Process for making enantiomers of ar-degraders

Abstract

Disclosed, inter alia, are methods of preparing a phthalazinone Compound 1, which is useful for degradation of androgen receptor (AR). Also disclosed are methods of preparing intermediate compounds useful in the preparation of Compound 1. (Compound 1).

Description

PROCESS FOR MAKING ENANTIOMERS OF AR-DEGRADERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to PCT application No. PCT / CN24 / 81300, filed March 13, 2024; and U.S. Provisional Application No. 63 / 572,805, filed April 1, 2024; each of which is incorporated by reference herein in its entirety for all purposes.TECHNICAL FIELD

[0002] The present disclosure relates, for example, to processes for preparing N-(trans-3-(3- chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3- yl)- 1 -oxo- 1 ,2-dihydrophthalazin-6-yl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)benzamide. The present disclosure additionally relates to the preparation of various compounds that are intermediates employed in these processes.BACKGROUND

[0003] N-(trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2- ((S)-2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin-6-yl)piperazin-l- yl)methyl)piperidin-l-yl)benzamide, referred to herein as Compound 1, is a small molecule proteolysis targeting chimeras (PROTAC) and is an androgen receptor degrader. Compound 1 is disclosed in, for example, U.S. Patent No. 11,767,312 (see, e.g., Embodiment 28), as well as International Patent Application Publication No. WO / 2021 / 249534, both of which are incorporated by reference herein for all purposes.

[0004] There is a need in the art for improved methods for making anticancer agents due to due to the high prevalence of cancer worldwide. Provided herein are methods that address this and other needs in the art.SUMMARY

[0005] The present disclosure provides processes for preparing Compound 1 (also referred to

[0006] In an embodiment, provided is a method for preparing Compound 1 comprising reacting a compound of formula D4with a compound of formula D5:wherein X is an acid, in the presence of a reducing agent to form Compound 1.

[0007] In an embodiment, provided is a method for preparing Compound 1 comprising reacting a compound of formulaor salt thereof with a compound of formula D2:in the presence of an amide coupling reagent to form the compound of formula D3:and converting the compound of formula D3 to the compound of formula DI.DETAILED DESCRIPTION OF EMBODIMENTS

[0008] The present application will be described in detail below with reference to embodiments, but it does not mean that there is any unfavorable limitation to the presentapplication. The present application has been described in detail herein, and the specific embodiments thereof are also disclosed. For those skilled in the art, it would be obvious to make various changes and improvements to the specific embodiments of the present application without departing from the spirit and scope of the present application.Definitions

[0009] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered to be indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to a corresponding commercial product or an active ingredient thereof.

[0010] As used in the present invention, it should be appreciated that the phrase "at least one", when referring to a list of one or more elements, is intended to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of the elements in the list of elements. This definition further allows that elements, other than those specifically determined within the list of elements to which the phrase "at least one" refers, may be optionally present, no matter whether they are related or unrelated to those specifically determined elements.

[0011] The compounds disclosed herein may exist in a specific geometric or stereoisomeric form. Except where otherwise specified, all such compounds contemplated in the present invention comprise cis and trans isomers, (-)- and (+)-enantiomers, ( / ?)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, for example, enantiomerically or diastereomerically enriched mixtures, and all these mixtures shall fall within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and the mixtures thereof are incorporated into the scope claimed in the present methods.

[0012] Unless otherwise stated, a wedged solid bond ( ^*) and a wedged dotted bond () are used to represent an absolute configuration of a stereocenter.

[0013] The compounds disclosed herein may exist in a specific form. Unless otherwise specified, the term "tautomers" or "tautomeric forms" means that isomers of different functional groups are in a dynamic equilibrium and can be rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (such as in a solution). For example, a proton tautomer (also referred to as a prototropic tautomer) comprises an interconversion via migration of a proton, such as keto-enol and imineenamine isomerizations.

[0014] The solvents used in the present invention are commercially available.

[0015] Compounds were named according to conventional nomenclature in the art or by using ChemDraw® software, and commercially available compounds were named in supplier catalogs.Compound 1

[0016] In one aspect, provided is a method of preparing Compound 1 comprising reacting a compound of formulawith a compound of formula D5:wherein X is an acid, in the presence of a reducing agent to form Compound 1. In embodiments, X is tetrafluoroboric acid. In embodiments, X is methanesulfonic acid. In embodiments, the reducing agent is, e.g., sodium cyanoborohydride or sodium triacetoxyborohydride. In embodiments, the reducing agent is sodium triacetoxyborohydride. In embodiments, reacting the compound of formula D4 with the compound of formula D5 in the presence of a reducing agent further comprises the presence of a base. In embodiments, the base is, e.g., sodium acetate, potassium acetate, ammonium acetate, sodium bicarbonate, or potassium bicarbonate. In embodiments, the base is sodium acetate. In embodiments, reacting the compound of formula D4 with a compound of formula D5 is performed in the presence of sodium triacetoxyborohydride and sodium acetate. In embodiments, reacting the compound of formula D4 with the compound of formula D5 in the presence of a reducing agent is performed in a solvent, e.g., dichloromethane (DCM), tetrahydrofuran (THF), 2-MeTHF, methanol, ethanol, 1 -propanol, 2-propanol, or a combination thereof. In embodiments, the solvent is dichloromethane, methanol, or a combination thereof.

[0017] In another aspect, provided is a method of preparing a compound of formula D3, comprising reacting a compound of formula DI:or salt thereof with a compound of formula D2:in the presence of an amide coupling reagent to form the compound of formula D3:In embodiments, the compound of formula DI is an HC1 salt of the formula:In another aspect, provided is a method of preparing Compound 1 comprising reacting a compound of formula DI or salt thereof with a compound of formula D2 in the presence of an amide coupling reagent to form the compound of formula D3, and converting the compound of formula D3 to Compound 1. In embodiments, the compound of formula DI is an HC1 salt of the formula:In embodiments, the amide coupling reagent is an aminium coupling reagent, e.g. HBTU, HATU, HCTU, TPTU, TSTU, or COMU. In embodiments, the amide coupling reagent is a phosphonium reagent, e.g. PyBOP, PyAOP, or BOP. In embodiments, the amide coupling reagent is a carbodiimide reagent, e.g., dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). In embodiments, the carbodiimide is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). In embodiments, reacting the compound of formula DI with the compound of formula D2 in the presence of the amide coupling reagent further comprises a peptide synthesis additive, e.g., hydroxybenzotriazole (HOBt), 6-Cl-HOBt, hydroxy-7-azabenzotriazole (HOAt), Ethyl cyanohydroxyiminoacetate (Oxyma), 2-hydroxypyridine-N-oxide (HOPO), or N- hydroxy succinimide (NHS). In embodiments, the peptide synthesis additive is hydroxybenzotriazole (HOBt). In embodiments, the peptide synthesis additive is 2- hydroxypyridine-N-oxide (HOPO). In embodiments, reacting the compound of formula DI with the compound of formula D2 is performed in the presence of EDC and HOBt. Inembodiments, reacting the compound of formula DI with the compound of formula D2 is performed in the presence of EDC and HOPO. In embodiments, reacting the compound of formula DI with the compound of formula D2 is performed in the presence of a base. In embodiments, the base is an organic base. In embodiments, the base is an amine base. In embodiments, the base is N,N-diisopropylethylamine (DIEA or DIPEA). In embodiments, reacting the compound of formula DI with the compound of formula D2 is performed in an organic solvent, e.g., dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-2- pyrrolidone (NMP), dimethylsulfoxide (DMSO), or N-butylpyrrolidinone (NBP). In embodiments, the solvent is dimethylformamide (DMF).

[0018] In embodiments, the compound of formula D3 is purified by the addition of an antisolvent to a solution of crude compound of formula D3 in DMF. In embodiments, the antisolvent is water. In embodiments, the compound of formula D3 is recrystallized by anti-solvent addition to a solution of crude compound of formula D3 in tetrahydrofuran (THF). In embodiments, the anti-solvent is n-heptane.

[0019] In embodiments, the method of preparing Compound 1 (i.e., converting the compound of formula D3 to Compound 1) comprises reacting the compound of formula D3 with an acid to form a compound of formula D4:In embodiments, the acid is trifluoroacetic acid. In embodiments, the acid is sulfuric acid. In embodiments, reacting the compound of formula D3 with an acid to form a compound of formula D4 is performed in a solvent, e.g., water, methanol, ethanol, acetonitrile, dichloromethane (DCM), or a combination thereof. In embodiments, the solvent is dichloromethane. In embodiments, the solvent is dichloromethane and water. In embodiments, the solvent is acetonitrile. In embodiments, reacting the compound of formula D3 with an acid to form a compound of formula D4 comprises reacting the compound of formula D3 with trifluoroacetic acid in the presence of dichloromethane and water. In embodiments, reacting the compound of formula D3 with an acid to form a compound of formula D4 comprises reacting the compound of formula D3 with aqueous sulfuric acid in the presence of acetonitrile.

[0020] In embodiments, the compound of formula D4 is purified by anti-solvent addition to a solution of crude compound of formula D4 in DCM. In embodiments, the anti-solvent is n- heptane.

[0021] In embodiments, the method of preparing Compound 1 (i.e., converting the compound of formula D3 to Compound 1) further comprises reacting the compound of formula D4 with a compound of formula D5:wherein X is an acid, in the presence of a reducing agent to form Compound 1. In embodiments, X is tetrafluoroboric acid. In embodiments, X is methanesulfonic acid. In embodiments, the reducing agent is, e.g., sodium cyanoborohydride or sodium triacetoxyborohydride. In embodiments, the reducing agent is sodium triacetoxyborohydride. In embodiments, reacting the compound of formula D4 with the compound of formula D5 in the presence of a reducing agent further comprises the presence of a base. In embodiments, the base is, e.g., sodium acetate, potassium acetate, ammonium acetate, sodium bicarbonate, or potassium bicarbonate. In embodiments, the base is sodium acetate. In embodiments, reacting the compound of formula D4 with a compound of formula D5 is performed in the presence of sodium triacetoxyborohydride and sodium acetate. In embodiments, reacting the compound of formula D4 with the compound of formula D5 in the presence of a reducing agent is performed in a solvent, e.g., DCM, THF, 2-MeTHF, methanol, ethanol, 1-propanol, 2-propanol, or a combination thereof. In embodiments, the solvent is dichloromethane, methanol, or a combination thereof.

[0022] In embodiments, the method of preparing Compound 1 further comprises preparing the compound of formula D5 as disclosed herein.

[0023] In embodiments, the method of preparing Compound 1 further comprises preparing the compound of formula DI as disclosed herein.

[0024] In embodiments, the method of preparing Compound 1 further comprises preparing the compound of formula D2 as disclosed herein.

[0025] In embodiments, Compound 1 is purified by anti-solvent addition to a solution of crude Compound 1 in DCM, methanol, or a combination thereof. In embodiments, Compound 1 is purified by anti- solvent addition to a solution of crude Compound 1 in DCM and methanol. In embodiments, Compound 1 is purified by anti-solvent addition to a solution of crude Compound 1 in DCM. In embodiments, the anti-solvent is acetone, methyl isobutyl ketone (MIBK), THF, ethyl acetate (EtOAc), isopropyl acetate, or 2-MeTHF. In embodiments, the anti- solvent is EtOAc.Intermediate DI

[0026] In embodiments, provided is a method of preparing a compound of formula DI or salt thereof comprising (1) reacting a compound of formula DI -3 with a reducing agent to form a compound of formula DI -4, (2) reacting the compound of formula DI -4 with an acid to form a compound of formula Dl-5, wherein Y is the acid, and (3) converting the compound of formula Dl-5 to the compound of formula DI.In embodiments, the reducing agent is hydrogen gas in the presence of a hydrogenation catalyst, e.g., Raney nickel, palladium on carbon, palladium hydroxide, or platinum oxide. In embodiments, the reducing agent is nickel-aluminum alloy in the presence of an activator. In embodiments, the activator is a strong base, e.g., sodium hydroxide. In embodiments, the acid Y is, e.g., phosphoric acid, L-lactic acid, DL-lactic acid, 2-naphthalenesulfonic acid, D- camphorsulfonic acid, or D-3-bromocamphos-10-sulfonic acid. In embodiments, the acid is phosphoric acid. In embodiments, step (1) of reacting a compound of formula DI -3 with a reducing agent to form a compound of formula DI -4 is performed in a solvent, e.g. THF, 2- MeTHF, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), ethyl acetate, isopropyl acetate, or water. In embodiments, reacting a compound of formula DI -3 with a reducing agent to form a compound of formula DI -4 is performed in tetrahydrofuran and water. In embodiments, reacting a compound of formula DI -3 with a reducing agent to form a compound of formula DI -4 is performed in isopropyl acetate. In embodiments, step (2) of reacting the compound of formula Dl-4 with an acid to form a compound of formula Dl-5, is performed in a solvent, e.g., MeOH, EtOH, 1-PrOH, 2-PrOH, water, or a combination thereof. In embodiments, reacting the compound of formula Dl-4 with an acid to form a compound of formula Dl-5, is performed in ethanol, water, or a combination thereof.

[0027] In embodiments, the method of preparing a compound of formula DI (i.e., converting the compound of formula Dl-5 to the compound of formula DI) comprises reacting the compound of formula Dl-5 with 2-chloro-4-fluorobenzonitrile in the presence of a base to form the compound of formula DI, or a salt thereof. In embodiments, the base is, e.g., lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodium hydride. In embodiments, the base is sodium tert-butoxide or potassium tert-butoxide. In embodiments, reacting the compound of formula Dl-5 with 2- chloro-4-fluorobenzonitrile in the presence of a base is performed in a solvent, e.g. DMSO, acetonitrile, NMP, DMF, DMA, THF, 2-MeTHF, or toluene. In embodiments, the solvent is N- methyl-2-pyrrolidone (NMP). In embodiments, the solvent is 2-MeTHF.

[0028] In embodiments, the method of preparing a compound of formula DI further comprises reacting the compound of formula DI -5 with di-tert-butyl dicarbonate in the presence of a base to form a compound of formula Dl-6In embodiments, the base is, e.g., sodium carbonate, sodium bicarbonate, or potassium bicarbonate. In embodiments, the base is potassium carbonate. In embodiments, reacting the compound of formula DI -5 with di-tert-butyl dicarbonate in the presence of a base is performed in a solvent, e.g., 1,4-dioxane, THF, 2-MeTHF, water or a combination thereof. In embodiments, the solvent is 1,4-dioxane, water, or a combinatoin thereof. In embodiments, the solvent is 2-methyltetrahydrofuran, water, or a combination thereof.

[0029] In embodiments, the method of preparing a compound of formula DI further comprises reacting the compound of formula DI -6 with 2-chloro-4-fluorobenzonitrile in the presence of a base to form a compound of formula DI -7In embodiments, the base is, e.g., lithium tert-butoxide, sodium tert-butoxide, potassium tert- butoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodium hydride. In embodiments, the base is sodium hydride. In embodiments, the base is sodium tert-butoxide. In embodiments, reacting the compound of formula Dl-6 with 2-chloro-4-fluorobenzonitrile in the presence of a base is performed in a solvent, e.g., DMSO, acetonitrile, NMP, DMF, DMA, THF, 2-MeTHF, toluene, or a combination thereof. In embodiments, the solvent is DMF. In embodiments, the solvent is NMP.

[0030] In embodiments, the method of preparing a compound of formula DI further comprises deprotecting the compound of formula Dl-7 in the presence of an acid to form the compound of formula DI or salt thereof. In embodiments, the acid is hydrochloric acid. In embodiments, deprotecting the compound of formula Dl-7 in the presence of an acid is performed in a solvent. In embodiments, the solvent is 1-propanol or 1-butanol. In embodiments, the compound of formula DI is

[0031] In embodiments, the method of preparing a compound of formula DI further comprises reacting a compound of formula DI -2with a reducing agent to form the compound of formula DI -3. In embodiments, the reducing agent is sodium borohydride. In embodiments, reacting a compound of formula Dl-2 with a reducing agent is performed in a solvent. In embodiments, the solvent is isopropyl alcohol.

[0032] In embodiments, the method of preparing a compound of formula DI further comprises reacting a compound of formula Dl-1with hydroxylamine to form the compound of formula DI -2. In embodiments, the hydroxylamine is hydroxylamine hydrochloride. In embodiments, reacting a compound of formula Dl-1 with hydroxylamine is performed in the presence of a base. In embodiments, the base is sodium acetate. In embodiments, reacting a compound of formula Dl-1 with hydroxylamine is performed in the presence of a solvent. In embodiments, the solvent is THF. In embodiments, the solvent is ethanol.Intermediate D2

[0033] In one aspect, provided is a compound of formula D2.In embodiments, the compound of formula D2 exhibits improved solid-state stability, hygroscopicity, and / or shelf life for long-term storage, in comparison to the free acid 4-(4- (dimethoxymethyl)piperidin- l-yl)benzoic acid.

[0034] In another aspect, provided is a method of preparing a compound of formula D2 comprising reacting a compound of formula D2-4with a base to form the compound of formula D2. In embodiments, the base is sodium hydroxide. In embodiments, reacting the compound of formula D2-4 with a base is performed in a solvent, e.g., THF, 1,4-dioxane, methanol, ethanol, water, or a combination thereof. Inembodiments, the solvent is tetrahydrofuran (THF), water, or a combination thereof. In embodiments, the solvent is methanol, water, or a combination thereof.

[0035] In embodiments, the method of preparing a compound of formula D2 further comprises reacting a compound of formula D2-3with methyl 4-bromobenzoate in the presence of a catalyst to form the compound of D2-4. In embodiments, the catalyst is a palladium catalyst. In embodiments, the catalyst is provided as a palladium catalyst and a ligand. In embodiments, the catalyst is provided as palladium acetate and RuPhos. In embodiments, reacting a compound of formula D2-3 with methyl 4- bromobenzoate in the presence of a catalyst is performed in the presence of a base, e.g. potassium phosphate tribasic, potassium carbonate, cesium carbonate, sodium tert-butoxide, or potassium tert-butoxide. In embodiments, the base is potassium phosphate tribasic. In embodiments, reacting a compound of formula D2-3 with methyl 4-bromobenzoate in the presence of a catalyst is performed in the presence of a solvent, e.g. 1,4-dioxane, toluene, 2- MeTHF, or THF. In embodiments, the solvent is 1,4-dioxane.

[0036] In embodiments, the method of preparing a compound of formula D2 further comprises reacting a compound of formula D2-2with hydrogen in the presence of a catalyst to from the compound of formula D2-3. In embodiments, the catalyst is palladium on carbon. In embodiments, reacting a compound of formula D2-2 with hydrogen in the presence of a catalyst is performed in the presence of a solvent, e.g. methanol, ethanol, 1 -propanol, 2-propanol, THF, ethyl acetate, or isopropyl acetate. In embodiments, the solvent is methanol.

[0037] In embodiments, the method of preparing a compound of formula D2 further comprises reacting a compound of formula D2- 1(D2-1) with trimethyl orthoformate in the presence of a catalyst to form the compound of formula D2- 2. In embodiments, the catalyst is p-toluenesulfonic acid. In embodiments, reacting a compound of formula D2-1 with trimethyl orthoformate in the presence of a catalyst is performed in a solvent, e.g., methanol, ethanol, 1-propanol, or 2-propanol. In embodiments, the solvent is methanol.

[0038] In embodiments, the method of preparing a compound of formula D2 comprising reacting a compound of formula D2-4 with a base to form the compound of formula D2 further comprises reacting a compound of formula D2-7with methanol in the presence of an acid to form the compound of formula D2-4. In embodiments, the acid is p-toluenesulfonic acid.

[0039] In embodiments, the method of preparing a compound of formula D2 further comprises reacting a compound of formula D2-6with an oxidant to form the compound of formula D2-7. In embodiments, the oxidant is activated DMSO. In embodiments, the oxidation is performed under Swern conditions using oxalyl chloride as the activator of DMSO. In embodiments, the oxidation is performed under Parikh-Doering conditions, using pyridine sulfur trioxide complex as the activator of DMSO. In embodiments, reacting a compound of formula D2-6 with an oxidant is performed in the presence of a base, e.g., triethylamine or diisopropylethylamine. In embodiments, the base is triethylamine. In embodiments, reacting a compound of formula D2-6 with an oxidant is performed in a solvent, e.g. DCM, THF, or 2-MeTHF. In embodiments, the solvent is dichloromethane .

[0040] In embodiments, the method of preparing a compound of formula D2 further comprises reacting a compound of formula D2-5with methyl 4-fluorobenzoate in the presence of a base to form the compound of formula D2-6. In embodiments, the base is sodium carbonate, potassium carbonate, lithium carbonate, potassium phosphate tribasic, DIEA, or sodium phosphate tribasic. In embodiments, the base is sodium carbonate. In embodiments, reacting a compound of formula D2-5 with methyl 4- fluorobenzoate in the presence of a base is performed in a solvent, e.g. DMSO, DMF, DMA, or NMP. In embodiments, the solvent is DMSO.Intermediate D5

[0041] In one aspect, provided is a compound of formula D5 wherein X is tetrafluoroboric acid or methanesulfonic acid, which has the structure:In embodiments, the acid X (e.g., tetrafluoroboric acid or methanesulfonic acid) enables isolation of the compound without racemization.

[0042] In embodiments, provided is a method of preparing the compound of formula D5, comprising reacting a compound of formula D5-6with an acid to form the compound of formula D5. In embodiments, the acid is hydrochloric acid, sulfuric acid, tetrafluoroboric acid, or methanesulfonic acid. In embodiments, the acid is tetrafluoroboric acid. In embodiments, the acid is methanesulfonic acid. In embodiments, reacting a compound of formula D5-6 with an acid is performed in the presence of a solvent, e.g. THF, MeOH, EtOH, 1-propanol, 2-propanol, or a combination thereof. In embodiments, the solvent is ethanol. In embodiments, the solvent is tetrahydrofuran.

[0043] In embodiments, the method of preparing a compound of formula D5 further comprises chiral purification of a compound of formula D5-5to obtain the compound of formula D5-6.

[0044] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-4(D5-4) with 3-bromopiperidine-2, 6-dione in the presence of a base to form the compound of formula D5-5. In embodiments, the base is lithium tert-butoxide, sodium tert-butoxide, potassium tert- butoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or sodium hydride. In embodiments, the base is sodium hydride. In embodiments, the base is lithium tert-butoxide. In embodiments, reacting a compound of formula D5-4 with 3-bromopiperidine-2, 6-dione in thepresence of a base is performed in a solvent, e.g. DMSO, acetonitrile, NMP, DMF, DMA, THF, 2-MeTHF, toluene, or a combination thereof. In embodiments, the solvent is DMSO,THF, or a combination thereof.

[0045] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-3with tert-butyl piperazine- 1 -carboxylate in the presence of a catalyst and a base to form the compound of formula D5-4. In embodiments, the catalyst is a palladium catalyst. In embodiments, the catalyst is provided as Pd2(dba)3 and XPhos. In embodiments, the base is lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. In embodiments, the base is sodium tert-butoxide. In embodiments, reacting a compound of formula D5-3 with tert-butyl piperazine- 1 -carboxylate in the presence of a catalyst and a base is performed in a solvent, e.g. 1,4-dioxane, toluene, DMA, DMF, NMP, 2-MeTHF, or THF. In embodiments, the solvent is 1,4-dioxane.

[0046] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-2with hydrazine to form the compound of D5-3. In embodiments, reacting a compound of formula D5-2 with hydrazine is performed in a solvent, e.g. methanol, ethanol, 1-propanol, 2- propanol, THF, or 2-MeTHF. In embodiments, the solvent is ethanol.

[0047] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-1with a bromination reagent to form the compound of formula D5-2. In embodiments, the method further comprises a radical initiator. In embodiments, the bromination reagent is N- bromosuccinimide. In embodiments, the radical initiator is azabisisobutyronitrile (AIBN). In embodiments, reacting a compound of formula D5-1 with a bromination reagent is performed in a solvent, e.g., acetonitrile, chloroform, or dichloromethane. In embodiments, the solvent is chloroform.

[0048] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-10with tert-butyl piperazine- 1 -carboxylate in the presence of a base to form the compound of formula D5-4. In embodiments, the base is DIEA, triethylamine, l,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), or 1,4-diazabicyclo 2.2.2 octane (DABCO). In embodiments, the base is N,N- diisopropylethylamine. In embodiments, reacting a compound of formula D5-10 with tert-butyl piperazine- 1 -carboxylate in the presence of a base is performed in a solvent, e.g., DMF, DMA, NMP, or DMSO. In embodiments, the solvent is NMP.

[0049] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-9with hydrazine to form the compound of formula D5-10. In embodiments, reacting a compound of formula D5-9 with hydrazine is performed in the presence of an acid. In embodiments, the acid is acetic acid. In embodiments, reacting a compound of formula D5-9 with hydrazine is performed in a solvent, e.g. methanol, ethanol, 1 -propanol, or 2-propanol. In embodiments, the solvent is ethanol.

[0050] In embodiments, the method of preparing a compound of formula D5 further comprises subjecting a compound of formula D5-8to conditions suitable to achieve metal-halogen exchange, followed by reaction with a formylation reagent to form the compound of formula D5-9. In embodiments, the conditions suitable to achieve metal-halogen exchange comprise treating the compound of formula D5-8 with n-butyllithium. In embodiments, the formylation reagent is N,N-dimethylformamide. In embodiments, subjecting a compound of formula D5-8 to conditions suitable to achieve metal- halogen exchange is performed in the presence of a solvent, e.g. THF, 2-MeTHF. In embodiments, the solvent is THF.

[0051] In embodiments, the method of preparing a compound of formula D5 further comprises reacting a compound of formula D5-7with a carboxylic acid activation agent followed by diethylamine to form the compound of formula D5-8. In embodiments, the carboxylic acid activation agent is oxalyl chloride. In embodiments, reacting a compound of formula D5-7 with a carboxylic acid activation agent is performed in a solvent, e.g. DCM, THF, 2-MeTHF. In embodiments, the solvent is dichloromethane .EXAMPLESExample 1: Preparation of intermediate DI,Step 1: Preparation of 3-(hydroxyimino)-2,2,4,4-tetramethylcyclobutan-l-one (Dl-2)

[0052] To a suspension of 2,2,4,4-tetramethylcyclobutane-l,3-dione (DI- 1, 79.4 kg, 1.0 equiv) in THF (382 kg) was added NaOAc (48.9 kg, 1.05 equiv). The resulting mixture was stirred at 15-25 °C for 0.5 h. A solution of NH2OH HCI (41 kg, 1.05 equiv) in water (249 kg) was added, and the resulting mixture was stirred at 15-25 °C for 16 h. The reaction mixture was then concentrated under reduced pressure to 238-318 L, followed by addition of water (162 kg) and DCM (788 L). The resulting suspension was filtered and the filter cake washed with DCM (206 kg). The layers of the filtrate were separated, and the organic layer was collected. The aqueous phase was extracted with DCM (401 L). The combined organic phases were washed with 25 wt% NaCl solution (165.9 kg). The organic layer was then concentrated under reduced pressure to 238-397 L, and the resulting mixture diluted with DCM (146 kg) followed by addition of n-hcptanc (334 kg). The mixture was concentrated under reduced pressure to 238-318 L, then n-hcptanc (336 kg) was added. The resulting mixture was further concentrated under reduced pressure to 238-318 L, then n -heptane (130 kg) was added.Finally, the mixture was cooled to 5 °C and stirred for 10 h. The slurry was filtered, and thefilter cake was washed with 77-hcptanc (108 kg). The wet cake was dried at 40 °C for 8 h to afford 71.6 kg of 3-(hydroxyimino)-2,2,4,4-tetramethylcyclobutan-l-one (Dl-2) in 76.9% corrected yield.

[0053] JH NMR (400 MHz, CD30D): 5 1.42 (s, 6H), 1.30 (s, 6H);13C NMR (101 MHz, CD3OD): 5 218.4, 164.8, 65.4, 62.6, 21.9, 20.1; HRMS (ESI): exact mass calculated for C8HI3NO2(M+H)+, 156.1019; found 156.1017; Melting Point: 143-145 °C.Step 2: Preparation of 3-hydroxy-2,2,4,4-tetramethylcyclobutan-l-one oxime (Dl-3)

[0054] 3-(Hydroxyimino)-2,2,4,4-tetramethylcyclobutan-l-one (Dl-2, 71.45 kg) and z-PrOH (332 kg) were charged into a reactor. After the solution was stirred at 0-15 °C for 1 h, NaBH4 (17.6 kg, 1.05 equiv) was added in portions. The reaction mixture was stirred at 15-25 °C for 10 h. The reaction mixture was then slowly quenched with 5 wt% NaOH solution (605 kg) 10- 25 °C. The resulting mixture was stirred at 20-30 °C for 3 h. The resulting mixture was then extracted with 2-MeTHF (521 L), and the organic layer was collected. The aqueous layer was extracted with 2-MeTHF (2 x 664 E). The combined organic layers were washed with 25% NaCl solution twice (182 kg and 178 kg) and dried with Na2SO4 (119.3 kg). After filtration, the filtrate was concentrated under reduced pressure to 71-142 E and diluted with 2-MeTHF (134 kg) followed by n -heptane (280 kg). The resulting mixture was concentrated under reduced pressure to 141-213 L and 77-hcptanc (284 kg) was added. The mixture was cooled to 5 °C and aged for 4 h. The precipitated solid was collected by filtration. The filter cake was dried at 40 °C for 24 h to give 61.4 kg of 3-hydroxy-2,2,4,4-tetramethylcyclobutan-l-one oxime (Dl-3) in 85% yield.

[0055] ’ H NMR (400 MHz, CD3OD): 5 3.63 (s, 1H), 1.35 (s, 3H), 1.26 (s, 3H), 1.20 (s, 3H), 1.15 (s, 3H);13C NMR (101 MHz, CD3OD): 5 170.8, 80.1, 49.9, 46.9, 26.6, 25.5, 20.8, 18.6; HRMS (ESI): exact mass calculated for CsHisNCE (M+H)+, 158.1176; found 158.1172; Melting Point: 154 °C.Steps 3 & 4: Preparation of (lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutan-l-ol (Dl-4) and (lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutan-l-ol phosphate (Dl-5)

[0056] A reactor was charged with 3-hydroxy-2,2,4,4-tetramethylcyclobutan-l-one oxime (Dl-3, 60.1 kg, 1.0 eq.), THF (761 kg), and aluminum / nickel alloy (138 kg, 4.2 eq.). After the mixture was adjusted to 40-60 °C, 16.7 wt% NaOH solution (428 kg) was charged at 40-60 °C over 5 h. After aging at 40-60 °C for 17 h, the mixture was filtered and the filter cake rinsed with EtOH (586 kg). The combined filtrate was concentrated to 60-120 L under reduced pressure. Then, water (63 kg) and 2-MeTHF (1031 kg) were charged 20-30 °C. The mixture was stirred for 1 h, and the layers were separated. The organic layer was concentrated to 60- 120 L under reduced pressure. EtOH (900 kg) was added, and the mixture was concentrated to 540-660 L. The resulting solution was diluted with water (18 kg) and the temperature wasadjusted to 65-75 °C. A solution of phosphoric acid (53 kg, 1.3 equiv) in EtOH (82 kg) was then slowly added at 65-75 °C over 9 h. Following complete addition, the mixture was aged at 65-75 °C for 3 h, then cooled to 10-20 °C over 3 h and aged for another 7 h at 10-20 °C. The precipitated solid was collected by filtration and the filter cake was washed with EtOH (48 kg). The wet cake was dried at 40-50 °C for 30 h to give (lr,3r)-3-amino-2,2,4,4- tetramethylcyclobutan-l-ol phosphate (Dl-5, 32.4 kg) in 34% yield over 2 steps.

[0057] ‘ H NMR (400 MHz, D2O): 5 3.66 (s, 1H), 3.10 (s, 1H), 1.11 (s, 6H), 1.08 (s, 6H);13C NMR (101 MHz, D2O): 5 78.9, 59.3, 38.0, 22.1, 22.0; HRMS (ESI): exact mass calculated for C8HI7NO (M+H)+, 144.1383; found 144.1379; Melting Point: 249 °C.Step 5: Preparation of tert-butyl ((lr,3r)-3-hydroxy-2,2,4,4- tetramethylcyclobutyl)carbamate (Dl-6)

[0058] (lr,3r)-3-Amino-2,2,4,4-tetramethylcyclobutan-l-ol phosphate (Dl-5, 32.4 kg), 2- MeTHF (212 kg), and water (141 kg) were charged to a reactor. The resulting solution was stirred at 5-15 °C, and K2CO2(54 kg) and Boc2O (31 kg) were added. The mixture was stirred at 15-25 °C for 16 h. Water (187 kg) and EtOAc (223 kg) were added, and the mixture was stirred for 2.5 h. The layers were separated, and the aqueous phase was extracted with EtOAc (210 kg). The combined organic layers were washed with water (94 kg), and concentrated under reduced pressure to 32-64 L. n- Heptane (132 kg) was then added, and the mixture concentrated under reduced pressure to 64-96 L, followed by the addition of / / -heptane (132 kg). The mixture was concentrated under reduced pressure to 64-96 L, and 77-hcptanc (131 kg) was added. The resulting suspension was adjusted to 75 °C to afford a clear solution. The mixture was then cooled to 45 °C and aged for 2 h. The resulting suspension was cooled to 25 °C and aged for 3 h before being further cooled to 5 °C and aged for 6 h. The product was collected by filtration and the filter cake was washed with / / -heptane (39 kg). The wet cake was dried at 35 °C for 20 h to give 29.7 kg of tert-butyl (( lr,3r)-3-hy droxy-2, 2,4,4- tetramethylcyclobutyl)carbamate in 92.2% yield.

[0059] ’ H NMR (400 MHz, CD3OD): 5 6.21-6.24 (m, 1H), 3.36-3.47 (m, 2H), 1.44 (s, 9H), 1.09 (s, 6H), 0.99 (s, 6H);13C NMR (101 MHz, CD3OD): 5 158.6, 80.9, 80.1, 41.4, 28.9, 24.1; HRMS (ESI): exact mass calculated for C H^NCh (M+H)+, 244.1907; found 244.1909; Melting Point: 95-97 °C.Step 6: Preparation of tert-butyl ((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)carbamate (Dl-7)

[0060] tert-Butyl ((lr,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutyl)carbamate (Dl-6, 28.6 kg), NMP (308 kg), and 2-chloro-4-fluorobenzonitrile (20.0 kg, 1.1 equiv.) were charged to a reactor, and the temperature was adjusted to -5 to 5 °C. tert-BuONa (13.4 kg, 1.1 equiv) was added over 2 h, and the mixture was stirred at -5 to 5 °C for 13 h. The mixture was thenadjusted to 0-10 °C followed by the addition of water (432 kg) below 25 °C. The mixture was aged at 20-30 °C for 2 h, and the precipitated solid was collected by filtration. Together with n-PrOH (105 kg), the wet cake was charged back into the reactor. To obtain a clear solution, the mixture was heated to 50-60 °C and aged for 1 h. Water (95 kg) was then added over 1 h. The resulting suspension was cooled to 10-20 °C and aged at 15 °C for 5 h. The solids were isolated by filtration, and the filter cake was dried at 40-50 °C for 22 h to give 36.1 kg of tertbutyl ((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)carbamate (DI -7) in 80% yield.

[0061] JH NMR (400 MHz, DMSO-76): 8 7.68 (d, 7=8.0, 1H), 7.06 (s, 1H), 6.93 (d, 7=8.0, 1H), 4.14 (s, 1H), 3.65-3.67 (m, 1H), 1.45 (s, 9H), 1.18 (s, 6H), 1.12 (s, 6H);13C NMR (101 MHz, DMSO-76): 8 164.5, 158.5, 139.0, 136.8, 118.1. 117.2, 115.8, 105.8, 86.0, 80.4, 61.2, 49.2, 41.8, 28.9, 24.5, 23.8; HRMS (ESI): exact mass calculated for C20H27CIN2O3 (M+H)+, 379.1783; found 379.1781; Melting Point: 103-104 °C.Step 7: Preparation of 4-((lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2- chlorobenzonitrile, hydrochloric aid salt (DI, HC1 salt)

[0062] tert-Butyl ((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)carbamate (35.4 kg, 1.0 equiv) and n-PrOH (115 kg) were charged into a reactor, and the suspension was heated to 45-55 °C and stirred until a clear solution was obtained. The solution was then cooled to 40 °C, and a solution of HC1 in n-PrOH (19.8 wt%; 59 kg, 3 equiv) was slowly added. The mixture was aged at 35-45 °C for 16 h. n-Hcptanc (370 kg) was added over 0.5-2 h, and the resulting suspension was cooled to 10-20 °C and aged for 8 h. The solids were collected by filtration, and the wet cake was dried at 45 °C for 20 h to give 28.2 kg of 4-((lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride in 95.4% yield.

[0063] ’ H NMR (400 MHz, CD3OD): 8 7.72 (d, J=8.0, 1H), 7.13 (d, 7=4.0, 1H), 6.68 (dd, J=8.0, 4.0, 1H), 4.37 (s, 1H), 3.24 (s, 1H), 1.38 (s, 6H), 1.20 (s, 6H);13C NMR (101 MHz, CD3OD): 8 163.9, 139.1, 137.0 118.3, 117.1, 115.7, 106.4, 85.0, 61.2, 49.2, 40.0, 23.9, 23.1; HRMS (ESI): exact mass calculated for C15H19CIN2O (M+H)+, 279.1259; found 279.1259; Melting Point: 239-241 °C (decomposition).Example 2: Preparation of intermediate DID1-1 D1-2 D1-3,Steps 1 & 2: Preparation of 3-(hydroxyimino)-2,2,4,4-tetramethylcyclobutan-l-one (Dl-2) and 3-hydroxy-2,2,4,4-tetramethylcyclobutan-l-one oxime (Dl-3)

[0064] Dl-2 and Dl-3 are prepared as disclosed in Example 1, or by other methods known in the art.Steps 3 & 4: Preparation of trans-3-amino-2,2,4,4-tetramethylcyclobutan-l-ol (Dl-4) and (lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutan-l-ol phosphate salt (Dl-5)

[0065] Reaction. A reactor was charged with Dl-3 (140 g, 891 mmol, 1.00 equiv), z-PrOAc (2800 mL, 20.0 mL / g), Raney-Ni (14.0 g, 10.0 wt%, 20.0 g of 70.0 wt% aq. slurry) and the mixture stirred at 20 °C. After purging of the reactor atmosphere with hydrogen for three times, the hydrogen pressure was adjusted to 200-250 psi and the reaction performed at 40 °C for 16 h. After completion of the reaction (>99.9% conversion by GC), the temperature was reduced to 20-25 °C and the reactor atmosphere was purged with nitrogen for three times. The reaction suspension was then filtered with celite (70.0 g, 50.0 wt%) and the filter was washed with z-PrOAc (70.0 mL, 0.50 mL / g). Afterwards, the solvent was swapped at 15-25 °C internal temperature (Tjacket = 45 °C) to EtOH (3 x 840 mL, 6.00 mL / g) via put-take distillation under reduced pressure (residual z-PrOAc = 0.93 wt%, target: NMT 2.00 wt%). Compound Dl-4 was obtained as a solution in EtOH (862 g, 463 mmol, 7.70 wt%, 52.0%).

[0066] Isolation. To the solution of Dl-4 in EtOH (862 g, 463 mmol, 7.70 wt%) was added EtOH (298 mL, 4.50 mL / ga) and water (33.0 mL, 0.50 mL / g) and the temperature was adjusted to 70-75 °C. A solution of concentrated phosphoric acid (149 g, 1292 mmol, 2.79 equiv, 85.0 wt%) in EtOH (199 mL, 3.00 mL / g) was then added to the solution of Dl-4 over 4 h at 70- 75 °C (the first quarter was added over 2 h, the second over 1 h and the second half over 1 h). The reaction suspension was stirred for 3 h at 70-75 °C, then cooled down to 10-20 °C over 3 h, and stirred for another 8 h. After filtration, the cake was washed with EtOH (2 x 199 mL, 3.00 mL / g) and then dried at 40 °C for 16 h in vacuo. The desired Dl-5 (95.8 g, 380 mmol, 95.7 wt%, 98.2 A% GC, 98.2:1.8 trans:cis, 42.7% over two steps) was afforded as a colorless crystalline solid.aAll solvent volumes refer to actual amount of G03548963 in wt%.

[0067] Recrystallization. The isolated Dl-5 (93.0 g, 369 mmol, 1.00 equiv) was dissolved in zz-PrOH (186 mL, 2.00 mL / g), water (116 mL, 1.25 mL / g) and phosphoric acid (22.2 g, 193 mmol, 0.52 equiv, 85.0 wt%) were added and the mixture reacted at 70-75 °C for 30 min. Then, another portion of zz-PrOH (1674 mL, 18.0 mL / g) was added over 3 h. The mixture was cooled to -5-5 °C over 5 h, filtered, and the filter cake rinsed twice with zz-PrOH (279 mL,3.00 mL / g). After drying at 40 °C for 18 h, Dl-5 (85.0 g, 346 mmol, 38.8% over three steps) was obtained as a colorless crystalline solid.

[0068] GC: 99.4 A% (99.9:0.1 trans:cis) 98.0 wt%. ^-NMR (400 MHz, D2O) 5 3.62 (bs, 1H), 3.06 (bs, 1H), 1.07 (s, 6H), 1.04 (s, 6H).13C-NMR (101 MHz, D2O) 5 79.0, 59.4, 38.0, 22.2, 22.1.Step 5: Preparation of 4-((lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2- chlorobenzonitrile, hydrogen chloride salt (DI, HC1 salt)

[0069] A reactor was charged with Dl-5 (70.0 g, 285 mmol, 98.0 wt%, 1.00 equiv), and MeTHF (350 mL, 5.00 mL / g). A solution of KOt-Bu (136 g, 1212 mmol, 4.25 equiv) in MeTHF (350 mL, 5.00 mL / g) was then added at 15 °C over 30 min, and the mixture stirred for 3 h at 25 °C. Then, a solution of 2-chloro-4-fluorobenzonitrile (48.7 g, 313 mmol, 1.10 equiv) in MeTHF (140 mL, 2.00 mL / g) was then added over 30 min and the mixture was stirred for 18 h. After completion of the reaction, the reactor content was cooled to 5 °C and water (700 mL, 10.0 mL / g) was added over 1 h. After phase separation, the organic phase was washed twice with water (350 mL, 5.00 mL / g). Subsequently, the volume was reduced to -350 mL, 5.00 mL / g and the solvent swapped to / / -PrOH (700 mL, 10.0 mL / g) through constant volume distillation at 25 °C internal temperature (Tjacket = 40 °C) under reduced pressure and addition of / / -PrOH (1400 mL, 20.0 mL / g). A solution of hydrochloric acid (151 mL, 3.70 M in n- PrOH, 1.96 equiv) was charged over 1 h at 60 °C and then DI HC1 salt seeds (700 mg, 1.00 wt%) were added. After 77-hcptanc (700 mL, 10.0 mL / g) addition over 1 h, the mixture was cooled to 15 °C over 2 h. After filtration, the cake was washed twice with / / -heptane (140 mL, 2.00 mL / g) and dried at 40 °C for 18 h to afford DI HC1 salt (76.0 g, 237 mmol, 83.2%) as a colorless crystalline solid.

[0070] HPLC: 99.7 A%; 98.2 wt%. Mp (DSC): 239-241 °C (decomposition). ^-NMR (400 MHz, CD3OD) 5 7.74 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 1.5 Hz, 1H), 6.96 (d, J= 8.8, 1.5 Hz, 1H), 4.35 (bs, 1H), 3.24 (s, 1H), 1.35 (s, 6H), 1.19 (s, 6H).13C-NMR (101 MHz, CD3OD) 5 162.4, 137.6, 135.5, 116.7, 115.6, 114.2, 105.0, 83.4, 59.7, 38.5, 22.3, 21.4.Example 3: Preparation of intermediate D2Step 4: Preparation of sodium 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate (D2)

[0071] A solution of Pd(OAc)2 (0.35 kg, 1.6 mol, 0.04 equiv) and RuPhos (1.80 kg, 3.85 mol, 0.1 equiv) in 1,4-dioxane (190.0 kg) was aged at 25 °C for 30 min. Then, methyl 4- bromobenzoate (8.30 kg, 38.6 mol), 4-(dimethoxymethyl)piperidine (7.14 kg, 44.8 mol, 1.16 equiv), and K3PO4 (42.0 kg, 198 mol, 5.1 equiv) were successively added to the mixture. The mixture was degassed under vacuum and rendered inert with N2. Then, the reaction was heated to 91-96 °C and aged for 15 h. After cooling to 25 °C, the mixture was filtered, and the filter cake was washed with 1,4-dioxane (12.0 kg) to provide a solution of methyl 4-(4- (dimethoxymethyl)piperidin-l-yl)benzoate. To the solution of the intermediate was added a solution of NaOH (3.0 kg, 75 mol, 1.9 equiv) in water (130 kg) at 25 °C. The resulting mixture was heated to 65-70 °C and aged for 2 h. Then, the mixture was concentrated under reduced pressure at 60 °C until 1,4-dioxane was removed. Water (130 kg) was added, and the mixture was aged for 30 min. Following filtration, the filtrate was washed with tert-butyl methyl ether (2 x 56.2 kg), and the resulting aqueous phase was treated with acetic acid (2.74 kg) to adjust the pH to 8. The mixture was then slowly cooled to 7 °C to crystallize the product. After aging at 7 °C for 12 h, the solids were collected by filtration, and the filter cake was washed with 1,4- dioxane (25.0 kg). The wet cake was dried under reduced pressure to provide 3.8 kg of sodium 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate in 47% yield.

[0072] 1H NMR (400 MHz, CDCI3): 5 7.74 (d, J = 8.9, 2H), 6.99 (d, J = 9.0, 2H), 4.11 (d, J = 6.9, 1H), 3.63 (d, J= 12.5, 2H), 3.30 (s, 6H), 2.60 (t, J= 11.5, 2H), 1.68 (d, J= 11.8, 3H), 1.29 (dd, J= 12.5, 2.5, 2H);13C NMR (101 MHz, CDCI3): 5 175.2, 153.4, 130.5, 127.9, 116.5, 108.1, 54.2, 49.1, 37.9, 25.9; HRMS (ESI): exact mass calculated for CI5H22NO4+(M+H)+, 280.1543; found 280.1545; Melting Point: 220 °C (decomposition).Example 4: Preparation of intermediate D2Step 1: Preparation of methyl 4-(4-(hydroxymethyl)piperidin-l-yl)benzoate (D2-6)

[0073] To an azeotropically dried solution of piperidin-4-ylmethanol (D2-5, 48.8 kg, 423.7 mol, 1.6 equiv) in toluene (50-55 L total volume) was added DMSO (294 kg). Methyl 4- fluorobenzoate (41 kg, 266 mol) was added, and the mixture was heated to 95-105 °C and aged for 18 h. After cooling the mixture to 20-30 °C, solid Na2COa (28 kg, 264 mol, 1 equiv) was added followed by the addition of water (1125 kg). The mixture was stirred at 20-30 °C for 30 min before being cooled to 10-20 °C. The crude product was filtered, and the cake washed with water (100 kg, displacement wash), slurry-washed with water (495 kg) for 45 min at 20- 30 °C, and again with water (100 kg, displacement wash). The wet cake and MeOH (97 kg) were charged into a reactor and heated to 45-50 °C. Water (330 kg) was slowly added over 1 h, followed by cooling of the mixture to 0-10 °C. The solids were collected by filtration, and the filter cake washed with MeOH / water (1:3 v / v; 60 kg). The wet cake was dried at 55-60 °C for 54 h to afford 48.5 kg of methyl 4-(4-(hydroxymethyl)piperidin-l-yl)benzoate (D2-6) in 72% corrected yield.

[0074] JH NMR (400 MHz, DMSO-ri6): 8 7.76 (d, J = 9.1, 2H), 6.95 (d, J = 9.1, 2H), 4.49 (t, J= 5.3, 1H), 3.92 (d, J= 12.9, 2H), 3.77 (s, 3H), 3.27 (t, J= 5.8, 2H), 2.81 (td, J= 12.7, 2.4, 2H), 1.73 (d, J= 12.7, 2H), 1.61 (qd, J= 11.4, 5.2, 1H), 1.17 (qd, J= 12.5, 4.0, 2H);13C NMR (101 MHz, DMSO-ri6): 8 166.6, 154.3, 131.3, 117.7, 113.7, 66.1, 51.8, 47.4, 38.7, 28.4; HRMS (ESI): exact mass calculated for Ci4H2oN03+(M+H)+, 250.1438; found 250.1440; Melting Point: 115 °C.Step 2: Preparation of methyl 4-(4-formylpiperidin-l-yl)benzoate (D2-7)

[0075] A mixture of DCM (272 kg) and methyl 4-(4-(hydroxymethyl)piperidin-l-yl)benzoate (D2-6, 23.2 kg, 93.1 mol) was cooled to 5-15 °C, and DMSO (40.6 kg, 519.6 mol, 5.6 equiv) was added followed by slow addition of EhN (49.6 kg, 490.2 mol, 5.3 equiv). A mixture of SOa-pyridine (44.1 kg, 277.1 mol, 3.0 equiv) in DMSO (51 kg) and DCM (66 kg) was slowly added at 5-15 °C over 1 h. The mixture was then cooled to 0-10 °C and quenched with sat. aq. NH4CI solution (113 kg NH4CI in 382 kg water). The layers were separated, and the aqueous phase was extracted with DCM (223 kg). The combined organic layers were washed with water (230 kg), then with 3 wt% aqueous Na2CO3 (2 x 230 kg), and with 12 wt% aqueous NaCl (2 x 230 kg). The organic phase was combined with a second batch, and the mixture was concentrated under reduced pressure to 120 L. n- Heptane (261 kg) was added at 30-40 °C over1 h followed by a concentration of the mixture under reduced pressure to 312 L. Additional n- heptane (325 kg) was added, and the mixture was stirred for 40 min before being cooled to 10- 15 °C. The solids were collected by filtration, and the filter cake was washed with n-hcptanc (32 kg). The wet cake was dried under reduced pressure at 35-45 °C for 30 h to provide 41.4 kg of methyl 4-(4-formylpiperidin-l-yl)benzoate (D2-7) in 85% corrected yield.

[0076] JH NMR (400 MHz, DMSO-d6): 8 9.62 (s, 1H), 7.81-7.72 (m, 2H), 7.03-6.91 (m, 2H), 3.87-3.73 (m, 5H), 3.10-2.96 (m, 2H), 2.65-2.53 (m, 1H), 1.98-1.85 (m, 2H), 1.63-1.46 (m, 2H);13C NMR (101 MHz, DMSO-tfe): 8 204.7, 166.6, 154.0, 131.3, 118.1, 113.9, 51.8, 47.3, 46.6, 24.6; HRMS (ESI): exact mass calculated for CuHisNOa* (M+H)+, 248.1281; found 248.1283; Melting Point: 112 °C.

[0077] 1H NMRStep 3: Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate (D2-4)

[0078] A mixture of MeOH (323 kg), methyl 4-(4-formylpiperidin-l-yl)benzoate (D2-7, 41.2 kg, 166.6 mol), and TSOH H2O (3.2 kg, 16.8 mol, 0.1 equiv) was heated to 60-65 °C over 2 h and aged for another 3 h. Then, the mixture was cooled to 0-10 °C over 2 h, and water (75 kg) followed by Na COa (8.5 kg) were added. The pH was adjusted to 9-10 with aq. Na COa (10 wt%), and water (410 kg) was added. The resulting slurry was aged at 10-15 °C for 1 h. The solids were collected by filtration, and the filter cake was washed with MeOH (32 kg). The wet cake was slurry- washed with MeOH (162 kg) at 25-35 °C for 1 h, then cooled to 0-5 °C over 3 h, and filtered after being aged for 1 h. The cake was washed with MeOH (32 kg) and then dried at 45-50 °C for 15 h to afford 44.1 kg of methyl 4-(4-(dimethoxymethyl)piperidin-l- yl)benzoate (D2-4) in corrected yield.

[0079] 1H NMR (400 MHz, CDCh): 8 7.98-7.83 (m, 2H), 6.87 (d, J = 8.9, 2H), 4.07 (d, J =6.8, 1H), 3.97-3.77 (m, 5H), 3.38 (s, 6H), 2.82 (td, J = 12.7, 2.2, 2H), 1.92-1.79 (m, 3H), 1.51-1.35 (m, 2H);13C NMR (101 MHz, CDCh): 8 167.1, 154.2, 131.2, 119.0, 113.7, 107.7,53.8, 51.5, 47.7, 38.5, 26.8; HRMS (ESI): exact mass calculated for CI6H24NO4+(M+H)+, 294.1700; found 294.1701; Melting Point: 127 °C.Step 4: Preparation of sodium 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate (D2)

[0080] To a mixture of MeOH (136 kg) and methyl 4- (4- (dimethoxy methyl)piperidin-l- yl)benzoate (D2-4, 42.7 kg, 144.7 mol) was added a solution of NaOH (11.7 kg, 292.5 mol, 2.0 equiv) in water (344 kg) at 20-35 °C. The mixture was heated to 55-65 °C and aged for 4 h. Then, the mixture was cooled to 25-30 °C followed by a polish filtration and a distillation under reduced pressure to 171-214 L. Water (172 kg) was added, and distillation under reduced pressure was continued until a volume of 171-214 L. Water (152 kg) was added, and the suspension was cooled to 15-25 °C over 1 h. The pH of the mixture was adjusted to 8.0- 8.1 with a solution of acetic acid (8.7 kg) and water (21 kg). The resulting mixture was heatedto 45-55 °C to obtain a clear solution. The mixture was then slowly cooled to 2-4 °C to crystallize the product. The solids were filtered, and the filter cake washed with water (86 kg). The wet cake was dried at 55-60 °C to provide 37.7 kg of sodium 4-(4- (dimethoxymethyl)piperidin-l-yl)benzoate (D2) in 86% corrected yield.

[0081] *H NMR (400 MHz, CDC13): 8 7.74 (d, J = 8.9, 2H), 6.99 (d, J = 9.0, 2H), 4.11 (d, J = 6.9, 1H), 3.63 (d, J= 12.5, 2H), 3.30 (s, 6H), 2.60 (t, J= 11.5, 2H), 1.68 (d, J= 11.8, 3H), 1.29 (dd, J= 12.5, 2.5, 2H);13C NMR (101 MHz, CDCh): 8 175.2, 153.4, 130.5, 127.9, 116.5, 108.1, 54.2, 49.1, 37.9, 25.9; HRMS (ESI): exact mass calculated for CI5H22NO4+(M+H)+, 280.1543; found 280.1545; Melting Point: 220 °C (decomposition).Example 5: Preparation of intermediate D5Step 3: Preparation of tert-butyl 4-(l-oxo-l,2-dihydrophthalazin-6-yl)piperazine-l- carboxylate (D5-4)

[0082] XPhos (212 g, 0.44 mol, 0.025 equiv) and Pd2(dba)3(81.3 g, 0.089 mol, 0.005 equiv) were added to a solution of 6-bromophthalazin-l(277)-one (4.0 kg, 17.8 mol) and tert-butyl piperazine- 1 -carboxylate (4.3 kg, 23.1 mol, 1.3 equiv) in 2-methyl-2-butanol (80 L) at 25 °C. NaOt-Bu (3.42 kg, 35.6 mol, 2.0 equiv) was added to the inert mixture, and the reaction was heated to reflux and aged for 16 h at reflux conditions under N2. Then, the reaction was cooled to 60 °C, and most of the solvent was removed by distillation under reduced pressure. The residue was slurry-washed with a mixture of EtOH (20 L) and water (80 L) at 25 °C for 4 h. The solids were collected by filtration and the filter cake was washed with water (4.0 L). The resulting wet cake was slurry-washed with water (50 L) at 25 °C for 2 h. The wet cake was washed with water (4.0 L) and dried under reduced pressure at 45 °C for 24 h to provide 4.0 kg of tert-butyl 4-(l -oxo- l,2-dihydrophthalazin-6-yl)piperazine-l -carboxylate in 68% yield.Step 4: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l-carboxylate (D5-5)

[0083] NaH (650 g, 16.4 mol, 3.0 equiv) was added in 6 portions to a solution of tert-butyl 4- (l-oxo-l,2-dihydrophthalazin-6-yl)piperazine-l-carboxylate (1.8 kg, 5.5 mol) in DMSO (20 L) and THF (30 L) at 0-5 °C. KI (0.90 kg, 5.5 mol, 1.0 equiv) was added into the mixture at 0-5 °C. Then, a solution of 3-bromopiperidine-2, 6-dione (1.25 kg, 6.51 mol, 1.2 equiv) in anhydrous THF (9.0 L) was added at 0-10 °C. The resulting mixture was aged at 0-10 °C for 16 h. A 5% aqueous solution of NH4CI was added to quench the reaction, and the mixture was diluted with EtOAc (20 L). The phases were separated, and the aqueous layer was extracted with EtOAc (20 L). The combined organic layers were washed with 20% aqueous NaCl (2 x 9.0 L) and then treated with activated carbon (0.90 kg) followed by filtration. The filtrate was concentrated under reduced pressure to 7-8 L when EtOH (7.2 L) was added. The mixture was again concentrated under reduced pressure to 7-8 L. EtOH (7.2 L) and water (7.2 L) were added, and the mixture was heated to 65-75 °C until a clear solution was obtained. Then, the solution was gradually cooled to 10 °C. The resulting solids were collected by filtration, and the filter cake washed with EtOH / water 2:1 (v / v) (10 L). The wet cake was dried under reduced pressure at 50 °C for 24 h to reveal 2.0 kg of tert-butyl 4-(l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l -carboxylate in 75% yield.Step 5: Preparation of tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l-carboxylate (D5-6)

[0084] tert-Butyl 4-(l -oxo- l,2-dihydrophthalazin-6-yl)piperazine-l -carboxylate (7.2 kg, 16.3 mol) was separated into its enantiomers by means of a chiral separation by preparative HPLC. Portions of 500 g of starting material were dissolved in a mixture of MeOH / DCM 1:1 (v / v) (10 L) and separated by HPLC (ChiralPak IC, 250x100 mm I.D., 10 pm; Mobile Phase: MeOH / DCM 1:1 (v / v); Flow Rate: 480 mL / min; Column Temperature: 25 °C). The combined product fractions were concentrated in vacuo at 42 °C to provide the crude product. The crude product (3.18 kg) was charged to EtOH (12 L), and the resulting mixture was aged at 20-30 °C for 6 h. Water (6 L) was added, and the mixture was aged at 20-30 °C for 16 h. The solids were collected by filtration, and the filter cake was washed with water (1.5 L). The wet cake was dried under reduced pressure at 35 °C for 24 h to afford 2.64 kg of tert-butyl 4-(2-(2,6- dioxopiperidin-3-yl)-l -oxo- l,2-dihydrophthalazin-6-yl)piperazine-l -carboxylate in 37% yield. Step 6: Preparation of (S)-3-(l-oxo-6-(piperazin-l-yl)phthalazin-2(lH)-yl)piperidine-2,6- dione, tetrafluoroboric acid salt (D5, HBF4 salt)

[0085] A 40 wt% solution of HBF4 in water (4.4 L, 28.1 mol, 1.7 equiv) was added to a mixture of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin-6- yl)piperazine- 1 -carboxylate (1.14 kg, 16.3 mol) in EtOH (6.84 L) and z-PrOH (2.25 L) at 20-30 °C. The reaction mixture was aged at 25 °C for 24 h. The resulting solids were isolated by filtration, and the filter cake was slurry-washed with a mixture of z-PrOH (6.3 L) and EtOH (2.25 L) for 30 min. The slurry wash was repeated with a mixture of z-PrOH (6.3 L) and EtOH (2.25 L). Following filtration, the wet cake was dried under reduced pressure at 45 °C for 48 h to provide 1.05 kg of (5')-3-(l-oxo-6-(piperazin-l-yl)phthalazin-2(177)-yl)piperidine-2, 6-dione tetrafluoroborate in 95% yield.

[0086] ’ H NMR (500 MHz, DMSO-d6): 8 11.02 (s, 1H), 8.75 (s, 2H), 8.27 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.56 (dd, J = 9.0, 2.5 Hz, 1H), 7.35 (d, J = 2.6 Hz, 1H), 5.77 (dd, J = 12.2, 5.4 Hz, 1H), 3.63 (dd, J = 6.7, 3.8 Hz, 4H), 3.28 (dd, J= 6.3, 4.0 Hz, 4H), 2.92 (ddd, J = 16.9, 13.5, 5.4 Hz, 1H), 2.66-2.52 (m, 2H), 2.15-2.06 (m, 1H);13C NMR (126 MHz, DMSO-zfe): 8 172.3, 169.8, 157.7, 152.5, 137.7, 130.5, 126.9, 119.4, 117.6, 108.5, 56.9, 43.5, 41.8, 39.5, 39.4, 39.3, 39.2, 39.2, 39.1, 39.0, 38.9, 38.8, 38.7, 38.6, 38.4, 30.0, 22.1; HRMS (ESI): exact mass calculated for C17H20N5O3 (M+H)+, 342.1561; found 342.1550; Melting Point: 170 °C.Example 6: Preparation of intermediate D5,Steps 1-3: Preparation of 2-bromo-N,N-diethyl-4-fhiorobenzamide (D5-8), N,N-diethyl-4- fluoro-2-formylbenzamide (D5-9), and 6-fluorophthalazin-l(2H)-one (D5-10)

[0087] To a mixture of 2-bromo-4-fluorobenzoic acid (D5-7, 85.0 kg, 388.1 mol) in DCM (563 kg) was added oxalyl chloride (73.9 kg) at 20-30 °C. The mixture was heated to 30-40 °C, aged for 30 hours, and then concentrated to 85-170 L. DCM (338 kg) was added, and the mixture was concentrated to 85-170 L. Again, DCM (561 kg) was added, and the mixture was cooled to 0 °C. Diethylamine (70.8 kg) was slowly added at 0 °C, and the mixture was aged for 1 h. 10 wt% aqueous citric acid (425 kg) was added, and the biphasic mixture allowed to warm to 25 °C. The layers were separated, and the organic layer washed with 10% aqueous NaCl(425 kg). The organic layer was concentrated under reduced pressure to 255-340 L, and THF (378 kg) was added. The mixture was concentrated again under reduced pressure to 255-340 L, and THF (378 kg) was charged. The mixture was concentrated under reduced pressure to 255-340 L, and THF (378 kg) was added prior to a last concentration under reduced pressure to 255-340 L. (90%) The solution of the intermediate (90 kg by assay) in THF was diluted with THF (558 kg), and the solution was cooled to -78 °C. n-BuLi (134 kg) was added at -78 °C over 1 h, and the mixture was aged for 30 min. Then, DMF (47.7 kg) was added over 1 h, and the mixture was aged at -78 °C for another hour. The reaction was warmed to 0 °C and quenched by the addition of 10% aqueous citric acid (900 kg). n-Heptane (307 kg) was added, and the biphasic mixture was warmed to 25 °C. The layers were separated, and the organic phase was concentrated under reduced pressure to a volume of 360-450 L. EtOH (375 kg) was added, and the mixture was again concentrated to 360-450 L. This process was repeated twice, then AcOH (19.8 kg) was added. Hydrazine hydrate (30.6 kg) was charged, and the mixture was heated to 75 °C and aged for 16 h. Then, the mixture was cooled to 20 °C, aged for 2 h, and the solids were collected by filtration. The wet cake was dried under reduced pressure to provide 30.1 kg of 6-fluorophthalazin-l(27 )-one (D5-10) in 52.2% yield over 3 steps.

[0088] 1H NMR (300 MHz, DMSO-d6): 8 12.74 (s, 1H), 8.34 (d, J = 0.7, 1H), 8.29 (dd, J = 8.8, 5.5, 1H), 7.78 (dd, J = 9.1, 2.6, 1H), 7.70 (td, J = 8.9, 2.6, 1H);13C NMR (75 MHz, DMSO-tfe): 8 166.8, 163.5, 159.5, 137.9, 137.9, 132.7, 132.6, 129.8, 129.6, 125.0, 125.0, 120.9, 120.6, 112.5, 112.2; HRMS (ESI): exact mass calculated for C8H6FN2O (M+H)+, 165.0459; found 165.0460; Melting Point: 236 °C.Step 4: Preparation of tert-butyl 4-(l-oxo-l,2-dihydrophthalazin-6-yl)piperazine-l- carboxylate (D5-4)

[0089] A mixture of NMP (154 kg), 6-fluorophthalazin-l(27 )-one (D5-10, 30 kg), tert-butyl piperazine- 1 -carboxylate (51 kg), and DIPEA (47.2 kg) was heated to 120 °C and aged for 72 h. The reaction was cooled to 60 °C, and water (300 kg) was added. The mixture was cooled to 25 °C and aged for 2 h. The resulting solids were collected by filtration, and the filter cake was washed with water (30 kg). The cake was further slurry- washed with EtOH (237 kg) at 25 °C for 2 h and then filtered. The cake was washed with EtOH (23.7 kg), and the wet cake dried under reduced pressure to provide 41.3 kg of tert-butyl 4-(l-oxo-l,2-dihydrophthalazin-6- yl)piperazine- 1 -carboxylate (D5-4) in 68% yield.

[0090] ’ H NMR (300 MHz, DMSO-d6): 8 12.28 (s, 1H), 8.14 (s, 1H), 8.01 (d, J = 8.9, 1H), 7.44 (dd, J= 9.0, 2.5, 1H), 7.21 (d, J= 2.5, 1H), 3.49 (q, J= 3.5, 4H), 3.40 (dd, J= 6.7, 3.6, 4H), 1.43 (s, 9H);13C NMR (75 MHz, DMSO-d6): 8 159.9, 154.4, 154.1, 138.6, 132.3, 127.3, 119.7, 118.8, 108.7, 79.6, 47.0, 28.5; HRMS (ESI): exact mass calculated for C17H23N4O3 (M+H)+, 331.1765; found 331.1769; Melting Point: 243 °C.Step 5: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l-carboxylate (D5-5)

[0091] To a suspension of tert-butyl 4-(l-oxo-l,2-dihydrophthalazin-6-yl)piperazine-l- carboxylate (D5-4, 42.2 kg, 127.8 mol) in THF (350 L) and DMSO (71.8 L) was added t- BuOLi (25.6 kg, 320.1 mol) slowly at -5 to 5 °C. The solution was aged for 1 h, then 3- bromopiperidine-2, 6-dione (29.5 kg, 153.6 mol) was slowly added to the mixture at -5 to 5 °C. The mixture was stirred at -5 to 5 °C for 3 h. 2-MeTHF (211 L) was then charged. In the meantime, 5 wt% aqueous citric acid solution (422 L) and 2-MeTHF (844 L) were charged to a different reactor and the temperature set to -5 to 0 °C. The reaction mixture was then slowly charged to the citric acid mixture at -5 to 5 °C, and the temperature was adjusted to 15-25 °C. The layers were separated, and the organic layer was washed with 20 wt% NaCl solution (168.8 L) twice. The organic layer was concentrated under reduced pressure to 232-274 L. EtOH (253 L) was added to the residue, and the mixture was concentrated to 232-274 L. Then, EtOH (84.4 L) and H2O (168.8 L) were added to the suspension. The mixture was heated to 65-75 °C and stirred until a clear solution was obtained. The mixture was then cooled to 0-10 °C and stirred for 5 h. The resulting solids were collected by filtration, and the filter cake was washed with EtOH / water 2:1 (84.4 L). The wet cake was dried at 40-50 °C for 12 h to provide 47.9 kg of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin-6- yl)piperazine- 1 -carboxylate (D5-5) in 87.1% yield.

[0092] 1H NMR (300 MHz, DMSO-<6): 5 11.02 (s, 1H), 8.24 (s, 1H), 8.06 (d, J = 9.0, 1H), 7.48 (dd, J= 9.0, 2.5, 1H), 7.24 (d, J= 2.4 Hz, 1H), 5.77 (dd, J= 12.2, 5.3, 1H), 3.60-3.25 (m, 9H), 3.05-2.84 (m, 1H), 2.62 (dt, J= 19.0, 4.5, 1H), 2.21-2.03 (m, 1H), 1.44 (s, 9H);13C NMR (75 MHz, CDCh): 5 171.8, 169.3, 159.3, 154.6, 154.2, 138.9, 131.6, 128.6, 119.8, 118.7, 108.4, 80.4, 57.5, 47.4, 30.9, 28.4, 23.2; HRMS (ESI): exact mass calculated for C22H28N5O5 (M+H)+, 442.2085; found 442.2089; Melting Point: 199 °C.Step 6: Preparation of tert-butyl (S)-4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l-carboxylate (D5-6)

[0093] Racemic tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin-6- yl)piperazine- 1 -carboxylate (D5-5, 45 kg) was dissolved in THF / DCM 4:1 (v / v) (920 L) to obtain a concentration of approximately 49 mg / mL, and the solution was filtered. The feed solution was then purified by preparative HPLC (Chiralpak IB, 150x100 mm I.D., 10 pm; Mobile Phase: THF; Flow Rate: 300 mL / min; Column Temperature: 25 °C) to provide a solution of tert-butyl (5')-4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin-6- yl)piperazine- 1 -carboxylate in THF in fractions of ~40 L / kg. The fractions were then concentrated to 1-2 L / kg under reduced pressure and below 45 °C. n-Hcptanc (2-4 L / kg) was added to the residue and the resulting slurry aged at 20-30 °C for 2-10 h. The solids wereisolated by filtration, and the filter cake was washed with n-hcptanc (0.5 L / kg). The wet cake was dried at 40-50 °C under reduced pressure for 48 h to afford, after combination of the solid fractions, 20.45 kg of tert-butyl (5')-4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l -carboxylate (D5-6) in 45% yield.

[0094] JH NMR (400 MHz, CD3OD): 5 8.08 (s, 1H), 8.02 (dd, J= 8.0, 4.0, 1H), 7.36 (dd, J = 8.0, 4.0, 1H), 7.04 (d, J= 4.0, 1H), 5.70 (dd, J= 12.0, 8.0, 1H), 3.36-3.51 (m, 4H), 3.34-3.35 (m, 4H), 2.69-2.77 (m, 1H), 2.62-2.69 (m, 1H), 2.14-2.15 (m, 1H), 1.39 (s, 9H);13C NMR (101 MHz, CD3OD): 5 173.4, 170.6, 159.9, 155.0, 154.5, 139.4, 131.8, 127.4, 119.6, 117.7, 108.2, 80.2, 58.1, 30.4, 27.3, 22.8; HRMS (ESI): exact mass calculated for C22H27N5O5 (M+H)+, 442.2085; found 442.2083; Melting Point: 214 °C.Step 7: Preparation of (S)-3-(l-oxo-6-(piperazin-l-yl)phthalazin-2(lH)-yl)piperidine-2,6- dione, methanesulfonate (D5, MsOH salt)

[0095] A solution of tert-butyl (5')-4-(2-(2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazine-l -carboxylate (D5-6, 27.3 kg, 61.8 mol) and THF (486 kg) was filtered over CUNO activated carbon, then the temperature was adjusted to 15-25 °C. Methanesulfonic acid (59.5 kg, 619.1 mol, 10 equiv) was added at 15-25 °C, and the mixture was heated to 35-45 °C and aged for 30 h. The resulting suspension was cooled to 15-25 °C, and the solids were collected by filtration. The filter cake was washed with THF (273 E), and the wet cake was dried under reduced pressure at 45 °C for 24 h to afford 23.2 kg of (5)-3-( 1- oxo-6-(piperazin-l-yl)phthalazin-2(177)-yl)piperidine-2, 6-dione methanesulfonate (D5, MsOH salt) in 86.0% yield.

[0096] 1H NMR (400 MHz, D2O): 5 8.03 (s, 1H), 7.90 (d, J = 12.0, 1H), 7.30 (dd, J = 12.0, 4.0, 1H), 6.88 (d, J= 4.0, 1H), 5.70-5.75 (m, 1H), 3.39-3.60 (m, 4H), 3.36-3.39 (m, 4H), 2.83-2.89 (m, 2H), 2.83 (s, 3H), 2.58-2.82 (m, 1H), 2.27-2.56 (m, 1H);13C NMR (101 MHz, D2O): 5 175.7, 172.1, 160.2, 153.3, 141.0, 131.1, 127.5, 120.6, 117.9, 109.4, 67.8, 58.6, 44.1, 42.9, 38.5, 30.3, 25.0, 22.5; HRMS (ESI): exact mass calculated for C17H19N5O3 (M+H)+, 342.1561; found 342.1559; Melting Point: 321 °C.Example 7: Preparation of Compound 1Compound 1Step 1: Preparation of N-(trans-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcy clobutyl) -4- (4- (dimethoxymethyl)piperidin- 1 -yl)benzamide (D3)

[0097] To a solution of sodium 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate (925 g, 3.07 mol, 1.05 equiv) in anhydrous DMF (7.36 L) were added EDCI (730 g, 3.80 mol, 1.3 equiv) and HOBt (515 g, 3.80 mol, 1.3 equiv) successively. DIPEA (1.13 kg, 8.75 mol, 3.0 equiv) was then slowly added to the reaction mixture at 15-30 °C. After aging the mixture at 25 °C for 45 min, 4-((lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-chlorobenzonitrile hydrochloride (920 g, 2.92 mol) was added followed by a rinse with DMF (1.84 L). The resulting reaction mixture was aged at 20-30 °C for 12 h. Water (6.44 L) was added, and the mixture was aged for 2 h. The solids were collected by filtration, and the filter cake was slurry- washed with water (9.20 L) and then washed with additional water (4.60 L) in a displacement wash. The wet cake was dried under reduced pressure at 40-50 °C for 14 h to provide 1.61 kg of the crude product. The crude product (1.61 kg) was added to DCM (16.0 L), and the mixture was aged at 25 °C for 10 min when n-hcptanc (16.0 L) was added slowly. Following complete addition, the mixture was aged at 25 °C for 1 h. The solids were collected by filtration. The wet cake was dried under reduced pressure at 45 °C for 8 h to afford 1.29 kg of A-((lr,3r)-3-(3- chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(dimethoxymethyl)piperidin-l- yl)benzamide in 82% yield.

[0098] JH NMR (500 MHz, THF-ds): 5 7.69 (d, J = 4.9 Hz, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.8, 2.5 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.2 Hz, 1H), 4.21 (d, J = 0.9 Hz, 1H), 4.13 (dd, J= 8.2, 0.9 Hz, 1H), 4.03 (d, J= 6.6 Hz, 1H), 3.90-3.81 (m, 2H), 3.29 (s, 6H), 2.72 (td, J= 12.5, 2.4 Hz, 2H), 2.46 (s, 1H), 1.85-1.75 (m, 3H), 1.43-1.35 (m, 2H), 1.27 (s, 6H), 1.19 (s, 6H);13C NMR (126 MHz, DMSO) 5 166.2, 162.0, 152.2, 136.3, 135.5, 128.3, 122.5, 116.2, 115.7, 114.1, 113.0, 106.5, 102.9, 83.3, 57.4, 52.9, 46.7, 39.7, 37.3, 25.6, 23.4, 22.5; HRMS (ESI): exact mass calculated for C30H39CIN3O4 (M+H)+, 540.2624; found 540.2624; Melting Point: 202 °C.Step 2: Preparation of N-(trans-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcyclobutyl)-4-(4-formylpiperidin-l-yl)benzamide (D4)

[0099] To a mixture of A-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-(dimethoxymethyl)piperidin-l-yl)benzamide (1.29 kg, 2.38 mol) in DCM (7.73 L) and water (1.93 L) was slowly added TFA (1.93 L, 2.87 mol, 1.2 equiv) at 20-27 °C. After aging at 25 °C for 16 h, the mixture was treated with a 14.3 wt% aqueous solution of NaOH until pH 3-4 was obtained. Then, the pH was further adjusted to 7-8 by the addition of 30 wt% aqueous K3PO4 solution. After diluting with DCM (34.2 kg) and MeOH (2.58 L), the layers were separated. The aqueous layer was diluted with water (9.0 L) and extracted with DCM (4.54 L). The combined organic phases were washed with a solution of NaCl (0.71 kg) in water (4.5 L), then dried over anhydrous Na2SO4 (0.42 kg), filtered, and concentrated under reduced pressure to provide 1.15 kg of the crude product. A mixture of the crude product (1.15 kg) and DCM (23.0 kg) was heated to 30-40 °C until a clear solution was obtained. Then, n-hc tanc (15.8 kg) was slowly added. Following complete addition, the mixture was slowly cooled to 18-22 °C. The solids were collected by filtration, and the filter cake was dried under reduced pressure at 45 °C for 8 h to give 1.02 kg of A-((lr,3r)-3-(3- chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-formylpiperidin-l-yl)benzamide in 87% yield.

[0100] ’ H NMR (500 MHz, DMSO-d6): 8 9.63 (s, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.50 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.03-6.94 (m, 3H), 4.32 (s, 1H), 4.05 (d, J= 9.1 Hz, 1H), 3.79-3.72 (m, 2H), 2.97 (ddd, J= 13.2, 11.0, 2.9 Hz, 2H), 2.62-2.53 (m, 1H), 1.96-1.87 (m, 2H), 1.62-1.50 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H);13C NMR (126 MHz, DMSO) 8 203.9, 166.2, 162.0, 151.9, 136.3, 135.5, 128.4, 122.8, 116.2, 115.7, 114.1, 113.2, 102.9, 83.3, 57.4, 46.2, 23.5, 23.4, 22.5; HRMS (ESI): exact mass calculated for C28H33CIN3O3 (M+H)+, 494.2205; found 494.2196; Melting Point: 231 °C.Step 3: Preparation of N-(trans-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcyclobutyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazin-l-yl)methyl)piperidin-l-yl)benzamide (Compound 1)

[0101] NaOAc (0.51 kg, 6.21 mol, 3.0 equiv) was added to a solution of (5)-3-(l-oxo-6- (piperazin-l-yl)phthalazin-2(17 )-yl)piperidine-2, 6-dione tetrafluoroborate (0.93 kg, 2.17 mol, 1.05 equiv) and A-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4- formylpiperidin-l-yl)benzamide (1.02 kg, 2.07 mol) in DCM (40.7 kg) and MeOH (10.2 L) at 25 °C. The resulting slurry was aged at 20-25 °C for 30 min. Then, NaBH(OAc)3 (0.61 kg, 2.89 mol, 1.4 equiv) was slowly added at 15-20 °C, and the reaction mixture was aged at 20- 25 °C for 20 min. Water (2.84 L) was added as a quench, and the mixture was aged for 20 min. The pH of the mixture was adjusted to 7-8 by the addition of saturated aqueous NaHCO ,. Thephases were then separated, and the organic layer was diluted with DCM (3.94 L). The mixture was washed with a solution of NaCl (0.35 kg) in water (3.93 L). The combined aqueous layers were extracted with DCM (3.94 L). The combined organic layers were then dried over Na2SO4 (1.19 kg), filtered, and the filtrate concentrated under reduced pressure to provide 1.80 kg of the crude product. The crude product (1.80 kg) was charged to DMF (13.6 kg), and the mixture was aged at 40 °C until a clear solution was obtained. Water (3.60 L) was added slowly, then the mixture was gradually cooled to 18-22 °C. The resulting solids were collected by filtration, and the filter cake was slurry- washed with water (18.0 L) for 30 min. The cake was washed with additional water (9.0 L) and then dried under reduced pressure at 45 °C for 14 h to obtain 1.53 kg of the purified product. To this material were then added EtOH (7.67 L) and THF (7.67 L), and the resulting mixture was heated to 80 °C and aged for 30 min. The temperature was gradually reduced to 18-22 °C, and the formed solids were isolated by filtration. The wet cake was dried under reduced pressure at 45 °C for 8 h to afford 1.44 kg of further purified product. This material was then dissolved in DCM (10.1 L) and MeOH (1.44 L), aged for 30 min, and concentrated in vacuo to afford the amorphous purified product, which was further dried under reduced pressure at 45 °C for 8 h. The obtained material was further refined by jet milling until the desired particle size was obtained. The resulting material was dried under reduced pressure at 41 °C for 16 h to afford 1.23 kg of purified and micronized W((lr,3r)-3-(3-chloro-4- cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-((4-(2-((5')-2,6-dioxopiperidin-3-yl)-l- oxo-l,2-dihydrophthalazin-6-yl)piperazin-l-yl)methyl)piperidin-l-yl)benzamide in 73% yield.

[0102] JH NMR (500 MHz, CDCh): 5 8.27 (s, 1 H), 8.23 (d, J = 9.0 Hz, 1 H), 8.03 (d, J = 0.7 Hz, 1 H), 7.71-7.66 (m, 2 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.30 (dd, J = 9.1, 2.5 Hz, 1 H), 6.96 (d, J= 2.4 Hz, 1 H), 6.94-6.90 (m, 2 H), 6.89 (d, J = 2.5 Hz, 1 H), 6.80 (dd, J = 8.7, 2.4 Hz, 1 H), 6.13 (d, 7 = 8.1 Hz, 1 H), 5.82 (dd, 7= 11.3, 5.4 Hz, 1 H), 4.14 (dd, 7= 8.1, 0.8 Hz, 1 H), 4.04 (d, 7 = 0.9 Hz, 1 H), 3.85 (dt, 7= 12.8, 3.3 Hz, 2H), 3.47-3.37 (m, 4 H), 2.94-2.68 (m, 5 H), 2.60 (t, 7 = 5.0 Hz, 4 H), 2.35-2.20 (m, 3 H), 1.90 (d, 7 = 12.4 Hz, 2 H), 1.83-1.69 (m, 2 H), 1.40-1.28 (m, 2 H), 1.25 (s, 6 H), 1.21 (s, 6 H);13C NMR (126 MHz, CDCh): 5 171.6, 169.2,167.3, 162.8, 159.5, 154.6, 153.8, 139.1, 138.4, 135.2, 131.7, 128.5, 128.4, 123.4, 119.6,118.4, 116.9, 116.5, 114.6, 114.3, 108.1, 105.1, 85.0, 64.5, 58.5, 57.5, 53.3, 48.5, 47.5, 40.4,33.4, 31.0, 30.4, 23.7, 23.6, 23.4; HRMS (ESI): exact mass calculated for C45H52CIN8O5 (M+H)+, 819.3744; found 819.3747; Melting Point: 291 °C.Example 8: Preparation of Compound 1Compound 1Step 1: Preparation of N-((lr, 3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcy clobutyl) -4- (4- (dimethoxymethyl)piperidin- 1 -yl)benzamide (D3)

[0103] To a mixture of 4-((lr,3r)-3-amino-2,2,4,4-tetramethylcyclobutoxy)-2- chlorobenzonitrile hydrochloride (DI, 22.7 kg), sodium 4-(4-(dimethoxymethyl)piperidin-l- yl)benzoate (D2, 23.8 kg, 1.05 equiv), HOPO (10.5 kg, 1.3 equiv), and DMF (216 kg) was added EDCI (19.0 kg, 1.3 equiv) at 20-30 °C. The resulting mixture was aged at 20-30 °C for 20 h. Water (159 kg) was added, and the mixture was aged at 20-30 °C for 3 h. The precipitated solids were collected by filtration, and the filter cake was washed with water (228 kg). The wet cake was dried at 30 °C for 24 h and at 60 °C for 28 h under reduced pressure to give 36.7 kg of crude W((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)- 4-(4-(dimethoxymethyl)piperidin-l-yl)benzamide (D3) in 88.2% corrected yield.

[0104] The crude product (36.7 kg) was added to a mixture of water (5.7 kg, 1 wt%) and THF (588 kg), and the mixture was heated to 60-70 °C and aged at that temperature for 2 h until a clear solution was obtained. n-Hcptanc (194 kg) was added over 1.5 h at 60-70 °C. The resulting mixture was aged at 60-70 °C for 1 h and then cooled to 15-25 °C over 4 h. Following aging at 15-25 °C for 12 h, the solids were collected by filtration, and the filter cake was washed with a mixture of THF (80 kg) and n-hcptanc (62 kg). The wet cake was dried at 35 °C for 13 h and at 50 °C for 24 h under reduced pressure to afford 31.1 kg 7V-((lr,3r)-3-(3- chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-(dimethoxymethyl)piperidin-l- yl)benzamide (D3) in 88.4% corrected yield.

[0105] JH NMR (500 MHz, THF-ds): 5 7.69 (d, J = 4.9 Hz, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.8, 2.5 Hz, 1H), 6.90 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 8.2 Hz, 1H), 4.21 (d, J = 0.9 Hz, 1H), 4.13 (dd, J= 8.2, 0.9 Hz, 1H), 4.03 (d, J= 6.6 Hz, 1H), 3.90-3.81 (m, 2H), 3.29 (s, 6H), 2.72 (td, J= 12.5, 2.4 Hz, 2H), 2.46 (s, 1H), 1.85-1.75 (m, 3H), 1.43-1.35 (m, 2H), 1.27 (s, 6H), 1.19 (s, 6H);13C NMR (126 MHz, DMSO) 5 166.2, 162.0, 152.2, 136.3, 135.5, 128.3, 122.5, 116.2, 115.7, 114.1, 113.0, 106.5, 102.9, 83.3, 57.4, 52.9, 46.7, 39.7, 37.3, 25.6, 23.4, 22.5; HRMS (ESI): exact mass calculated for C30H39CIN3O4 (M+H)+, 540.2624; found 540.2624; Melting Point: 202 °C.Step 2: Preparation of N-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-formylpiperidin-l-yl)benzamide (D4)

[0106] To a mixture of N-((lr, 3r)-3-(3-chloro-4-cyanophenoxy)-2, 2,4,4- tetramethylcyclobutyl)-4-(4-(dimethoxymethyl)piperidin-l-yl)benzamide (D3, 30 kg) and MeCN (120 kg) was added 2 M aqueous H2SO4 (145 kg) at 15-25 °C over 1 h. The resulting mixture was aged at 15-25 h for 20 h. 5% aqueous NaHCCE solution (351 kg) was slowly added at 20-30 °C to adjust the pH to 2.1. The resulting mixture was aged at 20-30 h for 5 h. The solids were collected by filtration, and the filter cake was washed twice with water (2 x 146 kg). The wet cake was dried at 30 °C for 5.5 h and at 50 °C for 24 h to provide 26.7 kg of A-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-formylpiperidin- l-yl)benzamide (D4) in 98.4% corrected yield.

[0107] A mixture of the crude product (26.6 kg) and DCM (892 kg) was heated to 30-40 °C and aged for 2 h until a clear solution was obtained. The mixture was then concentrated to 505-559 L under reduced pressure and below 40 °C. The mixture was aged for 1 h at 30-40 °C and 77-hcptanc (215 kg) was added. The resulting mixture was concentrated to 479-585 L under reduced pressure and below 40 °C. The mixture was cooled to 15-25 °C over 2 h and then aged for 16 h. The solids were collected by filtration, and the filter cake was washed with a mixture of DCM (212 kg) and n-hcptanc (110 kg). The wet cake was dried at 50 °C for 48 h to give 24.2 kg of A-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4- (4-formylpiperidin-l-yl)benzamide (D4) in 92% corrected yield.

[0108] ’ H NMR (500 MHz, DMSO-d6): 8 9.63 (s, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.77-7.71 (m, 2H), 7.50 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.03-6.94 (m, 3H), 4.32 (s, 1H), 4.05 (d, J= 9.1 Hz, 1H), 3.79-3.72 (m, 2H), 2.97 (ddd, J= 13.2, 11.0, 2.9 Hz, 2H), 2.62-2.53 (m, 1H), 1.96-1.87 (m, 2H), 1.62-1.50 (m, 2H), 1.22 (s, 6H), 1.13 (s, 6H);13C NMR (126 MHz, DMSO) 8 203.9, 166.2, 162.0, 151.9, 136.3, 135.5, 128.4, 122.8, 116.2, 115.7, 114.1, 113.2, 102.9, 83.3, 57.4, 46.2, 23.5, 23.4, 22.5; HRMS (ESI): exact mass calculated for C28H33CIN3O3 (M+H)+, 494.2205; found 494.2196; Melting Point: 231 °C.Step 3: Preparation of N-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-((4-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxo-l,2- dihydrophthalazin-6-yl)piperazin-l-yl)methyl)piperidin-l-yl)benzamide (Compound 1)

[0109] To a mixture of DCM and MeOH 3:1 (v / v) (302 kg) was added A-((lr,3r)-3-(3- chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)-4-(4-formylpiperidin-l-yl)benzamide (D4, 22.6 kg), (5')-3-(l-oxo-6-(piperazin-l-yl)phthalazin-2(177)-yl)piperidine-2, 6-dione methanesulfonate (D5 MsOH salt, 21.3 kg, 1.05 equiv), and NaOAc (11.3 kg, 3.0 equiv) at 0- 10 °C. After aging for 1 h, NaBH(OAc)3 (14.2 kg, 1.4 equiv) was added in portions at 0-10 °C. The mixture was aged at 0-10 °C for another 1.5 h. Additional DCM / MeOH 3:1 (v / v) (218 kg) as well as water (115 kg) were added, and the temperature was set to 20-30 °C. The mixture was aged for 1 h followed by the addition of 5 wt% aqueous NaHCOa (220 kg) to adjust the pH to 5.8. After aging of 0.5 h, the layers were separated at 20-30 °C. The organic layer was further processed by diluting with DCM (548 kg). The product solution was then polish filtered, and the temperature was adjusted to 20-30 °C. The mixture was concentrated to 203- 249 L under reduced pressure and below 30 °C. To the resulting solution was added a slurry of product seeds (0.4 kg) in EtOAc (4 kg) at 20-30 °C. The resulting mixture was aged at 20-30 °C for 1.5 h followed by the slow addition of EtOAc (428 kg) over 1 h. Following aging at 20- 30 °C for 14 h, the solids were collected by filtration, and the filter cake washed with a mixture of DCM (102 kg) and EtOAc (94 kg). The wet cake was dried at 60 °C for 30 h under reduced pressure to give 34.3 kg of A-((lr,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4- tetramethylcyclobutyl)-4-(4-((4-(2-((5')-2,6-dioxopiperidin-3-yl)-l-oxo-l,2-dihydrophthalazin- 6-yl)piperazin-l-yl)methyl)piperidin-l-yl)benzamide (Compound 1) in 91% corrected yield.

[0110] 1H NMR (500 MHz, CDCE): 5 8.27 (s, 1 H), 8.23 (d, J = 9.0 Hz, 1 H), 8.03 (d, J = 0.7 Hz, 1 H), 7.71-7.66 (m, 2 H), 7.55 (d, J = 8.7 Hz, 1 H), 7.30 (dd, J = 9.1, 2.5 Hz, 1 H), 6.96 (d, J= 2.4 Hz, 1 H), 6.94-6.90 (m, 2 H), 6.89 (d, J = 2.5 Hz, 1 H), 6.80 (dd, J = 8.7, 2.4 Hz, 1 H), 6.13 (d, 7 = 8.1 Hz, 1 H), 5.82 (dd, 7= 11.3, 5.4 Hz, 1 H), 4.14 (dd, 7= 8.1, 0.8 Hz, 1 H), 4.04 (d, 7 = 0.9 Hz, 1 H), 3.85 (dt, 7= 12.8, 3.3 Hz, 2H), 3.47-3.37 (m, 4 H), 2.94-2.68 (m, 5 H), 2.60 (t, 7 = 5.0 Hz, 4 H), 2.35-2.20 (m, 3 H), 1.90 (d, 7 = 12.4 Hz, 2 H), 1.83-1.69 (m, 2 H), 1.40-1.28 (m, 2 H), 1.25 (s, 6 H), 1.21 (s, 6 H);13C NMR (126 MHz, CDCh): 5 171.6, 169.2,167.3, 162.8, 159.5, 154.6, 153.8, 139.1, 138.4, 135.2, 131.7, 128.5, 128.4, 123.4, 119.6,118.4, 116.9, 116.5, 114.6, 114.3, 108.1, 105.1, 85.0, 64.5, 58.5, 57.5, 53.3, 48.5, 47.5, 40.4,33.4, 31.0, 30.4, 23.7, 23.6, 23.4; HRMS (ESI): exact mass calculated for C45H52CIN8O5 (M+H)+, 819.3744; found 819.3747; Melting Point: 291 °C.Example 9: Alternative Preparation of methyl 4-(4-(dimethoxymethyl)piperidin-l- yl)benzoate (D2-4)

[0111] A mixture of MeOH (1659 kg), methyl 4-(4-formylpiperidin-l-yl)benzoate (210 kg, 849 mol), and TsOH-thO (16.2 kg, 84.9 mol, 0.1 equiv) was heated to 60-65 °C over 1 h and aged for another 4 h. Then, the mixture was cooled to 0-10 °C over 2 h, and water (294 kg) followed by Na COs (31.5 kg) were added. The pH was adjusted to 9-10 with aq. Na COs (10 wt%), and water (2100 kg) was added. The resulting slurry was aged at 10-15 °C for 1 h. The solids were collected by filtration, and the filter cake was washed with MeOH (170 kg). The wet cake was slurry-washed with MeOH (830 kg) at 30-40 °C for 2 h, then cooled to 0-5 °C over 3 h, and filtered after being aged for 1 h. The cake was washed with MeOH (170 kg) and then dried at 45-50 °C for 24 h to afford 223.4 kg of methyl 4-(4-(dimethoxymethyl)piperidin- l-yl)benzoate in 90% corrected yield.

[0112] To further purify the material, methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate (223.4 kg) was charged to THF (719 kg), and the slurry was heated to 50-60 °C until the solids were dissolved. After aging at 50-60 °C for 30 min, the mixture was cooled to 15-25 °C over 2 h. / / -Heptane (1222 kg) was added over 1 h, and the mixture aged for 30 min. Then it was cooled to 0-5 °C over 1 h and aged for another hour. The solids were collected by filtration, and the filter cake was washed with cold THF / n-heptane (1:2 v / v; 224 L) followed by a wash with n-hcptanc (155 kg). The wet cake was dried at 45-50 °C for 24 h to afford 206.2 kg of purified methyl 4-(4-(dimethoxymethyl)piperidin-l-yl)benzoate in 93% yield.

[0113] 1H NMR (400 MHz, CDC13): 5 7.98-7.83 (m, 2H), 6.87 (d, J = 8.9 Hz, 2H), 4.07 (d, J = 6.8 Hz, 1H), 3.97-3.77 (m, 5H), 3.38 (s, 6H), 2.82 (td, J= 12.7, 2.2 Hz, 2H), 1.92-1.79 (m, 3H), 1.51-1.35 (m, 2H);13C NMR (101 MHz, CDCI3): 5 167.1, 154.2, 131.2, 119.0, 113.7, 107.7, 53.8, 51.5, 47.7, 38.5, 26.8; HRMS (ESI): exact mass calculated for CI6H24NO4+(M+H)+, 294.1700; found 294.1701; Melting Point: 127 °C.Example 10: Alternative Preparation of 6-fluorophthalazin- l(2H)-one (D5-10)

[0114] To a mixture of 2-bromo-4-fluorobenzoic acid (1.0 kg, 4.6 mol) in THF (3.3 L), cooled to -5 to 0 °C, was slowly added isopropylmagnesium chloride (2 M in THF; 5.7 L, 11.5 mol, 2.5 equiv) at -5 to 0 °C. The mixture was aged for 16 h at 0 °C, and then DMF (0.67 kg, 9.2 mol, 2.0 equiv) was added at -5 to 0 °C. The mixture was aged at 0 °C for 16 h. Upon complete conversion, AcOH (1.4 kg, 23 mol, 5 equiv) was added followed by the slow addition of water (4 kg). The phases were separated, and the aqueous layer was extracted with THF (4 L). The combined organic layers were distilled under vacuum and 30-40 °C to a volume of 2.0-2.5 L to afford a THF solution of the intermediate aldehyde.

[0115] A reactor was charged with EtOH (9.0 kg), AcOH (225 g, 3.7 mol) and hydrazine hydrate (375 g, 7.5 mol) and the temperature was set to 15-20 °C. Then, the THF solution of the intermediate aldehyde was slowly added at 15-20 °C and the reaction was aged for 1 h. Upon complete conversion, water (2 kg) was slowly added, and the resulting mixture was aged for 1 h. The mixture was then cooled to 0-5 °C and aged for another hour. The solids were collected by filtration and the filter cake was washed with EtOH (2 kg). The wet cake was dried under reduced pressure to provide 575 g of 6-fluorophthalazin- 1 (2 / 7)-onc in 77% yield over 2 steps.

[0116] 1H NMR (300 MHz, DMSO-d6): 5 12.74 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 8.29 (dd, J = 8.9, 5.5 Hz, 1H), 7.78 (dd, J = 8.9, 2.6 Hz, 1H), 7.70 (td, J = 8.9, 2.6 Hz, 1H);13C NMR (75 MHz, DMSO-d6): 5 166.8, 163.5, 159.5, 137.9, 137.9, 132.7, 132.6, 129.8, 129.6, 125.0, 125.0, 120.9, 120.6, 112.5, 112.2; HRMS (ESI): exact mass calculated for C8H6FN2O (M+H)+, 165.0459; found 165.0460; Melting Point: 236 °C.

Claims

CLAIMS1. A method of preparing a compound of formula I:wherein the method comprises reacting a compound of formula D4with a compound of formula D5:in the presence of a reducing agent to form the compound of formula I, wherein X is an acid.

2. A method of preparing a compound of formula I:wherein the method comprises reacting a compound of formula DI:or salt thereof with a compound of formula D2:in the presence of an amide coupling reagent to form the compound of formula D3:converting the compound of formula D3 to the compound of formula I.

3. The method of claim 2, wherein the compound of formula DI or salt thereof is:

4. The method of claim 2 or 3, wherein the amide coupling reagent is a carbodiimide.

5. The method of claim 4, wherein the carbodiimide is l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC).

6. The method of any one of claims 2-5, wherein reacting the compound of formula DI with the compound of formula D2 in the presence of the amide coupling reagent further comprises a peptide synthesis additive.

7. The method of claim 6, wherein the additive is hydroxybenzotriazole (HOBt).

8. The method of claim 6, wherein the additive is 2-hydroxypyridine-N-oxide (HOPO).

9. The method of any one of claims 2-8, further comprising reacting the compound of formula D3 with an acid to form a compound of formula D4:

10. The method of claim 9, wherein the acid is trifluoroacetic acid.

11. The method of claim 9, wherein the acid is sulfuric acid.

12. The method of any one of claims 9-11, further comprising reacting the compound of formula D4 with a compound of formula D5:wherein X is an acid, in the presence of a reducing agent to form the compound of formula I.

13. The method of claim 39 or 12, 12wherein X is tetrafluoroboric acid and the compound of formula D5 is:

14. The method of claim 39 or 12, wherein X is methanesulfonic acid and the compound of formula D5 is:

15. The method of any one of claims 39 or 12-14, wherein the reducing agent is sodium triacetoxyborohydride.

16. The method of any one of claims 39 or 12-14, wherein reacting the compound of formula D4 with the compound of formula D5 in the presence of a reducing agent further comprises the presence of a base.

17. The method of claim 16, wherein the base is sodium acetate.

18. A method of preparing a compound of formula DIor a salt thereof, comprising:( 1 ) reacting a compound of formula D 1 - 3 :with a reducing agent, to form a compound of formula DI -4:(2) reacting the compound of formula DI -4 with an acid to form a compound of formulaDl-5:(Dl-5), wherein Y is the acid, and(3) converting the compound of formula Dl-5 to the compound of formula DI.

19. The method of claim 18, wherein the acid is phosphoric acid.

20. The method of claim 18 or 19, wherein the reducing agent is nickel aluminum alloy.

21. The method of claim 18 or 19, wherein the reducing agent is hydrogen in the presence of Raney nickel.

22. The method of any one of claims 18-21, wherein the method further comprises reacting the compound of formula DI -5 with 2-chloro-4-fluorobenzonitrile in the presence of a base to form the compound of formula DI, or a salt thereof.

23. The method of claim 22, wherein the base is potassium tert-butoxide.

24. The method of any one of claims 18-21, wherein converting the compound of formula DI -5 to the compound of formula DI comprises reacting the compound of formula DI -5 with di-tert-butyl dicarbonate in the presence of a base to form a compound of formula Dl-6:

25. The method of claim 24, wherein the base is potassium carbonate.

26. The method of claim 24 or 25, wherein the method further comprises reacting the compound of formula DI -6 with 2-chloro-4-fluorobenzonitrile in the presence of a base to form a compound of formula Dl-7:

27. The method of claim 26, wherein the base is sodium hydride.

28. The method of claim 26, wherein the base is sodium tert-butoxide.

29. The method of any one of claims 26-28, wherein the method further comprises deprotecting the compound of formula Dl-7 in the presence of an acid to form the compound of formula DI or salt thereof.

30. The method of any one of claims 18-29, wherein the method further comprises treating the compound of formula DI with an acid to form the salt of formula DI.

31. The method of any one of claims 18-30, wherein the acid is hydrdochloric acid and the compound of formula DI or salt thereof is32. A method of preparing a compound of formula D2:comprising reacting the compound of formula D2-4with a base to form the compound of D2.

33. The method of claim 32, wherein the base is sodium hydroxide.

34. The method of claim 32 or 33, wherein the method further comprises reacting a compound of formula D2-3with methyl 4-bromobenzoate in the presence of a catalyst to form the compound of D2-4.

35. The method of claim 34, wherein the catalyst is a palladium catalyst.

36. The method of claim 35, wherein the catalyst is provided as palladium acetate and RuPhos.

37. The method of any one of claims 34-36, wherein the method further comprises reacting a compound of formula D2-2with hydrogen in the presence of a catalyst to form the compound of formula D2-3.

38. The method of claim 37, wherein the catalyst is palladium on carbon.

39. The method of claim 37 or 38, wherein the method further comprises reacting a compound of formula D2- 1with trimethyl orthoformate in the presence of a catalyst to form the compound of formula D2- 2.

40. The method of claim 39, wherein the catalyst is p-toluenesulfonic acid.

41. The method of claim 32, wherein the method further comprises reacting a compound of formula D2-7with methanol in the presence of an acid to form the compound of formula D2-4.

42. The method of claim 41, wherein the acid is p-toluenesulfonic acid.

43. The method of claim 41 or 42, wherein the method further comprises reacting a compound of formula D2-6with an oxidant to form the compound of formula D2-7.

44. The method of claim 43, wherein the oxidant is DMSO activated by oxalyl chloride.

45. The method of claim 43, wherein the oxidant is DMSO activated by sulfur trioxide pyridine complex.

46. The method of any one of claims 43-45, wherein the method further comprises reacting a compound of formula D2-5with methyl 4-fluorobenzoate in the presence of a base to form the compound of formula D2-6.

47. The method of claim 44, wherein the base is sodium carbonate.

48. A method of preparing a compound of formula D5 :wherein X is an acid, comprising reacting a compound of formula D5-6with the acid to form the compound of formula D5.

49. The method of claim 48, wherein the acid is tetrafluoroboric acid.

50. The method of claim 48, wherein the acid is methanesulfonic acid.

51. The method of any one of claims 48-50, wherein the method further comprises chiral purification of a compound of formula D5-5to obtain the compound of formula D5-6.

52. The method of claim 51, wherein the method further comprises reacting a compound of formula D5-4with 3-bromopiperidine-2, 6-dione in the presence of a base to form the compound of formula D5-5.

53. The method of claim 52, wherein the base is sodium hydride.

54. The method of claim 52, wherein the base is lithium tert-butoxide.

55. The method of any one of claims 52-54, wherein the method further comprises reacting a compound of formula D5-3(D5 3)with tert-butyl piperazine- 1 -carboxylate in the presence of a catalyst and a base to form the compound of formula D5-4.

56. The method of claim 55, wherein the catalyst is a palladium catalyst.

57. The method of claim 56, wherein the catalyst is provided as Pd2(dba)3 and XPhos.

58. The method of any one of claims 55-57, wherein the base is sodium tert-butoxide.

59. The method of any one of claims 55-58, wherein the method further comprises reacting a compound of formula D5-2with hydrazine to form the compound of D5-3.

60. The method of claim 59, wherein the method further comprises reacting a compound of formula D5-1with a bromination reagent and a radical initiator to form the compound of formula D5-2.

61. The method of claim 60, wherein the bromination reagent is N-bromosuccinimde.

62. The method of claim 60 or 61, wherein the radical initiator is azobisisobutyronitrile.

63. The method of any one of claims 52-54, wherein the method further comprises reacting a compound of formula D5-10with tert-butyl piperazine- 1 -carboxylate in the presence of a base to form the compound of formula D5-4.

64. The method of claim 63, wherein the base is N,N-diisopropylethylamine.

65. The method of claim 63 or 64, wherein the method further comprises reacting a compound of formula D5-9with hydrazine to form the compound of formula D5-10.

66. The method of claim 65, wherein the method further comprises subjecting a compound of formula D5-8to conditions suitable to achieve metal-halogen exchange, followed by reaction with a formylation reagent to form the compound of formula (D5-9).

67. The method of claim 66, wherein the conditions suitable to achieve metal-halogen exchange comprise treating the compound of formula D5-8 with n-butyllithium.

68. The method of claim 66 or 67, wherein the formylation reagent is N,N- dimethy Iformamide .

69. The method of any one of claims 66-68, further comprising reacting a compound of formula D5-7with a carboxylic acid activation agent followed by diethylamine to form the compound of formula D5-8.

70. The method of claim 69, wherein the carboxylic acid activation agent is oxalyl chloride.

71. A compound, which iA compound, which i73. A compound, which i