Process for preparation of intermediates for heteroaryl-ketone fused azanaphthane glucocorticoid receptor modulators

Abstract

The present invention provides processes for preparing intermediates for heteroaryl-ketone fused azanaphthane glucocorticoid receptor modulators and compositions with low impurity levels.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 486,753, filed February 24, 2023, which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] There are two types of high-affinity receptors for corticosteroids: type I (mineralocorticoid receptor, MR) and type II (glucocorticoid receptor (GR) or cortisol receptor, GR). In most species, including humans, the physiological glucocorticoid is cortisol (hydrocortisone). Glucocorticoids are secreted in response to ACTH (adrenocorticotropic hormone), which shows both circadian variations and increases in response to stress and food. Cortisol levels rise within minutes in response to many physical and physiological stresses, including trauma, surgery, exercise, anxiety and depression. Cortisol is a steroid and exerts its effects by binding to the intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: a 777-amino acid ligand-binding GR-α; and a GR-β isoform that lacks 50 carboxyl-terminal residues. Because these include a ligand-binding domain, GR-β cannot bind to a ligand, is constantly located in the nucleus and has no transcriptional activity.

[0004] Receptor modulators (such as agonists, partial agonists, and antagonists) can be used to modulate the biological effects of Cortisol at the GR level, including those caused by hypercortisolism. Several different types of agents are capable of blocking the physiological effects of GR agonist binding. These antagonists include compositions that inhibit the ability of agonists to effectively bind to and / or activate the GR by binding to the GR. One such known GR antagonist, mifepristone, has been found to be an effective anti-glucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to the GR with high affinity, with a dissociation constant (K d ) is 10 -9M. Cadepond (1997) Annu. Rev. Med. 48: 129. Additional glucocorticoid receptor modulator compounds include dazucorilant (CORT113176) and relacorilant (CORT125134) previously described in PCT Publication No. WO 2013 / 177559 and U.S. Patent No. 8,859,774, exicorilant (CORT125281) and zavacorilant (CORT125329) previously described in PCT Publication No. WO 2015 / 077530 and U.S. Patent No. 10,047,082, and CORT108297 previously described in PCT Publication No. WO 2010 / 132445 and U.S. Patent No. 8,889,867. What is needed in the art are new methods of making intermediates for GR receptor modulators with higher purity. Surprisingly, the present invention meets these and other needs. SUMMARY

[0005] In one embodiment, the present invention provides a method of making a compound of Formula I:

[0006]

[0007] The method comprises: (a) forming a first reaction mixture comprising a compound of Formula II:

[0008]

[0009] Mg(OAc)2, and 4-fluorophenylhydrazine HC1:

[0010]

[0011] under conditions suitable to make the compound of Formula I in at least 80% yield and at least 98% purity.

[0012] In another embodiment, the present invention provides a method of making a compound of Formula II:

[0013]

[0014] The method comprises: (c) forming a third reaction mixture comprising a carboxylic acid alkyl ester, a non-nucleophilic base, and a compound of Formula III:

[0015]

[0016] thereby making the compound of Formula II.

[0017] In another embodiment, the present application provides a composition comprising: a compound of Formula I in an amount of at least 99%:

[0018] and

[0019] one or more impurities in an amount of 0.01 to 1%. DETAILED DESCRIPTION

[0020] I. SUMMARY

[0021] The present disclosure describes a new process for preparing the intermediate compound (R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester of Formula I with lower impurity levels than previously described processes. The new process for preparing the compound of Formula I has improved process safety and cost benefits compared to known processes and can be prepared on a larger scale. The compound of Formula I can be prepared as in Example 33 of U.S. Patent No. 7,928,237.

[0022] II. DEFINITIONS

[0023] When referring to a value, "about" includes the stated value + / - 10% of the stated value. For example, about 50% includes the range of 45% to 55%, and about 20 molar equivalents includes the range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" means each of the values stated in the range + / - 10% of the stated value. For example, a ratio of about 1 to about 3 (w / w) encompasses the range of 0.9 to 3.3.

[0024] "Forming a reaction mixture" means the process of bringing at least two different substances into contact such that they mix together and can react. However, it will be appreciated that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents, which can be produced in the reaction mixture.

[0025] "Dissolve, dissolving, or dissolution" means a solid material that is substantially soluble in a particular solvent. For example, a solid material can be greater than 90% soluble in a solvent, or greater than 91, 92, 93, 94, 95, 96, 97, 98, or greater than 99% soluble in a solvent.

[0026] "Substantially free" means that the composition has less than 5%, less than 1%, less than 0.5%, or even less than 0.1% of an undesirable component by weight percent (w / w) or HPLC peak area.

[0027] "aqueous phase" or "aqueous mixture" refers to a mixture containing water and other water-miscible solvents capable of dissolving water-soluble organic and inorganic compounds. The aqueous phase is substantially immiscible with the organic phase.

[0028] "organic phase" refers to a mixture containing water-miscible or immiscible solvents capable of dissolving either or both of water-soluble and water-insoluble organic compounds. The organic phase of the present application can be formed from one or more organic solvents. Exemplary organic solvents can be nonpolar aprotic solvents, polar aprotic solvents, and polar protic solvents. Representative solvents include, but are not limited to, pentane, hexane, hexanes, heptane, benzene, toluene, cyclopentyhnethyl ether (CPME), diethyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetone, methyl ethyl ketone, N,N-dimethylacetamide (DMA / DMAc), N-methylpyrrolidone (NMP), ethyl acetate, isopropyl acetate (iPrOAc), acetonitrile, dichloromethane, chloroform, and the like. The organic phase is substantially immiscible with the aqueous phase.

[0029] "separating" or "separation" refers to one or more methods of physically separating one or more components of a mixture, the primary purpose of which is to remove one or more unwanted components (byproducts, minor products, contaminants, and / or impurities) present in the mixture to provide the desired component or product substantially free of the unwanted components.

[0030] "acid" refers to a compound that can donate a proton (H + ) according to the Bronsted-Lowry definition, or a compound that is an electron pair acceptor according to the Lewis definition. Acids useful in the present application are Bronsted-Lowry acids, which include, but are not limited to, alkanes or carboxylic acids [formic acid, acetic acid, citric acid, lactic acid, oxalic acid, trifluoroacetic acid (TFA), and the like] as defined herein, sulfonic acids, and mineral acids. Mineral acids are inorganic acids such as hydrogen halides [hydrofluoric acid (HF), hydrochloric acid (HC1), hydrobromic acid (HBr), and the like], halogen oxoacids (hypochlorous acid, perchloric acid, and the like), as well as sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), chromic acid, and boric acid. Sulfonic acids include methanesulfonic acid (CH3SO3H; MSA), benzenesulfonic acid (C6H5SO3H), p-toluenesulfonic acid (4-CH3C6H4SO3H; pTsOH), trifluoromethanesulfonic acid (CF3SO3H; TfOH), camphorsulfonic acid, and the like.

[0031] "Non-nucleophilic base" means a base that is moderately to strongly basic but also weakly nucleophilic. Representative non-nucleophilic bases include bases such as potassium carbonate, sodium carbonate, alkoxides such as potassium tert-butoxide and sodium tert-butoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt; DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, and quinuclidine. Non-nucleophilic bases include non-nucleophilic amine bases.

[0032] "Solvent" means a substance, such as a liquid, capable of dissolving a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents generally have a dielectric constant greater than about 5 or a dipole moment higher than about 1.0, and nonpolar solvents have a dielectric constant lower than about 5 or a dipole moment lower than about 1.0. Protic solvents are characterized by having protons available for removal, such as having hydroxyl or carboxyl groups. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.), and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative nonpolar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents can be used in the present application.

[0033] "Antisolvent" means a solvent or solvent system in which a compound, composition, or mixture has low solubility. The antisolvent can be any suitable solvent as described above.

[0034] "Heating" means increasing the temperature of a mixture above room temperature, or from a lower temperature to a higher temperature.

[0035] "Cooling" means decreasing the temperature of a mixture below room temperature, or from a higher temperature to a lower temperature.

[0036] "Room temperature" is the range of air temperatures generally considered suitable for human habitation, or between about 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0037] "Vacuum" or "reduced pressure" refers to a pressure less than atmospheric pressure. Atmospheric pressure measures about 1013 mbar, 760 mm Hg, or about 14.7 psi. Thus, a vacuum can be less than 1013 mbar, or less than 100, 10, 1, 0.1, or less than 0.01 mbar.

[0038] "Alkyl" refers to a straight or branched chain saturated aliphatic group having the number of carbon atoms indicated. Alkyl groups can include any number of carbons, such as C 1-2 ,C 13 ,C 14 ,C 15 ,C 16 ,C 17 ,C 18 ,C 19 ,C 110 ,C 23 ,C 24 ,C 25 ,C 26 ,C 34 ,C 35 ,C 36 ,C 4-5 ,C 4-6 and C 5-6 . For example, C 1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0039] "Alkyl formate" refers to a compound of the formula HC(O)OR, wherein R is alkyl. Representative alkyl formates include methyl formate, HC(O)OMe; ethyl formate, HC(O)OEt; n-butyl formate, HC(O)OCH2CH2CH2CH3; and isoamyl formate, HC(O)OCH2CH2CH(CH3)2.

[0040] "Alkoxide" refers to the anion - OR, wherein R is alkyl. Representative alkoxides include, but are not limited to, methoxide, ethoxide, isopropoxide, and t-butoxide.

[0041] As used herein, "composition" is intended to encompass products comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.

[0042] III. Methods of making a compound of Formula I

[0043] (R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)- dicarboxylic acid 6-(tert-butyl) 4a-methyl ester:

[0044]

[0045] may be prepared as described in Example 33 of USPN 7,928,237. In some embodiments, the present application provides a method of preparing a compound of Formula I:

[0046]

[0047] The method comprises: (a) forming a first reaction mixture comprising a compound of Formula II:

[0048]

[0049] Mg(OAc)2and 4-fluorophenylhydrazine HC1:

[0050]

[0051] of Formula II.

[0052] Conditions suitable for preparing a compound of Formula I can include any suitable time and temperature, as described below in the Examples section.

[0053] Mg(OAc)2may be any suitable hydrate. For example, Mg(OAc)2may be a monohydrate, dihydrate, trihydrate, or tetrahydrate. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein Mg(OAc)2is Mg(OAc)2·4H2O.

[0054] Mg(OAc)2may be present in any amount suitable for the compound of Formula II. For example, Mg(OAc)2may be present in an amount of 0.1 to 5 molar equivalents relative to the compound of Formula II, or 0.1 to 4, 0.1 to 3, 0.1 to 2, 0.1 to 1.5, 0.1 to 1.0, 0.2 to 1.0, 0.3 to 0.9, 0.4 to 0.8, or 0.5 to 0.7 molar equivalents relative to the compound of Formula II. Representative amounts of Mg(OAc)2include, but are not limited to, about 0.1 molar equivalents relative to the compound of Formula II, or about 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, or 3.0 molar equivalents relative to the compound of Formula II.

[0055] In some embodiments, the method of preparing a compound of Formula I comprises a method wherein Mg(OAc)2is present in an amount of 0.5 to 1.0 molar equivalents relative to the compound of Formula II. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein Mg(OAc)2is present in an amount of about 0.6 molar equivalents relative to the compound of Formula II.

[0056] In some embodiments, the method of preparing a compound of Formula I comprises a method wherein the first reaction mixture further comprises a first solvent. Any suitable solvent can be used as the first solvent in the first reaction mixture. The first solvent can include, but is not limited to, pentane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, dichloromethane, and chloroform. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein the first solvent comprises pentane, hexane, heptane, benzene, or toluene. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein the first solvent comprises benzene or toluene. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein the first reaction mixture further comprises toluene.

[0057] A compound of Formula I can be prepared in any suitable yield. For example, a compound of Formula I can be prepared in a yield of at least 10%, 20, 30, 40, 50, 60, 65, 70, 75, 80, 85%, 90%, or at least 95%. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein a compound of Formula I can be prepared in a yield of at least 80%.

[0058] A compound of Formula I can be prepared in any suitable purity. For example, a compound of Formula I can be prepared in a purity of at least 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein a compound of Formula I can be prepared in a purity of at least 96%. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein a compound of Formula I can be prepared in a purity of at least 97%. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein a compound of Formula I can be prepared in a purity of at least 98%. In some embodiments, the method of preparing a compound of Formula I comprises a method wherein a compound of Formula I can be prepared in a purity of at least 99%.

[0059] In some embodiments, the method of preparing a compound of Formula I comprises a method comprising the step of: (a) forming a mixture comprising the compound of Formula II:

[0060]

[0061] Mg(OAc)2-4H2O, acetic acid, water, toluene, and 4-fluorobenzylhydrazine HC1 in an amount of about 0.6 molar equivalents relative to the amount of the compound of Formula II:

[0062]

[0063] the first reaction mixture to prepare the compound of Formula I in a yield of at least 80% and a purity of at least 98%:

[0064]

[0065] A. Purification of the compound of Formula I via crystallization

[0066] The compound of Formula I can be purified by a variety of methods, including crystallization. In some embodiments, the method of preparing the compound of Formula I comprises a method further comprising the steps of: (al) heating a first crystallization mixture comprising isopropyl alcohol, heptane, and the compound of Formula I, such that the compound of Formula I dissolves in the first crystallization mixture; and (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I.

[0067] The first crystalline compound of Formula I can include a variety of impurities, such as, but not limited to, one or more of the following:

[0068] Impurity A, (4aR,8R)-1-(4-fluorophenyl)-8-hydroxy-1,4,7,8-tetrahydro-6H- pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester:

[0069]

[0070] Impurity C, (R)-2-(4-fluorophenyl)-2,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline- 4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester:

[0071] and

[0072] Impurity D, (R)-1-(4-fluorophenyl)-1,4,7,9-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline- 4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester:

[0073]

[0074] Impurities present in the compound of Formula I may include impurity A in an amount less than 1%. For example, the compound of Formula I may include impurity A in an amount less than 1.0%, or less than 0.9%, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02%, or less than 0.01% impurity A. In some embodiments, the compound of Formula I may contain impurity A in an amount less than 0.1%. In some embodiments, the compound of Formula I may contain impurity A in an amount less than 0.05%.

[0075] Impurities present in the compound of Formula I may include impurity C in an amount less than 1%. For example, the compound of Formula I may include impurity C in an amount less than 1.0%, or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or less than 0.01%. In some embodiments, the compound of Formula I may contain impurity C in an amount less than 0.5%. In some embodiments, the compound of Formula I may contain impurity C in an amount less than 0.1%. In some embodiments, the compound of Formula I may contain impurity C in an amount less than 0.05%.

[0076] Impurities present in the compound of Formula I may include impurity D in an amount less than 1%. For example, the compound of Formula I may include impurity D in an amount less than 1.0%, or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.24, 0.23, 0.22, 0.21, 0.2, or less than 0.1%. In some embodiments, the compound of Formula I may contain impurity D in an amount less than 0.25%. In some embodiments, the compound of Formula I may contain impurity D in an amount less than 0.2%.

[0077] The amount of impurities in a composition containing a compound of Formula I can be measured by any suitable method, such as by weight percent (w / w), or by HPLC peak area with UV detection.

[0078] In some embodiments, the method of preparing a compound of formula I includes a method wherein after step (a2), the compound of formula I comprises:

[0079] Less than 0.05% of impurity A:

[0080]

[0081] Less than 0.5% impurity C:

[0082] and

[0083] Less than 0.25% impurity D:

[0084]

[0085] In some embodiments, the method of preparing a compound of Formula I includes a method further comprising the steps of: (a3) ​​heating a second crystallization mixture comprising toluene, heptane, and the first crystalline compound of Formula I such that the first crystalline compound of Formula I dissolves in the second crystallization mixture; and (a4) cooling the second crystallization mixture to form a second crystalline compound of Formula I.

[0086] The first and second crystallization mixtures can be heated to any suitable temperature. Representative temperatures include above room temperature, such as, but not limited to, from room temperature to reflux of the first crystallization mixture, from room temperature to 65°C, or from about room temperature to 40°C, or from 40°C to 65°C, or from 40°C to 60°C. In some embodiments, the first crystallization mixture may be at a temperature of about 30°C, or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C.

[0087] The first and second crystallization mixtures may also be cooled to any suitable temperature. Representative temperatures include below room temperature, at room temperature, or above room temperature.

[0088] In some embodiments, the method of preparing a compound of formula I includes a method wherein after step (a4), the compound of formula I comprises:

[0089] Less than 0.05% of impurity A:

[0090]

[0091] Less than 0.05% impurity C:

[0092] and

[0093] Less than 0.20% impurity D:

[0094]

[0095] In some embodiments, the method of preparing a compound of Formula I comprises a method comprising the steps of:

[0096] (a) forming a compound comprising the formula II:

[0097]

[0098] About 0.6 molar equivalents of Mg(OAc)2·4H2O, acetic acid, water, toluene and 4-fluorophenylhydrazine HCl were added relative to the amount of the compound of formula II:

[0099]

[0100] The first reaction mixture is prepared in a yield of at least 80% and a purity of at least 98% to produce the compound of formula I:

[0101]

[0102] (a1) heating the first crystallization mixture comprising isopropyl alcohol, heptane and the compound of formula I, so that the compound of formula I is dissolved in the first crystallization mixture;

[0103] (a2) cooling the first crystallization mixture to form the first crystalline compound of formula I;

[0104] (a3) heating the second crystallization mixture comprising toluene, heptane and the first crystalline compound of Formula I, so that the first crystalline compound of Formula I is dissolved in the second crystallization mixture; and

[0105] (a4) cooling the second crystallization mixture to form the second crystalline compound of formula I, wherein the second crystalline compound of formula I contains

[0106] Less than 0.05% of impurity A:

[0107]

[0108] Less than 0.05% impurity C:

[0109] and

[0110] Less than 0.20% impurity D:

[0111]

[0112] B. Preparation of Formula II

[0113] Compound of formula II (R, Z)-7-(hydroxymethylene)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylic acid 2-(tert-butyl) 8a-methyl ester:

[0114]

[0115] It can be prepared by the method provided in Example 32 of USPN 7,928,237. In some embodiments, the present invention provides a method for preparing a compound of formula II:

[0116]

[0117] The method comprises: (c) forming a compound comprising an alkyl formate, a non-nucleophilic base and a compound of formula III:

[0118]

[0119] A third reaction mixture is prepared to prepare the compound of formula II.

[0120] The alkyl formate of the third reaction mixture may have the formula HC(O)OC 1-6 Representative alkyl formate include, but are not limited to, methyl formate, ethyl formate, n-propyl formate, or n-butyl formate.

[0121] In some embodiments, the method of preparing the compound of formula II includes a method wherein the alkyl formate is methyl formate or ethyl formate. In some embodiments, the method of preparing the compound of formula II includes a method wherein the alkyl formate is methyl formate.

[0122] The alkyl formate can be present in any amount suitable for the compound of formula III. For example, the alkyl formate can be present in an amount of 1 to 10 molar equivalents relative to the compound of formula III, or in an amount of 1 to 7.5, 1 to 5, 2 to 4, 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.2, or 2.9 to 3.1 molar equivalents relative to the compound of formula III. Representative amounts of alkyl formate include, but are not limited to, about 1 molar equivalent relative to the compound of formula III, or about 1.5, 2.0, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 4.0, 4.5, 5.0, 6, 7, 8, 9, or about 10 molar equivalents relative to the compound of formula III.

[0123] In some embodiments, the method for preparing the compound of formula II comprises a method wherein methyl formate is present in an amount of 1 to 10 molar equivalents relative to the compound of formula III. In some embodiments, the method for preparing the compound of formula II comprises a method wherein methyl formate is present in an amount of about 3.0 molar equivalents relative to the compound of formula III.

[0124] Non-nucleophilic bases that can be used in the process for preparing the compound of formula III include, but are not limited to, potassium carbonate, sodium carbonate, alkoxides such as potassium tert-butoxide and sodium tert-butoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine bases such as triethylamine (Et3N), N,N-diisopropylethylamine (iPr2NEt; DIPEA), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diethylaniline, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine. In some embodiments, the method for preparing the compound of formula II includes a method wherein the non-nucleophilic base is an alkoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, or n-butyllithium. In some embodiments, the method for preparing the compound of formula II includes a method wherein the non-nucleophilic base is an alkoxide.

[0125] The alkoxides that can be used in the method for preparing the compound of formula II include but are not limited to methoxide, ethanolate, isopropoxide, tert-butoxide or tert-amyl alcoholate. Representative counterions of the alkoxides that can be used in the method for preparing the compound of formula II include but are not limited to sodium or potassium. In some embodiments, the method for preparing the compound of formula II includes a method in which the non-nucleophilic base is sodium tert-butoxide (NaOtBu), sodium tert-amyl alcoholate (NaOtPent) or potassium tert-amyl alcoholate (KOtPent). In some embodiments, the method for preparing the compound of formula II includes a method in which the non-nucleophilic base is sodium tert-amyl alcoholate (NaOtPent).

[0126] Alkoxide can be present in any amount suitable for the compound of formula III. For example, alkoxide can be present in an amount of 1 to 10 molar equivalents relative to the compound of formula III, or in an amount of 1 to 7.5, 1 to 5, 2 to 4, 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.2 or 2.9 to 3.1 molar equivalents relative to the compound of formula III. Representative amounts of alkyl formate include but are not limited to about 1 molar equivalent relative to the compound of formula III, or about 1.5, 2.0, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 4.0, 4.5, 5.0, 6, 7, 8, 9 or about 10 molar equivalents relative to the compound of formula III. In some embodiments, the method for preparing the compound of formula II includes a method in which sodium tert-amyl alcohol is present in an amount of about 3.0 molar equivalents relative to the compound of formula III.

[0127] The third reaction mixture may further comprise an inorganic salt. Representative inorganic salts include, but are not limited to, lithium chloride, lithium bromide, lithium iodide, sodium chloride, sodium bromide, sodium iodide, potassium chloride, potassium bromide, or potassium iodide. In some embodiments, the method for preparing the compound of formula II includes a method wherein the third reaction mixture comprises lithium chloride.

[0128] Inorganic salts can be present in any amount suitable for compounds of formula III. For example, inorganic salts can be present in an amount of 0.1 to 10 molar equivalents relative to compounds of formula III, or in an amount of 0.1 to 5, 0.2 to 4, 0.5 to 3.5, 0.5 to 3.0, 0.5 to 2.0 or 1.0 to 1.4 molar equivalents relative to compounds of formula III. Representative amounts of inorganic salts include, but are not limited to, about 1 molar equivalent relative to compounds of formula III, or about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or about 10 molar equivalents relative to compounds of formula III. In some embodiments, the method for preparing a compound of formula II includes a method in which lithium chloride is present in an amount of about 1.2 molar equivalents relative to compounds of formula III.

[0129] In some embodiments, the method for preparing the compound of formula II includes a method in which the third reaction mixture also includes a third solvent. Any suitable solvent can be used as the third solvent in the third reaction mixture. The third solvent may include but is not limited to pentane, hexane, heptane, benzene, toluene, ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, acetonitrile, dichloromethane and chloroform. In some embodiments, the method for preparing the compound of formula II includes a method in which the third solvent includes ether, tetrahydrofuran or 2-methyltetrahydrofuran. In some embodiments, the method for preparing the compound of formula II includes a method in which the third reaction mixture also includes 2-methyltetrahydrofuran.

[0130] Suitable conditions for preparing compounds of Formula I may include any suitable time and temperature, as described in the Examples section below.

[0131] The third reaction mixture can be cooled to any suitable temperature. Representative temperatures include being at or below room temperature. Representative temperatures include below room temperature, such as but not limited to -78°C to room temperature, -78°C to 0°C, -60°C to -10°C, -50°C to -20°C or -40°C to -30°C. Other temperatures of the third reaction mixture include but are not limited to about -78°C or about -70°C, -60°C, -50°C, -40°C, -30°C, -20°C, -10°C or about 0°C. In some embodiments, the method for preparing the compound of formula II includes a method wherein the third reaction mixture is at a temperature of about -40°C.

[0132] Compounds of Formula II can include a variety of impurities, such as, but not limited to, Impurity X, (R,4E,7Z)-4,7-bis(hydroxymethylidenyl)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylic acid 2-(tert-butyl) 8a-methyl ester:

[0133]

[0134] Impurities present in compounds of Formula II can include Impurity X in an amount of less than 1%. For example, compounds of Formula II can include Impurity X in an amount of less than 1.0%, or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or less than 0.01%. In some embodiments, compounds of Formula II can contain Impurity X in an amount of less than 0.1%. In some embodiments, compounds of Formula II can contain Impurity X in an amount of less than 0.01%.

[0135] In some embodiments, the method of making a compound of Formula II includes methods in which the compound of Formula II contains Impurity X in an amount of less than 0.01%.

[0136]

[0137] In some embodiments, the method of making a compound of Formula II includes methods comprising the step of: (c) forming the third reaction mixture comprising about 3.0 molar equivalents of methyl formate, sodium tert-pentoxide, lithium chloride, 2-methyltetrahydrofuran, and the compound of Formula III relative to the amount of the compound of Formula III:

[0138]

[0139] at a temperature of about -40 °C,

[0140] to thereby make the compound of Formula II:

[0141]

[0142] In some embodiments, the method of making a compound of Formula I includes methods in which the compound of Formula II is made by a method of the present application.

[0143] In some embodiments, the method of making a compound of Formula II includes methods comprising the step of: (c) forming the third reaction mixture comprising about 3.0 molar equivalents of methyl formate, sodium tert-pentoxide, lithium chloride, 2-methyltetrahydrofuran, and the compound of Formula III relative to the amount of the compound of Formula III:

[0144]

[0145] the third reaction mixture at a temperature of about -40 °C,

[0146] to thereby produce the compound of Formula II:

[0147] and

[0148] (a) forming a first reaction mixture comprising the compound of Formula II, about 0.6 molar equivalents of Mg(OAc)2-4H2O relative to the amount of the compound of Formula II, acetic acid, water, toluene, and 4-fluorophenylhydrazine HC1:

[0149]

[0150] the first reaction mixture to produce the compound of Formula I in a yield of at least 80% and a purity of at least 98%:

[0151]

[0152] In some embodiments, the method of producing the compound of Formula II comprises a method further comprising the steps of:

[0153] (a1) heating the first crystallization mixture comprising isopropyl alcohol, heptane, and the compound of Formula I, such that the compound of Formula I dissolves in the first crystallization mixture;

[0154] (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I;

[0155] (a3) heating the third crystallization mixture comprising toluene, heptane, and the first crystalline compound of Formula I, such that the first crystalline compound of Formula I dissolves in the third crystallization mixture; and

[0156] (a4) cooling the third crystallization mixture to form a third crystalline compound of Formula I, wherein the third crystalline compound of Formula I contains

[0157] less than 0.05% of Impurity A:

[0158]

[0159] less than 0.05% of Impurity C:

[0160] and

[0161] less than 0.20% of Impurity D:

[0162]

[0163] C. Preparation of Formula III

[0164] Compound of formula III (R)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylic acid 2-(tert-butyl)8a-methyl ester:

[0165]

[0166] It can be prepared by the method of Example 31 of USPN 7,928,237.

[0167] In some embodiments, the method of preparing a compound of formula II includes a method wherein the compound of formula III is prepared by a process comprising the steps of: (d) forming a pyrrolidine, acetic acid, and a compound of formula IV:

[0168]

[0169] A fourth reaction mixture of:

[0170]

[0171] Pyrrolidine can be present in any amount suitable for the compound of formula IV. For example, pyrrolidine can be present in an amount of 0.05 to 1.0 molar equivalents relative to the compound of formula IV, or 0.1 to 1.0 or 0.1 to 0.5 molar equivalents relative to the compound of formula IV. Representative amounts of pyrrolidine include, but are not limited to, about 0.1 molar equivalents relative to the compound of formula IV, or about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or about 1 molar equivalents relative to the compound of formula IV. In some embodiments, the method for preparing the compound of formula III includes a method wherein pyrrolidine is present in an amount of about 0.3 molar equivalents relative to the compound of formula IV.

[0172] Acetic acid can be any suitable acetic acid. For example, acetic acid can be glacial acetic acid. Acetic acid can be present in any amount suitable for the compound of formula IV. For example, acetic acid can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of formula IV, or in an amount of 0.5 to 5, or 1 to 2, or 1 to 1.5 molar equivalents relative to the compound of formula IV. Representative amounts of acetic acid include, but are not limited to, about 0.5 molar equivalents relative to the compound of formula IV, or about 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or about 1.5 molar equivalents relative to the compound of formula IV. In some embodiments, the method for preparing the compound of formula III includes a method wherein acetic acid is present in an amount of about 1.5 molar equivalents relative to the compound of formula IV.

[0173] In some embodiments, the method for preparing the compound of formula III includes a method in which the fourth reaction mixture further comprises a fourth solvent. Any suitable solvent can be used as the fourth solvent in the fourth reaction mixture. The fourth solvent may include but is not limited to methanol, ethanol, n-propanol, isopropanol, ether, tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether. The fourth solvent may include but is not limited to methanol, ethanol, n-propanol, isopropanol, ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and toluene. In some embodiments, the method for preparing the compound of formula III includes a method in which the fourth solvent includes isopropanol, methyl tert-butyl ether and a combination thereof. In some embodiments, the method for preparing the compound of formula III includes a method in which the fourth reaction mixture further comprises methyl tert-butyl ether.

[0174] The compound of formula III can be purified by various methods, including crystallization. In some embodiments, the method of preparing the compound of formula III includes a method further comprising the steps of: forming a fourth crystallization mixture comprising isopropanol and the compound of formula III, such that the compound of formula III is dissolved in the fourth crystallization mixture; and adding water to the fourth crystallization mixture to form the crystalline compound of formula III.

[0175] The ratio of isopropyl alcohol to water can be any suitable ratio. For example, the ratio of isopropyl alcohol to water can be 1:1 to 1:10 (volume / volume), or 1:1 to 2:10, or 1:2 to 3:10 (volume / volume). Representative ratios of isopropyl alcohol to water include but are not limited to approximately 1:8 (volume / volume), or approximately 1:7, 1:6, 1:5, 1:4, 3:8, 4:8, 5:8 or approximately 6:8 (volume / volume). In some embodiments, the method for preparing the compound of formula III includes a fourth crystalline mixture of isopropyl alcohol and water with 3:8 (volume / volume).

[0176] In some embodiments, the method of preparing a compound of formula II includes a method wherein the compound of formula III is prepared by a process comprising the steps of: (d) forming a mixture comprising 0.3 molar equivalents of pyrrolidine relative to the amount of the compound of formula IV, 1.2 molar equivalents of glacial acetic acid relative to the amount of the compound of formula IV, isopropanol, and the compound of formula IV:

[0177]

[0178] A fourth reaction mixture of:

[0179]

[0180] D. Preparation of Formula IV

[0181] Compound of formula IV (S)-4-oxo-3-(3-oxobutyl)piperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-methyl ester:

[0182]

[0183] It can be prepared by the method of Example 30 of USPN 7,928,237.

[0184] In some embodiments, the method of preparing a compound of formula II includes a method wherein the compound of formula IV is prepared by a process comprising the steps of: (e) forming a mixture comprising a compound of formula V at a temperature of 10 to 25°C:

[0185]

[0186] A fifth reaction mixture of about 1.6 molar equivalents of methyl vinyl ketone (MVK), Cu(OAc)2 (anhydrous) and dimethylformamide relative to the amount of the compound of formula V, thereby preparing the compound of formula IV:

[0187]

[0188] The fifth reaction mixture can be at any suitable temperature. Representative temperatures include, but are not limited to, 0°C to 50°C, 5°C to 40°C, 10°C to 30°C, 15°C to 25°C, 18°C ​​to 25°C, or 20°C to 23°C. Other temperatures of the third reaction mixture include, but are not limited to, about 0°C or about 10°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or about 30°C. In some embodiments, the method for preparing the compound of formula IV includes a method wherein the fifth reaction mixture has a temperature of 20 to 23°C.

[0189] In some embodiments, the method of preparing the compound of formula IV includes a method further comprising the step of: (e1) adding an aqueous mixture comprising HCl and LiCl to the fifth reaction mixture under conditions suitable for preparing the compound of formula IV.

[0190] In some embodiments, the method of making a compound of Formula IV includes methods wherein the compound of Formula IV contains less than 5% MVK polymer. In some embodiments, the method of making a compound of Formula IV includes methods wherein the compound of Formula IV contains less than 1% MVK polymer. In some embodiments, the method of making a compound of Formula IV includes methods wherein the compound of Formula IV contains less than 0.1% MVK polymer. In some embodiments, the method of making a compound of Formula IV includes methods wherein the compound of Formula IV contains less than 0.05% MVK polymer. The amount of MVK polymer present with the compound of Formula IV can be determined by weight percent (w / w) or by HPLC peak area with UV detection.

[0191] IV. Low Impurity Compositions

[0192] The present application provides a composition of Formula I having a low impurity content. The impurity content can be expressed in a number of different ways. For example, the impurity content can be expressed as weight percent (w / w) or % (HPLC peak area). In some embodiments, the impurity content can be expressed as % (HPLC peak area). In some embodiments, the present application provides a composition comprising: a compound of Formula I in an amount of at least 99%:

[0193] and

[0194] one or more impurities in an amount of 0.01 to 1%.

[0195] The composition of Formula I can comprise one or more impurities present in a total amount of 0.01 to 1%.

[0196] The impurities present in the composition of compound of Formula I can include Impurity A in an amount of less than 1%. For example, the composition of compound of Formula I can comprise less than 1.0% or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or less than 0.01% of Impurity A. In some embodiments, the composition comprising the compound of Formula I can contain less than 0.1% of Impurity A. In some embodiments, the composition comprising the compound of Formula I can contain less than 0.05% of Impurity A.

[0197] Impurities present in compositions of compounds of Formula I can include Impurity C in an amount of less than 1%. For example, compositions of compounds of Formula I can include less than 1.0% or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or less than 0.01% of Impurity C. In some embodiments, compositions comprising compounds of Formula I can contain less than 0.5% of Impurity C. In some embodiments, compositions comprising compounds of Formula I can contain less than 0.1% of Impurity C. In some embodiments, compositions comprising compounds of Formula I can contain less than 0.05% of Impurity C.

[0198] Impurities present in compositions of compounds of Formula I can include Impurity D in an amount of less than 1%. For example, compositions of compounds of Formula I can include less than 1.0% or less than 0.9, 0.8, 0.75, 0.7, 0.6, 0.5, 0.4, 0.3, 0.25, 0.24, 0.23, 0.22, 0.21, 0.2, or less than 0.1% of Impurity D. In some embodiments, compositions comprising compounds of Formula I can contain less than 0.25% of Impurity D. In some embodiments, compositions comprising compounds of Formula I can contain less than 0.2% of Impurity D.

[0199] In some embodiments, compounds of Formula I include compounds in which the impurities include at least one of the following:

[0200] less than 0.05% of Impurity A

[0201]

[0202] less than 0.05% of Impurity C:

[0203] and

[0204] less than 0.20% of Impurity D:

[0205]

[0206] In some embodiments, compounds of Formula I include compounds prepared by the methods of the present application.

[0207] V. Examples

[0208] The following abbreviations are used in the following methods:

[0209]

[0210]

[0211] X-ray powder diffraction (XRPD). XRPD analysis was performed using a Panalytical X’Pert Pro diffractometer equipped with a Cu X-ray tube and Pixcel detector system. Samples were analyzed in transmission mode and held between low density polyethylene films. The XRPD procedure used included the following parameters: (1) range 3-40° 2-theta, (2) step size 0.013°, (3) count time 99 seconds, and (4) ~22 min run time. XRPD patterns were sorted using HighScore Plus 2.2c software.

[0212] Differential scanning calorimetry (DSC). DSC analysis was performed on a Perkin Elmer Jade differential scanning calorimeter. Accurately weighed samples were placed in crimped aluminum pans. Each sample was heated at a rate of 10 °C / min to a maximum of 300 °C under nitrogen. Metal indium was used as a calibration standard. Temperatures were reported to the nearest 0.01 degree at the onset of transition.

[0213] The reaction steps of the present application can be conducted for any suitable reaction time. For example, the reaction time can last for minutes, hours, or days. In some embodiments, the reaction time can last for several hours, such as at least eight hours. In some embodiments, the reaction time can last for several hours, such as at least overnight. In some embodiments, the reaction time can last for several days. In some embodiments, the reaction time can last for at least two hours. In some embodiments, the reaction time can last for at least eight hours. In some embodiments, the reaction time can last for at least several days. In some embodiments, the reaction time can last for about two hours or about 4 hours or about 6 hours, or about 8 hours, or about 10 hours, or about 12 hours, or about 14 hours, or about 16 hours, or about 18 hours, or about 20 hours, or about 22 hours, or about 24 hours. In some embodiments, the reaction time can last for about 1 day, or about two days, or about three days, or about four days, or about five days, or about six days, or about one week, or about more than one week.

[0214] The reaction steps of the present application can be conducted at any suitable reaction temperature. Representative temperatures include, but are not limited to, below room temperature, at room temperature, or above room temperature. Other temperatures that can be used in the methods of the present application include about -40 °C to about 65 °C, or about room temperature to about 40 °C, or about 40 °C to about 65 °C, or about 40 °C to about 60 °C. In some embodiments, the reaction mixture can be at a temperature of about room temperature, or at a temperature of about 15 °C, or at about 20 °C, or at about 25 °C, or at about 30 °C, or at about 35 °C, or at about 40 °C, or at about 45 °C, or at about 50 °C, or at about 55 °C, or at about 60 °C, or at about 65 °C.

[0215] Example 1. Preparation of Formula V (Compound 6) (S)-4-((l-(diethylamino)-3- methyl- 1 -oxobutan-2-yl ) amino)- Preparation of 5,6-dihydropyridine- 1,3(2H)-dicarboxylic acid 1 -(tert-butyl) 3-methyl ester

[0216]

[0217] To a 100 L vessel previously rinsed with MTBE, (tert-butoxycarbonyl)-L- valine (Compound 1) [3.5 kg, 16.11 mol, 1.0 equiv] and MTBE [25.9 kg, 35 L, 10 vol] were added at 25 °C with stirring. After 88 min, the solids dissolved. The vessel was then cooled to 0 °C and at -5-5 °C, neopentylchloride [2.14 kg, 17.74 mol, 1.1 equiv] followed by N-methylmorpholine [2.45 kg, 24.21 mol, 1.5 equiv] were charged to the reactor. After the addition was complete, the reactor was heated to 20 °C. The resulting mixture was aged at 20 °C for 3 h, where conversion of Compound 1 to neopentanoate (mixed anhydride) was determined by HPLC.

[0218] The reaction mixture was then cooled to 0 °C and diethylamine [2.14 kg, 17.74 mol, 1.1 equiv] was charged to the reactor over 20 min, maintaining the temperature at -5-5 °C. The resulting mixture was aged at 20 °C for 10 min. The temperature was increased to 20 °C. The resulting mixture was aged at 20 °C for 5 h, where the area of Compound 1 was analyzed by HPLC. A 1 N hydrochloric acid solution [21.00 kg, 17.5 L, 5 vol] was charged to the vessel, stirred for 15 min, and aged for 15 min, allowing the biphasic mixture to settle, and the aqueous layer was drained. The organic layer was retained in the reactor. A 5 wt% sodium bicarbonate [11.03 kg, 10.5 L, 3 vol] was charged to the vessel, stirred for 15 min, and aged for 15 min, allowing the biphasic mixture to settle, and the aqueous layer was drained from the reactor, retaining the organic phase in the reactor.

[0219] Purified water [7 kg, 7 L, 2 volumes] was then charged to the vessel containing the organic phase and the biphasic mixture was stirred for 15 min. Stirring was stopped and the mixture was allowed to age for 15 min to allow the biphasic mixture to settle. The aqueous layer was separated and the organic phase was concentrated under reduced pressure to about 14.0-17.5 L [about 4.5 volumes] while maintaining the batch temperature below 40 °C. Isopropyl alcohol [13.83 kg, 17.5 L, 5 volumes] was charged to the vessel and concentrated under reduced pressure to about 14 L to 17.5 L [4.5 volumes] while maintaining the batch temperature below 55 °C. Isopropyl alcohol [13.83 kg, 17.5 L, 5 volumes] was charged to the vessel and concentrated under reduced pressure to about 14.0-17.5 L [about 4.5 volumes] while maintaining the batch temperature below 55 °C. HPLC analysis of the resulting isopropyl acetate solution contained (S)-(1-(diethylamino)-3-methyl-1- oxobutan-2-yl)carbamic acid tert-butyl ester (Compound 2) at 97.3 area% chemical purity, 3.95 kg (90% assay yield).

[0220] The 50 L vessel was dried under vacuum prior to use. The solution of Compound 2 [(S)-(1-(diethylamino)-3-methyl-1-oxobutan-2-yl)carbamic acid tert-butyl ester; 3.66 kg, 13.44 moles, 1.11 equivalents] in IPA was charged to the vessel at 20-21 °C over 20 min. IPA [7.90 kg, 10.0 L, 3 volumes] was charged to the vessel at 5-10 °C over 20 min to bring the total volume to 16.5 L [5 volumes]. 95 wt% concentrated H2SO4 [1.40 kg, 14.24 moles, 1.11 equivalents] was added at 7-17 °C over 50 min. (Alternatively, the H2SO4 was added over about 10 hours or more.) The temperature was increased to 60 °C. The resulting mixture was aged at 60-61 °C for 29 hours.

[0221] The temperature was increased to 60 °C. The resulting mixture was aged at 60-61 °C for 29 hours.

[0222] The batch was cooled to 25 °C and seeded with compound 6 (9.9 g, 0.038 mol, 0.3 wt%) and then aged for 1 hour. Purified water [15.84 kg, 15.84 L, 4.8 volumes] was added over 33 minutes at 25 °C and the batch was aged for 30 minutes. The batch was cooled to 0 °C and aged for 1 hour at 0 °C. The batch was filtered and deliquored under nitrogen pressure. A mixture of IPA [2.6 kg, 3.3 L, 1 volume] and purified water [6.6 kg, 6.6 L, 2 volumes] was charged to the vessel followed by transfer to the oyster filter as a first cake wash. Purified water [6.6 kg, 6.6 L, 2 volumes] was charged as a second cake wash. The cake was dried under vacuum at 40 °C with minimal nitrogen purge for 20 hours and analysed for weight percent. 4.0 kg of compound 6 was obtained.

[0223] Example 2. Preparation of Formula IV (Compound 7) (S)-4-oxo-3-(3-oxobutyl)piperidine- 1,3- dicarboxylic acid 1 -(tert-butyl) 3-methyl ester Example 3. Preparation of Formula III (Compound 8) (R)-6-oxo-4,6,7,8- tetrahydroisoquinoline-2,8a(lH,3H)-dicarboxylic acid 2-(tert-butyl) 8a-methyl ester

[0224]

[0225] A 400 L vessel was dried under vacuum prior to use. Compound 6 [11 kg] and Cu(OAc)2[0.97 kg, 20 mol%] were charged to the vessel and degassed three times under vacuum. DMF [3 volumes] was charged to the vessel, degassed three times under a positive pressure of nitrogen and stirred at 35 °C for 10 minutes. The batch was cooled to 21 °C and 90% MVK [3.33 kg, 1.6 equivalents] was charged over 97 minutes, maintaining the batch temperature at 22 °C. After the addition of MVK, the vessel was purged to 2+500 mBar of argon pressure. The batch was aged with stirring for 22 hours and analysed by HPLC for conversion of compound 6. The HPLC showed a conversion of 96.9 area% of compound 6.

[0226] The batch was cooled to 1 °C and methyl tert-butyl ether [81.4 kg, 110 L, 10 volumes] was charged. Maintaining the temperature below 11 °C, approximately 0.5M HCI / 10 wt% LiCI [116.6 kg, 10 volumes] was charged to the vessel. After the addition, the vessel was purged to 2+500 mBar of argon pressure. The batch was warmed to 22 °C and aged with rapid stirring for 22 minutes before sampling and analysing by HPLC for hydrolysis of the imine intermediate to compound 7. The HPLC showed a conversion to compound 7 of 97.3 area% (2.7 LCAP imine intermediate remaining).

[0227] The biphasic mixture was allowed to settle and the aqueous layer was drained. The organic layer was drained into a second tank for temporary storage. The aqueous layer and methyl tert-butyl ether [40.7 kg, 55 L, 5 volumes] were charged to the vessel, stirred and aged for 5 minutes. The vessel was purged with 2+500 mBar argon pressure during the addition and stirring. The biphasic mixture was allowed to settle and the aqueous layer was drained. The first organic fraction was charged to the vessel along with the second organic fraction. The vessel was purged with 2+500 mBar argon pressure during the addition and stirring.

[0228] Lithium chloride 10 wt% [23.2 kg, 22 L, 2 volumes] was charged to the vessel. The vessel was purged with 2+500 mBar argon pressure during the addition and stirring. The wash was aged for 3 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. Sodium bicarbonate 5 wt% [23.2 kg, 22 L, 2 volumes] was charged to the vessel. The vessel was purged with 2+500 mBar argon pressure during the addition and stirring. The wash was aged for 2 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. The batch was cooled to 0 °C and diethylamine [4.11 kg, 2.1 equivalents] was added over 13 minutes, keeping the temperature below 5 °C. The batch was warmed to 22 °C and aged for 31 minutes before sampling and analysis for removal of excess MVK. HPLC showed 0.6 LCAP of MVK remaining.

[0229] The batch was cooled to 0 °C and 1 M hydrochloric acid solution [67.3 kg, 6 volumes] was charged, keeping the temperature below 10 °C. The batch was warmed to 22 °C and aged for 2 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. Lithium chloride 10 wt% [23.2 kg, 22 L, 2 volumes] was charged to the vessel, stirred, aged for 2 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. Sodium bicarbonate 3 wt% [23.2 kg, 22 L, 2 volumes] was charged to the vessel, stirred, aged for 7 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. The organic layer was drained. The solution contained 8.43 kg of compound 7 (96% measured yield, 94.6 LCAP at 210 nm, 99.8% ee) in 114 kg of methyl tert-butyl ether solution (6.89 wt%). The solution was stored at 2-8 °C.

[0230] Example 4. Preparation of Formula II (Compound 8a) (R,Z)-7-(hydroxymethylene)-6- oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(lH,3H)-dicarboxylic acid 2-(tert-butyl) 8a-methyl ester Example 5. Preparation of Formula I (Compound 9) (R)-l-(4-fluorophenyl)-l,4,7,8- tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester

[0231]

[0232] The 400 L vessel was dried under vacuum before use. A solution of compound 7 [8.25 kg, 120.1 kg in MTBE] was added to the reactor. Concentrate to 3 volumes [approximately 26 L], maintaining the internal temperature below 40°C. IPA [19.6 kg, 3 volumes] was added. Concentrate to 3 volumes [approximately 25 L], maintaining the internal temperature below 40°C. IPA [52.3 kg, 8 volumes] was added. The reactor contents were cooled to 1°C. Glacial acetic acid [1.84 kg, 1.2 eq] was added, maintaining the internal temperature below 10°C. Pyrrolidine [0.543 kg, 0.3 eq] was added, maintaining the internal temperature below 10°C. 563 g was added, corresponding to a 3.8% excess. The reactor contents were warmed to 20°C and aged at 20-21°C for 18.2 h before analysis for reaction conversion.

[0233] An aqueous solution of NH4Cl [10% wt / wt; 69.2 kg, 8 volumes] was added to the reactor, and the reaction mixture was aged at 25°C for at least 18 hours. The mixture was then concentrated to 7 volumes [approximately 61 L], maintaining the internal temperature below 40°C. Next, methyl tert-butyl ether [61.6 kg, 10 volumes] was added to the vessel, and the mixture was stirred for 5 minutes. Stirring was stopped, and the biphasic mixture was allowed to settle. The phases were separated, and the organic layer was washed with water [16.6 kg, 2 volumes]. The organic phase was then washed twice with a solution of 10% wt / wt K3PO4 in water [45.8 kg; 5 volumes]. The organic phase was then washed with water [16.6 kg, 2 volumes]. HPLC analysis of the separated organic phase showed that the MTBE solution contained 7.40 kg of the compound of Formula III, which corresponds to an assay yield of 95%. Subsequent workup operations, solvent additions, and volumes involving this solution are based on this 95% assay yield.

[0234] The MTBE solution containing the compound of Formula III was concentrated to 3 volumes relative to the assay yield (approximately 22 L), maintaining the internal temperature below 40°C. IPA (52.2 kg, 9 volumes) was added to the reactor, and the resulting solution was again concentrated to 3 volumes (approximately 22 L). Water (14.5 kg, 2 volumes) was then added to the reactor over 30 minutes, followed by seeding the mixture with a sample of the compound of Formula III (39.0 g; approximately 0.5% wt / wt relative to the assay, 7.4 kg) at 22°C and aging for 1 hour and 18 minutes. A second portion of water (7.24 kg, 1 volume) was then added to the reactor over a 32-minute period, and the resulting seed bed was aged at 22°C for at least 16.25 hours. A third portion of water (36.2 kg, 5 volumes) was added over 1.3 hours, and the resulting seed bed was aged for 1 hour. The reactor contents were then cooled to 0°C over 1.3 hours and then aged for an additional hour. The slurry was then filtered and the filter cake was washed with 3 volumes of a 1:4 mixture (v / v) of IPA [4.34 kg; 0.5 volume] and water [17.4 kg; 2 volumes]. The resulting solid was then dried in an oven at 30°C under a substantial stream of nitrogen until most of the water was removed. The solid was further dried in an oven at 40°C under a nitrogen purge to give 6.79 kg of Formula III, corresponding to an isolated yield of 87%. HPLC analysis of the dry solid showed that the material had an assay of 99.9% wt / wt and a chemical purity of 99.7 area %. Karl Fischer (KF) titration showed that the solid contained 0.08% wt / wt of water.

[0235] Example 6. First crystallization of Formula I (Compound 9) Example 7. Second crystallization of Formula I (Compound 9)

[0236]

[0237] Compound 8 (50 g, 1.0 equiv) and lithium chloride (1.2 equiv) were added to a 2 L three-necked round-bottom flask with an overhead stirrer at ambient temperature and degassed by three vacuum / N2 cycles. Degassed 2-MeTHF (10 volumes) was added, and the solution was then sparged with N2 for 5 min for degassed. Methyl formate (4.0 equiv) was added. The contents of the flask were cooled to -40 ° C while stirring under overhead stirring. NaOtPent (2.5 M in THF) (3.0 equiv) was added over 30 min, keeping the internal temperature below -40 ° C. The reaction mixture was aged at -40 ° C for 1.5 hours. The reaction was sampled and analyzed by HPLC using the X-Bridge analytical method, showing 2 area % compound 8 remaining.

[0238] The reaction mixture was quenched with a solution of AcOH (3.5 equivalents) in 2-MeTHF (5 volumes), keeping the internal temperature below -35 ° C. The reaction mixture was warmed to 5 ° C and then diluted with H2O (10 volumes). The organic matter was then washed with H2O (5 volumes). The organic stream was determined and analyzed via HPLC using X-Bridge and FFP2 analytical methods:

[0239] X bridge: compound 8a 88.7%, 96.2LCAP, compound 82.0%, 2.1LCAP, dimer 0.9LCAP.

[0240] FFP2: Impurity X was not detected.

[0241] Compound 8a was extracted into an aqueous solution with 10 wt% K PO (15 volumes) followed by 3 vol. Toluene (15 volumes) was added to the K PO layer, followed by portionwise addition of 6 M HCl (2.5 volumes), closely monitoring the internal temperature and pH. The aqueous layer was acidified to pH 5. The organic acidic toluene stream was washed with H O (2 x 5 volumes). The organic stream was determined and analyzed via HPLC using X-Bridge and FFP2 analytical methods:

[0242] X bridge: Compound 8a 86.2%, 99.4LCAP, Compound 8 <0.1%

[0243] FFP2: Impurity X was not detected.

[0244] Example 8. Alternative preparation of Formula I (Compound 9) (R)-l-(4-fluorophenyl)-l,4,7,8- tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester ​

[0245]

[0246] The 180 L vessel was dried under vacuum before use. A solution of compound 8a (6.5 kg; 1.0 equivalent) in toluene (approximately 6.00 wt %) was added to the reactor. Concentrated to 10 volumes [approximately 60 L], maintaining the batch temperature ≤ 40°C. Acetic acid (10.4 kg; 9.0 equivalents) was added, followed by water (0.3 volumes). The reactor contents were degassed via a vacuum nitrogen cycle. Magnesium acetate tetrahydrate (2.58 kg; 0.6 equivalents) was added and the contents of the reactor were stirred at 20°C for 15 minutes. 4-Fluorophenylhydrazine HCl (3.45 kg; 1.1 equivalents) was added, maintaining the internal temperature < 25°C. The reaction was aged at 20°C for 18 hours and 31 minutes and analyzed for conversion. HPLC analysis showed 100% conversion (0.0 area % compound 8a relative to compound 9).

[0247] Water (29.7 kg, 5 volumes) was added, aged at 20-22°C for 1 hour and 10 minutes, and the resulting layers were separated. The organic phase was washed twice with 1M aqueous HCl (30.3 kg, 5 volumes). The organic phase was washed with 10 wt% aqueous K3PO4 (31.2 kg, 5 volumes). The organic phase was washed with 5 wt% aqueous NaCl (30.8 kg, 5 volumes). The organic phase was washed with water (30.1 kg, 5 volumes).

[0248] The organic phase was discharged and the assay yield and LCAP of compound 9 were determined. HPLC analysis of the organic stream showed the presence of 7.47 kg of compound 9, corresponding to an assay yield of 99.6%, in 98.7 LCAP (0.03 LCAP impurity A, 1.07 LCAP impurity C, 0.24 LCAP impurity D). MVK polymer analysis showed SEC impurities at 1.84 area %.

[0249] ​

[0250] The reactor was rinsed with IPA (30.0 kg) and discharged to waste. The organic stream was fed to the reactor via an in-line filter and concentrated under reduced pressure to 3 volumes [approximately 22 L] relative to compound 9, maintaining T < 40°C. IPA (60.0 kg, 10 volumes relative to compound 9) was fed to the reactor. The mixture was concentrated under reduced pressure to 3 volumes [approximately 23 L] relative to compound 9, maintaining T < 40°C. IPA (6.4 kg, 1 volume relative to compound 9) was fed to the reactor. The resulting solution was heated to 58.6°C, aged until homogeneous, and analyzed by NMR for toluene content. The stirred solution was cooled to 50°C and seed crystals (41 g of compound 9; 0.55 wt%) were added. The mixture was cooled to 45°C and the seed bed was aged at 46°C for 30 minutes. Heptane (20.5 kg, 4 volumes relative to compound 9) was added at 45°C over 1 hour and 42 minutes. The resulting slurry was cooled to 21°C over 2 hours and 8 minutes. The slurry was aged at 20°C for 14 hours and 53 minutes. The slurry was cooled to 0°C using the upper and lower vessel jackets at -15°C over 14 minutes and aged at 0°C for 1 hour and 21 minutes. The slurry was filtered and washed with 3 volumes of a 1:1 volume mixture of IPA (8.8 kg, 1.5 volumes) and heptane (7.7 kg, 1.5 volumes) at 0°C. The filter cake was dehydrated with nitrogen for 30 minutes.

[0251] The 180 L vessel was dried under vacuum prior to use. Compound 9 (6.52 kg) was charged to the reactor. Toluene (14.1 kg, 2.5 volumes relative to Compound 9) and heptane (11.4 kg, 2.5 volumes relative to Compound 9) were charged. The reactor contents were warmed to 69 °C and aged until homogeneous. The stirred solution was cooled to 54 °C, seed crystals (32 g, 0.5 wt%) were charged and aged for 1 hour 40 minutes. Heptane (22.0 kg, 5 volumes relative to Compound 9) was charged over 2 hours 37 minutes. The contents of the reactor were cooled to 20 °C over 4 hours 16 minutes and then aged for 10 hours 51 minutes. Filtered and washed with 3 volumes of a 1 :3 volume mixture of 20 °C toluene (3.5 kg) and heptane (8.4 kg). Dried under nitrogen in an oven at 40 °C for 20 hours 36 minutes. This resulted in 5.65 kg (75% yield) of Compound 9 at 99.9 area% LCAP (0.03 LCAP Impurity A; 0.02 LCAP Impurity C; 0.14 LCAP Impurity D). An additional 2% of Compound 9 material formed a dome on top of the bottom outlet value. MVK polymer analysis showed <0.05 area% impurities.

[0252] ​

[0253] The 180 L vessel was dried under vacuum prior to use. Compound 9 (6.52 kg) was charged to the reactor. Toluene (14.1 kg, 2.5 volumes relative to Compound 9) and heptane (11.4 kg, 2.5 volumes relative to Compound 9) were charged. The reactor contents were warmed to 69 °C and aged until homogeneous. The stirred solution was cooled to 54 °C, seed crystals (32 g, 0.5 wt%) were charged and aged for 1 hour 40 minutes. Heptane (22.0 kg, 5 volumes relative to Compound 9) was charged over 2 hours 37 minutes. The contents of the reactor were cooled to 20 °C over 4 hours 16 minutes and then aged for 10 hours 51 minutes. Filtered and washed with 3 volumes of a 1 :3 volume mixture of 20 °C toluene (3.5 kg) and heptane (8.4 kg). Dried under nitrogen in an oven at 40 °C for 20 hours 36 minutes. This resulted in 5.65 kg (75% yield) of Compound 9 at 99.9 area% LCAP (0.03 LCAP Impurity A; 0.02 LCAP Impurity C; 0.14 LCAP Impurity D). An additional 2% of Compound 9 material formed a dome on top of the bottom outlet value. MVK polymer analysis showed <0.05 area% impurities.

[0254] Table 1. Impurity data for products of Examples 4 to 7

[0255]

[0256] *Analytical method: HPLC with UV detection. ND: not detected. NA: not applicable.

[0257] ​ ​

[0258]

[0259] Compound 9 can also be prepared according to the methods of Examples 30 to 33 in U.S. Patent No. 7,928,237.

[0260] Formula II (Compound 8a) (R,Z)-7-(hydroxymethylene)-6-oxo-4,6,7,8-tetrahydroisoquinoline- 2,8a(1H,3H)-dicarboxylic acid 2-(tert-butyl) 8a-methyl ester

[0261]

[0262] Methyl tert-butyl ether (232.0 kg) was charged to a 3000 L stainless steel reactor at 15-25 °C and sampled for KF analysis to ensure it was <0.1%. Hexamethyldisilazane (102.0 kg) was added to the reactor at 15-25 °C. The stirrer was started. The oxygen content was checked to confirm it was <0.1%. The mixture was cooled to -40 to -20 °C under nitrogen protection. The oxygen content was checked to confirm it was <0.1%.

[0263] The temperature was maintained at -40 to -20 °C and n-butyllithium (2.5 mol / L, 174.2 kg) was added to the reactor. N,N,N,’N-tetramethylethylenediamine (73.4 kg) was added dropwise to the mixture at a rate of 50-80 kg / h at -40 to -20 °C. After the addition, the mixture was maintained at -40 to -20 °C for 30 min.

[0264] The methyl tert-butyl ether solution of compound 8 (628.0 kg of solution, 65.0 kg after correction) was added to the mixture at -40 to -20 °C. After the addition, the mixture was stirred for 1-2 h. The mixture was cooled to -60 to -50 °C.

[0265] Methyl tert-butyl ether (156.0 kg) was charged to a 3000 L glass lined reactor at 15-25 °C and sampled for KF analysis to ensure it was <0.1%. Formic acid 2,2,2-trifluoroethyl ester (60.6 kg) was added to the 3000 L glass lined reactor at 15-25 °C. The solution in the 300 L glass lined reactor was transferred to the 3000 L stainless steel reactor at -60 to -40 °C under nitrogen protection.

[0266] The mixture was allowed to react at -60 to -40 °C. After 1 h, the mixture was sampled for HPLC analysis every 1-2 h to ensure the area % of compound 8 was <15% or the difference between two consecutive samples was <1%.

[0267] A portion of the solution of hydrochloric acid in purified water (810.0 kg) was added to the mixture at T < 0 °C. The addition was stopped when the temperature rose above 0 °C. The pH of the aqueous phase was sampled to ensure it was 6-7 (FIO).

[0268] A solution of hydrochloric acid (250.0 kg) in water (1254.0 kg) was added to the mixture at 0-20°C. The pH of the aqueous phase was sampled to ensure it was 3-5 (FIO). The mixture was stirred for 0.5-1 h and allowed to settle at 15-25°C for 0.5-1 h before separation. A solution of potassium carbonate in purified water (682.6 kg) was added to the organic phase at 0-10°C to adjust the pH to 9-10.

[0269] The mixture was stirred for 0.5-1 h and allowed to settle at 15-25° C. for 0.5-1 h, then separated. Methyl tert-butyl ether (190.0 kg) was added to the aqueous phase for extraction. The mixture was stirred for 0.5-1 h and allowed to settle at 15-25° C. for 0.5-1 h, then separated. All organic phases were combined.

[0270] The combined organic phases were washed with 1 ns. 15 potassium carbonate solution (225.0 kg) at 15-25°C. The mixture was stirred for 0.5-1 h and allowed to settle for 0.5-1 h before separation. A solution of hydrochloric acid in purified water (850.0 kg) was added to the aqueous phase at 0-10°C. The pH of the aqueous phase was sampled to ensure it was between 3 and 4.

[0271] The mixture was extracted twice with dichloromethane (232.2 kg x 2) at 15-25°C. In each extraction, the mixture was stirred for 0.5-1 h and allowed to settle for 0.5-1 h before separation. A solution of sodium chloride (95.6 kg) in water (464.0 kg) was added to the combined organic phases. The mixture was stirred for 0.5-1 h and allowed to settle for 0.5-1 h at 15-25°C before separation. The organic phase was sampled for purity and compound 8awt% analysis.

[0272] Formula I (Compound 9) (R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylic acid 6-(tert-butyl) 4a-methyl ester

[0273] Compound 8a (1133.4 kg, 119.3 kg after correction) in DCM was added to a 3000 L glass-lined reactor (1). The mixture was then concentrated under reduced pressure (P ≤ -0.06 MPa) until 130-195 L of the mixture remained. Acetic acid (597.8 kg) was added to the mixture at 20-40°C and stirred until the mixture was clear. The mixture was adjusted to 15-25°C, and sodium acetate (37.8 kg) was added to the mixture at 15-25°C and stirred for 1-1.5 hours.

[0274] At 15-25 °C, 4-fluorophenylhydrazine hydrochloride (84.0 kg, 75.6 kg after correction) was added in several batches of 4-6 kg to the mixture, with intervals of 20-40 min. The mixture was allowed to react at 15-25 °C. After 1 h, the mixture was sampled every 1-4 h for HPLC analysis to ensure that the area% of compound 8a was < 1 area%.

[0275] The mixture was transferred to a 5000 L glass-lined reactor 2. At 15-25 °C, purified water (1309.0 kg) and methyl tert-butyl ether (1206.0 kg) were added to reactor 1. The mixture was then stirred for 0.5 h before being transferred to reactor 2.

[0276] At 15-25 °C, the mixture was allowed to settle until the layers were separated, then separated. The aqueous phase was extracted with methyl tert-butyl ether (869.4 kg). The mixture was stirred at 15-25 °C for NLT 20-40 min and allowed to settle until the layers were separated, then separated.

[0277] At 15-25 °C, a solution of potassium carbonate was added to wash the combined organic phases. The mixture was stirred at 15-25 °C for 20-40 min and allowed to settle until the layers were separated, then separated. The organic phase was washed with a solution of potassium carbonate while maintaining the temperature at 15-25 °C. The pH of the aqueous phase was sampled to ensure that it was > 7. The mixture was stirred and allowed to settle until the layers were separated, then separated, at 15-25 °C.

[0278] The organic phase was filtered through a stainless steel nutsche filter pre-packed with silica gel (31.2 kg). The filter cake was rinsed three times with methyl tert-butyl ether (339.8 kg + 339.1 kg + 337.4 kg), with a 0.5-1 h soak of the nutsche filter each time. The filtrate was concentrated under reduced pressure (P < -0.06 MPa) at T < 40 °C until 455-520 L remained.

[0279] The mixture was adjusted to 35-45 °C, then at 35-45 °C, n-heptane (265.2 kg) was added to the concentrated mixture at a reference rate of 20-45 kg / h. After the addition, the mixture was stirred for 2-3 h. The mixture was cooled to 15-25 °C at a reference rate of 3-5 °C / h.

[0280] At 15-25 °C, the mixture was stirred to crystallize. After 2-3 h, the mixture was sampled every 2-3 h for mother liquor wt% analysis until it was < 4.0%, or the difference between two consecutive samples was < 0.5%. The mixture was filtered with a Φ 1250 stainless steel centrifuge. The filter cake was rinsed with n-heptane (176.8 kg).

[0281] Table 2. Impurity data of the product of Example 8

[0282]

[0283]

[0284] *Analytical method: HPLC with UV detection. ND: Not Detected. NA: Not Available.

[0285] The purity, impurity profile, and percent yield of three batches of crude compound 9 obtained from the reaction of compound 8a with 4-fluorophenylhydrazine hydrochloride are reported as averages. The values ​​in parentheses correspond to the range of results obtained for the three batches of crude compound 9.

[0286] The average values ​​of the yield and purity of eight batches of compound 8a made from compound 8 are reported. The values ​​in parentheses correspond to the range of yield and purity results obtained for each of the eight batches of compound 8a.

[0287] Although the foregoing invention has been described in detail by way of illustration and example for purposes of clarity of understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and the references provided herein, the present application shall prevail.

Claims

1. A method for preparing a compound of formula I: The method comprises: (a) forming a compound of formula II under conditions suitable for preparing the compound of formula I in a yield of at least 80% and a purity of at least 98%: Mg(OAc)2 and 4-fluorophenylhydrazine HCl: The first reaction mixture.

2. The method of claim 1, wherein the Mg(OAc)2 is Mg(OAc)2·4H2O.

3. The method of claim 1 or 2, wherein the Mg(OAc)2 is present in an amount of 0.5 to 1.0 molar equivalents relative to the compound of formula II.

4. The method of any one of claims 1 to 3, wherein the Mg(OAc)2 is present in an amount of about 0.6 molar equivalents relative to the compound of formula II.

5. The method of any one of claims 1 to 4, wherein the first reaction mixture further comprises toluene.

6. The method according to any one of claims 1 to 5, further comprising (a1) heating a first crystallization mixture comprising isopropyl alcohol, heptane and the compound of formula I, so that the compound of formula I is dissolved in the first crystallization mixture; and (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I.

7. The method of claim 6, wherein after step (a2), the compound of formula I contains Less than 0.05% of impurity A: Less than 0.5% impurity C: and Less than 0.25% impurity D:

8. The method according to claim 6 or 7, further comprising: (a3) heating a second crystallization mixture comprising toluene, heptane, and the first crystalline compound of Formula I, such that the first crystalline compound of Formula I is dissolved in the second crystallization mixture; and (a4) cooling the second crystallization mixture to form a second crystalline compound of Formula I.

9. The method of claim 8, wherein after step (a4), the compound of formula I contains Less than 0.05% of impurity A: Less than 0.05% impurity C: and Less than 0.20% impurity D:

10. The method according to any one of claims 1 to 9, comprising: (a) forming a compound comprising the formula II: About 0.6 molar equivalents of Mg(OAc)2·4H2O, acetic acid, water, toluene and 4-fluorophenylhydrazine HCl were added relative to the amount of the compound of formula II: The first reaction mixture is prepared in a yield of at least 80% and a purity of at least 98% to produce the compound of formula I: (a1) heating the first crystallization mixture comprising isopropyl alcohol, heptane and the compound of formula I, so that the compound of formula I is dissolved in the first crystallization mixture; (a2) cooling the first crystallization mixture to form the first crystalline compound of formula I; (a3) heating the second crystallization mixture comprising toluene, heptane and the first crystalline compound of Formula I, so that the first crystalline compound of Formula I is dissolved in the second crystallization mixture; as well as (a4) cooling the second crystallization mixture to form a second crystalline compound of formula I, wherein the second crystalline compound of formula I comprises Less than 0.05% of impurity A: Less than 0.05% impurity C: and Less than 0.20% impurity D:

11. A method for preparing a compound of formula II: The method comprises: (c) forming a compound comprising an alkyl formate, a non-nucleophilic base and a compound of formula III: A third reaction mixture is prepared to prepare the compound of formula II.

12. The method of claim 11, wherein the alkyl formate is methyl formate or ethyl formate.

13. The process of claim 11 or 12, wherein the alkyl formate is methyl formate.

14. The method of claim 13, wherein the methyl formate is present in an amount of 1 to 10 molar equivalents relative to the compound of formula III.

15. The method of claim 13 or 14, wherein the methyl formate is present in an amount of about 3.0 molar equivalents relative to the compound of formula III.

16. The method of any one of claims 11 to 15, wherein the non-nucleophilic base is an alkoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, lithium diisopropylamide (LDA), lithium hydride, sodium hydride, potassium hydride, or n-butyllithium.

17. The method of any one of claims 11 to 16, wherein the non-nucleophilic base is sodium tert-butoxide (NaOtBu), sodium tert-pentoxide (NaOtPent), or potassium tert-pentoxide (KOtPent).

18. The method of any one of claims 11 to 17, wherein the non-nucleophilic base is sodium tert-pentoxide (NaOtPent).

19. The method of any one of claims 11 to 18, wherein the third reaction mixture is at a temperature of about -40°C.

20. The method of any one of claims 11 to 19, wherein (c) forming a mixture comprising about 3.0 molar equivalents of methyl formate, sodium tert-amylate, lithium chloride, 2-methyltetrahydrofuran, and the compound of formula III relative to the compound of formula III: the third reaction mixture, wherein the third reaction mixture is at a temperature of about -40°C, Thereby preparing the compound of formula II:

21. The process of any one of claims 1 to 10, wherein the compound of formula II is prepared by the process of any one of claims 11 to 20.

22. The method of claim 21, comprising: (c) forming a mixture comprising about 3.0 molar equivalents of methyl formate, sodium tert-amylate, lithium chloride, 2-methyltetrahydrofuran, and the compound of formula III relative to the compound of formula III: the third reaction mixture, wherein the third reaction mixture is at a temperature of about -40°C, Thereby preparing the compound of formula II: as well as (a) forming a reaction mixture comprising the compound of formula II, about 0.6 molar equivalents of Mg(OAc)2.4H2O, acetic acid, water, toluene, and 4-fluorophenylhydrazine HCl relative to the compound of formula II: The first reaction mixture is prepared in a yield of at least 80% and a purity of at least 98% to produce the compound of formula I:

23. The method according to 22, further comprising: (a1) heating the first crystallization mixture comprising isopropyl alcohol, heptane and the compound of formula I, so that the compound of formula I is dissolved in the first crystallization mixture; (a2) cooling the first crystallization mixture to form the first crystalline compound of formula I; (a3) heating the third crystallization mixture comprising toluene, heptane and the first crystalline compound of Formula I, so that the first crystalline compound of Formula I is dissolved in the third crystallization mixture; as well as (a4) cooling the third crystallization mixture to form the third crystalline compound of formula I, wherein the third crystalline compound of formula I contains Less than 0.05% of impurity A: Less than 0.05% impurity C: and Less than 0.20% impurity D:

24. The method of any one of claims 11 to 23, wherein the compound of formula III is prepared by a method comprising the steps of: (d) forming a compound comprising pyrrolidine, acetic acid and a compound of formula IV: A fourth reaction mixture of:

25. The method of claim 24, wherein the compound of formula IV is prepared by a method comprising the steps of: (e) forming a mixture comprising a compound of formula V at a temperature of 10 to 25°C: A fifth reaction mixture of about 1.6 molar equivalents of methyl vinyl ketone (MVK), Cu(OAc)2 (anhydrous) and dimethylformamide relative to the amount of the compound of formula V, thereby preparing the compound of formula IV:

26. The method of claim 25, wherein the fifth reaction mixture has a temperature of 20 to 23°C.

27. The method of claim 25 or 26, further comprising: (e1) adding an aqueous mixture comprising HCl and LiCl to the fifth reaction mixture under conditions suitable for preparing the compound of formula IV.

28. The method of any one of claims 25 to 27, wherein the compound of formula IV contains less than 0.1% (w / w) MVK polymer.

29. The method of any one of claims 25 to 28, wherein the compound of formula IV contains less than 0.05% (w / w) MVK polymer.

30. A composition comprising: An amount of at least 99% of a compound of formula I: and One or more impurities in an amount of 0.01 to 1%.

31. The composition of claim 30, wherein the composition comprises: Less than 0.05% of impurity A: Less than 0.05% impurity C: and Less than 0.20% impurity D:

32. A composition as claimed in claim 30 or 31 , wherein the compound of formula I is prepared by a process as claimed in any one of claims 1 to 29.

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