d 6, 25℃) δ 8.66 (dd, J = 4.6, 1.3 Hz, 1H), 8.22 (dd, J = 8.2, 1.3 Hz, 1H), 7.52(dd, J = 8.2, 4.6 Hz, 1H), 2.61 (s, 3H).

[0166] Synthesis of part of the 2-compound 13a-(S)-1-(3-bromopyridin-2-yl)ethanol-1-ol.

[0167] At 25–30 °C, add a solution of potassium phosphate buffer (0.2 M, pH = 6–8–7.2, 2,000 L, 10 V), glucose (594 kg, 3,297 mol, 3.3 equivalents), GDH (4 kg, 2% w / w), NADP (2 kg, 1% w / w), KRED (2 kg, 1% w / w), and 1-(3-bromopyridin-2-yl)ethyl-1-one (compound 13) (200 kg, 999.83 mol, 1 equivalent) in DMSO (200 L, 1 V). Note: Maintain the pH at 6–5–7 using 2 M NaOH aqueous solution as needed. Maintain the reaction mixture at 28–32 °C for 6 hours, at which point HPLC analysis indicates the reaction is complete.

[0168] Diatomaceous earth (40 kg, 20% w / w) and MTBE (800 L, 4 V) were added to the reaction mixture. The resulting mixture was filtered, and the filter cake was washed with MTBE (200 L, 1 V). The resulting phases were separated, and the aqueous phase was extracted again with MTBE (500 L × 3, 2.5 V × 3). The combined organic phases were washed with brine (100 L, 0.5 V) and concentrated (45–55 °C, -0.08 MPa) to give (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (compound 13a) (204 kg, 97.8% a / a purity, 89.6% w / w determination, 90% yield).

[0169] Substitutional synthesis of some 3-compound 13a-(S)-1-(3-bromopyridin-2-yl)ethanol-1-ol.

[0170] Triethylamine (47 kg, 464.46 mol, 2.8 equivalents) was charged into the reactor. It was cooled to and maintained at 0–10 °C. Formic acid (19 kg, 412.82 mol, 2.5 equivalents) and RuCl (p-isopropyltoluene) [(S,S)-Ts-DPEN] (0.55 kg, 864.49 mmol, 0.005 equivalents) were charged into the reactor. The resulting mixture was heated to and maintained at 30–35 °C. 1-(3-bromopyridin-2-yl)ethyl-1-one (compound 13) (36.7 kg, 165.12 mol, 1 equivalent) was charged into the reactor, and the charging port was flushed with additional triethylamine (2 kg, 19.76 mol, 0.12 equivalents). The reaction mixture was maintained at 30–35 °C for 6 hours, at which point HPLC analysis indicated the reaction was complete.

[0171] The reaction mixture was concentrated (30-35°C) to remove triethylamine. Water (170 kg) and EtOAc (310 kg) were added to the resulting mixture at 15-25°C. The phases were separated, and the aqueous phase was extracted with EtOAc (160 kg × 2). The combined organic phases were washed with brine (158 kg × 2), dried over anhydrous Na₂SO₄, filtered, and the waste desiccant filter cake was washed with EtOAc (40 kg). The combined filtrate was cooled to and maintained at 0-10°C, and MeOH (55 kg, 3.2 equivalents) containing 35% w / w HCl was added. The resulting mixture was maintained at 0-10°C for 12 hours, then filtered, and the product was washed with EtOAc (40 kg). The product was dissolved in water (66 kg) and EtOAc (170 kg), and the resulting solution was cooled to and maintained at 5-15°C. A solution of NaHCO3 (33 kg) in water (170 kg) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (170 kg × 3). The combined organic phases were washed with brine (158 kg × 2), dried over anhydrous Na2SO4, filtered, and the waste desiccant filter cake was washed with EtOAc (120 kg). The filtrate was concentrated (40-45 °C) to give (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (compound 13a) (30.0 kg, >99.9% a / a purity, 95% w / w determination, 86% yield, Table 2), which is a dark brown oil.

[0172] Table 2. HPLC methods used for portions 2 and 3 of Example 1

[0173] LRMS (ESI+)

[0174] 1 H NMR (400 MHz, DMSO- d 6, 25℃) δ 8.56 (dd, J = 4.6, 1.4 Hz, 1H), 8.02 (dd, J = 8.0, 1.4 Hz, 1H), 7.26(dd, J = 8.0, 4.6 Hz, 1H), 5.13 - 5.04 (m, 2H), 1.37 (d, J = 6.0 Hz, 3H).

[0175] Synthesis of part 4-compound 13b-(S)-3-bromo-2-(1-methoxyethyl)pyridine.

[0176] THF (2,025 L, 5 V) was added to the reactor and t -BuONa (231 kg, 2,404 mol, 1.2 equivalents). Cool the resulting mixture to and maintain it at 0–10 °C. Add (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (405 kg, 2,004 mol, 1 equivalent) to a solution of THF (800 L, 2 V) and MeI (340 kg, 2,395 mol, 1.2 equivalents). Maintain the resulting reaction mixture at 0–10 °C for 16 hours, at which point HPLC analysis indicates the reaction is complete.

[0177] At 0–10 °C, a 7.5% w / w aqueous solution of NH3 (520 L, 1.3 V) and MTBE (1,200 L, 3 V) were added to the reaction mixture. The phases were separated, and the aqueous layer was extracted with MTBE (1,200 L, 3 V). The combined organic phases were washed with brine (200 L, 0.5 V) and concentrated (50–60 °C, -0.08 MPa) to give crude (S)-3-bromo-2-(1-methoxyethyl)pyridine (compound 13b). The crude (S)-3-bromo-2-(1-methoxyethyl)pyridine was distilled (120 °C, 600 Pa) to give (S)-3-bromo-2-(1-methoxyethyl)pyridine as a colorless solid (445 kg, 99.3% a / a purity, 90.2% w / w determination, 93% yield, Table 3) (cured after packaging).

[0178] Table 3. HPLC method used for part 4 of Example 1

[0179] LRMS (ESI+)

[0180] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 8.61 (d, J = 3.2 Hz, 1H), 7.83 (q, J = 1.6, 6.8 Hz, 1H), 7.08 (q, J =3.6, 4.8 Hz, 1H), 4. 92 (q, J = 6.4 Hz, 1H), 3.31 (s, 3H), 1.48 (d, J = 6.8 Hz, 3H).

[0181] Example 2. Synthesis procedure of 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione.

[0182] Synthesis of part of 1,4,4-dimethyl-5-oxopentanonilonitrile.

[0183] 1,4-Dioxane (1,552 L, 5 V), hydroquinone (1.55 kg, 14.1 mol, 0.0033 equivalents), and 5% w / w NaOH aqueous solution (341.4 kg, 426.78 mol, 0.1 equivalents) were charged into the reactor. The resulting mixture was heated to and maintained at 70–75 °C. After 8 hours, isobutyraldehyde (310.6 kg, 4,307.3 mol, 1 equivalent) and acrylonitrile (2) (285.7 kg, 5,384.5 mol, 1.25 equivalents) were charged into the reactor. The reaction mixture was maintained at 70–75 °C for 8 hours, at which point GC analysis indicated that the reaction was complete.

[0184] The reaction mixture was then cooled to and maintained at 20–25°C. The pH was adjusted to 5–6 with a 3.5% w / w aqueous HCl solution (172.5 kg required) and concentrated (45°C, approximately 0.03 atm) until no organic solvent distilled off. The remaining residue was cooled to and maintained at 20–25°C. DCM (1,552 L, 5 V) and water (620 L, 2 V) were added. The phases were separated, and the organic phase was concentrated (45°C, approximately 0.03 atm) until no solvent distilled off, yielding crude 4,4-dimethyl-5-oxopentanonitrile (626.6 kg, 70.8% a / a purity, 43.5% w / w determination, 51% yield, Table 4) as a brown oil.

[0185] Table 4. GC method for part 1 of Example 2

[0186] LRMS (ESI+)

[0187] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 9.37 (s, 1H), 2.30 - 2.19 (m, 2H), 1.88 - 1.77 (m, 2H), 1.06 (s, 6H).

[0188] Synthesis of part of 2-crude 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione.

[0189] Water (1,115 kg, 5 V), KH₂PO₄ (13.8 kg, 101.4 mol, 0.057 equivalents), DMSO (164.0 kg, 2,099.1 mol, 1.2 equivalents), and crude 4,4-dimethyl-5-oxopentanonitrile (455.3 kg, 49.0% w / w determination, 1,782.3 mol, 1 equivalent) were added to the reactor. The resulting mixture was cooled to and maintained at 10–20 °C. After 20 hours, a 20% w / w NaClO₂ aqueous solution (1,185.0 kg, 2,620.5 mol, 1.5 equivalents) was added. The reaction mixture was then maintained at 10–20 °C for 1 hour, at which point GC analysis indicated the reaction was complete. This yielded crude 4-cyano-2,2-dimethylbutyric acid, which was used directly in the next step.

[0190] A mixture of crude 4-cyano-2,2-dimethylbutyric acid was charged with KOH (361.5 kg, 6,442.7 mol, 3.6 equivalents). The resulting mixture was extracted with MTBE (800 kg × 2, 4.9 V × 2). The aqueous phase was then heated to and maintained at 90–100 °C for 15 hours, at which point GC analysis indicated that the reaction was complete.

[0191] Cool the reaction mixture to and maintain it at 15–25 °C. Adjust the pH to 1–2 with 30% w / w HCl aqueous solution (requires 1,058 kg, 4.9 equivalents). Extract the resulting mixture with MTBE (1,058 kg × 2, 6.4 V × 2). Wash the combined organic phases with 5% w / w NaCl aqueous solution (378 kg × 2, 1.7 V × 2) and concentrate (40–45 °C, approximately 0.03 atm) to 670 L (3 V) to give crude 2,2-dimethylglutaric acid, which is used directly in the next step.

[0192] Ac₂O (614.6 kg, 6,020.1 mol, 3.4 equivalents) was charged into a mixture of crude 2,2-dimethylglutaric acid at 40–45 °C. The resulting mixture was concentrated (40–45 °C, approximately 0.03 atm) to remove MTBE. The reaction mixture was heated to and maintained at 80–85 °C for 2 hours, at which point GC analysis indicated that the reaction was complete.

[0193] The reaction mixture was then concentrated (70-75 °C, approximately 0.03 atm) to remove AcOH and Ac2O until no solvent was distilled off. This yielded crude 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (390.5 kg, 86.3% a / a purity, 69.3% w / w determination, 107% crude yield), which was used directly in the next step.

[0194] Synthesis of part of 3,3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione .

[0195] Heptane (574.0 kg, 1.86 V, crude weight) was charged into the reactor. It was cooled to and maintained at -10 to -5 °C. After 10 hours, a solution of crude 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (454.0 kg, 84.1% w / w determined) in MTBE (667.2, 2 V, crude weight) was charged into the reactor. The resulting mixture was maintained at -10 to -5 °C for 1.5 hours and then filtered.

[0196] Dissolve the filter cake in MTBE (572 kg, 2 V, determined weight). Add activated carbon (19.1 kg, 0.05% w / w, determined weight) to the resulting solution. Maintain it at 15–25 °C for 8 hours. Then filter the resulting solution and wash the waste carbon filter cake with MTBE (18 kg, 0.05 V). After 9 hours, add the filtrate to pre-cooled (-10 to -5 °C) n-heptane (518.4 kg, 2 V, determined weight). Maintain the resulting mixture at -10 to -5 °C for 2 hours. Then filter it at -10 to -5 °C. The product was dried (25-30℃, about 0.03 atm) for 16 hours to obtain 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione as a grayish-white solid (212.0 kg, 100% a / a purity, 98.3% w / w determination, 55% yield).

[0197] Substitutional synthesis of some 4-3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione.

[0198] Ac₂O (5.4 L) and 2,2-dimethylglutaric acid (2,573 g, 98.8% w / w and 506 g, 90.9% w / w, 18.74 mol, 1 equivalent) were charged into the reactor. The resulting reaction mixture was heated to and maintained at 110 °C for 1 hour, at which point GC analysis indicated that the reaction was complete.

[0199] The reaction mixture was concentrated (70 °C, about 0.03 atm) to remove AcOH and Ac2O until no solvent was distilled off. The residue was combined with another batch (2,2-dimethylglutaric acid (6,610 g, 90.8% w / w determination)) and distilled (110–120 °C, about 0.005 atm) until no product was distilled off. The resulting fraction was wet-milled with n-heptane (35 L), filtered, and the product was dried (25 °C, about 0.005 atm) to give 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione as a grayish-white solid (6.66 kg, 99.6% a / a purity, 98.56% w / w determination, 82% yield, Table 5).

[0200] Table 5. GC methods used for parts 2, 3, and 4 of Example 2

[0201] LRMS (ESI+)

[0202] 1 ¹H NMR (300 MHz, CDCl₃, 25 °C) δ 2.82 (t, J = 7.0 Hz, 2H), 1.85 (t, J = 7.0 Hz, 2H), 1.35 (s, 6H).

[0203] Partial substitution synthesis of 5-2,2-dimethylglutaric acid.

[0204] A 65% w / w aqueous solution of HNO3 (3.3 L) and concentrated H2SO4 (500 mL) were charged into the reactor at 25 °C. The resulting mixture was heated to and maintained at 70–80 °C. 4,4-Dimethyl-5-oxopentanilonitrile (2.21 kg, 90.5% w / w determination, 15.98 mol, 1 equivalent) was then added fractionally over 24 hours. The reaction mixture was then maintained at 70–75 °C for 1 hour, at which point GC analysis indicated the reaction was complete.

[0205] The reaction mixture was cooled to 25°C and then placed in ice-cold water (10 kg), during which time a solid precipitate formed. The resulting mixture was extracted with MTBE (10 L × 1, then 5 L × 2). The combined organic phases were washed with water (2 L × 1), washed with brine (2 L × 1), dried over anhydrous Na₂SO₄, filtered, and then concentrated (45°C, about 0.03 atm) until no solvent was distilled off. This yielded 2,2-dimethylglutaric acid as a white solid (2.6 kg, 98.8% w / w determination, 100% yield, Table 6).

[0206] Table 6. GC method for part 5 of Example 2

[0207] LRMS (ESI-)

[0208] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 2.42 (t, J = 7.5 Hz, 2H), 1.92 (t, J = 7.5 Hz, 2H), 1.23 (s, 6H).

[0209] Example 3. Synthesis procedure of compound 2a-(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate methyl ester.

[0210] Synthesis of part 1 - compound 2c-L-serine methyl ester hydrochloride.

[0211] MeOH (1,650 L, 3 V) and L-serine (compound 2b) (550 kg, 5,233 mol, 1 equivalent) were charged into the reactor. The resulting mixture was cooled to and maintained at 0–10 °C. After 12 hours, SOCl2 (695 kg, 5,842 mol, 1.1 equivalent) was charged into the reactor. The resulting reaction mixture was heated to and maintained at 20–30 °C for 5 hours, at which point HPLC monitoring showed that the reaction was complete.

[0212] The reaction mixture was concentrated (40–45 °C, -0.09 MPa) to 1.5 V. MTBE (1,650 L, 3 V) was added to the resulting residue, and the mixture was concentrated (40–45 °C, -0.09 MPa) to 1.5 V. MTBE (1,650 L, 3 V) was added to the resulting residue, and the mixture was cooled and maintained at 5–15 °C for 1 hour. The mixture was then filtered at 5–15 °C, and the filter cake was washed with MTBE (203.5 kg, 0.5 V). The filter cake was dried (40–50 °C, -0.09 MPa) to give L-serine methyl ester hydrochloride (compound 2c) (814.0 kg, 99.7% a / a purity, 100% yield, Table 7).

[0213] Table 7. HPLC method used for part 1 of Example 3

[0214] LRMS (ESI+)

[0215] 1 H NMR (400 MHz, CD3OD, 25℃) δ 4.16-4.10 (m, 1H), 4.03-3.88 (m, 2H), 3.83 (s, 3H).

[0216] Synthesis of part of the 2-compound 2e-(tert-butoxycarbonyl)-L-serine methyl ester.

[0217] Water (813 kg, 2 V) and L-serine methyl ester hydrochloride (compound 2c) (407 kg, 2,616 mol, 1 equivalent) were added to the reactor. The resulting mixture was cooled to and maintained at 10–20 °C.

[0218] THF (723 kg, 2 V) and NaHCO3 (659 kg, 7,844 mol, 3 equivalents) were charged into another reactor. The resulting mixture was cooled to and maintained at 10–20 °C. After 1 hour, a solution of L-serine methyl ester hydrochloride (compound 2c) was charged into the mixture. After 2.5 hours, Boc2O (627 kg, 2,873 mol, 1.1 equivalents) was charged into the resulting mixture. The resulting reaction mixture was heated to and maintained at 20–30 °C for 1 hour, at which point HPLC monitoring showed the reaction was complete.

[0219] The reaction mixture was filtered, and the filter cake was washed with DCM (541.3 kg × 2, 1 V × 2). The filtrate was then concentrated (45–55 °C) to 1.5 V. The resulting residue was loaded with DCM (2,706 kg, 5 V). The phases were separated, and the aqueous phase was extracted with DCM (2,706 kg, 5 V). The combined organic phases were washed with water (1,221 kg × 3, 3 V × 3), washed with brine (1,628 kg, 3 V), dried over anhydrous Na₂SO₄, filtered, and the filter cake was washed with DCM (272.7 kg, 0.5 V). The resulting filtrate was concentrated (≤ 40 °C) to 5 V to give crude (tert-butoxycarbonyl)-L-serine methyl ester (compound 2e, Table 8), which was used directly in the next step.

[0220] Table 8. HPLC method used for part 2 of Example 3

[0221] LRMS (ESI+)

[0222] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 5.56 (d, J = 8.1 Hz, 1H), 4.32 (d, J = 7.8 Hz, 1H), 3.95-3.78 (m, 2H), 3.73 (s, 3H), 2.83 (s, 1H), 1.40 (s, 9H).

[0223] Synthesis of part 3-compound 2d-N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester.

[0224] TsCl (472.14 kg, 2,477 mol, 0.95 equivalents) was added to a DCM solution of crude (tert-butoxycarbonyl)-L-serine methyl ester (compound 2e) (assumed to be 573.54 kg, 2,616 mol, 1 equivalent). The resulting mixture was cooled to and maintained at -5 to 5 °C. Pyridine (268.6 kg, 3,396 mol, 1.3 equivalents) was added over 3.5 hours. The reaction mixture was then heated to and maintained at 20–30 °C for 5 hours, at which point HPLC monitoring indicated the reaction was complete.

[0225] The reaction mixture was diluted with DCM (2,706 kg, 5 V). A 5% w / w NaHCO3 aqueous solution (3 V, 61 kg NaHCO3, 1,221 kg water) was added over 0.5 h. The phases were separated, and the organic phase was washed twice with 10% w / w citric acid (3 V, 133 kg citric acid, 1,219 kg water), washed with brine (3 V, 407 kg NaCl, 1,221 kg water), and concentrated (≤40 °C) to 1.5 V. MTBE (903.5 kg, 3 V) was added to the resulting residue and concentrated to 1.5 V. MTBE (602.3 kg, 2 V) was added to the resulting residue and cooled to and maintained at -15 to -5 °C. Then, n-heptane (1,443 kg, 5 V) was added over 1 h, and the resulting slurry was maintained at -15 to -5 °C for 6 h. The filter cake was then filtered and washed with pre-cooled (-15 to -5 °C) n-heptane (138 kg × 2, 0.5 V × 2). The filter cake was dried (35–45 °C, -0.09 MPa) for 8 hours to give N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (compound 2d) (444 kg, 92.8% a / a purity, 45% yield from L-serine methyl ester hydrochloride (compound 2c), Table 9).

[0226] Table 9. HPLC method used for part 3 of Example 3

[0227] LRMS (ESI+)

[0228] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 7.81-7.72 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 5.28 (d, J= 8.1 Hz, 1H),4.53-4.45 (m, 1H), 4.38 (dd, J = 10.2, 3.1 Hz, 1H), 4.27 (dd, J = 10.1, 3.1 Hz,1H), 3.69 (s, 3H), 2.44 (s, 3H), 1.41 (s, 9H).

[0229] Synthesis of methyl 2a-(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate, a partial 4-compound.

[0230] The reactor was charged with NaI (201.6 kg, 1,345 mol, 1.1 equivalents), citric acid (119.0 kg, 619 mol, 0.5 equivalents), N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (compound 2d) (458.2 kg, 1,227 mol, 1 equivalent), and acetone (2,433 kg, 7 V). The reaction mixture was heated to and maintained at 35–45 °C for 20 hours, at which point HPLC monitoring indicated the reaction was complete.

[0231] Filter the reaction mixture and wash the filter cake with EtOAc (824 kg, 2 V). Concentrate the filtrate to 2.5 V and dilute with EtOAc (2,061 kg, 5 V). Add a 5% w / w Na2S2O3 aqueous solution (5 V, 114 kg Na2S2O3, 2,290 kg water). Separate the phases and extract the aqueous phase with EtOAc (1,236 kg, 3 V). Dry the combined organic phases with anhydrous Na2SO4 and filter, washing the filter cake with EtOAc (207 kg × 2, 0.5 V × 2). Concentrate the filtrate (35–45 °C) to 1.5 V. Add n-heptane (622 kg, 2 V) and concentrate (35–45 °C) to 1.5 V. Add MTBE (33 kg, 0.1 V) and n-heptane (590 kg, 1.9 V). The resulting mixture was heated to 30°C, then cooled and maintained at -15 to -5°C for 6 hours. It was filtered, and the filter cake was washed with pre-cooled (-5°C) n-heptane (155 kg × 2, 0.5 V × 2). The filter cake was dried (35°C, -0.09 MPa) for 8 hours to give crude (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate methyl ester (compound 2a).

[0232] Crude (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate (compound 2a) was then dissolved in MeCN (288 kg, 0.8 V) and filtered. The filtrate was extracted with n-heptane (124 kg, ×5, 0.4 V ×5). The MeCN phase was then cooled to and maintained at -5 °C. Water (1,833 kg, 4 V) was added. The resulting mixture was maintained at -5 °C for 2 hours, filtered, and the filter cake was washed with water (916 kg, 2 V). The filter cake was dissolved in MTBE (33 kg, 0.1 V) and n-heptane (280 kg, 0.9 V) at 30 °C. The resulting mixture was then cooled to and maintained at -5 °C for 2 hours. It was then filtered, and the filter cake was washed with pre-cooled (-5 °C) n-heptane (155 kg ×2, 0.5 V ×2). The filter cake was dried (35°C, -0.09 MPa) for 8 hours to give methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropionate (compound 2a) as a white solid (144.6 kg, 99.7% a / a purity, 36% yield, Table 10).

[0233] Table 10. HPLC method used for part 4 of Example 3

[0234] HRMS (ESI+)

[0235] 1 ¹H NMR (600 MHz, CDCl₃, 25 °C) δ 5.39 (d, J = 6.6 Hz, 1H), 4.53 (t, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.60-3.55 (m, 2H), 1.46 (s, 9H).

[0236] Example 4. Synthesis procedure of compound 3-(1S,2S)-2-methylcyclopropane-1-carboxylic acid.

[0237] Synthesis of part 1-compound 3c-(1S,2S)-2-methylcyclopropane-1-carboxylic acid ethyl ester.

[0238] The reactor was charged with n-BuLi (1.6 M solution in hexane, 9.79 L, 15.67 mol, 0.91 equivalents), ethyl 2-(diethoxyphosphoryl)ethyl acetate (3.74 kg, 16.70 mol, 0.97 equivalents), and 2-MeTHF (10 L, 10 V). It was maintained at 10-25 °C for 1 hour. Then, (R)-2-methylethylene oxide (compound 3a) (1.00 kg, 17.22 mol, 1 equivalent) was added, and the resulting mixture was maintained at 10-25 °C for 0.5 hours. NMP (10 L, 10 V) was added, and the resulting mixture was maintained at 10-25 °C for 10 minutes. The reaction mixture was then passed through a flow reactor (143 °C, retention time = 30 minutes), at which point GC monitoring indicated completion of the reaction. The reaction mixture yields crude (1S,2S)-2-methylcyclopropane-1-carboxylic acid ethyl ester (compound 3c, Table 11), which is used directly in the next step.

[0239] Table 11. GC method for part 1 of Example 4

[0240] HRMS (ESI+)

[0241] Synthesis of part of the 2-compound 3-(1S,2S)-2-methylcyclopropane-1-carboxylic acid.

[0242] A crude (1S,2S)-2-methylcyclopropane-1-carboxylate (compound 3) reaction mixture (starting with (R)-2-methylethylene oxide (compound 3a) (1.00 kg, 17.22 mol, 1 equivalent)) was charged with NaOH (2.07 kg, 51.73 mol, 3 equivalents), water (3 L, 3 V), and MeOH (3 L, 3 V). The resulting reaction mixture was heated to and maintained at 40 °C for 14 hours, at which point GC monitoring indicated the reaction was complete.

[0243] Concentrate the reaction mixture (40°C) until no more distillate is observed (approximately 20 L, approximately 20 V final volume). Cool the residue to and maintain at ≤ 30°C and add water (10 L, 10 V). Adjust the pH to 1 with concentrated HCl (approximately 6 L required). Extract the resulting mixture with MTBE (10 L × 3, 10 V × 3). Wash the combined organic phases with brine (10 L, 10 V), dry over anhydrous MgSO4, and filter. Concentrate the filtrate (30°C) to a final volume of approximately 12 L (approximately 12 V). Add dicyclohexylamine (2.64 kg, 14.56 mol, 0.84 equivalents) and maintain the resulting mixture at room temperature for 12 hours. Then filter and wash the filter cake with MTBE (1 L, 1 V). Dissolve the filter cake in water (20 L, 20 V) and adjust the pH to 1 with concentrated HCl (approximately 1 L required). Then MTBE (10 L, 10 V) was added and the two-phase mixture was filtered. The filter cake was washed with MTBE (2 L, 2 V). The phases were separated and the aqueous phase was extracted with MTBE (10 L, 10 V). The combined organic phases were washed with brine (10 L, 10 V), dried over anhydrous MgSO4, filtered, and concentrated (30 °C) to give crude (1S,2S)-2-methylcyclopropane-1-carboxylic acid (compound 3) (711.5 g, 41% yield from (R)-2-methylethylene oxide (1)) as a yellow oil.

[0244] Crude (1S,2S)-2-methylcyclopropane-1-carboxylic acid (compound 3) was dissolved in MeCN (9 L, 9 V) and (R)-(+)-N-benzyl-1-phenylethylamine (1.50 kg, 1 equivalent) was added. The resulting mixture was heated to and maintained at 40 °C for 1 hour. It was then cooled to and maintained at 20 °C for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeCN (2 L, 2 V). The filter cake was dried and then placed in a pre-cooled (5–10 °C) solution of NaOH (200 g) and water (1.3 kg). The resulting mixture was extracted with MTBE (2.6 L × 3, 2.6 V × 3). The pH of the aqueous phase was adjusted to 1 with 3 M concentrated HCl, and then extracted with MTBE (2.6 L × 3, 2.6 V × 3). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated (40 °C) to give (1S,2S)-2-methylcyclopropane-1-carboxylic acid (compound 3) (397.4 g, 56% yield, Table 12).

[0245] Table 12. GC method for part 2 of Example 4

[0246] LRMS (ESI-)

[0247] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 11.43 (br s, 1H), 1.49-1.43 (m, 1H), 1.35-1.30 (m, 1H), 1.25-1.22(m, 1H), 1.12 (d, J = 6.4 Hz, 3H), 0.77-0.73 (m, 1H).

[0248] Example 5 - Compound 6a - (1 2 Synthetic procedure for M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid.

[0249] Part 1 - Compound 7 - (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridine-3- Synthesis of 1H-indol-3-yl)-2,2-dimethylprop-1-ol.

[0250] Water (19 L, 3 V), MTBE (51 L, 8 V), and (1) were added to the reactor. 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol hydrochloride (compound 7HCl) (6.35 kg, 13.18 mol, equivalent) and K2CO3 (1.27 kg, 9.19 mol, 0.7 equivalent). The resulting mixture was maintained at 15–25 °C for 30 minutes.

[0251] Separate the phases. Wash the organic phase with water (19 L, 3 V), combine it with another organic phase reacted at the same scale, and concentrate to about 25 L (about 2 V). Exchange the solvent for n-heptane (63 L × 2, 5 V × 2, concentrated to 25 L, 2 V). Filter the resulting mixture and wash the filter cake with n-heptane (12 L, 1 V). Dry the filter cake to obtain (1 2M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 7) (11.3 kg, 96% yield, Table 13).

[0252] Table 13. HPLC method used for part 1 of Example 5

[0253] LRMS (ESI+)

[0254] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 8.82 (dd, J = 4.8, 1.8 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.69 (dd, J =7.7, 1.8 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.24 (d, J = 8.6 Hz, 1H), 4.10 (q, J = 6.2Hz, 1H), 4.06 - 3.93 (m, 1H), 3.93 - 3.80 (m, 1H), 3.33 - 3.17 (m, 2H), 3.07(s, 3H), 2.72 (d, J = 14.2 Hz, 1H), 2.24 (d, J = 14.3 Hz, 1H), 1.47 (d, J = 6.3 Hz,3H), 1.29 (s, 1H), 1.18 (t, J = 7.2 Hz, 3H), 0.77 (s, 6H).

[0255] Partial 2a-compound compound 4a- (1 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl) Methyl-1,3,2-dioxaborane-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4, Synthesis of 4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-3-yl)-1H-indole.

[0256] The reactor was charged with n-heptane (17.7 L, 3.3 V), THF (9.1 L, 1.7 V), and (1... 2M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 7) (5.37 kg, 12.06 mol, 1 equivalent). HBpin (2.32 kg, 18.13 mol, 1.5 equivalent) was added to the mixture over 2.5 hours. The resulting mixture was heated to and maintained at 50°C for 4 hours, then cooled to 25°C.

[0257] B2pin2 (3.67 kg, 14.47 mol, 1.2 equivalents), Me4phen (22.8 g, 96.48 mmol, 0.008 equivalents), and [Ir(OMe)(COD)]2 (16.0 g, 24.14 mmol, 0.002 equivalents) were charged into the reaction mixture. The resulting mixture was heated to and maintained at 50 °C for 14 hours, at which point HPLC monitoring indicated that the reaction was complete.

[0258] The reaction mixture was cooled to and maintained at 15°C for 1 hour, then concentrated to approximately 13.4 L (approximately 2.5 V). Its solvent was replaced with n-heptane (16 L × 2, 3 V × 2, concentrated to approximately 13.4 L, approximately 2.5 V). The resulting mixture was cooled to and maintained at 10–15°C for 15 hours. It was then filtered, and the filter cake was washed with n-heptane (5 L, 1 V). The filter cake was dried to give a light brown solid (1... 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-3-yl)-1H-indole (compound 4a) (8.37 kg, 98.7% a / a purity, 91.5% w / w determination, 91% yield, Table 14).

[0259] Partial 2b-compound compound 4a-(1 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl) Methyl-1,3,2-dioxaborane-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4, Substitutional synthesis of 4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-3-yl)-1H-indole.

[0260] Water (601 kg, 3V), MTBE (1186.9 kg, 8V), and (1) were added to the reactor. 2M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 7) HCl salt (200 kg, 1.0 equivalent) and K2CO3 (37.29 kg, 0.65 equivalent). The solution was stirred at 20 °C for 0.5 h, then left unstirred for 0.5 h. The phases were separated, and the organic phase was washed with water (600.5 kg, 3 V). The MTBE solution was concentrated under reduced pressure until the residue volume was about 400 L. THF (354.3 kg, 2 V) was added to the solution. The resulting solution was concentrated under reduced pressure until the residue volume was about 400 L. The solvent exchange was repeated twice. The solution of compound 7 in THF was added with n-heptane (407.7 kg, 3.05 V). N2 was bubbled below the surface of the solution for 1 h. HBpin (59.5 kg, 1.1 equivalents) was added dropwise to the reactor at 20°C under a N2 atmosphere. The reaction mixture was heated at 30°C for 2 hours and then cooled to 20°C. B2pin2 (126 kg, 1.2 equivalents) and Me4phen (779 g, 0.8 mol%) were added to the reactor under a N2 atmosphere. N2 was bubbled below the solution surface for 1 hour. [IrOMe(COD)]2 (545 g, 0.2 mol%) was added to the reactor under a N2 atmosphere. The reaction mixture was heated at 45°C for 6 hours and then cooled to 20°C. After the reaction, EtOH (28.6 kg, 1.5 equivalents) was added to the reaction mixture and stirred at 20°C for 17 hours. The reaction mixture was concentrated under reduced pressure until the residual volume was about 400 L. n-Heptane (273.10 kg, 2 V) was added to the suspension. The resulting suspension was concentrated under reduced pressure until the residual volume was about 400 L. The solvent exchange was repeated once more. The resulting suspension was cooled to 5°C, stirred for 20 hours, and filtered to obtain a wet filter cake, which was washed with n-heptane (14 kg). The washed wet filter cake was dried at below 45°C for 16 hours to obtain 277.74 kg of a grayish-white solid (1... 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-3-yl)-1H-indole (compound 4a), with a purity of 97.0%, a determination of 96.4%, and a yield of 92.5%, is a grayish-white solid.

[0261] Table 14: HPLC methods used for portions 2a and 2b of Example 5

[0262] LRMS (ESI+)

[0263] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 9.11 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.6, 1.9 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 4.08 (q, J = 6.3 Hz,1H), 4.02 - 3.91 (m, 1H), 3.90 - 3.80 (m, 1H), 3.55 - 3.43 (m, 2H), 3.09 (s,3H), 2.76 (d, J = 14.2 Hz, 1H), 2.14 (d, J = 14.2 Hz, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.35 (d, J = 2.9 Hz, 12H), 1.25 (s, 12H), 1.17 (t, J = 7.2 Hz, 3H), 0.76 (s, 3H), 0.68 (s, 3H).

[0264] Part 3 - compound 5a - (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4- Synthesis of methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol.

[0265] Add (1) to the reactor 2M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-3-yl)-1H-indole (compound 4a) (11.88 kg, 17.04 mol, 1 equivalent), 1-methylpiperazine (compound 6b) (17.11 kg, 170.82 mol, 10 equivalent), Cu(OAc)2 (19.01 kg, 104.66 mol, 6 equivalent), TMP (8.91 kg, 63.01 mol, 3.7 equivalent) and DCM (238 L, 20 V). The resulting mixture was maintained at 20-25°C and bubbled with N2 containing 21% O2 for 16 hours. At this time, HPLC monitoring showed that the reaction was complete.

[0266] The reaction mixture was concentrated to 119 L (10 V). The resulting mixture was charged into a mixture of 28% w / w NH3 aqueous solution (35.6 L, 3 V) and water (71.3 L, 6 V). The two-phase mixture was filtered and the filtrate phase was separated. The organic phase was washed with 28% w / w NH3 aqueous solution (35.6 L, 3 V), washed with 0.1 M EDTA aqueous solution (35.6 L, 3 V), and concentrated to 17.8 L (1.5 V). 2-MeTHF (35.6 L, 3 V) and water (11.9 L, 1 V) were charged into the residue. The pH was adjusted to 1–2 with 6 M HCl aqueous solution (23.5 L required). The phases were separated and the aqueous phase was extracted with 2-MeTHF (35.6 L × 2, 3 V × 2). DCM (35.6 L, 3 V) was charged into the aqueous phase. Adjust the pH to 8-9 using 30% w / w NaOH aqueous solution (4.5 L required). Separate the phases and concentrate the organic phase to 12 L (1 V). Add n-heptane (65.3 L, 5.5 V). Maintain the resulting mixture at 35°C for 3 hours, then cool and maintain at -5°C for 12 hours. Filter the mixture and wash the filter cake with n-heptane (5.9 L, 0.5 V). Dry the filter cake to obtain a grayish-white solid (1... 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 5a) (7.28 kg, 98.7% a / a purity, 91.7% w / w determination, 72% yield).

[0267] Part of the 4a-compound 5a- (1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4- Alternative synthesis of methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol.

[0268] Make (1) 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-3-yl)-1H-indole (compound 4a) (6.5 kg, 9.32 mol, 1 equivalent) in a solution of DCM (65 L, 10 V) and 1-methylpiperazine (compound 6b) (12.53 kg, 125.09 mol, 13.4 equivalent), Cu(OAc)2 (11.36 kg, 62.54 mol, 6.7 equivalent) and TMP (8.84 kg, 62.58) Another solution (mol, 6.7 equivalents) in DCM (65 L, 10 V) was passed through a flow reactor (35-45 °C, retention time = 1.5 h), at which point HPLC monitoring showed that the reaction was complete.

[0269] The reaction mixture with another reaction mixture (total input 13.2 kg, 18.93 mol, 1 equivalent (1 2 M)-(S)-5-bromo-3-(2,2-dimethyl-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)oxy)propyl)-1-ethyl-2-(2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridin-3-yl)-1H-indole (compound 4a)) combined.

[0270] The reaction mixture was concentrated to 132 L (10 V). The resulting mixture was loaded into a mixture of 28% w / w NH3 aqueous solution (43.6 L, 3.3 V) and water (87.1 L, 6.6 V). The two-phase mixture was filtered and the filtrate phase was separated. The organic phase was washed with 28% w / w NH3 aqueous solution (43.6 L, 3.3 V), washed with 0.1 M EDTA aqueous solution (43.6 L, 3.3 V), and concentrated to about 20 L (about 1.5 V). 2-MeTHF (39.6 L, 3 V) and water (13 L, 1 V) were loaded into the residue. The pH was adjusted to 1–2 with 6 M HCl aqueous solution. The phases were separated and the aqueous phase was extracted with 2-MeTHF (39.6 L × 2, 3 V × 2). DCM (39.6 L, 3 V) was loaded into the aqueous phase. The pH was adjusted to 8–9 with 1 M NaOH aqueous solution. The phases were separated and the organic phase was concentrated to approximately 20 L (approximately 1.5 V). Heptane (73 L, 5.5 V) was added over 2 hours. The resulting mixture was maintained at 35°C for 3 hours, then cooled and maintained at 0°C for 15 hours. The mixture was filtered, and the filter cake was washed with heptane (7 L, 0.5 V). The filter cake was dried to obtain a grayish-white solid (1... 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 5a) (7.2 kg, 98.2% a / a purity, 83.4% w / w determination, 58% yield, Table 15).

[0271] Part of 4b-compound 5a-(1 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4- Alternative synthesis of methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol.

[0272] DCM (2493 kg, 16 V), Cu(OAc)₂ (143 kg, 5.0 equivalents), N-methylpiperazine (160 kg, 10 equivalents), and TMP (83 kg, 3.7 equivalents) were charged into a reactor at 23 °C. The solution was stirred at 23 °C for 0.5 h. A mixture of N₂-O₂ (21% O₂) gas was bubbled under the surface of the reaction mixture at 23 °C for 2 h. Compound 4a (114.5 kg, 1.0 equivalents) was charged into the reactor at 23 °C. A mixture of N₂-O₂ (21% O₂) gas was bubbled under the surface of the reaction mixture at 23 °C for 6 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure until the residual volume was about 1100 L. In another reactor, water (306 kg, 6 V) and 28% ammonium hydroxide (306 kg, 3 V) were charged together with the concentrated reaction mixture at 20 °C. The phases were separated. The organic layer was collected and washed with an EDTA-Na2 aqueous solution (340 kg (0.1 N), 3 V) at 20 °C to purge copper salts. The DCM solution was concentrated until the volume of the residue was approximately 220 L.

[0273] Two more batches of Chan-Lam were performed (the net input of compound 4a in these two batches was 400 kg) and washed with NH3 and EDTA to obtain DCM solution; the DCM solutions of the three batches of crude compound 5a were combined for acidic MeTHF washing, free alkalization, DCM extraction, water washing and ACN crystallization.

[0274] 2-MeTHF (1333 kg, 3 V) and water (510 kg, 1 V) were charged into the reactor. The pH of the biphasic solution was adjusted to 1.29 with 6N HCl. The biphasic solution was stirred at 20 °C for 30 min. The phases were separated. The aqueous phase was collected and washed twice with 2-MeTHF (1340 kg × 2, 3 V × 2). DCM (2029 kg, 3 V) and NaOH aqueous solution (30% W / W) were added to the aqueous layer to adjust the pH to 8.39. The DCM phase was separated and washed with water (1533 kg, 3 V). The DCM solution was concentrated under vacuum until the residue volume was 1250 L. The resulting solution was exchanged three times with ACN (835.9 kg × 3, V × 3). The resulting solution was heated to 75 °C and stirred at 75 °C until all solids dissolved. The solution was slowly cooled to 60 °C over 2 h. At 60 °C, seed crystals of compound 5a were added to the reactor. The suspension was stirred at 60°C for 2 hours and cooled to 25°C for 5 hours, then stirred at 25°C for 3 hours. The suspension was concentrated under vacuum until the volume of the residue was approximately 230 L. The suspension was further cooled to 5°C for 4 hours. The resulting suspension was stirred at 5°C for 12 hours. The suspension was filtered and washed with pre-cooled ACN (481 kg). The wet filter cake was dried under vacuum at 45°C for 15 hours to give 307.6 kg of compound 5a as a grayish-white solid, with a purity of 99.3% and a yield of 75.8% (98.0% determination).

[0275] Table 15. HPLC methods used for portions 3, 4a, and 4b of Example 5

[0276] LRMS (ESI+)

[0277] 1 ¹H NMR (400 MHz, CDCl₃, 25 °C) δ 8.51 (d, J = 2.9 Hz, 1H), 7.88 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.7, 1.9 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 4.06 - 3.85 (m,3H), 3.35 - 3.17 (m, 6H), 3.05 (s, 3H), 2.70 (d, J= 14.2 Hz, 1H), 2.60 (t, J =5.1 Hz, 4H), 2.37 (s, 3H), 2.27 (d, J = 14.2 Hz, 1H), 1.44 (d, J = 6.2 Hz, 3H),1.35 (s, 1H), 1.20 (t, J = 7.2 Hz, 3H), 0.78 (s, 6H).

[0278] Part of the 5a-compound 6a-(1 2 M)-(S)-(1-Ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2- Synthesis of (1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indole-5-yl)boronic acid.

[0279] 2-MeTHF (18.7 L, 6.6 V), MeOH (6.2 L, 2.2 V), KOPiv (1.60 kg, 11.41 mol, 2.2 equivalents), (1) were charged into the reactor. 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 5a) (2.85 kg, 5.25 mol, 1 equivalent), XPhos (54.3 g, 113.90 mmol, 0.02 equivalent), XPhos Pd G3 (48.2 g, 56.94 mmol, 0.01 equivalent), and B2(OH)4 (307 g, 3.42 mol, 0.7 equivalent). The resulting mixture was heated to and maintained at 30 °C for 2 hours. Additional B2(OH)4 (307 g, 3.42 mol, 0.7 equivalent) was added, and the resulting mixture was maintained at 30 °C for 2 hours, at which point HPLC monitoring showed the reaction was complete.

[0280] The reaction mixture was concentrated to about 11 L (about 4 V) and then cooled to 20 °C. Water (3.1 L, 1 V) was added. The resulting mixture was maintained at 20 °C for 12 hours, during which time it was filtered, and the filter cake was washed with water (6.2 L, 2 V). The filter cake was combined with a filter cake from another reaction of the same scale, and then slurried at 20 °C in MeOH (37.2 L, 6.5 V) and water (12.4 L, 2.2 V) for 12 hours. The resulting mixture was then filtered, and the filter cake was washed with a mixture of MeOH:water (3:1, v / v, 6 L, 1 V). The filter cake was dried to give a grayish-white solid (1 2M)-(S)-(1-Ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid (compound 6a) (5.19 kg, 97.2% purity, 92.7% w / w determination, 90% yield, Table 16).

[0281] Partial 5b-compound 6a-(1 2 M)-(S)-(1-Ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2- Alternative synthesis of (1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid.

[0282] 2-MeTHF (870 L, 3.03 V) was added to the reactor (1) 2 M)-(S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 5a) (287.6 kg, 529.79 mol, 1 equivalent), KOPiv (148 kg, 2025 mol, 2.1 equivalent), XPhos (4.0 kg, 8.39 mol, 0.02 equivalent), XPhos G3 Pd (3.4 kg, 4.02 mol, 0.01 equivalent) and B2(OH)4 (71.0 kg, 791 mol, 1.5 equivalent). A solution of compound 5a in 2-MeTHF (870 L, 3.03 V) and MeOH (580 L, 2.02 V) was added to the reactor at 30 °C for 1 hour. The resulting mixture was maintained at 30 °C for 3 hours, at which point HPLC monitoring showed that the reaction was complete.

[0283] Water (28 L, 0.1 V) was added to the reactor. The reaction mixture was concentrated to 987 L (approximately 3.5 V) and then cooled to 20 °C. Water (256 L, 0.9 V) was added to the mixture. The resulting mixture was maintained at 20 °C for 16 hours, at which point it was filtered, and the filter cake was washed with water (471 L, 1.7 V). The filter cake was slurried in MeOH (1690 L, 6.0 V) and water (571 L, 2.0 V) at 15 °C for 8 hours. The resulting mixture was then filtered, and the filter cake was washed with a mixture of MeOH:water (3:1, v / v, 674 L, 2.4 V). The filter cake was dried to obtain (12M)-(S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid (compound 6a) as a grayish-white solid (250.18 kg, 99.0% purity, 97.5% w / w determination, 94.2% yield).

[0284] Table 16. HPLC methods used for portions 5a and 5b of Example 5

[0285] LRMS (ESI+)

[0286] 1 H NMR (400 MHz, CD3OD, 25℃) δ 8.40 (d, J = 2.9 Hz, 1H), 8.06 (s, 1H), 7.53 (s, 1H), 7.45 - 7.35 (m,2H), 4.17 - 4.05 (m, 1H), 4.01 (q, J = 6.3 Hz, 1H), 3.92 - 3.80 (m, 1H), 3.40 -3.30 (m, 6H), 3.28 (d, J = 12.0, 1H), 3.17 (d, J = 12.0 Hz, 1H), 2.99 (s, 3H), 2.80 (d, J = 14.0 Hz, 1H), 2.64 (t, J = 5.1 Hz, 4H), 2.36 (s, 3H), 2.27 (d, J =14.1 Hz, 1H), 1.40 (d, J= 6.3 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.76 (d, J = 23.5Hz, 6H).

[0287] Example 6. Synthetic procedure for compound 9-(S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carbamate)propionyl)hexahydropyridazine-3-carboxylic acid Part 1 - Compound 9b (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)methyl propionate Preparation DMF (689 kg, 5 vol., water content approximately 100 ppm by KF titration) and Zn (57.6 kg, 881.1 mol, 2.0 equivalent) were charged into reactor 1. Reactor 1 was evacuated and backfilled with argon (Ar) three times, followed by bubbling with Ar for 1 hour. 1,2-Dibromoethane (24.8 kg, 132.2 mol, 0.3 equivalent) was added to reactor 1. The resulting mixture was heated to 85-95 °C and maintained for 30 minutes. TMSCl (2.87 kg, 26.4 mol, 0.06 equivalent) was added to reactor 1 at 20-30 °C and stirred for 30 minutes. DMF (276 kg, 2 vol., water content approximately 100 ppm by KF titration) and Zn (…) were charged into reactor 2. RMethyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (compound 2a) (145.0 kg, 440.6 mol, 1.0 equivalent). Reactor 2 was evacuated and backfilled with Ar three times, then bubbled with Ar for 1 hour. A DMF solution of compound 2a from reactor 2 was added to reactor 1 at 20-30°C. The resulting mixture in reactor 1 was heated to 30-40°C and maintained for 30 minutes. MeTHF (624 kg, 5 vol.) and 2,4-dibromothiazole (compound 9a) (96 kg, 359.2 mol, 0.9 equivalent) were added to reactor 3. Reactor 3 was evacuated and backfilled with Ar three times, then bubbled with Ar for 1 hour. Pd(PPh3)2Cl2 (6.2 kg, 8.81 mol, 0.02 equivalent) was added to reactor 3. The Reformatsky reagent in reactor 1 was filtered, and the filtrate was added directly to reactor 3 at 20–40 °C. The mixture in reactor 3 was heated to 60–70 °C and maintained for 4 hours. A sample was taken for IPC (HPLC: 45.6% of compound 9b was produced). The reaction mixture was concentrated under reduced pressure to about 300 L (about 2 vol.) at 60–70 °C. MTBE (537 kg, 5 vol.) and 10 wt% NaCl aqueous solution (1450 kg, 10.0 vol.) were added to the mixture at 20–30 °C. The mixture was separated, and the aqueous phase was extracted with MTBE (537 kg, 5.0 vol.). The MTBE solution was combined and washed with 10 wt% NaCl aqueous solution (1450 kg × 3, 10 vol. × 3). The MTBE phase was concentrated under reduced pressure to about 200 L (1.5 vol.) at 35–45 °C. The resulting solution was subjected to two solvent exchanges with THF at 35–45 °C (645 kg × 2, 5 Vol. × 2). A total of 290.4 kg of THF solution of compound 9b was obtained, with a purity of 59.5% HPLC and a corrected yield of 32.8 wt% (Table 17). The crude product was used in the next step without further purification.

[0288] Table 17. HPLC methods used for compound 9b

[0289] MS (ESI+): C 12 H 17 BrN2O4S (M+H + The calculated value is 365.01. Experimental value: 365.10 1 H NMR (400 MHz, CDCl3): δ 7.12 (s, 1H), 5.47 (d, J = 7.2 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 3.75(s, 3H), 3.51 (d, J = 5.1 Hz, 2H), 1.43 (s, 9H).

[0290] Preparation of part of compound 9c: ( S 3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid Load ( into the reactor) S 3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid (compound 9b) (290.4 kg of THF solution, 59.5% purity, 32.8 wt%, 260.8 mol, 1.0 equivalent) and THF (847.7 kg, 10.0 vol.). The reactor was evacuated and backfilled with nitrogen three times. Water (667 kg, 7.0 vol.) in LiOH·H2O (16.4 kg, 391.2 mol, 1.5 equivalent) was added dropwise to the mixture at -2 to 2 °C. The mixture was stirred at 0–5 °C for 3 hours, and then samples were taken for IPC (HPLC purity: 58.3% for compound 9c and 0.3% for compound 9b). The reaction mixture was adjusted to pH 8–9 with 1 M HCl (approximately 100 kg) at 2–10 °C (IT). Add water (667 kg, 7.0 vol.) to the mixture. Concentrate the resulting mixture under reduced pressure at 30–40 °C until the residual volume reaches 1300 L (14.0 vol.). Add EtOAc (429 kg, 7.0 vol.) to the mixture at 15–20 °C and stir for 30 minutes. Filter the mixture and separate the filtrate to remove the organic layer. Wash the aqueous phase with EtOAc (429 kg × 2). Adjust the pH of the aqueous phase to 2.8–3.0 with 3 M HCl aqueous solution (approximately 300 kg) at 5–10 °C. Extract the aqueous phase with DCM (633 kg × 4). Combine the DCM phases and wash with water (476 kg, 5.0 vol.). Concentrate the DCM phase under reduced pressure at 30–40 °C to approximately 7 vol. (approximately 660 L). Then, at 15–20 °C... S1-Phenylacetylamine (44.2 kg, 364.7 mol, 1.4 equivalents) was added to the solution. The mixture was stirred at 15–20 °C for 30 min. Heptane (1557 kg, 25 vol.) was added at 15–20 °C (IT) and stirred for 60 min, then stirred again at 0–10 °C for 60 min. The mixture was filtered and the filter cake was washed with 2.5:1 (vol. / vol.) heptane / DCM (183 kg, 2 vol.). The wet filter cake was dried under reduced pressure at 40–45 °C for 12 h. A total of 129.0 kg of compound 9c as a white solid was obtained. S )-1-phenylethylamine salt, with an HPLC purity of 96.7% and a yield of 65.3 wt% as determined by HPLC. This makes compound 9c ( S (S)-1-phenylethylamine salt was dissolved in water (1684 kg, 20.0 vol.) and DCM (1120 kg, 10.0 vol.) was added. The mixture was adjusted to pH 10-10.5 with 1 M NaOH aqueous solution (270 kg) at 5-10 °C. The phases were separated and the aqueous phase was washed with DCM (560 kg × 2) to remove (S)-1-phenylethylamine. Samples were taken for IPC (without any (S)-1-phenylethylamine salt). S (1-Phenylethylamine remaining). The aqueous phase was adjusted to pH 2.8-3.0 with 1 M HCl aqueous solution (300 kg) at 5-10 °C. The aqueous phase was extracted with DCM (560 kg × 3). The DCM phases were combined and washed with water (421 kg, 5.0 vol.). The DCM phases were dried with Na2SO4 (84 kg, 1.0 w). After filtration, the filter cake was washed with DCM (168 kg, 2.0 vol.). The filtrate was concentrated under reduced pressure at 30-40 °C. A total of 1176.1 kg of free acid compound 9c in DCM solution was obtained (based on HPLC determination, equivalent to 83.5 kg of pure compound 9c), with 97.4% HPLC purity and 7.1 wt% determination, and 91.6% corrected yield (Table 18).

[0291] Table 18a. HPLC methods for compound 9c in part 2a

[0292] MS (ESI+): C6H 14 N2O2(M+H + The calculated value is 350.99. Experimental value: 350.80 1 H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 7.16 (s, 1H), 5.63 (d, J = 6.3 Hz, 1H), 4.68 (d, J = 5.0Hz, 1H), 3.58 (d, J = 4.7 Hz, 2H), 1.44 (s, 9H).

[0293] Alternative preparation of some 2b-compound 9c: ( S 3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid Steps 1 and 2: Preparation of compound 9c Prepare the following three solutions: i) Solution 1: THF (10 L, 5.0 vol.) and compound 9c-1 (2.0 kg, 8.2 mol, 1.0 equivalent) were charged into the reactor to produce a clear solution; ii) Solution 2: 2M THF i -PrMgCl (14.4 L, 7.2 mol, 0.875 equivalents); and iii) Solution 3: DMF (1.2 kg, 16.5 mol, 2.0 equivalent).

[0294] The flow rate of pump 1 for solution 1 was adjusted to 44.1 mL / min, the flow rate of pump 2 for solution 2 to 15.9 mL / min, and the flow rate of pump 3 for solution 3 to 5.4 mL / min. After heating the oil bath to 20°C, pumps 1 and 2 were started simultaneously, followed by pump 3. The reaction mixture was collected after 2 minutes. The reaction was monitored by IPC after 5 minutes (HPLC purity: 3.6 A% for compound 9c-1; 92.9 A% for compound 9c-2). DCM (30 L, 15 vol.) and water (10 L, 5.0 vol.) containing hydrochloric acid (628.5 g, 17.2 mol, 2.1 equivalents) were then added to the reactor. The reaction mixture was then added to 1.5 M HCl solution (12 L, 6 vol.) at 15 ± 5°C. The organic phase was then collected and washed with water (20 L × 3). The organic phase was concentrated under reduced pressure at NMT 35 °C until a residual volume of 6 L (3.0 vol.) was reached, and then the solvent was exchanged with MeCN (6.0 L × 2). A total of 4.95 kg of compound 9c-2 in MeCN solution (26 wt%) was obtained. Compound 9c-2 (4.95 kg of MeCN solution, 26 wt%, 6.7 mol, 1.0 equivalent) and MeCN (6.5 L, 5.0 vol.) were charged into the reactor. Malonic acid (766.5 g, 1.1 equivalent) and pyridine (2.1 kg, 4.0 equivalent) were added to the reactor at 15–25 °C, followed by pyrrolidine (95 g, 0.2 equivalent). The mixture was stirred at 80 ± 5 °C for 10 h. After confirming the completion of the reaction, the reaction mixture was cooled to 5 ± 5 °C. DCM (650 mL, 0.5 vol.) was added to the mixture. Dilute HCl (980 g HCl in 32.5 L, 25.0 vol.) was added dropwise to the mixture until the pH was adjusted to approximately 2 at 5 ± 5 °C. The mixture was stirred at 5 ± 5 °C for 2 hours. The mixture was filtered, and the filter cake was washed with water (2.6 L, 2.0 vol.). The filter cake was washed with DCM (650 mL, 0.5 vol.). The wet filter cake was dried under reduced pressure at 50–55 °C for 12 hours. A total of 1.45 kg of compound 9c-3 was obtained as a solid, 99.7% HPLC purity, as a grayish-white solid (Table 18b).

[0295] 1 H NMR (400 MHz, DMSO-d6): δ 12.92 (s, 1H), 8.03 (s, 1H), 7.67 (d,1H), 6.70 (d, 1H).

[0296] Table 18b. HPLC methods for compound 9c in part 2b.

[0297] Step 3: Compound 9c-4•H 2 O synthesis (NH4)2CO3 buffer solution (600 mL, 10.0 vol., pH 9.8) was added to the reactor at 34 ± 2 °C with stirring. Enzyme PH-AML-118 (600 mg, 1.0 wt%) and compound 9c-3 (60 g, 257.6 mmol, 1.0 equivalent) were added to the reactor. The mixture was stirred at 34 ± 2 °C for 10 h and the reaction was monitored by IPC (HPLC purity: 96.3 A% of compound 9c-4 and 2.4 A% of compound 9c-3, ee: 97.4%). The mixture was cooled to 25 ± 5 °C and maintained at this temperature for 10 min. The mixture was then adjusted to pH 1.0 ± 0.2 with 12 M HCl (382 mL, 4.7 vol.). The mixture was filtered, and the filter cake was washed with water (30 mL, 0.5 vol.). The filtrate was collected and added to the reactor. The pH of the filtrate was adjusted to 1.8 ± 0.1 using a 50% NaOH aqueous solution. Then, seed crystals of compound 9c-4 were added to the mixture and stirred for 2 hours. The pH of the mixture was adjusted to 5.0 ± 0.5 using a 50% NaOH aqueous solution (6 mL, 0.2 vol.). The mixture was heated to 50 ± 5 °C and stirred for 2 hours, then cooled to 40 ± 5 °C and stirred for 30 minutes. The temperature of the mixture was gradually decreased by 10 ± 5 °C and stirred for 30 minutes, repeated four times until a temperature of 0 ± 5 °C was reached. The mixture was then stirred at 0 ± 5 °C for 5 hours. The mixture was filtered, and the filter cake was washed with water (60 mL, 1.0 vol.). The wet filter cake was dried under reduced pressure at 45 ± 5 °C for 16 hours. A total of 57.5 g of compound 9c-4 H₂O in solid form was obtained, with a purity of 99.9% HPLC, ee ≥ 99.9% (Table 18c).

[0298] Table 18c. HPLC methods for compound 9c-4

[0299] 1 H NMR (400 MHz, D2O): δ 7.49 (s, 1H), 4.13 (dd, 1H), 3.58 (dd, 1H).

[0300] Step 4: Synthesis of compound 9c K₂CO₃ (14.4 g, 10⁴ mmol, 1.4 equivalences) and water (60 mL, 3.0 vol.) were charged into the reactor. The mixture was adjusted to 20 ± 5 °C. Compound 9c⁻⁴ H₂O (20.0 g, 74.3 mmol, 1.0 equivalences) was added to the reactor. The mixture was heated to 45 ± 5 °C and stirred until a clear solution was obtained. (Boc)₂O solution (17.8 g, 81.7 mmol, 1.1 equivalences, in 20 mL THF) was added to the reactor. The mixture was stirred at 45 ± 5 °C for 1 hour, and the reaction was monitored by IPC (HPLC purity: 98.8 A% of compound 9c, compound 9c⁻⁴ not detected). The mixture was cooled to 20 ± 5 °C. DCM (40 mL, 2.0 vol.) was added to the reactor. The mixture was adjusted to pH 2–3 with 3M HCl and stirred for 30 minutes. The mixture was separated and the organic phase was collected. The aqueous phase was extracted with DCM (40 mL, 2.0 vol.), and the organic phases were combined. DCM (100 mL, 5.0 vol.) was added to the organic phase, and the mixture was concentrated under reduced pressure at NMT 40 °C until 4–5 vol was obtained. DCM (100 mL, 5.0 vol.) was added to the residue. The mixture was concentrated under reduced pressure at NMT 40 °C until 4–5 vol was obtained. DCM (100 mL, 5.0 vol.) was added to the residue, and 180 g of compound 9c in its free acid form was obtained, with a DCM solution of 99.92% HPLC purity and a corrected yield of 14 wt% by 90%.

[0301] 1 H NMR (400 MHz, CDCl3): δ 9.35 (s, 1H), 7.16 (s, 1H), 5.63 (d, 1H), 4.68 (d, 1H), 3.58 (d, 2H), 1.44 (s, 9H).

[0302] Preparation of part 3-compound 9d(S)-hexahydropyridazine-3-carboxylic acid methyl ester dihydrochloride MeOH (371 kg, 5.0 vol.) and ( S1,2-Bis(tert-butoxycarbonyl)hexahydropyridazine-3-carboxylic acid (compound 9h) (93.9 kg, 284.2 mol, 1.0 equivalent). SOCl2 (67.6 kg, 568.4 mol, 2.0 equivalent) was added dropwise to the mixture at 10–20 °C. The reaction mixture was heated to 35–40 °C and stirred for 43 hours. Samples were taken for IPC (HPLC purity showed: 98.5% for compound 9d and 0% for compound 9h). The reaction mixture was concentrated under reduced pressure to 2 vol. (approximately 190 L) at 35–40 °C. Dioxane (193 kg, 2 vol.) was added to the mixture and concentrated under reduced pressure to 2 vol. (approximately 190 L) at 35–40 °C. Dioxane (193 kg, 2 vol.) was added to the mixture and concentrated under reduced pressure to 2 vol. (approximately 190 L) at 35–40 °C (OT). Dioxane (193 kg, 2 vol.) was added to the mixture and concentrated under reduced pressure at 35–40 °C to 2 vol. (approximately 190 L). The resulting mixture was diluted with DCM (250 kg, 2 vol.). A dioxane / DCM solution of 598 kg of compound 9d was obtained, with a purity of 95.7% HPLC and a yield quantified by HPLC at 10.3 wt% (Table 19).

[0303] Table 19. HPLC methods for compound 9d

[0304] MS (ESI+): C6H 14 N2O2(M+H + The calculated value is: 145.09 Experimental value: 145.10 1 H NMR (400 MHz, DMSO- d 6 ): δ 3.96 (dd, J = 10.5, 2.5 Hz, 1H), 3.63 (s, 3H), 3.06 (s, 1H), 2.91(dd, J = 16.2, 7.4 Hz, 1H), 1.89 (d, J = 10.6 Hz, 2H), 1.78 (dd, J = 9.8, 3.4 Hz, 1H), 1.65 - 1.47 (m, 1H).

[0305] Part of the 4-compound 9e (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propane Preparation of methyl methyl hexahydropyridazine-3-carboxylate (acyl) Compound 9d (598.0 kg of dioxane / DCM solution, 10.3 wt%, 284.1 mol, 1.2 equivalents) and DCM (553 kg, 5.0 vol.) were charged into the reactor. The reactor was evacuated and backfilled with nitrogen three times. The mixture was cooled to 0–5 °C. NMM (38.3 kg, 378.8 mol, 1.6 equivalents) was added dropwise to the mixture at 0–5 °C and stirred for another 30 minutes. Compound 9c (1176 kg of DCM solution, 7.1 wt%, 236.7 mol, 1.0 equivalents) was added dropwise to the mixture at 0–5 °C and stirred for another 30 minutes. HOBt (0.64 kg, 4.7 mol, 0.02 equivalents) and EDCI (81.7 kg, 426.1 mol, 1.8 equivalents) were added to the mixture at 0–5 °C and stirred for another hour. Samples were taken for IPC (HPLC purity: 86.5% A% for compound 9e, no compound 9c remaining). The reaction mixture was washed with water (831 kg × 4, 10 vol. × 4). The DCM phase was concentrated under reduced pressure at 25–30 °C to 2 vol. (approximately 200 L). MTBE (307 kg, 5 vol.) was added to the above DCM solution. The organic phase was concentrated under reduced pressure at 25–30 °C to 2 vol. (approximately 200 L). MTBE (307 kg, 5 vol.) was added to the above solution. The mixture was concentrated under reduced pressure at 25–30 °C to 2 vol. (approximately 200 L). MTBE (307 kg, 5 vol.) was added to the above solution. The mixture was concentrated under reduced pressure at 25–30 °C to 2 vol. (approximately 200 L). MTBE (184 kg, 3 vol.) was added to the above solution. Heptane (141 kg, 2.5 vol.) was added dropwise to the above solution at 25–30 °C. The resulting mixture was stirred at 15–20 °C for 30 minutes. The mixture was then cooled to 0–10 °C and stirred for another 60 minutes. The resulting slurry was filtered and the filter cake was washed with a 1:1 (vol. / vol.) heptane / MTBE (141 kg, 2 vol.). The filter cake was dried under reduced pressure at 35–40 °C. A total of 105.5 kg of compound 9e as a white solid was obtained, with a purity of 99.6 Å and a wt% determination by HPLC, and a corrected yield of 92.8% (Table 20).

[0306] Table 20. HPLC methods for compound 9e

[0307] MS (ESI+): C 17 H 25 BrN4O5S (M+H + The calculated value is: 477.07 Experimental value: 477.20 1 H NMR (400 MHz, CD3OD- d 4 ): δ 7.44 (s, 1H), 5.64 - 5.31 (m, 1H), 3.92 (s, 1H), 3.74 (s, 3H), 3.61(d, J = 3.9 Hz, 1H), 3.39 (dd, J = 14.5, 5.0 Hz, 1H), 3.29 - 3.18 (m, 2H), 1.99(dd, J = 8.4, 5.0 Hz, 1H), 1.86 - 1.62 (m, 3H), 1.40 (d, J = 18.6 Hz, 9H).

[0308] Partial 5-compound 9f ((S)-1-((S)-2-amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine- Preparation of methyl 3-carboxylate MeOH (960 kg, 10 vol.) and (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylate (compound 9e) (121.5 kg, 254.5 mol, 1.0 equivalent) were charged into the reactor. The reactor was evacuated and backfilled with nitrogen three times. SOCl2 (90.8 kg, 763.6 mol, 3.0 equivalent) was added dropwise to the mixture at 0–10 °C. The resulting mixture was heated to 30–40 °C and stirred at this temperature for 2 hours. Samples were taken for IPC (HPLC: 98.2 A% of compound 9f and 0 A% of compound 9e). The reaction mixture was concentrated to 150–250 L at 30–40 °C and diluted with DCM (808 kg, 5 vol.). The mixture was adjusted to pH 10.0–10.4 at 0–10 °C with a 15 wt% Na₂CO₃ aqueous solution (2673 kg, 22 wt). After phase separation, the aqueous phase was extracted with DCM (808 kg × 2, 2 × 5 vol.). The DCM phases were combined and washed with a 26% NaCl aqueous solution (3 × 1215 kg, 3 × 10 vol.). The DCM phases were concentrated under reduced pressure to 1200–1500 L at 30–40 °C. A DCM solution of compound 9f (1612.3 kg, 5.35 wt%) was obtained with a purity of 99.3% and a corrected yield of 91.1% (Table 21).

[0309] Table 21. HPLC methods used for compound 9f

[0310] LCMS (ESI+) C 12 H 17 BrN4O3S (M+H + The calculated value is 377.02. Experimental value: 377.10 1 H NMR (400 MHz, CD3OD) δ 7.57 (s, 1H), 5.45 (br, 1H), 3.80 (br, 1H), 3.77 (s, 3H), 3.67 (dd, J = 16.1, 4.3 Hz, 2H), 3.51 (dd, J = 16.1, 8.0 Hz, 2H), 1.91-2.09 (m, 2H), 1.83- 1.67 (m, 2H).

[0311] Part of the 6-compound 9g-(S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((1S,2S)-2-methylcyclopropane) Preparation of methyl alkyl-1-carbamate (propionyl)hexahydropyridazine-3-carboxylate Will( S )-1-(( S Methyl 2-amino-3-(4-bromothiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylate (compound 9f) (1612.3 kg of DCM solution, 5.4 wt%, 230.8 mol, 1.0 equivalent, determined by HPLC) and 212.4 kg of DCM were charged into the reactor. The reactor was evacuated and backfilled with nitrogen three times. NMM (37.3 kg, 369.2 mol, 1.6 equivalent) was added dropwise to the mixture at 0–10 °C and stirred at this temperature for 10 min. Compound 3 (30.0 kg, 300.0 mol, 1.3 equivalent) was added dropwise to the mixture at 0–10 °C and stirred at this temperature for 10 min. HOBt (0.62 kg, 4.6 mol, 0.02 equivalents) and EDCI (79.6 kg, 415.4 mol, 1.8 equivalents) were added to the mixture at 0–10 °C. The mixture was stirred at 0–10 °C for 1–3 hours. Samples were taken for IPC (HPLC: 9 g of compound 92.5 A% and 9 f of compound 0 A%). The DCM phase was washed three times with water (871 kg × 3, 10 vol. × 3). The DCM phase was concentrated under reduced pressure to 2–3 vol. (180–270 L) at 30–40 °C. n-Heptane (355 kg, 6 vol.) was added dropwise to the above solution at 20–40 °C. The resulting mixture was stirred at 10–20 °C for 30 minutes and then at 0–5 °C for 5 hours. The resulting mixture was filtered and the filter cake was washed with 2:1 (vol. / vol.) n-heptane / DCM (174 kg, 2 vol.). The filter cake was dried under reduced pressure at 30–40 °C for 12 hours. A total of 94.8 kg of the compound was obtained as 9 g of white solid, with a purity of 99.8% HPLC and a determination of 99.5% wt%, and a corrected yield of 89% (Table 22).

[0312] Table 22. HPLC methods for compound 9g

[0313] LCMS (ESI+): C 17 H 23 BrN4O4S (M+H + The calculated value is: 459.06 Experimental value: 459.30 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.15 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 5.59 (td, J = 8.0, 5.3 Hz,1H), 5.32 (d, J = 9.7 Hz, 1H), 3.93 - 3.76 (m, 1H), 3.66 (s, 3H), 3.50 (dd, J= 15.9, 7.8 Hz, 1H), 3.33 - 3.24 (m, 1H), 3.23 - 2.92 (m, 2H), 1.95 - 1.76(m, 1H), 1.78 - 1.39 (m, 4H), 1.17 - 0.93 (m, 4H), 0.83 (dt, J = 7.8, 3.9 Hz, 1H), 0.47 (dt, J = 8.1, 4.4 Hz, 1H).

[0314] Part of compound 7 - 9-(S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((1S,2S)-2-methylcyclopropane) Preparation of alkyl-1-carbamate-propionyl-hexahydropyridazine-3-carboxylic acid Will(( S )-1-(( S )-3-(4-bromothiazol-2-yl)-2-((1 S ,2 SMethyl 2-methylcyclopropane-1-carbamate (9 g) (94.0 kg, 204.6 mol, 1.0 equivalent) and MeOH (743 kg, 10 vol.) were charged into a reactor. An aqueous LiOH solution was added dropwise to the mixture at 2–4 °C. The mixture was stirred at 0–5 °C for 7 hours. Samples were taken for IPC 1 (HPLC: 99.4 A% of compound 9 and 0.2 A% of compound 9 g). The solution was filtered through a filter tank and an inline precision filter. Samples were taken for IPC 2 (HPLC: 99.4 A% of compound 9 and 0.2 A% of compound 9 g). The reaction mixture was adjusted to pH 6.2–7.2 with 1 M HCl aqueous solution at 0–5 °C, and then concentrated under reduced pressure at 25–35 °C (OT) until a residual volume of 650–750 L was reached. EtOAc (846 kg, 10 vol.) was loaded into the reactor. The reaction mixture was adjusted to pH 2.8–3.2 with 1 M HCl aqueous solution at 0–5 °C. The layers were separated. The aqueous phase was extracted twice with EtOAc (846 kg, 10 vol. and 423 kg, 5 vol.). The EtOAc phases were combined and washed with 26 wt% NaCl aqueous solution (1050 kg, 10 vol.). The EtOAc phase was filtered through a filter tank. The EtOAc phase was concentrated under reduced pressure to 380–470 L at 35–45 °C (OT). Seed crystals (45 g) were added to the mixture and stirred at 5–15 °C for 10 min. n-Heptane (320 kg, 5 vol.) was added to the above EtOAc solution. The resulting mixture was concentrated under reduced pressure to 380–470 L at 35–45 °C. 320 kg, 5 vol. of n-heptane was added to the above EtOAc solution. The resulting mixture was concentrated under reduced pressure to 380-470 L at 35-45 °C. The mixture was stirred at 10-20 °C for 0.5-1.5 h and then at 1-5 °C for 2-4 h. The mixture was filtered and the filter cake was washed with 128 kg, 2 vol. of n-heptane. The filter cake was dried under reduced pressure at 35-45 °C for 10 h. A total of 87.7 kg of compound 9 as a white solid was obtained, with a purity of 99.2% by HPLC and a corrected yield of 97.9 wt% and 94.2% by HPLC determination (Table 23).

[0315] Table 23. HPLC methods used for compound 9

[0316] LCMS (ESI+): C 16 H 21 BrN4O4S (M+H + The calculated value is: 445.05 Experimental value: 445.20 1 H NMR (400 MHz, CD3OD) δ 7.39 (d, J = 5.3 Hz, 1H), 5.70 (dd, J = 6.9, 5.8 Hz, 1H), 4.05 (d, J =7.3 Hz, 1H), 3.46 (dd, J = 9.5, 3.6 Hz, 1H), 3.39 (dd, J = 14.6, 5.6 Hz, 1H), 3.27 (dt, J = 3.3, 2.0 Hz, 1H), 2.99 (s, 1H), 2.06 - 1.91 (m, 1H), 1.79 (td, J =9.0, 4.2 Hz, 1H), 1.73 - 1.60 (m, 2H), 1.36 (dt, J = 8.3, 4.3 Hz, 1H), 1.18(dtd, J = 10.0, 6.1, 4.0 Hz, 1H), 1.04 (d, J = 6.0 Hz, 3H), 0.97 (dt, J = 8.6, 4.2Hz, 1H), 0.55 (ddd, J = 8.1, 6.2, 3.9 Hz, 1H).

[0317] Example 7. Synthetic procedure for compound A - (1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,27,28-tetraazapentacyclo[17.5.2.1^{2,5}.1^{9,13}.0^{22,26}]octadec-1(25),2,5(28),19,22(26),23-hexen-7-yl]-2-methylcyclopropane-1-carboxamide Part 1 - Compound 10 (3-(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1- (3-yl)pyridin-5-(tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-indol-3-yl)-2,2-dimethyl Synthesis of propan-1-ol DCM (36.25 kg), MeOH (7.05 kg), [1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-1H-indol-5-yl]boronic acid (compound 6a) (8.90 kg, 17.50 mol, 1.0 equivalent) and pinacol (3.12 kg, 26.40 mol, 1.5 equivalent) were charged into the reactor. The solution was stirred at 25 °C for 18 hours. A sample was taken and diluted with DMSO for HPLC analysis (standard: area % of compound 6a ≤ 3%, result: area % of compound 6a = 0.4%). The solution was concentrated under reduced pressure until the residual volume was about 11 L. DCM (36.10 kg) was charged, and the resulting solution was concentrated under reduced pressure until the residual volume was about 11 L. The same process was repeated 9 times to obtain acceptable residual MeOH. Samples were taken for GC analysis to check for residual MeOH (standard: MeOH content ≤ 100 ppm, result: MeOH content = 60 ppm). The resulting solution of compound 10 in DCM was used in the next step without further purification (DCM solution weight: 30.74 kg, 95.2% a / a purity, compound 10 content: 32.0% w / w determination, 16.66 mol, 95.2% yield, Table 24).

[0318] Table 24. HPLC method used for part 1 of Example 7

[0319] LCMS (ESI+) C 34 H 51 Calculated value of BN4O4(M+H+): 591.40 Experimental value: 591.40 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 2.9 Hz, 1H), 8.23 ​​(s, 1H), 7.72 (dd, J = 8.3, 1.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.17 (d, J= 2.9 Hz, 1H), 4.12 - 3.88 (m, 3H), 3.30(dt, J = 11.7, 3.9 Hz, 6H), 3.04 (s, 3H), 2.81 (d, J = 14.1 Hz, 1H), 2.63 (t, J =5.0 Hz, 3H), 2.38 (s, 3H), 2.33 (d, J = 14.1 Hz, 1H), 1.44 (d, J = 6.2 Hz, 3H),1.39 (s, 12H), 1.22 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 6.8 Hz, 2H), 0.83 (d, J = 7.3Hz, 6H)。

[0320] Part 2 - Compound 11 - (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl-2-yl)-2-{[(1S,2S)-2- [Methylcyclopropyl]formamido}propionyl]-1,2-diazin-3-carboxylic acid 2-[(1-ethyl-2-{2-[(1S)-1-methoxyethyl] [[5-(4-methylpiperazin-1-yl)pyridin-3-yl]-5-(tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-] Synthesis of indole-3-yl)methyl]-2-methylpropyl ester A DCM solution (30.56 kg, compound 10 content: 32.0% w / w, 16.56 mol, 1.0 equivalent) of 3-(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-5-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-3-yl)-2,2-dimethylprop-1-ol (compound 10) was added to the reactor, along with DCM (100.45 kg), (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(1S,2S)-2-methylcyclopropyl]formamido}propionyl]-1,2-diazinane-3-carboxylic acid (compound 9) (8.52 kg, 19.13 kg). 1.16 mol) and DMAP (3.05 kg, 2.50 mol, 1.5 equivalents). The solution was cooled to 19°C and EDCI (6.39 kg, 3.33 mol, 2.0 equivalents) was added fractionally with stirring at 15–20°C. The resulting solution was stirred at 15–20°C for 14 hours. A sample was taken and diluted with MeCN to check the IPC purity by HPLC analysis (standard: area % of compound 10 ≤ 5%, actual result: area % of compound 10: 3%). The reaction mixture was quenched with water and then washed with aqueous HCl (0.2 M, 171.5 kg), aqueous NaHCO3 (8% w / w, 155.7 kg), and water (98.4 kg). The DCM phase was then separated and concentrated under reduced pressure until the residue volume was about 25 L. MTBE (37.05 kg, 3V) was added and the resulting solution was concentrated under reduced pressure until the residue volume was about 25 L. The solvent exchange process was repeated three times. The resulting MTBE solution was added dropwise to pre-cooled n-heptane (25 L) at -10 °C. The resulting suspension was then stirred at -10 °C for 12.5 h. The slurry was filtered, and the filter cake was washed with n-heptane (6.8 kg). The wet filter cake was dried under vacuum at 30 °C to give compound 11 as a white solid (17.29 kg, 86.5% a / a purity, 81.9% w / w determination, 13.91 mol, 84% yield, Table 25).

[0321] Table 25. HPLC method used for part 2 of Example 7

[0322] LCMS (ESI+) C 50 H 70 Calculated value of BBrN8O7S (M+H+): 1017.44 Experimental value: 1017.4 1 H NMR (400 MHz, CDCl3) δ: 8.52 (d, J = 2.8 Hz, 1H), 8.12 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.37(d, J = 8.3 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 7.09 (s, 1H), 6.73 (d, J = 7.2 Hz,1H), 5.50 (dt, J = 7.0, 4.9 Hz, 1H), 4.32 (d, J = 12.9 Hz, 1H), 4.03 (dd, J = 12.7,7.8 Hz, 2H), 3.95 (d, J = 6.1 Hz, 1H), 3.88 (dd, J = 14.6, 7.3 Hz, 1H), 3.73 (d, J = 4.8 Hz, 1H), 3.68 (dd, J = 10.9, 3.1 Hz, 1H), 3.62 (d, J = 11.6 Hz, 1H), 3.43(d, J = 4.8 Hz, 2H), 3.31 (t, J = 5.1 Hz, 4H), 2.99 (s, 3H), 2.84 (d, J = 14.2 Hz,1H), 2.61 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H), 2.32 (d, J = 14.2 Hz, 1H), 2.04 -1.95 (m, 1H), 1.85 - 1.75 (m, 2H), 1.41 (d, J = 6.2 Hz, 3H), 1.37 (s, 12H),1.25 (d, J = 7.3 Hz, 2H), 1.21 (d, J = 7.1 Hz, 3H), 1.19 - 1.08 (m, 3H), 1.06 (d, J= 6.0 Hz, 3H), 0.90 (s, 3H), 0.85 (s, 3H), 0.61 - 0.55 (m, 1H).

[0323] Part 3 - Compound A free base - (1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1-methoxy [[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[] ... ⇌-9,21,27,28-tetraazapentacyclo[17.5.2.1^{2,5}.1^{9,13}.0^{22,26}]octadec-1(25),2,5 Synthesis of (28),19,22(26),23-hexen-7-yl]-2-methylcyclopropane-1-carboxamide 1,4-Dioxane (134.65 kg), (3S)-1-[(2S)-3-(4-bromo-1,3-thiazo-2-yl)-2-{[(1S,2S)-2-methylcyclopropyl]formamido}propionyl]-1,2-diazinyl-3-carboxylic acid 2-[(1-ethyl-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-5-(tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-indol-3-yl)methyl]-2-methylpropyl ester (compound 11) (5.50 kg, 81.9% w / w determined, 4.43 mol, 1.0 equivalent) and P(t-Bu)3-HBF4 (256.5 kg) were charged into a reactor at 25 °C. (504.0 g, 0.089 mol, 0.2 equivalent). Nitrogen gas was bubbled under the surface of the mixture at 25°C for 1 hour. P(t-Bu)3Pd G3 (504.0 g, 0.089 mol, 0.2 equivalent) was added to the mixture. Nitrogen gas was again bubbled under the surface of the mixture at 25°C for 1 hour. The resulting reaction mixture was then heated to 45°C. A solution of K2CO3 (1.22 kg, 8.84 mol, 2.0 equivalent) in water (27.00 kg) was added dropwise over a period of one hour. The resulting reaction mixture was stirred at 45–50°C for 7 hours. A sample was taken and diluted with MeOH to test the IPC by HPLC (standard: area % of compound 11 ≤ 3%, actual result: area % of compound 11 = 0.1%). The reaction mixture was then concentrated under reduced pressure to 25 L. The mixture was then diluted with EtOAc (49.0 kg) and water (45.5 kg). The organic phase was separated and washed three times with water (22.8 kg × 3). The organic phase was concentrated under reduced pressure and co-distilled with EtOAc to remove 1,4-dioxane (GC area % of dioxane: ≤3%, result: GC area % of dioxane: 1.3%). The product obtained in the EtOAc solution was stored to be combined with two other batches for further processing.

[0324] Two more batches of Suzuki coupling were performed following the same procedure described above. Water (11.00 kg) and EtOAc (33.50 kg) were added to the combined three batches. The resulting biphasic solution was then cooled to 10°C. An aqueous HCl solution (prepared by mixing 13.9 kg of water and 2.4 kg of hydrochloric acid) was slowly added to the solution over a period of 90 minutes at 10°C. Seed crystals (136.5 g) were then added, and the resulting suspension was stirred at 10°C for another hour. The slurry was further cooled to 0°C and held for 1 hour. This temperature cycle between 10°C and 0°C was repeated three times. The suspension was stirred at 0°C for 10 hours, and the resulting slurry was filtered. The filter cake was washed with water (5.00 kg). The wet filter cake was suspended in a mixed solvent of EtOAc (20.0 kg) and water (5.0 kg) at 5°C and stirred for 1 hour. The suspension was filtered and washed with cold water (5.0 kg, pre-cooled to 5°C) to obtain a wet compound A HCl salt (6.1 kg, 97.6% a / a purity, LOD: 29.2%, Pd: 595 ppm) as a yellow solid.

[0325] Compound A HCl salt was suspended in a mixture of 2-MeTHF (35.70 kg) and water (24.10 kg) at 5 °C, and the pH of the aqueous solution was adjusted to 8–9 by adding 10% sodium carbonate solution. The organic phase was then separated and washed twice with water (2 × 24 kg). Water (16.1 kg) was added to the organic phase and the pH was adjusted to 3.7 with 1M HCl solution. The aqueous phase was then separated and washed twice with 2-MeTHF (2 × 13.5 kg). 2-MeTHF (27.7 kg) was added to the aqueous phase and the pH was adjusted to 5.5 by adding 1M sodium hydroxide aqueous solution. The organic phase was separated and washed with water and NaCl solution. SiliaMets thiol (1.290 kg) was added to the organic phase and the resulting suspension was stirred at 25 °C for 22 hours. The slurry was filtered and the filter cake was washed with 2-MeTHF (2 × 5.5 L). The combined organic phases were concentrated under reduced pressure to 12 L. The resulting MeTHF solution was added to pre-cooled n-heptane (55.80 kg, pre-cooled to -10 °C) for 1 hour at -10 °C. The resulting suspension was stirred at -10 °C for 12 hours. The suspension was filtered and the wet filter cake was washed twice with n-heptane (2 × 2.3 kg). The wet filter cake was dried under reduced pressure at 40 °C to give compound A free base as a grayish-white solid (2.46 kg, 99.2% a / a purity, 3.03 mol, 22.8% yield, Table 26).

[0326] Table 26. HPLC method used for part 3 of Example 7

[0327] LCMS (ESI+)

[0328] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78(s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32-4.15 (m, 5H),3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H),3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m,5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H),1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz,1H), 0.37 (s, 3H)。

[0329] Part 4 - Compound A - (1S,2S)-N-[(7S,13S)-21-ethyl-20-{2-[(1S)-1-methoxyethyl [[5-(4-methylpiperazin-1-yl)pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-] 9,21,27,28-Tetraazapentacyclo[17.5.2.1^{2,5}.1^{9,13}.0^{22,26}]octadec-1(25),2,5 Purification of (28),19,22(26),23-hexen-7-yl]-2-methylcyclopropane-1-carboxamide MeOH (7.76 kg) and free base of compound A (2.46 kg, 3.03 mol, 1.0 equivalent) were charged into a reactor at 25°C. The resulting suspension was stirred until the solid was completely dissolved. The resulting methanol solution was filtered through a microfiltration filter and transferred to another reactor. The reactor temperature was then maintained at 25°C, and water (2.41 kg, 1.0 V) was slowly added over a 30-minute period. The resulting turbid solution was stirred at 25°C for another 30 minutes. Then, a methanol and water solution (3.42 kg, 1:2, v / v) was slowly added over 1 hour. The resulting suspension was stirred at 25°C for 2 hours. Again, additional water (2.48 kg) was slowly added to the suspension over 1 hour. The final suspension was stirred for another 1 hour. Water (9.29 kg, 3.75 V) was slowly added to the suspension over 2 hours, and the mixture was stirred at 25°C for at least 16 hours. The resulting suspension was filtered and washed twice (2 × 2.2 kg) with a water:MeOH (3:2, v / v) mixed solvent, and then washed with water (4.91 kg). The wet filter cake was dried under reduced pressure and controlled humidity (temperature: 25 ± 5 °C, vacuum ≥ -0.085 MPa, humidity: 10%-20%) for 37 hours to give compound A as a white solid (2.68 kg, 99.4% a / a purity, 93.0% w / w determination, KF: 6.7%, 3.07 mol, 92% yield, Table 27).

[0330] Table 27. HPLC method for step 5

[0331] MS (ESI+) C 44 H 58 Calculated value of N8O5S (M+H): 811.43 Experimental value: 811.40 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78(s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J= 2.4Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32-4.15 (m, 5H), 3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H), 3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m,5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz, 1H), 0.37 (s, 3H).

[0332] Example 8. Substitutional Synthesis of Compound A Part of compound 1a - 12 - (S)-1-((S)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)- 2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazole-2- Synthesis of 1,2,2-((1S,2S)-2-methylcyclopropane-1-carbamate)propionyl)hexahydropyridazine-3-carboxylic acid The reactor was charged with (S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid (compound 6a) (54.5 kg, 95 wt%, 107.2 mol, 1.0 equivalent), (S)-1-((S)-3-(4-bromothiazolyl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)propionyl)hexahydropyridazin-3-carboxylic acid (compound 9, 49.0 kg, 110.3 mol, 1.03 equivalent), and dioxane (514.2 kg). Then, anhydrous potassium carbonate (45.4 kg) from purified water (166.5 kg) was added. The mixture was purged with nitrogen for about 1.5 hours. Then, under nitrogen protection, 3.6 kg (0.06–0.07 × 0.05 equivalents) of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) was added to the mixture. The reactor was injected with dioxane (70 kg). The reaction mixture was purged with nitrogen again for another 1.5 hours. The reaction mixture was then slowly heated to 75 °C over a 4-hour period. The reaction mixture was stirred at 75 °C for another 10 hours. HPLC analysis indicated that the starting material (compound 6a) was less than 1%. The reaction mixture was cooled to room temperature and filtered through 10.2 μL of diatomaceous earth to remove insoluble material, resulting in a dark color. The filter cake was washed with 23% NaCl aqueous solution (206.9 kg) and dioxane (185 kg). The filtrate was separated, and the organic phase was separated and distilled to 429 L. Water (272 kg) and 2-methyltetrahydrofuran (242 kg). The alkaline mixture was adjusted to pH 9.1 with 7% HCl (25.6 kg), and the aqueous phase was separated. The aqueous phase was acidified to pH 2 to 3 with 7% HCl (139 kg). The aqueous phase was then washed with MeTHF (277 kg). The aqueous phase was neutralized to pH 7 to 8 with 15% sodium carbonate aqueous solution (130 kg). The product was extracted from the aqueous phase using DCM-MeOH (2 × 563.4 kg + 100 kg). The combined organic phases were evaporated and diluted with IPA (275 L) and MeOH (6 kg). MTBE (1274 kg) was slowly added in three portions over a 5-hour period. During the addition, the product began to crystallize. The resulting slurry was cooled to 0°C and held for 12 hours. The slurry was then filtered, and the wet compound was dried to give compound 12 as a gray solid (76.6 kg, 95.9% a / a purity, 87.9 wt%, 76% yield, Table 28).

[0333] Partial substitution synthesis of compound 1b-12 The reactor was charged with (S)-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)boronic acid (compound 6a) (118.4 kg, 233 mol, 1.0 equivalent), (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)propionyl)hexahydropyridazin-3-carboxylic acid (compound 9, 108.8 kg, 244 mol, 1.04 equivalent), and dioxane (1,102 kg). Then, anhydrous potassium carbonate (91.7 kg; 5.5 equivalent) was added from purified water (352 kg). The mixture was purged with nitrogen for approximately 1.5 hours. Then, under nitrogen protection, 7.80 kg (0.065 × 0.05 equivalents) of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) was added to the mixture. The reactor was sprayed with dioxane (125 kg). The reaction mixture was purged with nitrogen again for another 1.5 hours. The reaction mixture was then slowly heated to 75°C over a period of 4 hours. The reaction mixture was stirred at 75°C for another 6 hours. The reaction IPC indicated by HPLC was less than 1% of the starting material (compound 6a). The reaction mixture was cooled to room temperature and filtered through 10.2 g of diatomaceous earth to remove insoluble material, resulting in a dark color. The filter cake was washed with additional dioxane (312 kg). In another reactor, an aqueous solution of sodium chloride (103 kg in water (312 kg)) and an aqueous solution of potassium carbonate (80 kg in water (122 kg)) were prepared. The filtrate (organic solution) was then mixed with a mixture of aqueous NaCl and aqueous K2CO3 solutions. The organic phase was then separated and concentrated to 1188 L (10 V). The resulting solution was co-distilled with IPA (6 × 1191 L) to achieve the minimum levels of dioxane and water. The resulting organic phase was adjusted to 946 L (8 V). The solution was slowly added to MTBE (3754 L, 31.8 V) over a period of 5 hours. The product began to crystallize / precipitate as a slurry. The resulting slurry was cooled to 0 °C and held for 12 hours. The slurry was then filtered and the wet compound was dried to give the sodium salt of compound 12 as a gray solid (184.6 kg, 96.1% a / a purity, 87.7 wt%, 84% yield).

[0334] Table 28. HPLC methods used for compound 12

[0335] LCMS (ESI+) C 44 H 60 N8O6S (M+H+ Calculated value of (): 829.44 Experimental value: 829.90 1 H NMR (400 MHz, DMSO- d 6) δ ppm 8.44 (d, J = 2.81 Hz, 1 H), 8.32 (s, 1 H), 8.05 (d, J = 8.19 Hz, 1 H), 7.74 - 7.71 (m, 2 H), 7.51 - 7.49 (m, 1 H), 7.30 - 7.27 (m, 1 H), 5.53 - 5.46 (m, 1 H), 4.53 - 4.50 (m, 1 H), 4.20 (br d, J = 12.72 Hz, 1 H), 4.10 - 4.01 (m, 2 H), 3.92 - 3.84 (m, 1 H), 3.28 - 3.20 (m, 7 H), 3.12 (br d, J = 10.72 Hz, 2 H), 3.08 (s, 3 H), 3.04 - 3.01 (m, 1 H), 2.88 (s, 3 H), 2.84 (m, 1 H), 2.72 (s, 1 H), 2.69 - 2.62 (m, 2 H), 2.53 - 2.52 (m, 1 H), 2.46 (br t, J = 4.77*(2) Hz, 5 H), 2.26 - 2.24 (m, 1 H), 2.21 - 2.16 (m, 4 H), 1.93 - 1.87 (m, 1 H), 1.68 (br dd, J = 9.11, 3.00 Hz, 1 H), 1.58 (d, J = 4.03 Hz, 1 H), 1.44 (d, J = 6.68 Hz, 1 H), 1.36 - 1.34 (m, 2 H), 1.15 (t, J = 7.15 Hz, 2 H), 0.93 - 0.85 (m, 1 H), 0.69 - 0.63 (m, 3 H), 0.63 - 0.58 (m, 3 H), 0.53 - 0.45 (m, 1 H) Part of the 2a-compound A lactate - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methyl) (Oxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63, 64,65,66-Hexahydro-11H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecan-4- Synthesis of 2-methylcyclopropane-1-carboxamide lactate 1-hydroxy-1H-benzotriazole (21.1 kg, 156 mol, 2.0 equivalents), 4-dimethylaminopyridine (4.9 kg, 0.5 equivalents), N,N-diisopropylethylamine (21 kg, 2.0 equivalents), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (45.5 kg, 237 mol, 3.0 equivalents) were charged into reactor-1 and dissolved in DCM (3601.3 kg). Subsequently, in reactor 2, (S)-1-((S)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazolyl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)propionyl)hexahydropyridazin-3-carboxylic acid (compound 12, 65.7 kg, 87.9 wt%, 79 mol, 1.0 equivalent) was dissolved in DCM (920 kg). The solution was transferred from reactor 2 to reactor 1 after 25 hours at 25–35 °C. The solution was stirred at 25–35 °C for 2.0 hours. After the reaction was complete, the mixture was quenched with water (330 kg) and the solution was concentrated to 2000 kg. Water (330 kg) was added to the mixture and the organic phase was separated. The organic phase was washed twice with water (720 kg), and 1708.8 kg of the organic phase was concentrated to 175 kg and co-evaporated twice with acetonitrile (460 kg). The concentration in the acetonitrile was adjusted to 300 kg. Then, 98% lactic acid (26.2 kg, 4.0 equivalent) was slowly added over 2 hours. Water (3.8 kg) was added to the solution. Then, seed crystals (0.54 kg) were added and the resulting slurry was stirred at 25 °C for 12 hours, then cooled to 0 °C, held for 5 hours, and stirred at 0 °C for 20 hours. The compound was separated after filtration and drying. The crude wet cake was slurried in MeCN (340 kg) at 0 °C for 18 hours. The slurry was then filtered and dried to give compound A lactate as a gray solid (35.6 kg, 99.0% a / a purity, 82.2% wt%, 48% yield, Table 29).

[0336] Part of the 2b-compound A lactate-(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methyl) (Oxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63, 64,65,66-Hexahydro-11H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecan-4- Synthesis of 2-methylcyclopropane-1-carboxamide lactate 1-H-hydroxy-1H-benzotriazole (24 kg, 177 mol, 2.0 equivalents), 4-dimethylaminopyridine (5.6 kg, 45.9 mol, 0.5 equivalents), N,N-diisopropylethylamine (24 kg, 186 mol, 2.0 equivalents), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl (52 kg, 272 mol, 3.0 equivalents) were then dissolved in DCM (4190 kg). In another reactor (reactor 2), (S)-1-((S)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indol-5-yl)thiazolyl)-2-((1S,2S)-2-methylcyclopropane-1-carboxamido)propionyl)hexahydropyridazin-3-carboxylic acid (compound 12, 75.3 kg, 90.8 mol, 1.0 equivalent) was dissolved in DCM (1000 kg). The solution from reactor 2 was then transferred to reactor 1 at 25–35 °C for 25 hours. The solution was stirred at 25–35 °C for 2 hours. After the reaction was complete, the mixture was quenched with water (350 kg) and then concentrated to approximately 2000 kg. Water (350 kg) was added to the mixture and the organic phase was separated. Water (approximately 750 kg) was added to the organic phase, and the pH of the aqueous phase was adjusted to 4-5 using 85% lactic acid. The organic phase was separated and concentrated to 232 L and co-evaporated three times with acetonitrile (740 L). The volume of the resulting organic phase was adjusted to approximately 300 kg. Then, 85% lactic acid (16.2 kg, 2.0 equivalent) was slowly added over 2 hours, and water (2.4 kg) was added to the solution. Then, seed crystals of compound 12 (0.23 kg) were added, and the resulting slurry was stirred at 25°C for 12 hours, then cooled to 0°C, held for 5 hours, and stirred at 0°C for 20 hours. Compound 12 was separated after filtration. The crude wet filter cake was recrystallized again in MeCN (approximately 340 kg), heated to 60°C, cooled to 0°C, and held for 20 hours. The slurry was then filtered and dried to give compound 12 L-lactate as a gray solid (57.07 kg, 99.0% a / a purity, 81.1% wt%, 63% yield).

[0337] Table 29. HPLC methods for compound A lactate

[0338] LCMS (ESI+).

[0339] C 44 H 58N8O5S+C3H6O3(M+H + The calculated value is 901.14 (in lactate form). Experimental value: 811.3 1 H NMR (400 MHz, CDCl3): δ ppm: 8.48 - 8.52 (m, 1 H), 8.39 - 8.45 (m, 1 H), 7.49 - 7.55 (m, 1H), 7.24 - 7.29 (m, 1 H), 7.03 (d, J =2.50 Hz, 1 H), 6.40 - 6.55 (m, 1 H), 5.80- 5.91 (m, 1 H), 5.15 - 5.22 (m, 1 H), 5.12 - 5.27 (m, 1 H), 4.47 - 4.56 (m, 1 H), 4.14 - 4.29 (m, 4 H) 4.01 - 4.12 (m, 4 H), 3.90 - 3.97 (m, 2 H), 3.71 -3.77 (m, 1 H), 3.60 - 3.68 (m, 1 H),, 3.35 - 3.40 (m, 4 H), 3.27 - 3.33 (m, 3H), 3.00 -3.12 (m, 2H), 2.91 - 2.96 (m, 3 H), 2.57 - 2.66 (m, 1 H), 2.47 -2.55 (m, 3 H), 2.32 - 2.41 (m, 1 H), 2.07 - 2.18 (m, 1 H), 1.85 - 1.91 (m, 1H), 1.68 - 1.79 (m, 1 H), 1.48 - 1.58 (m, 1 H), 1.31 - 1.39 (m, 6 H), 1.09 -1.22 (m, 3 H), 0.87 - 0.92 (m, 3 H), 0.78 - 0.86 (m, 3 H), 0.52 - 0.60 (m, 1H), 0.48 - 0.51 (m, 1 H), 0.47 - 0.51 (m, 1 H), 0.31 - 0.40 (m, 3 H).

[0340] Partial 3a-compound A free base - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methyl) (Oxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63, 64,65,66-Hexahydro-11H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecan-4- Synthesis of 2-methylcyclopropane-1-carboxamide The reactor was charged with 2-MeTHF (292 kg) and water (113 kg) in the form of (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazoza-1(5,3)-indolza-6(1,3)-pyridazinzacycloundecan-4-yl)-2-methylcyclopropane-1-carboxamide lactate (28.0 kg, 34.5 mol, 1.0 equivalent). The mixture was then cooled to 0–10 °C. Then, a 15% sodium carbonate aqueous solution (15 kg) was slowly added to the reactor at 0-10 °C to neutralize the pH to 8-9. The mixture was stirred for 30 minutes, and the organic phase was separated. The organic phase was washed with water (225 kg). It was then washed with 25% NaCl (120 kg). 11.2 kg of silica-thiol (0.38-0.42 X) was added to the organic phase, and the slurry was stirred at room temperature for 12 hours to remove residual palladium. The silica-thiol was then removed by filtration. The filtrate was concentrated to 112 L. The solution was added to heptane (1200 kg) over a period of 4 hours. The resulting slurry was filtered, and the filter cake was dried to give crude compound A free base as a white solid (24.9 kg, 98.9% a / a purity, 96.4% w / w 85.6% yield, Table 30).

[0341] Partial 3b-compound A free base - (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methyl) (Oxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63, 64,65,66-Hexahydro-11H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecan-4- Synthesis of 2-methylcyclopropane-1-carboxamide The reactor was charged with 2-MeTHF (440 kg, 8.9 V) and water (198 kg) in the form of (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazoza-1(5,3)-indolza-6(1,3)-pyridazinzacycloundecan-4-yl)-2-methylcyclopropane-1-carboxamide lactate (compound A lactate, 49.6 kg, 55 mol, 1.0 equivalent). The mixture was cooled to 0–10 °C. Then, a 15% sodium carbonate aqueous solution (27 kg) was slowly added to the reactor at 0-10 °C to neutralize the pH to 8-9. The mixture was stirred for 30 minutes, and the organic phase was separated. The organic phase was washed with water (398 kg) and then with 25% NaCl (198 kg). 11.2 kg of silica thiol (0.38-0.42 X) or 3-mercaptopropyl ethyl sulfide silica (SPM32) was added to the organic phase, and the slurry was stirred at room temperature for 12 hours to remove residual palladium. The silica-thiol was then removed by filtration. The filtrate was concentrated to 349 L (7 V). This solution was added to heptane (1857 L, 37.4 V) over a period of 4 hours. The resulting slurry was filtered, and the filter cake was dried to give crude compound A free base as a white solid (44.2 kg, 99.6% a / a purity, 94.9% w / w, 83% yield).

[0342] Table 30. HPLC methods for compound A (crude)

[0343] LCMS (ESI+)

[0344] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78(s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d,J = 2.4Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 4.32-4.15 (m, 5H),3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H),3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m,5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H),1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz,1H), 0.37 (s, 3H)。

[0345] Part of the 4a-compound A-(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl) (3-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65, 66-Hexahydro-11H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2- Methylcyclopropane-1-carboxamide (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazoza-1(5,3)-indolza-6(1,3)-pyridazinzacycloundecan-4-yl)-2-methylcyclopropane-1-carboxamide (compound A, free base, 23.9 kg, 29.47 mol, 1.0 equivalent) and MeOH (76 kg) were charged into reactor 2 over 3 hours at 20-30°C. Then, 0.29 kg of seed crystals were added and stirred at 20-30°C for 2-4 hours. Additional purified water (67 kg) was added dropwise to reactor 2 over 4-6 hours at 20-30°C. The resulting slurry was then stirred at 20-30°C for 8-12 hours. The slurry was filtered and the wet filter cake was dried to obtain crude compound A as a white solid (23.9 kg, 99.4% a / a purity, 96% w / w determination, 96% yield, Table 31).

[0346] Part of the 4b-compound A-(1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl) (3-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65, 66-Hexahydro-11H-8-oxa-2(4,2)-thiazo-1(5,3)-indolaz-6(1,3)-pyridazine-cycloundecaban-4-yl)-2- Methylcyclopropane-1-carboxamide (1S,2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazoza-1(5,3)-indolza-6(1,3)-pyridazinzacycloundecan-4-yl)-2-methylcyclopropane-1-carboxamide (compound A, free base, 41.9 kg, 51.7 mol, 1.0 equivalent) and MeOH (166 kg) were charged into reactor 1. Purified water (50 kg) was added dropwise to the resulting solution over 3 hours at 20–30 °C. Then, 0.42 kg of seed crystals were added to the mixture and the resulting slurry was stirred at 20–30 °C for 5 hours. Purified water (116 kg) was added dropwise over 4–6 hours at 20–30 °C. The resulting slurry was then stirred at 20–30 °C for 16–24 hours. The slurry was filtered, and the wet filter cake was washed with MeOH and water (30 kg; 34 kg). The wet filter cake was dried under a nitrogen stream at 35%–55% relative humidity to give compound A as a white solid (44.12 kg, 99.7% a / a purity, 92.5% w / w determination, 97% yield).

[0347] Table 31. HPLC methods for compound A

[0348] LCMS (ESI+)

[0349] 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.54 (d, J = 9.2 Hz, 1H), 8.51 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 7.78(s, 1H), 7.73 (dd, J = 8.8, 1.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 2.4Hz, 1H), 5.60 (t, J = 8.8 Hz, 1H), 5.09 (d, J= 12.0 Hz, 1H), 4.32-4.15 (m, 5H), 3.60 (br s, 2H), 3.35 (d, J = 14.0 Hz, 1H), 3.27 (br s, 4H), 3.22 (s, 3H), 3.19-3.15 (m, 1H), 2.97 (d, J = 14.4 Hz, 1H), 2.80-2.74 (m, 1H), 2.49-2.45 (m,5H), 2.21(s, 3H), 2.10 (d, J = 9.6 Hz, 1H), 1.80 (br s, 2H), 1.56-1.52 (m, 2H), 1.35 (d, J = 6.0 Hz, 3H), 1.08 (s, 4H), 0.92-0.89 (m, 7H), 0.56 (d, J = 5.2 Hz, 1H), 0.37 (s, 3H).

[0350] Other implementation plans Although the invention has been described in conjunction with specific embodiments thereof, it should be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses or adaptations of the invention that deviate from the disclosure of this invention and are generally followed in accordance with the principles of the invention and included within the scope of known or customary practices in the field to which this invention pertains, and may be applied to the essential features described herein.

[0351] All publications, patents and patent applications are incorporated herein by reference in their entirety as if each individual publication, patent or patent application were specifically and individually incorporated in its entirety.

Claims

1. A method for preparing compound 1: Compound 1 The method includes: a) React compound 1a and compound 1b to form compound 1c: ； b) Oxidate and hydrolyze compound 1c to form compound 1d: ;as well as c) Cyclate compound 1d to form compound 1: 。 2. The method of claim 1, wherein the oxidation and hydrolysis step (b) comprises a first step of oxidizing compound 1c to compound 1e and a second step of hydrolyzing compound 1e to compound 1d: 。 3. A compound having the structure of Formula II: Formula II or its salt, wherein R 1 The substituted C1-C6 alkyl, the substituted 3- to 10-membered cycloalkyl, or the substituted C6-C 10 Aryl.

4. The compound of claim 3, wherein the compound has the structure of formula IIa: Formula IIa Or its salt.

5. A method for preparing compound 2a, the method comprising: a) Esterify compound 2b to form compound 2c: ； b) Protecting and toluenesulfonating compound 2c to form compound 2d: ； as well as c) Iodize compound 2d to form compound 2a: 。 6. The method of claim 5, wherein the protection and toluenesulfonation step (b) comprises a first step of protecting compound 2c to form compound 2e and a second step of toluenesulfonating compound 2e to form compound 2d: 。 7. A method for preparing compound 3: Compound 3 The method includes: a) Contacting compounds 3a and 3b in the presence of a base to form compound 3c: ； as well as b) Hydrolyze compound 3c to form compound 3: 。 8. A compound having the structure of formula III, compound 5, or compound 6: Or its salt, wherein R is H or .

9. A method for preparing compound 6a, the method comprising: a) Boronize compound 7 to form compound 4a: ； b) Couple compound 4a and compound 6b to form compound 5a: ； as well as c) Boridate compound 5a to form compound 6a: 。 10. A compound having the structure of Formula I: Formula I or its salt, wherein R 1 It is H or C1-C6 alkyl.

11. A method for preparing compound 9c or a salt thereof: The method includes: a) Formylating compound 9c-1 to form compound 9c-2: ； b) Condensate compound 9c with malonic acid to form compound 9c-3: ； c) Amination of compound 9c-3 to form compound 9c-4 H2O: ； as well as d) Protecting compound 9c-4 to form compound 9c: 。 12. A method for preparing compound 9: Compound 9 The method includes: a) Couple compound 2a with compound 9a to form compound 9b: ； b) Hydrolyze compound 9b to form compound 9c: ； c) Couple compound 9c and compound 9d to form compound 9e: ； d) Deprotecting compound 9e to form compound 9f: ； e) Couple compound 9f with compound 3 to form compound 9g: ;as well as f) Hydrolyze compound 9g to form compound 9: 。 13. The method of claim 12, wherein the coupling step (a) comprises contacting compound 2a with a zinc source to form compound 2a-Zn: 。 14. A method for preparing compound A: Compound A The method includes: a) Contacting compound 6a with pinacol to form compound 10: ； b) Esterification of compound 9 with compound 10 to form compound 11: ;as well as c) Cyclate compound 11 to form compound A: 。 15. A method for preparing compound A: Compound A The method includes the following steps: a) Couple compound 6a and compound 9 to form compound 12: ； as well as b) Lactolation of compound 12 to form compound A: 。 16. The method of claim 14 or 15, wherein the method further comprises the step of purifying compound A.

17. The method of claim 16, wherein the purification comprises forming a salt of compound A.

18. The method of claim 17, wherein the salt of compound A is the hydrochloride salt of compound A or the lactate salt of compound A.

19. The method of claim 17 or 18, wherein the purification comprises the step of converting the salt of compound A into the free base form of compound A.

20. A compound having the structure of compound 10, compound 11, or compound 12: Or its salt.

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