Methods for preparing intermediates for heteroaryl-ketone fused azadecaline glucocorticoid receptor modulators

Abstract

The present invention provides methods for preparing heteroaryl-ketone fused azadecaline glucocorticoid receptor modulator intermediates and compositions with low impurity levels.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 486,753, filed February 24, 2023, which is incorporated herein by reference in its entirety for all purposes.

[0002] There are two types of receptors with high affinity 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 (corticotropin), which exhibits both circadian rhythmic changes and elevations in response to stress and food. Cortisol levels respond within minutes to many physical and psychological stressors, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid that acts by binding to the intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: the 777-amino acid ligand-binding GR-alpha and the GR-beta isoform, which lacks 50 carboxy-terminal residues. Because they contain a ligand-binding domain, GR-beta cannot bind ligand, is constitutively localized in the nucleus, and is transcriptionally inactive.

[0003] The biological effects of cortisol, including those caused by hypercortisolism, can be modulated at the GR level using receptor modulators, such as agonists, partial agonists, and antagonists. Several different classes of drugs can block the physiological effects of GR-agonist binding. These antagonists include compounds that bind to GR, thereby inhibiting the ability of agonists to effectively bind to and / or activate GR. One such known GR antagonist, mifepristone, has been found to be an effective antiglucocorticoid agent in humans (Bertagna (1984) J. Clin. Endocrinol. Metab. 59:25). Mifepristone binds to GR with high affinity, with a dissociation constant (K d ) is 10 -9 M (Cadepond (1997) Annu. Rev. Med. 48:129). Additional glucocorticoid receptor modulator compounds include dazcorilant (CORT113176) and relacorilant (CORT125134), previously described in PCT International Publication No. 2013 / 177559 and U.S. Patent No. 8,859,774; exicorilant (CORT125281) and zabacorilant (CORT125329), previously described in PCT International Publication No. 2015 / 077530 and U.S. Patent No. 10,047,082; and CORT108297, previously described in PCT International Publication No. 2010 / 132445 and U.S. Patent No. 8,889,867. What is needed in the art are new methods for preparing GR receptor modulator intermediates with higher purity. Surprisingly, the present invention meets these and other needs. Summary of the Invention

[0004] In one embodiment, the present invention provides a compound of formula I:

[0005] [ka] 1. A method for preparing a compound of formula II, comprising: (a) preparing a compound of formula II:

[0006] [ka] Mg(OAc)2, and 4-fluorophenylhydrazine HCl:

[0007] [ka] a first reaction mixture comprising: and forming under conditions suitable for preparing a compound of formula I in at least 80% yield and at least 98% purity.

[0008] In another embodiment, the present invention provides a compound of formula II:

[0009] [ka] 1. A method for preparing a compound of formula III, comprising: (c) reacting an alkyl formate, a non-nucleophilic base, and a compound of formula III:

[0010] [ka] forming a third reaction mixture comprising: The present invention provides a method for preparing a compound of formula II.

[0011] In another embodiment, the present invention provides a compound of formula I in an amount of at least 99%:

[0012] [ka] and A composition is provided that contains one or more impurities in an amount of 0.01 to 1%. DETAILED DESCRIPTION OF THE INVENTION

[0013] I. Overview This disclosure describes a new method for preparing the intermediate compound of formula I, 6-(tert-butyl)4a-methyl(R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate, which has a lower impurity concentration than previously described methods. The new method for preparing the compound of formula I improves process safety and cost-effectiveness and can be prepared on a larger scale compared to known methods. The compound of formula I can be prepared as described in Example 33 of U.S. Pat. No. 7,928,237.

[0014] II. Definition "About," when referring to a value, includes the stated value plus or minus 10% of the stated value. For example, about 50% includes a range of 45% to 55%, while about 20 molar equivalents includes a range of 18 to 22 molar equivalents. Thus, when referring to a range, "about" refers to the stated value at each of the upper and lower limits of that range plus or minus 10% of the stated value. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0015] "Forming a reaction mixture" refers to the process of contacting at least two separate species so that they can be mixed together and react. However, it will be understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate from one or more of the added reagents that may be produced in the reaction mixture.

[0016] "Dissolve," "dissolving," or "dissolution" refers to 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 99% soluble in a solvent.

[0017] By "substantially free" is meant a composition in which the undesirable component is present in an amount of less than 5% weight percentage (w / w) or HPLC peak area, less than 1% weight percentage (w / w) or HPLC peak area, less than 0.5% weight percentage (w / w) or HPLC peak area, or even less than 0.1% weight percentage (w / w) or HPLC peak area.

[0018] "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.

[0019] "Organic phase" refers to a mixture containing a water-miscible or water-immiscible solvent capable of dissolving either or both water-soluble and water-insoluble organic compounds. The organic phase of the present invention can be formed from one or more organic solvents. Exemplary organic solvents can include non-polar aprotic solvents, polar aprotic solvents, and polar protic solvents. Representative solvents include, but are not limited to, pentane(s), hexane(s), hexane, heptane, benzene, toluene, cyclopentyl methyl ether (CPME), diethyl ether, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), acetone, methyl ethyl ketone, N,N-dimethylacetamide (DMA / DMAc), N-methylpyrrolidinone (NMP), ethyl acetate, isopropyl acetate (iPrOAc), acetonitrile, methylene chloride, chloroform, and the like. The organic phase is substantially immiscible with the aqueous phase.

[0020] "Separating" or "separation" refers to one or more processes for physically isolating one or more components of a mixture, with the primary purpose of removing one or more undesired components (by-products, by-products, contaminants and / or impurities) present in the mixture to obtain a desired component or product substantially free of the undesired components.

[0021] "Acid" is defined as a group of protons (H + ) or a compound that is an electron pair acceptor according to the Lewis definition. Acids useful in the present invention include, but are not limited to, alkanoic or carboxylic acids (such as formic acid, acetic acid, citric acid, lactic acid, oxalic acid, trifluoroacetic acid (TFA)), sulfonic acids, and mineral acids, as defined herein. Mineral acids are inorganic acids such as hydrogen halides (such as hydrofluoric acid (HF), hydrochloric acid (HCl), hydrobromic acid (HBr)), halogen oxoacids (such as hypochlorous acid and perchloric acid), and sulfuric acid (HSO), nitric acid (HNO), phosphoric acid (HPO), chromic acid, and boric acid. Sulfonic acids that may be mentioned in particular are methanesulfonic acid (CH3SO3H; MSA), benzenesulfonic acid (C6H5SO3H), p-toluenesulfonic acid (4-CH3C6H4SO3H; pTsOH), trifluoromethanesulfonic acid (CF3SO3H; TfOH), camphorsulfonic acid.

[0022] "Non-nucleophilic base" refers to a base that is a moderate to strong base but at the same time poorly 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 hexamethyldisilazine, potassium hexamethyldisilazane, lithium diisopropylamine (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium, and amine salts. Examples of non-nucleophilic bases include triethylamine (EtN), N,N-diisopropylethylamine (iPrNEt, 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. Non-nucleophilic bases include non-nucleophilic amine bases.

[0023] A "solvent" refers to a substance, e.g., a liquid, capable of dissolving a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, while nonpolar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having a proton available for removal, e.g., a hydroxyl or carboxyl group. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (e.g., methanol, ethanol, propanol, isopropanol), acids (e.g., formic acid, acetic acid), 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 non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, and toluene. Other solvents are useful in the present invention.

[0024] "Anti-solvent" refers to a solvent or solvent system in which a compound, composition, or mixture has low solubility. The anti-solvent can be any suitable solvent described above.

[0025] "Heating" refers to raising the temperature of the mixture above room temperature or from a lower temperature to a higher temperature.

[0026] "Cooling" refers to lowering the temperature of a mixture below room temperature or from a higher temperature to a lower temperature.

[0027] "Room temperature" is the range of temperatures generally considered suitable for human habitation, i.e., between approximately 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0028] "Vacuum" or "reduced pressure" refers to a pressure that is less than atmospheric pressure. Atmospheric pressure is measured as approximately 1013 mbar, 760 mmHg, or approximately 14.7 psi. Thus, a vacuum can be less than 1013 mbar, or less than 100, 10, 1, 0.1 mbar, or less than 0.01 mbar.

[0029] "Alkyl" refers to a straight or branched chain saturated aliphatic group having the number of carbon atoms indicated. 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, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0030] "Alkyl formate" refers to a compound of formula HC(O)OR, where R is an alkyl group. Representative alkyl formates include methyl formate, HC(O)OMe, ethyl formate, HC(O)OEt, n-butyl formate, HC(O)OCHCHCHCHCH, and isoamyl formate, HC(O)OCHCHCH(CH).

[0031] "Alkoxide" is an anion -"alkoxide" refers to OR, where R is an alkyl group. Representative alkoxides include, but are not limited to, methoxide, ethoxide, isopropoxide, and t-butoxide.

[0032] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining 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 recipient thereof.

[0033] III. Methods for preparing Formula I The compound of formula I, 6-(tert-butyl)4a-methyl(R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate:

[0034] [ka] can be prepared as described in Example 33 of U.S. Patent No. 7,928,237. In some embodiments, the present invention provides a compound of Formula I:

[0035] [ka] 1. A method for preparing a compound of formula II, comprising: (a) preparing a compound of formula II:

[0036] [ka] Mg(OAc)2, and 4-fluorophenylhydrazine HCl:

[0037] [ka] a first reaction mixture comprising: and forming under conditions suitable for preparing a compound of formula I in at least 80% yield and at least 98% purity.

[0038] Suitable conditions for preparing compounds of formula I can include any suitable time and temperature, as described below in the Examples section.

[0039] Mg(OAc) can be any suitable hydrate. For example, Mg(OAc) can be a monohydrate, dihydrate, trihydrate, or tetrahydrate. In some embodiments, the method of preparing a compound of Formula I includes a method wherein Mg(OAc) is Mg(OAc) 4H0.

[0040] Mg(OAc) can be present in any suitable amount relative to the compound of Formula II. For example, Mg(OAc) can 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) include, but are not limited to, about 0.1 molar equivalent 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.

[0041] In some embodiments, the method of preparing a compound of Formula I includes a method wherein Mg(OAc) is 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 includes a method wherein Mg(OAc) is present in an amount of about 0.6 molar equivalents relative to the compound of Formula II.

[0042] In some embodiments, the method for preparing a compound of Formula I includes a method in which 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 may include, but is not limited to, pentane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride, and chloroform. In some embodiments, the method for preparing a compound of Formula I includes a method in which the first solvent comprises pentane, hexane, heptane, benzene, or toluene. In some embodiments, the method for preparing a compound of Formula I includes a method in which the first solvent comprises benzene or toluene. In some embodiments, the method for preparing a compound of Formula I includes a method in which the first reaction mixture further comprises toluene.

[0043] The compound of Formula I can be prepared in any suitable yield. For example, the 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 for preparing the compound of Formula I includes a method in which the compound of Formula I can be prepared in a yield of at least 80%.

[0044] The compound of Formula I can be prepared with any suitable purity. For example, the compound of Formula I can be prepared with 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 the compound of Formula I includes a method by which the compound of Formula I can be prepared with a purity of at least 96%. In some embodiments, the method of preparing the compound of Formula I includes a method by which the compound of Formula I can be prepared with a purity of at least 97%. In some embodiments, the method of preparing the compound of Formula I includes a method by which the compound of Formula I can be prepared with a purity of at least 98%. In some embodiments, the method of preparing the compound of Formula I includes a method by which the compound of Formula I can be prepared with a purity of at least 99%.

[0045] In some embodiments, the method of preparing a compound of Formula I comprises: (a) reacting a compound of Formula II:

[0046] [ka] Mg(OAc) 4H O, acetic acid, water, toluene, and 4-fluorophenylhydrazine HCl in an amount of about 0.6 molar equivalents relative to the compound of formula II:

[0047] [ka] forming a first reaction mixture comprising: Compounds of Formula I:

[0048] [ka] in at least 80% yield and at least 98% purity.

[0049] A. Purification of Formula I via Crystallization The compound of Formula I can be purified by various methods, including crystallization. In some embodiments, the method of preparing the compound of Formula I includes a method further comprising: (a1) heating a first crystallization mixture comprising isopropanol, 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.

[0050] The first crystalline compound of Formula I may contain various impurities, including, but not limited to, the following: Impurity A, 6-(tert-butyl)4a-methyl(4aR,8R)-1-(4-fluorophenyl)-8-hydroxy-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate:

[0051] [ka] Impurity C, 6-(tert-butyl)4a-methyl(R)-2-(4-fluorophenyl)-2,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate:

[0052] [ka] and Impurity D, 6-(tert-butyl)4a-methyl(R)-1-(4-fluorophenyl)-1,4,7,9-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate:

[0053] [ka] may include one or more of:

[0054] Impurities present in compositions of compounds of Formula I may include impurity A in an amount of less than 1%. For example, compounds of Formula I may contain impurity A 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% of impurity A. In some embodiments, compounds of Formula I may contain impurity A in an amount of less than 0.1%. In some embodiments, compounds of Formula I may contain impurity A in an amount of less than 0.05%.

[0055] Impurities present in the compound of Formula I may include impurity C in an amount of less than 1%. For example, the compound of Formula I may contain impurity C 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, the compound of Formula I may contain impurity C in an amount of less than 0.5%. In some embodiments, the compound of Formula I may contain impurity C in an amount of less than 0.1%. In some embodiments, the compound of Formula I may contain impurity C in an amount of less than 0.05%.

[0056] Impurities present in the compound of Formula I may include impurity D in an amount of less than 1%. For example, the compound of Formula I may contain impurity D 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, 0.24, 0.23, 0.22, 0.21%, less than 0.2%, or less than 0.1%. In some embodiments, the compound of Formula I may contain impurity D in an amount of less than 0.25%. In some embodiments, the compound of Formula I may contain impurity D in an amount of less than 0.2%.

[0057] The amount of impurities in a composition containing a compound of Formula I can be measured by any suitable method, such as weight percentage (w / w) or HPLC peak area with ultraviolet detection.

[0058] In some embodiments, the method for preparing a compound of Formula I comprises, after step (a2), providing a compound of Formula I: Impurity A less than 0.05%:

[0059] [ka] Impurity C less than 0.5%:

[0060] [ka] and Impurity D less than 0.25%:

[0061] [ka] The present invention also includes a method comprising the steps of:

[0062] In some embodiments, the method of preparing a compound of Formula I includes a method 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 dissolves in the second crystallization mixture; and (a4) cooling the second crystallization mixture to form a second crystalline compound of Formula I.

[0063] The first and second crystallization mixtures can be heated to any suitable temperature. Exemplary temperatures include above room temperature, such as, but not limited to, room temperature to reflux of the first crystallization mixture, room temperature to 65°C, or about room temperature to 40°C, or 40°C to 65°C, or 40°C to 60°C. In some embodiments, the first crystallization mixture can 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.

[0064] The first and second crystallization mixtures can also be cooled to any suitable temperature, with typical temperatures including below room temperature, room temperature, or above room temperature.

[0065] In some embodiments, the method for preparing a compound of Formula I comprises, after step (a4), providing a compound of Formula I: Impurity A less than 0.05%:

[0066] [ka] Impurity C less than 0.05%:

[0067] [ka] and Impurity D less than 0.20%:

[0068] [ka] The present invention also includes a method comprising the steps of:

[0069] In some embodiments, the method for preparing a compound of formula I comprises: (a) a compound of formula II:

[0070] [ka] Mg(OAc) 4H O, acetic acid, water, toluene, and 4-fluorophenylhydrazine HCl in an amount of about 0.6 molar equivalents relative to the compound of formula II:

[0071] [ka] forming a first reaction mixture comprising: Compounds of Formula I:

[0072] [ka] in a yield of at least 80% and a purity of at least 98%; (a1) heating a first crystallization mixture comprising isopropanol, heptane, and a compound of Formula I such that the compound of Formula I dissolves in the first crystallization mixture; (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I; (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; (a4) cooling the second crystallization mixture to form a second crystalline compound of Formula I; the second crystalline compound of formula I is Impurity A less than 0.05%:

[0073] [ka] Impurity C less than 0.05%:

[0074] [ka] and Impurity D less than 0.20%:

[0075] [ka] The present invention also includes a method comprising the steps of:

[0076] B. Preparation of Formula II The compound of formula II, 2-(tert-butyl)8a-methyl(R,Z)-7-(hydroxymethylene)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylate:

[0077] [ka] can be prepared by the method provided in Example 32 of U.S. Pat. No. 7,928,237. In some embodiments, the present invention provides a compound of formula II:

[0078] [ka] 1. A method for preparing a compound of formula III, comprising: (c) reacting an alkyl formate, a non-nucleophilic base, and a compound of formula III:

[0079] [ka] forming a third reaction mixture comprising: The present invention provides a method for preparing a compound of formula II.

[0080] The alkyl formate of the third reaction mixture has the formula HC(O)OC 1-6 Representative alkyl formates include, but are not limited to, methyl formate, ethyl formate, n-propyl formate, or n-butyl formate.

[0081] In some embodiments, the method of preparing a compound of formula II includes a method where the alkyl formate is methyl formate or ethyl formate. In some embodiments, the method of preparing a compound of formula II includes a method where the alkyl formate is methyl formate.

[0082] The alkyl formate can be present in any suitable amount relative to 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 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.

[0083] In some embodiments, the method of preparing a compound of formula II includes 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 of preparing a compound of formula II includes a method wherein methyl formate is present in an amount of about 3.0 molar equivalents relative to the compound of formula III.

[0084] Non-nucleophilic bases useful in the method of preparing compounds 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 hexamethyldisilazine, potassium hexamethyldisilazane, lithium diisopropylamine (LDA), lithium hydride, sodium hydride, potassium hydride, n-butyllithium , and amine bases such as triethylamine (EtN), N,N-diisopropylethylamine (iPrNEt, 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 a compound of Formula II includes a method in which the non-nucleophilic base is an alkoxide, hexamethylsilazane (HMDS), lithium hexamethyldisilazane, sodium hexamethyldisilazine, potassium hexamethyldisilazane, lithium diisopropylamine (LDA), lithium hydride, sodium hydride, potassium hydride, or n-butyllithium. In some embodiments, the method for preparing a compound of Formula II includes a method in which the non-nucleophilic base is an alkoxide.

[0085] Alkoxides useful in the method for preparing a compound of Formula II include, but are not limited to, methoxide, ethoxide, isopropoxide, tert-butoxide, or tert-pentoxide. Representative counterions of alkoxides useful in the method for preparing a compound of Formula II include, but are not limited to, sodium or potassium. In some embodiments, the method for preparing a compound of Formula II includes a method in which the non-nucleophilic base is sodium tert-butoxide (NaOtBu), sodium tert-pentoxide (NaOtPent), or potassium tert-pentoxide (K0tPent). In some embodiments, the method for preparing a compound of Formula II includes a method in which the non-nucleophilic base is sodium tert-pentoxide (NaOtPent).

[0086] The alkoxide can be present in any suitable amount relative to the compound of Formula III. For example, the alkoxide can be present in an amount of 1 to 10 molar equivalents relative to the compound of Formula III, or 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 of preparing a compound of formula II includes a method wherein sodium tert-pentoxide is present in an amount of about 3.0 molar equivalents relative to the compound of formula III.

[0087] The third reaction mixture may also contain an inorganic salt. Exemplary 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 a compound of Formula II includes a method in which the third reaction mixture contains lithium chloride.

[0088] The inorganic salt can be present in any suitable amount relative to the compound of Formula III. For example, the inorganic salt can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of Formula III, or 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 the compound of Formula III. Representative amounts of the inorganic salt include, but are not limited to, about 1 molar equivalent relative to the compound 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 the compound of Formula III. In some embodiments, the method of 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 the compound of Formula III.

[0089] In some embodiments, the method for preparing a compound of Formula II includes a method in which the third reaction mixture further comprises 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, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, ethyl acetate, acetonitrile, methylene chloride, and chloroform. In some embodiments, the method for preparing a compound of Formula II includes a method in which the third solvent comprises diethyl ether, tetrahydrofuran, or 2-methyltetrahydrofuran. In some embodiments, the method for preparing a compound of Formula II includes a method in which the third reaction mixture further comprises 2-methyltetrahydrofuran.

[0090] Suitable conditions for preparing compounds of formula I can include any suitable time and temperature, as described below in the Examples section.

[0091] The third reaction mixture can be cooled to any suitable temperature. Typical temperatures include room temperature or below. Typical temperatures include temperatures below room temperature, for example, but are 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 for 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 a compound of Formula II includes a method wherein the third reaction mixture is at a temperature of about -40°C.

[0092] The compound of formula II may include various impurities, such as, but not limited to, X, 2-(tert-butyl) 8a-methyl(R,4E,7Z)-4,7-bis(hydroxymethylene)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylate.

[0093] [ka] Impurities present in the compound of Formula II may include impurity X in an amount of less than 1%. For example, the compound of Formula II may contain 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, the compound of Formula II may contain impurity X in an amount of less than 0.1%. In some embodiments, the compound of Formula II may contain impurity X in an amount of less than 0.01%.

[0094] In some embodiments, the method for preparing a compound of Formula II comprises providing a compound of Formula II containing less than 0.01% of an impurity X:

[0095] [ka] The present invention also includes a method comprising the steps of:

[0096] In some embodiments, the method of preparing a compound of Formula II comprises (c) reacting methyl formate, sodium tert-pentoxide, lithium chloride, 2-methyltetrahydrofuran, and a compound of Formula III in an amount of about 3.0 molar equivalents relative to the compound of Formula III:

[0097] [ka] forming a third reaction mixture comprising: wherein the third reaction mixture is at a temperature of about −40° C.; Thereby, a compound of formula II:

[0098] [ka] The present invention also includes a method in which the compound is prepared.

[0099] In some embodiments, the method of preparing a compound of formula I includes a method in which a compound of formula II is prepared by a method of the present invention.

[0100] In some embodiments, the method of preparing a compound of Formula II comprises (c) reacting methyl formate, sodium tert-pentoxide, lithium chloride, 2-methyltetrahydrofuran, and a compound of Formula III in an amount of about 3.0 molar equivalents relative to the compound of Formula III:

[0101] [ka] forming a third reaction mixture comprising: wherein the third reaction mixture is at a temperature of about −40° C.; Thereby, a compound of formula II:

[0102] [ka] and (a) a compound of Formula II, Mg(OAc) 4H O in an amount of about 0.6 molar equivalents relative to the compound of Formula II, acetic acid, water, toluene, and 4-fluorophenylhydrazine HCl:

[0103] [ka] forming a first reaction mixture comprising: Compounds of Formula I:

[0104] [ka] in a yield of at least 80% and a purity of at least 98%; The method includes:

[0105] In some embodiments, the method for preparing a compound of formula II comprises: (a1) heating a first crystallization mixture comprising isopropanol, heptane, and a compound of Formula I such that the compound of Formula I dissolves in the first crystallization mixture; (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I; (a3) heating a 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; (a4) cooling the third crystallization mixture to form a third crystalline compound of Formula I; wherein the third crystalline compound of formula I is Impurity A less than 0.05%:

[0106] [ka] Impurity C less than 0.05%:

[0107] [ka] and Impurity D less than 0.20%:

[0108] [ka] The present invention also includes a method comprising:

[0109] C. Preparation of Formula III The compound of formula III, 2-(tert-butyl)8a-methyl(R)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylate:

[0110] [ka] can be prepared by the method of Example 31 of U.S. Pat. No. 7,928,237.

[0111] In some embodiments, the method for preparing a compound of formula II comprises: (d) reacting a compound of formula III with pyrrolidine, acetic acid, and a compound of formula IV:

[0112] [ka] forming a fourth reaction mixture comprising: Thereby, a compound of formula III:

[0113] [ka] The present invention includes a method for preparing the compound of the present invention.

[0114] Pyrrolidine can be present in any suitable amount relative to the compound of Formula IV. For example, pyrrolidine can be present in an amount of 0.05 to 1.0 molar equivalent relative to the compound of Formula IV, or 0.1 to 1.0 molar equivalent relative to the compound of Formula IV, or 0.1 to 0.5 molar equivalent relative to the compound of Formula IV. Representative amounts of pyrrolidine include, but are not limited to, about 0.1 molar equivalent 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 equivalent relative to the compound of Formula IV. In some embodiments, the method of preparing a compound of Formula III includes a method in which pyrrolidine is present in an amount of about 0.3 molar equivalent relative to the compound of Formula IV.

[0115] The acetic acid can be any suitable acetic acid. For example, the acetic acid can be glacial acetic acid. The acetic acid can be present in any suitable amount relative to the compound of Formula IV. For example, the acetic acid can be present in an amount of 0.1 to 10 molar equivalents relative to the compound of Formula IV, or 0.5 to 5 molar equivalents relative to the compound of Formula IV, or 1 to 2 molar equivalents, 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 molar equivalents, 0.7 molar equivalents, 0.8 molar equivalents, 0.9 molar equivalents, 1.0 molar equivalents, 1.1 molar equivalents, 1.2 molar equivalents, 1.3 molar equivalents, 1.4 molar equivalents, or about 1.5 molar equivalents relative to the compound of Formula IV. In some embodiments, the method of preparing a compound of Formula III includes a method in which acetic acid is present in an amount of about 1.5 molar equivalents relative to the compound of Formula IV.

[0116] In some embodiments, the method for preparing a 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 can include, but is not limited to, methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and methyl t-butyl ether. The fourth solvent can include, but is not limited to, methanol, ethanol, n-propanol, isopropanol, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether, and toluene. In some embodiments, the method for preparing a compound of Formula III includes a method in which the fourth solvent comprises isopropanol, methyl t-butyl ether, and combinations thereof. In some embodiments, the method for preparing a compound of Formula III includes a method in which the fourth reaction mixture further comprises methyl t-butyl ether.

[0117] 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 forming a fourth crystallization mixture containing 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 a crystalline compound of formula III.

[0118] The ratio of isopropanol to water can be any suitable ratio. For example, the ratio of isopropanol 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 isopropanol to water include, but are not limited to, about 1:8 (volume / volume), or about 1:7, 1:6, 1:5, 1:4, 3:8, 4:8, 5:8, or about 6:8 (volume / volume). In some embodiments, the method for preparing a compound of Formula III includes a fourth crystallization mixture having 3:8 (volume / volume) isopropanol and water.

[0119] In some embodiments, the method for preparing a compound of Formula II comprises: (d) reacting a compound of Formula III with pyrrolidine in an amount of 0.3 molar equivalents relative to the compound of Formula IV, glacial acetic acid in an amount of 1.2 molar equivalents relative to the compound of Formula IV, isopropanol, and a compound of Formula IV:

[0120] [ka] forming a fourth reaction mixture comprising: Thereby, a compound of formula III:

[0121] [ka] The present invention includes a method for preparing the compound of the present invention.

[0122] D. Preparation of Formula IV The compound of formula IV, 1-(tert-butyl) 3-methyl(S)-4-oxo-3-(3-oxobutyl)piperidine-1,3-dicarboxylate:

[0123] [ka] can be prepared by the method of Example 30 of U.S. Pat. No. 7,928,237.

[0124] In some embodiments, the method of preparing a compound of formula II comprises: (e) reacting a compound of formula IV with a compound of formula V:

[0125] [ka] A fifth reaction mixture comprising methyl vinyl ketone (MVK) in an amount of about 1.6 molar equivalents relative to the compound of formula V, Cu(OAc)2 (anhydrous), and dimethylformamide is formed at a temperature of 10 to 25°C, thereby producing a compound of formula IV:

[0126] [ka] The present invention includes a method for preparing the compound of the present invention.

[0127] The fifth reaction mixture can be at any suitable temperature. Exemplary 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 for 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 a compound of Formula IV includes a method wherein the fifth reaction mixture has a temperature of 20°C to 23°C.

[0128] In some embodiments, the method of preparing a compound of formula IV includes a method further comprising: (e1) adding an aqueous mixture comprising HCl and LiCl to the fifth reaction mixture under conditions suitable for preparing a compound of formula IV.

[0129] In some embodiments, the method of preparing a compound of Formula IV includes a method wherein the compound of Formula IV contains less than 5% MVK polymer. In some embodiments, the method of preparing a compound of Formula IV includes a method wherein the compound of Formula IV contains less than 1% MVK polymer. In some embodiments, the method of preparing a compound of Formula IV includes a method wherein the compound of Formula IV contains less than 0.1% MVK polymer. In some embodiments, the method of preparing a compound of Formula IV includes a method 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 percentage (w / w) or by HPLC peak area with ultraviolet detection.

[0130] IV. Low-Impurity Composition The present invention provides a composition of formula I having a low impurity content. The impurity content can be expressed in a variety of different ways. For example, the impurity content can be expressed as a weight percentage (w / w) or by % (HPLC peak area). In some embodiments, the impurity content can be expressed as % (HPLC peak area). In some embodiments, the present invention provides a composition of formula I having at least 99% of the compound of formula I:

[0131] [ka] and A composition is provided that contains one or more impurities in an amount of 0.01 to 1%.

[0132] The compositions of Formula I may contain one or more impurities present in a total amount of 0.01 to 1%.

[0133] Impurities present in a composition of a compound of Formula I may include impurity A in an amount of less than 1%. For example, a composition of a compound of Formula I may contain 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, a composition comprising a compound of Formula I may contain less than 0.1% impurity A. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.05% impurity A.

[0134] Impurities present in a composition of a compound of Formula I may include impurity C in an amount of less than 1%. For example, a composition of a compound of Formula I may contain 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%, less than 0.02%, or less than 0.01% impurity C. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.5% impurity C. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.1% impurity C. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.05% impurity C.

[0135] Impurities present in compositions of compounds of Formula I may include impurity D in amounts of less than 1%. For example, compositions of compounds of Formula I may contain less than 1.0%, or less than 0.9%, or less than 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 may contain less than 0.25% of impurity D. In some embodiments, compositions comprising compounds of Formula I may contain less than 0.2% of impurity D.

[0136] In some embodiments, the compound of Formula I is obtained by treating an impurity comprising: Impurity A less than 0.05%:

[0137] [ka] Impurity C less than 0.05%:

[0138] [ka] and Impurity D less than 0.20%:

[0139] [ka] The compound includes at least one of:

[0140] In some embodiments, compounds of formula I include compounds prepared by the methods of the present invention.

[0141] V. Working Example In the methods that follow, the following abbreviations are used:

[0142] [Table 1]

[0143] Powder X-ray diffraction (XRPD). XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Isothermal samples were analyzed by transmission and held between low-density polyethylene films. The XRPD program used included the following parameters: (1) 2θ range of 3–40°, (2) step size of 0.013°, (3) count time of 99 s, and (4) a run time of approximately 22 min. XRPD patterns were screened using HighScore Plus 2.2c software.

[0144] Differential Scanning Calorimetry (DSC). DSC analyses were 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 under nitrogen up to 300°C. Indium metal was used as the calibration standard. Temperatures were reported at the time of transition, rounded to two decimal places (0.01°C).

[0145] The reaction step of the present invention can be carried out for any suitable reaction time. For example, the reaction time can be minutes, hours, or days. In some embodiments, the reaction time can be several hours, such as at least 8 hours. In some embodiments, the reaction time can be several hours, such as at least overnight. In some embodiments, the reaction time can be several days. In some embodiments, the reaction time can be at least two hours. In some embodiments, the reaction time can be at least eight hours. In some embodiments, the reaction time can be at least several days. In some embodiments, the reaction time can be about 2 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 be about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or more than about 1 week.

[0146] The reaction steps of the present invention can be carried out at any suitable reaction temperature. Typical temperatures include, but are not limited to, below room temperature, room temperature, or above room temperature. Other temperatures useful in the methods of the present invention 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 about 15°C, or about 20°C, or about 25°C, or 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.

[0147] Example 1. Preparation of Compound of Formula V (Compound 6), 1-(tert-butyl) 3-methyl(S)-4-((1-(diethylamino)-3-methyl-1-oxobutan-2-yl)amino)-5,6-dihydropyridine-1,3(2H)-dicarboxylate

[0148] [ka]

[0149] To a 100 L vessel pre-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 with stirring at 25 °C. After 88 min, the solid dissolved. The vessel was then cooled to 0 °C, and pivaloyl chloride [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 at -5 to 5 °C. After the addition was complete, the reactor was heated to 20 °C. The resulting mixture was aged at 20 °C for 3 h, and the conversion of compound 1 to the pivorate ester (mixed anhydride) was determined by HPLC.

[0150] 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 minutes, maintaining the temperature at -5 to 5°C. The resulting mixture was aged at 20°C for 10 minutes. The resulting mixture was then warmed to 20°C. The resulting mixture was aged at 20°C for 5 hours, and the area of ​​compound 1 was analyzed by HPLC. 1N hydrochloric acid solution [21.00 kg, 17.5 L, 5 vol.] was charged to the vessel, stirred for 15 minutes, aged for 15 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. The organic layer was retained in the reactor. 5 wt. % sodium bicarbonate [11.03 kg, 10.5 L, 3 vol.] was charged to the vessel, stirred for 15 minutes, aged for 15 minutes, the biphasic mixture was allowed to settle, the aqueous layer was drained from the reactor, and the organic phase was retained in the reactor.

[0151] Purified water [7 kg, 7 L, 2 vol] was then charged to the vessel containing the organic phase, and the biphasic mixture was stirred for 15 minutes. Stirring was stopped, the mixture was aged for 15 minutes, and the biphasic mixture was allowed to settle. The aqueous layer was separated, and the organic phase was concentrated under reduced pressure to approximately 14.0-17.5 L [approximately 4.5 vol], maintaining the batch temperature below 40 °C. Isopropyl alcohol [13.83 kg, 17.5 L, 5 vol] was charged to the vessel, and concentrated under reduced pressure to approximately 14.0-17.5 L [approximately 4.5 vol], maintaining the batch temperature below 55 °C. Isopropyl alcohol [13.83 kg, 17.5 L, 5 vol] was charged to the vessel, and concentrated under reduced pressure to approximately 14.0-17.5 L [approximately 4.5 vol], maintaining the batch temperature below 55 °C. HPLC analysis of the resulting isopropyl acetate solution contained 3.95 kg (assay yield 90%) of tert-butyl (S)-(1-(diethylamino)-3-methyl-1-oxobutan-2-yl)carbamate (compound 2) with a chemical purity of 97.3 area %.

[0152] A 50 L vessel was dried under vacuum before use. A solution of compound 2 [tert-butyl (S)-(1-(diethylamino)-3-methyl-1-oxobutan-2-yl)carbamate; 3.66 kg, 13.44 mol, 1.11 eq] in IPA was added to the vessel over 20 min at 20–21 °C. IPA [7.90 kg, 10.0 L, 3 vol] was added to the vessel, and the total volume was adjusted to 16.5 L [5 vol] over 20 min at 5–10 °C. 95 wt% concentrated H2SO4 [1.40 kg, 14.24 mol, 1.11 eq] was added over 50 min at 7–17 °C. (H2SO4 was alternatively added over approximately 10 h.) The mixture was warmed to 60 °C. The resulting mixture was aged at 60–61 °C for 29 h.

[0153] Cool to 0°C over 45 minutes. Purified water [5.12 kg, 5.12 L, 1.55 vol] was charged to the vessel over 15 minutes at 0°C. TMEDA [3.40 kg, 29.24 mol, 2.28 eq] was charged to the vessel over 40 minutes at 0-4°C. 1-(tert-butyl) 3-methyl 4-oxopiperidine-1,3-dicarboxylate (compound 5) [3.3 kg, 12.83 mol, 1.0 eq] was charged to the vessel over 50 minutes at -5-3°C. The batch was warmed to 60°C over 50 minutes and aged at 60°C for 8 hours.

[0154] 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 vol] 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 at 0°C for 1 hour. The batch was filtered and deliquorized under nitrogen pressure. A mixture of IPA [2.6 kg, 3.3 L, 1 vol] and purified water [6.6 kg, 6.6 L, 2 vol] was charged to the vessel and subsequently transferred to an Oyster filter as the first cake wash. Purified water [6.6 kg, 6.6 L, 2 vol] was charged as the second cake wash. The cake was dried under vacuum at 40°C for 20 hours with a minimal nitrogen sweep and analyzed for weight percent. 4.0 kg of Compound 6 was obtained.

[0155] Example 2. Preparation of the compound of formula IV (compound 7), 1-(tert-butyl) 3-methyl (S)-4-oxo-3-(3-oxobutyl)piperidine-1,3-dicarboxylate

[0156] [ka]

[0157] 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 under vacuum three times. DMF [3 volumes] was charged to the vessel, degassed three times under positive nitrogen pressure, and stirred at 35°C for 10 minutes. The batch was cooled to 21°C, and 90% MVK [3.33 kg, 1.6 equiv.] was charged over 97 minutes while maintaining the batch temperature at 22°C. After the MVK addition, the vessel was subjected to a pressure purge of 2 + 500 mBArg. The batch was aged under stirring for 22 hours, and the conversion of compound 6 was analyzed by HPLC. HPLC showed a 96.9% conversion of compound 6.

[0158] The batch was cooled to 1°C and charged with methyl tert-butyl ether [81.4 kg, 110 L, 10 vol]. Maintaining a temperature below 11°C, approximately 0.5 M HCl / 10 wt% LiCl [116.6 kg, 10 vol] was charged to the vessel. After the addition, the vessel was subjected to a pressure purge of 2 + 500 mBArg. The batch was warmed to 22°C and aged under rapid stirring for 22 minutes, after which it was sampled and analyzed by HPLC for hydrolysis of the imine intermediate to form compound 7. HPLC showed 97.3 A% conversion to compound 7 (2.7 LCAP of imine intermediate remained).

[0159] The biphasic mixture was allowed to settle and the aqueous layer was drained. The organic layer was drained into a second drum for temporary storage. The aqueous layer and methyl tert-butyl ether [40.7 kg, 55 L, 5 volumes] were charged to a vessel, stirred, and aged for 5 minutes. After the addition and while stirring, the vessel was subjected to a pressure purge of 2 + 500 mBArg. The biphasic mixture was allowed to settle and the aqueous layer was drained. The first organic cut was charged into the vessel with the second organic cut. After the addition and while stirring, the vessel was subjected to a pressure purge of 2 + 500 mBArg.

[0160] 10 wt% lithium chloride [23.2 kg, 22 L, 2 volumes] was charged to the vessel. After the addition and while stirring, the vessel was subjected to a pressure purge of 2 + 500 mBArg. The wash was aged for 3 minutes, the biphasic mixture was allowed to settle, and the aqueous layer was drained. 5 wt% sodium bicarbonate [23.2 kg, 22 L, 2 volumes] was charged to the vessel. After the addition and while stirring, the vessel was subjected to a pressure purge of 2 + 500 mBArg. 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 equiv] was charged over 13 minutes while maintaining the temperature below 5°C. The batch was warmed to 22°C and aged for 31 minutes, then sampled and analyzed for excess MVK uptake. HPLC showed 0.6 LCAP of MVK remaining.

[0161] The batch was cooled to 0 °C and charged with 1 M hydrochloric acid solution [67.3 kg, 6 vol] while maintaining the temperature below 10 °C. The batch was warmed to 22 °C, aged for 2 minutes, the biphasic mixture allowed to settle, and the aqueous layer was drained. 10 wt% lithium chloride [23.2 kg, 22 L, 2 vol] was charged to the vessel, stirred, aged for 2 minutes, the biphasic mixture allowed to settle, and the aqueous layer was drained. 3 wt% sodium bicarbonate [23.2 kg, 22 L, 2 vol] was charged to the vessel, stirred, aged for 7 minutes, the biphasic mixture allowed to settle, and the aqueous layer was drained. The organic layer was drained. The solution contained 8.43 kg of compound 7 (96% assay yield, 94.6 L CAP 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.

[0162] Example 3. Preparation of Compound of Formula III (Compound 8), 2-(tert-butyl) 8a-methyl (R)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylate

[0163] [ka]

[0164] A 400 L vessel was dried under vacuum prior to use. A solution of compound 7 [8.25 kg, 120.1 kg in MTBE] was charged to the reactor. The mixture was concentrated to 3 volumes [approximately 26 L] while maintaining an internal temperature below 40° C. IPA [19.6 kg, 3 volumes] was charged. The mixture was concentrated to 3 volumes [approximately 25 L] while maintaining an internal temperature below 40° C. IPA [52.3 kg, 8 volumes] was charged. The contents of the reactor were cooled to 1° C. Glacial acetic acid [1.84 kg, 1.2 equivalents] was charged while maintaining an internal temperature below 10° C. Pyrrolidine [0.543 kg, 0.3 equivalents] was charged while maintaining an internal temperature below 10° C. 563 grams was charged, corresponding to a 3.8% excess. The reactor contents were warmed to 20°C and aged at 20-21°C for 18.2 hours, then analyzed for reaction conversion.

[0165] Aqueous NH4Cl solution [10% wt / wt; 69.2 kg, 8 volumes] was charged 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] while maintaining the internal temperature below 40°C. Next, methyl tert-butyl ether [61.6 kg, 10 volumes] was charged to the vessel, and the mixture was stirred for 5 minutes. The 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 10% wt / wt solution of 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 isolated organic phase indicated that the MTBE solution contained 7.40 kg of the compound of Formula III, corresponding to an assay yield of 95%. Subsequent processing operations, solvent inputs, and volumes involving this solution were based on this 95% assay yield.

[0166] The MTBE solution containing the compound of formula III was concentrated to 3 volumes relative to the assay yield [approximately 22 L] while maintaining an internal temperature below 40°C. IPA [52.2 kg, 9 volumes] was charged to the reactor, and the resulting solution was again concentrated to 3 volumes [approximately 22 L]. Water [14.5 kg, 2 volumes] was then charged to the reactor over 30 minutes, and the mixture was subsequently seeded with a sample of the compound of formula III (39.0 g, approximately 0.5% w / w relative to the assay value, 7.4 kg) at 22°C and aged for 1 hour and 18 minutes. A second portion of water [7.24 kg, 1 volume] was then charged to the reactor over 32 minutes, 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 charged 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 1 hour. The slurry was then filtered, and the filter cake was washed with a 1:4 mixture (v / v) of 3 volumes of IPA [4.34 kg, 0.5 volumes] and water [17.4 kg, 2 volumes]. The resulting solid was then dried in an oven at 30°C under a heavy nitrogen flow until most of the water was removed. The solid was further dried in an oven at 40°C under a nitrogen sweep to give 6.79 kg of the compound of Formula III, corresponding to an isolated yield of 87%. HPLC analysis of the dried solid showed the material to have an assay of 99.9% wt / wt and a chemical purity of 99.7 area%. Karl Fischer (KF) titration showed the solid contained 0.08% wt / wt of water.

[0167] Example 4. Preparation of Compound of Formula II (Compound 8a), 2-(tert-butyl)8a-methyl(R,Z)-7-(hydroxymethylene)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylate

[0168] [ka]

[0169] Compound 8 (50 g, 1.0 equiv.) and lithium chloride (1.2 equiv.) were charged to a 2 L, three-necked, round-bottom flask equipped with an overhead stirrer at ambient temperature and degassed three times with vacuum / N2 cycles. Degassed 2-MeTHF (10 vol.) was added, and the solution was then degassed for 5 minutes while sparging with N2. Methyl formate (4.0 equiv.) was added. The contents of the flask were cooled to -40°C with overhead stirring. NaOtPent (2.5 M in THF) (3.0 equiv.) was added over 30 minutes, maintaining the internal temperature below -40°C. The reaction mixture was aged at -40°C for 1.5 hours. The reaction was sampled and analyzed via HPLC using X-Bridge analysis, which showed 2 A% of compound 8 remaining.

[0170] The reaction mixture was quenched with a solution of AcOH (3.5 equiv) in 2-MeTHF (5 vol) while maintaining an internal temperature below -35°C. The reaction mixture was warmed to 5°C and then diluted with HO (10 vol). The organic layer was then washed with HO (5 vol). The organic stream was assayed and analyzed via HPLC using X-Bridge and FFP2 analytical methods: X-Bridge: Compound 8a 88.7%, 96.2 LCAP, Compound 8 2.0%, 2.1 LCAP, dimer 0.9 LCAP.

[0171] FFP2: Impurity X was not detected.

[0172] Compound 8a was extracted into aqueous solution with 10 wt% KPO (15 vol), then (3 vol). Toluene (15 vol) was added to the KPO layer, followed by the addition of 6M HCl (2.5 vol) in small portions while visually monitoring the internal temperature and pH. The aqueous layer was acidified to pH 5. The organic acidified toluene stream was washed with HO (2 x 5 vol). The organic stream was analyzed via assay and HPLC using X-Bridge and FFP2 analytical methods: X-Bridge: Compound 8a 86.2%, 99.4LCAP, Compound 8 <0.1% FFP2: Impurity X was not detected.

[0173] Example 5 Preparation of Compound of Formula I (Compound 9), 6-(tert-butyl)4a-methyl(R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate

[0174] [ka]

[0175] A 180 L vessel was dried under vacuum prior to use. A solution of compound 8a (6.5 kg, 1.0 equiv.) in toluene (approximately 6.00 wt.%) was charged to the reactor. The mixture was concentrated to 10 volumes [approximately 60 L] while maintaining a batch temperature of ≦40°C. Acetic acid (10.4 kg, 9.0 equiv.) was charged, followed by water (0.3 vol.). The contents of the reactor were degassed via a vacuum-nitrogen cycle. Magnesium acetate tetrahydrate (2.58 kg, 0.6 equiv.) was charged, and the contents of the reactor were stirred at 20°C for 15 minutes. 4-Fluorophenylhydrazine HCl (3.45 kg, 1.1 equiv.) was charged while maintaining an internal temperature of <25°C. The reaction was aged at 20°C for 18 hours and 31 minutes and then analyzed for conversion. HPLC analysis showed 100% conversion (0.0 A% of compound 8a relative to compound 9).

[0176] Water (29.7 kg, 5 vol) was charged and aged at 20-22 °C for 1 hour 10 minutes, and the layers were separated. The organic phase was washed twice with 1 M HCl (30.3 kg, 5 vol). The organic phase was washed with 10 wt% aqueous K3PO4 solution (31.2 kg, 5 vol). The organic phase was washed with 5 wt% aqueous NaCl solution (30.8 kg, 5 vol). The organic phase was washed with water (30.1 kg, 5 vol).

[0177] The organic phase was drained and the assay yield and LCAP of compound 9 were determined. HPLC analysis of the organic stream showed 7.47 kg of compound 9 in 98.7 LCAP (0.03 LCAP of impurity A, 1.07 LCAP of impurity C, 0.24 LCAP of impurity D), corresponding to an assay yield of 99.6%. MVK polymer analysis showed 1.84 A% SEC impurity.

[0178] Example 6. First crystallization of the compound of formula I (compound 9) The reactor was rinsed with IPA (30.0 kg) and discharged as waste. The organic stream was charged to the reactor through an in-line filter and concentrated under reduced pressure to 3 volumes relative to compound 9 [approximately 22 L] while maintaining T<40°C. IPA (60.0 kg, 10 volumes relative to compound 9) was charged to the reactor. The reactor was concentrated under reduced pressure to 3 volumes relative to compound 9 [approximately 23 L] while maintaining T<40°C. IPA (6.4 kg, 1 volume relative to compound 9) was charged to the reactor. The resulting solution was heated to 58.6°C, aged until homogeneous, and analyzed for toluene content by NMR. The stirred solution was cooled to 50°C and charged with seeds (41 g of compound 9, 0.55 wt%). After cooling to 45°C, the seed bed was aged at 46°C for 30 minutes. Heptane (20.5 kg, 4 volumes relative to compound 9) was charged 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. Using the upper and lower vessel jackets at −15° C., the slurry was cooled to 0° C. over 14 minutes and aged at 0° C. for 1 hour and 21 minutes. 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 cake was dewatered with nitrogen for 30 minutes.

[0179] The cake was dried in a 40°C oven under a nitrogen sweep for 20 hours and 36 minutes. 6.66 kg (88% yield, 99.2 wt%) of compound 9 was obtained with 99.4 A% LCAP (0.02 LCAP impurity A, 0.41 LCAP impurity C, 0.19 LCAP impurity D). The concentration of impurity C in the dried cake was not homogeneous. An 80 g sample was dissolved, analyzed, and found to contain 0.03 A% impurity A, 0.50 LCAP impurity C, and 0.20 A% impurity D. MVK polymer analysis showed 0.13 A%.

[0180] Example 7. Second Crystallization of the Compound of Formula I (Compound 9) A 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, seeds (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 reactor contents were cooled to 20°C over 4 hours 16 minutes and then aged for 10 hours 51 minutes. The contents were filtered and washed with 3 volumes of a 1:3 volume mixture of toluene (3.5 kg) and heptane (8.4 kg) at 20°C. The contents were dried in a 40°C oven under a nitrogen sweep for 20 hours 36 minutes. 5.65 kg (75% yield) of compound 9 was obtained with 99.9% A of LCAP (0.03 LCAP of impurity A, 0.02 LCAP of impurity C, and 0.14 LCAP of impurity D). An additional 2% of the compound 9 material formed a dome on top of the bottomed valve. MVK polymer analysis showed <0.05% impurity A.

[0181] [Table 2]

[0182] Example 8. Alternative Preparation of Compound of Formula I (Compound 9), 6-(tert-butyl)4a-methyl(R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate

[0183] [ka]

[0184] Compound 9 can also be prepared according to the methods of Examples 30-33 of US Pat. No. 7,928,237.

[0185] Compound of Formula II (Compound 8a), 2-(tert-butyl) 8a-methyl(R,Z)-7-(hydroxymethylene)-6-oxo-4,6,7,8-tetrahydroisoquinoline-2,8a(1H,3H)-dicarboxylate

[0186] [ka]

[0187] 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, which confirmed it was ≦0.1%. Hexamethyldisilazane (102.0 kg) was added to the reactor at 15-25°C. The agitator was started. The oxygen content was determined and confirmed to be ≦0.1%. The mixture was cooled to −40 to −20°C under nitrogen protection. The oxygen content was determined and confirmed to be ≦0.1%.

[0188] While maintaining the temperature at -40 to -20°C, 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 to 80 kg / h at -40 to -20°C. After addition, the mixture was maintained at -40 to -20°C for 30 minutes.

[0189] A solution of compound 8 in methyl tert-butyl ether (628.0 kg of solution, 65.0 kg corrected) was added to the mixture at −40 to −20° C. After the addition, the mixture was stirred for 1 to 2 hours. The mixture was cooled to −60 to −50° C.

[0190] Methyl tert-butyl ether (156.0 kg) was added to a 3000 L glass-lined reactor at 15-25°C and sampled for KF analysis to confirm it was ≦0.1%. 2,2,2-Trifluoroethyl formate (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 a 3000 L stainless steel reactor at −60 to −40°C under nitrogen protection.

[0191] The mixture was reacted at −60° C. to −40° C. After 1 h, the mixture was sampled every 1–2 h for HPLC analysis to ensure that the area % of compound 8 was ≦15% or the difference between two consecutive samples was ≦1%.

[0192] A solution of hydrochloric acid in purified water (810.0 kg) was added in portions to the mixture at T≦0° C. The addition was stopped once the temperature rose above 0° C. The aqueous phase was sampled to ensure the pH was 6-7 (F1O).

[0193] Hydrochloric acid (250.0 kg) in water (1254.0 kg) solution (580.0 kg) of hydrochloric acid in purified water was added to the mixture at 0-20°C. The aqueous phase was sampled to ensure the pH was 3-5 (F1O). The mixture was stirred for 0.5-1 hour and allowed to settle at 15-25°C for 0.5-1 hour 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.

[0194] The mixture was stirred for 0.5-1 hour and allowed to settle at 15-25°C for 0.5-1 hour before separation. Methyl tert-butyl ether (190.0 kg) was added to the aqueous phase for extraction. The mixture was stirred for 0.5-1 hour and allowed to settle at 15-25°C for 0.5-1 hour before separation. All organic phases were combined.

[0195] The combined organic phase was washed with 225.0 kg of potassium carbonate solution at 15-25°C. The mixture was stirred for 0.5-1 hour and allowed to settle for 0.5-1 hour before separation. A solution of hydrochloric acid (850.0 kg) in purified water was added to the aqueous phase at 0-10°C. The aqueous phase was sampled to ensure the pH was 3-4.

[0196] The mixture was extracted twice with dichloromethane (232.2 kg × 2) at 15-25 °C. For each extraction, the mixture was stirred for 0.5-1 hour and allowed to settle for 0.5-1 hour before separation. A solution of sodium chloride (95.6 kg) in water (464.0 kg) was added to the combined organic phase. The mixture was stirred for 0.5-1 hour and allowed to settle for 0.5-1 hour at 15-25 °C before separation. The organic phase was sampled for analysis of purity and wt% of compound 8a.

[0197] The compound of formula I (Compound 9), 6-(tert-butyl)4a-methyl(R)-1-(4-fluorophenyl)-1,4,7,8-tetrahydro-6H-pyrazolo[3,4-g]isoquinoline-4a,6(5H)-dicarboxylate A DCM solution of compound 8a (1133.4 kg, 119.3 kg corrected) was charged into a glass-lined 3000 L 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 became 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 the mixture was stirred for 1-1.5 hours.

[0198] 4-Fluorophenylhydrazine hydrochloride (84.0 kg, 75.6 kg corrected) was added to the mixture in several 4-6 kg portions at 20-40 minute intervals at 15-25°C. The mixture was allowed to react at 15-25°C. After 1 hour, the mixture was sampled every 1-4 hours for HPLC analysis, and the area % of compound 8a was confirmed to be ≦1 area %.

[0199] The mixture was transferred to a glass-lined 5000 L reactor 2. Purified water (1309.0 kg) and methyl tert-butyl ether (1206.0 kg) were added to reactor 1 at 15-25°C. The mixture was then stirred for 0.5 hours and then transferred to reactor 2.

[0200] The mixture was allowed to settle at 15-25°C until layered before separation. The aqueous phase was extracted with methyl tert-butyl ether (869.4 kg). The mixture was stirred for 20-40 minutes or more and allowed to settle at 15-25°C until layered before separation.

[0201] A solution of potassium carbonate was added to wash the combined organic phase at 15-25°C. The mixture was stirred for 20-40 minutes and allowed to settle until layered at 15-25°C before separation. The organic phase was washed with the potassium carbonate solution while maintaining the temperature at 15-25°C. The aqueous phase was sampled to ensure the pH was >7. The mixture was stirred and allowed to settle until layered at 15-25°C before separation.

[0202] The organic phase was filtered through a stainless steel Nutsche filter pre-loaded 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), soaking the Nutsche filter for 0.5–1 h each time. The filtrate was concentrated under reduced pressure (P ≤ 0.06 MPa) at T ≤ 40 °C until 455–520 L remained.

[0203] The mixture was adjusted to 35-45°C, and then n-heptane (265.2 kg) was added to the concentrated mixture at 35-45°C at a base rate of 20-45 kg / hr. After the addition, the mixture was stirred for 2-3 hours. The mixture was cooled to 15-25°C at a base rate of 3-5°C / hr.

[0204] The mixture was stirred at 15-25°C for crystallization. After 2-3 hours, the mixture was sampled every 2-3 hours for mother liquor weight percent analysis until it was ≤4.0% or the difference between two consecutive samples was ≤0.5%. The mixture was filtered through a Φ1250 stainless steel centrifuge. The filter cake was rinsed with n-heptane (176.8 kg).

[0205] [Table 3]

[0206] † Average values ​​reported for purity, impurity profile, and % yield for three batches of crude compound 9 obtained from the reaction of compound 8a with 4-fluorophenylhydrazine hydrochloride. Values ​​in brackets correspond to the range of results obtained for the three batches of crude compound 9.

[0207] ‡ Average yield and purity reported for eight batches of compound 8a prepared from compound 8. Values ​​in parentheses correspond to the range of yield and purity results obtained for each of the eight batches of compound 8a.

[0208] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, 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 this application and a reference provided herein, this application shall control.

Claims

1. A compound of formula I: 【Chemistry 1】 1. A method for preparing (a) a compound of formula II: 【Chemistry 2】 Mg(OAc) ２ , and 4-fluorophenylhydrazine HCl: 【Transformation 3】 a first reaction mixture comprising: under conditions suitable to prepare a compound of formula I in at least 80% yield and at least 98% purity.

2. The Mg(OAc) ２ Mg(OAc) ２ ・4H ２ The method of claim 1, wherein

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

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

5. 5. The method of claim 1, wherein the first reaction mixture further comprises toluene.

6. (a1) heating a first crystallization mixture comprising isopropanol, heptane, and the compound of Formula I such that the compound of Formula I dissolves in the first crystallization mixture; 6. The method of any one of claims 1 to 5, further comprising: (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I.

7. After step (a2), the compound of formula I is Impurity A less than 0.05%: 【Chemistry 4】 Impurity C less than 0.5%: 【Transformation 5】 and Impurity D: less than 0.25% 【Transformation 6】 7. The method of claim 6, comprising:

8. (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; 8. The method of claim 6 or 7, further comprising: (a4) cooling the second crystallization mixture to form a second crystalline compound of Formula I.

9. After step (a4), the compound of formula I is Impurity A less than 0.05%: 【Transformation 7】 Impurity C less than 0.05%: 【Transformation 8】 and Impurity D: less than 0.20% 【Chemistry 9】 9. The method of claim 8, comprising:

10. (a) a compound of formula II: 【Chemistry 10】 Mg(OAc) in an amount of about 0.6 molar equivalents relative to the compound of formula II ２ ・4H ２ 0, acetic acid, water, toluene, and 4-fluorophenylhydrazine HCl: 【Chemistry 11】 forming a first reaction mixture comprising: Compounds of Formula I: 【Chemistry 12】 is prepared in a yield of at least 80% and with a purity of at least 98%; (a1) heating a first crystallization mixture comprising isopropanol, heptane, and the compound of Formula I such that the compound of Formula I dissolves in the first crystallization mixture; (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I; (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; (a4) cooling the second crystallization mixture to form a second crystalline compound of Formula I; wherein said second crystalline compound of formula I is Impurity A less than 0.05%: 【Chemistry 13】 Impurity C less than 0.05%: 【Chemistry 14】 and Impurity D: less than 0.20% 【Chemistry 15】 10. The method of claim 1, comprising:

11. A compound of formula II: 【Chemistry 16】 1. A method for preparing a compound comprising: (c) an alkyl formate, a non-nucleophilic base, and a compound of formula III: 【Chemistry 17】 forming a third reaction mixture comprising: whereby a compound of formula II is prepared.

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

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

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

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

19. 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. (c) methyl formate, sodium tert-pentoxide, lithium chloride, 2-methyltetrahydrofuran, and the compound of Formula III in an amount of about 3.0 molar equivalents relative to the compound of Formula III: [Chemistry 18] forming a third reaction mixture comprising: wherein the third reaction mixture is at a temperature of about −40° C.; Thereby, a compound of formula II: 【Chemistry 19】 20. The method of any one of claims 11 to 19, wherein

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

22. (c) methyl formate, sodium tert-pentoxide, lithium chloride, 2-methyltetrahydrofuran, and the compound of Formula III in an amount of about 3.0 molar equivalents relative to the compound of Formula III: 【Chemistry 20】 forming a third reaction mixture comprising: wherein the third reaction mixture is at a temperature of about −40° C.; Thereby, a compound of formula II: 【Chemistry 21】 and a) the compound of Formula II, Mg(OAc) in an amount of about 0.6 molar equivalents relative to the compound of Formula II ２ ・4H ２ 0, acetic acid, water, toluene, and 4-fluorophenylhydrazine HCl: 【Chemistry 22】 forming a first reaction mixture comprising: Compounds of Formula I: 【Chemistry 23】 is prepared in a yield of at least 80% and with a purity of at least 98%; 22. The method of claim 21, comprising:

23. (a1) heating a first crystallization mixture comprising isopropanol, heptane, and the compound of Formula I such that the compound of Formula I dissolves in the first crystallization mixture; (a2) cooling the first crystallization mixture to form a first crystalline compound of Formula I; (a3) heating a 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; (a4) cooling the third crystallization mixture to form a third crystalline compound of Formula I; wherein said third crystalline compound of formula I is Impurity A less than 0.05%: 【Chemistry 24】 Impurity C less than 0.05%: 【Chemistry 25】 and Impurity D: less than 0.20% 【Chemistry 26】 23. The method of claim 22, further comprising:

24. The compound of formula III is 1123 (d) pyrrolidine, acetic acid, and a compound of formula IV: 【Chemistry 27】 forming a fourth reaction mixture comprising: Thereby, a compound of formula III: 【Chemistry 28】 24. The method of any one of claims 11 to 23, wherein

25. The compound of formula IV is (e) a compound of formula V: 【Chemistry 29】 A fifth reaction mixture comprising methyl vinyl ketone (MVK) in an amount of about 1.6 molar equivalents relative to the compound of formula V, Cu(OAc)2 (anhydrous), and dimethylformamide is formed at a temperature of 10-25°C, thereby producing a compound of formula IV: 【Transformation 30】 25. The method of claim 24, wherein the compound is prepared by a method comprising:

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

27. 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 to prepare the compound of formula IV.

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

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

30. 1. A composition comprising: At least 99% of the compound of formula I: 【Chemistry 31】 and A composition comprising one or more impurities in an amount of 0.01 to 1%.

31. The composition comprises: Impurity A less than 0.05%: 【Chemistry 32】 Impurity C less than 0.05%: 【Transformation 33】 and Impurity D: less than 0.20% 【Transformation 34】 31. The composition of claim 30, comprising:

32. 32. The composition of claim 1 or 29, wherein the compound of formula I is prepared by the method of any one of claims 30 to 31.

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