Methods of preparing heteroaryl-ketone-fused azanaphthyl steroid receptor modulators

Abstract

The present invention provides methods of preparing heteroaryl-ketone-fused azanaphthyl steroid glucocorticoid receptor modulators, as well as compositions having low levels of impurities.

Description

[0001] Cross-referencing related applications

[0002] This application claims a foreign priority interest in PCT application No. PCT / CN2020 / 139524, filed on December 25, 2020, which is incorporated herein in its entirety for all purposes. Background Technology

[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 exhibits circadian rhythm changes and increases in response to stress and food. Cortisol levels respond within minutes to many physical and physiological stresses, including trauma, surgery, exercise, anxiety, and depression. Cortisol is a steroid that functions by binding to the intracellular glucocorticoid receptor (GR). In humans, the glucocorticoid receptor exists in two forms: the 777-amino acid ligand-binding GR-α; and the GR-β isoform, lacking 50 carboxyl-terminal residues. Because these include a ligand-binding domain, GR-β cannot bind a ligand, is consistently located in the nucleus, and has no transcriptional activity. GR is also known as GR-II.

[0004] The biological effects of cortisol at GR levels can be modulated using receptor modulators (such as agonists, partial agonists, and antagonists), 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 and / or activate GR by binding to 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 GR with high affinity, with a dissociation constant (K). d ) is 10 -9 M (Cadepond (1997) *Annu. Rev. Med.* 48:129). Relakolan (CORT-125134) is another such glucocorticoid receptor modulator compound and has been previously described in PCT Publication No. WO 2013 / 177559 and U.S. Patent No. 8,859,774. There is a need in the art for novel methods to prepare relakolan with lower impurity content. Surprisingly, the present invention meets these and other needs. Summary of the Invention

[0005] In some embodiments, the present invention provides a method for preparing a compound of formula J or a pharmaceutically acceptable salt thereof:

[0006]

[0007] The method includes:

[0008] (a) Formation of compounds including formula IIb:

[0009]

[0010] The first reaction mixture of sulfonyl chloride:

[0011]

[0012] To prepare compounds of formula J in a yield of at least 60% and a purity of at least 98%.

[0013] in

[0014] X 1 It is -CH= or -N=;

[0015] HX is an acid solvate; and

[0016] The subscript n is from 1 to 4.

[0017] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0018]

[0019] The method includes:

[0020] (a) Formation of compounds including formula IIb:

[0021]

[0022] The first reaction mixture of 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0023]

[0024] To prepare compounds of formula I with a yield of at least 60% and a purity of at least 98%.

[0025] in

[0026] HX is an acid solvate; and

[0027] The subscript n is from 1 to 4.

[0028] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0029]

[0030] The method includes:

[0031] (a) Formation of compounds including formula IIb-1:

[0032]

[0033] The first reaction mixture of 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0034]

[0035] To prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%, wherein the compound of formula I contains less than 1% (w / w) of the compound of formula X-5:

[0036]

[0037] And the subscript n is from 1 to 4.

[0038] In some embodiments, the present invention provides a method for purifying a compound of formula I or a pharmaceutically acceptable salt thereof:

[0039]

[0040] The method includes:

[0041] (a) Use

[0042] (i) a first fluid mixture comprising at least 95% (v / v) water, 0.05% (v / v) to 0.2% (v / v) formic acid, and 1% (v / v) to 5% (v / v) acetonitrile.

[0043] (ii) a second fluid mixture comprising water at a content of 45% (v / v) to 55% (v / v), formic acid at a content of 0.01% (v / v) to 0.1% (v / v), and acetonitrile at a content of 45% (v / v) to 55% (v / v), and

[0044] (iii) The compound of Formula I is eluted by high-performance liquid chromatography (HPLC) using a third mobile phase comprising 5% (v / v) to 15% (v / v) water, 0.005% (v / v) to 0.02% (v / v) formic acid, and at least 85% (v / v) acetonitrile.

[0045] To form an elution mixture comprising a compound of formula I with a purity of at least 98% and a compound of formula X-5 with a content of less than 0.75% (w / w):

[0046]

[0047] (a1) Extracting the compound of Formula I from the elution mixture into ethyl acetate to form an extraction mixture;

[0048] (a2) The extraction mixture is mixed with methyl tert-butyl ether (MTBE) under vacuum to form an MTBE mixture comprising less than 5% (v / v) ethyl acetate;

[0049] (d) Filtering the MTBE mixture through a filter to form a filtered MTBE mixture, the filtered MTBE mixture comprising:

[0050] The compound of formula I,

[0051] Compounds of formula X-5 in a concentration of less than 0.5% (w / w)

[0052] Compounds of formula X-4 with a content of less than 0.3% (w / w):

[0053]

[0054] Compounds of formula X-6 with a content of less than 0.25% (w / w):

[0055]

[0056] (e) The filtered MTBE mixture is added to heptane to form a precipitated compound of formula I, wherein the precipitated compound of formula I comprises less than 20 ppm of 1,4-dibromopentane.

[0057] (f) Dissolving the precipitated compound of formula I in methanol to form a methanol mixture; and

[0058] (g) Add the methanol mixture to water to precipitate the purified compound of formula I, wherein the purified compound of formula I has a purity of at least 99% and includes...

[0059] Compounds of formula X-5 in a concentration of less than 0.5% (w / w)

[0060] 1,4-Dibromopentane at a concentration of less than 6 ppm

[0061] 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 6 ppm:

[0062]

[0063] 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 6 ppm:

[0064]

[0065] In some embodiments, the present invention provides a method for preparing compounds of formula IIa:

[0066]

[0067] The method includes the following steps:

[0068] (c) Formation of compounds including Grignard reagents and Formula III:

[0069]

[0070] The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0071]

[0072] The pyridine is present in a molar ratio of 1.0 to 1.5 with the compound of formula III, and the Grignard reagent is present in a molar ratio of 1.5 to 1.7 with the compound of formula III, to prepare the compound of formula IIa.

[0073] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0074]

[0075] The method includes:

[0076] (a) Formation of compounds including formula IIb-2:

[0077]

[0078] The fourth reaction mixture with 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0079]

[0080] To prepare the compound of formula I, the yield is at least 75% and the purity is at least 98%, wherein

[0081] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0082] The subscript n is from 1 to 4.

[0083] In some embodiments, the present invention provides a method for preparing compounds of formula IIb-2:

[0084]

[0085] The method includes:

[0086] (b) Formation of compounds including formula IIa:

[0087]

[0088] The fifth reaction mixture of sulfonic acid according to the following formula:

[0089]

[0090] To form compounds of formula IIb-2,

[0091] in

[0092] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0093] The subscript n is from 1 to 4.

[0094] In some embodiments, the present invention provides a composition comprising:

[0095] Compounds of formula I with a content of at least 99% (w / w):

[0096]

[0097] One or more impurities in a content of 0.01% (w / w) to 1% (w / w).

[0098] In some embodiments, the present invention provides a crystal form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid:

[0099]

[0100] The feature is that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 18.2°2-θ±0.2°2-θ, 18.3°2-θ±0.2°2-θ, and 19.7°2-θ±0.2°2-θ. Attached Figure Description

[0101] Figure 1A synthetic scheme for preparing (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid (Rellacolan) is shown according to Example 3.

[0102] Figure 2 The X-ray powder diffraction (XRPD) pattern of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid is shown.

[0103] Figure 3 Differential scanning calorimetry (DSC) thermogram of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid is shown.

[0104] Figure 4 Thermogravimetric analysis of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid is shown.

[0105] Figure 5 The X-ray powder diffraction (XRPD) pattern of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-oxalic acid is shown.

[0106] Figure 6 Differential scanning calorimetry (DSC) thermogram of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-oxalic acid is shown.

[0107] Figure 7 Thermogravimetric analysis of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-oxalic acid is shown.

[0108] Figure 8The X-ray powder diffraction (XRPD) pattern of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-hydrochloric acid is shown.

[0109] Figure 9 Differential scanning calorimetry (DSC) thermogram of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-hydrochloric acid is shown.

[0110] Figure 10 Thermogravimetric analysis of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-hydrochloric acid is shown. Detailed Implementation

[0111] I. Summary

[0112] This disclosure describes a novel method for preparing compounds of Formula I with impurity levels lower than those of previously described methods, namely (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone (Rellacolan). As shown in Example 18 of U.S. Patent No. 8,859,774, Rellacolan can also be named (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazololo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone. This disclosure also describes compositions of ryracoran with low levels of impurities.

[0113] II. Definition

[0114] When referring to a value, "about" includes the value plus or minus 10% of the 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. Therefore, when referring to a range, "about" means each of the values ​​at each end of the range plus or minus 10% of the value. For example, a ratio of about 1 to about 3 (weight / weight) includes a range of 0.9 to 3.3.

[0115] "Forming a reaction mixture" refers to the process of bringing at least two different substances into contact so that they mix together and can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate derived from one or more added reagents, which can be generated in the reaction mixture.

[0116] "Dissolve" refers to a solid material that is substantially soluble in a particular solvent. For example, a solid material may be more than 90% soluble in a solvent, or more than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or more than 99% soluble in a solvent.

[0117] Distilling (also known as distillation or distillation) refers to the separation of components in a liquid mixture using a combination of temperature and pressure. The target component is converted from a liquid to a gas, which is then condensed back into a liquid to separate the target component from the other components of the mixture.

[0118] "Eluting" or "elution" refers to the process of separating a target component from other components in a mixture by passing it through a stationary phase. The target component is eluted from the stationary phase using a mobile phase that may contain any suitable solvent or acid.

[0119] "Precipitation" refers to a solid formed from a solution, for example, when a first solvent in which a dissolved compound is added to an excess of a second solvent in which the compound is substantially insoluble, causing the dissolved compound to flow out of the solution and form a solid.

[0120] "Substantially free" means a composition having less than 5%, less than 1%, less than 0.5%, or even less than 0.1% of an undesirable component by weight.

[0121] "Aqueous phase" refers to a mixture containing water.

[0122] An "organic phase" refers to a mixture containing a water-miscible or water-immiscible solvent capable of dissolving any or both of water-soluble and water-insoluble organic compounds. The organic phase of this invention 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, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, dichloromethane, chloroform, etc.

[0123] "Acid" refers to the ability to donate protons (H) according to the Bronsted-Lowry definition.+ Compounds that are electron pair acceptors according to the Lewis definition. Acids that can be used in this invention are Bronsted-Lowry acids, which include, but are not limited to, alkyl acids or carboxylic acids (formic acid, acetic acid, citric acid, lactic acid, oxalic acid, etc.), sulfonic acids, and mineral acids as defined herein. Mineral acids are inorganic acids, such as hydrohalides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), halogenated oxoacids (hypochlorous acid, perchloric acid, etc.), as well as sulfuric acid, nitric acid, phosphoric acid, chromic acid, and boric acid. Sulfuric acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, etc.

[0124] "Graffic reagents" refer to reagents that can form carbon-carbon bonds containing magnesium metal, halides, and alkyl ligands. Representative Graffic reagents include, but are not limited to, iPrMgCl and iPrMgBr.

[0125] "Nonnucleophilic bases" refer to bases that are moderately to strongly bases but also weakly nucleophilic. Representative nonnucleophilic bases include bases such as potassium carbonate, sodium carbonate, potassium tert-butoxide, and sodium tert-butoxide, as well as amine bases such as triethylamine, diisopropylethylamine, N,N-diethylaniline, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, and quinine rings. This includes nonnucleophilic amine bases.

[0126] "Solvent" refers to a substance capable of dissolving a solute, such as a liquid. Solvents can be polar or nonpolar, proton or aproton. 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. Proton solvents are characterized by having protons that can be removed, such as hydroxyl or carboxyl groups. Aproton solvents lack such groups. Representative polar proton solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.), and water. Representative polar aproton 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 may be used in this invention.

[0127] "Room temperature" is the range of air temperature generally considered suitable for human use, or between about 15 degrees Celsius (59 degrees Fahrenheit) and 25 degrees Celsius (77 degrees Fahrenheit).

[0128] "Vacuum" or "decompression" refers to pressure less than atmospheric pressure. Atmospheric pressure is measured at approximately 10¹³ mbar, 760 mm Hg, or approximately 14.7 psi. Therefore, a vacuum can be less than 10¹³ mbar, or less than 100, 10, 1, 0.1, or less than 0.01 mbar.

[0129] "Alkyl" refers to a straight-chain or branched saturated aliphatic group having the indicated number of carbon atoms. Alkyl groups can contain any number of carbons, such as C64. 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C 1-9 C 1-10 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6 For example, C 1-6 Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyl groups can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, and decyl. Alkyl groups may be substituted or unsubstituted.

[0130] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0131] "Haloalkyl" refers to an alkyl group as defined above, in which some or all of its hydrogen atoms are replaced by halogen atoms. Regarding alkyl groups, haloalkyl groups can have any suitable number of carbon atoms, such as C... 1-6 For example, haloalkyl groups include trifluoromethyl, fluoromethyl, etc. The term "perfluorinated" can be used to define a compound or group in which all hydrogen atoms are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0132] "Pharmaceutically acceptable salt" refers to an acid or base salt of the compound used in the methods of this invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (iodomethane, iodoethane, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0133] As used herein, “composition” is intended to encompass products comprising specific amounts of specific ingredients, and any product resulting directly or indirectly from a combination of specific amounts of specific ingredients. “Pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to their receptors.

[0134] "Pharmaceutically acceptable excipients" are substances that facilitate administration of the active agent to a subject and its absorption by the subject. Pharmaceutical excipients that can be used in this invention include, but are not limited to, binders, fillers, disintegrants, lubricants, surfactants, coatings, sweeteners, flavorings, and pigments. Those skilled in the art will recognize that other pharmaceutical excipients can be used in this invention.

[0135] "Treatment" refers to any successful indication of treating or improving an injury, symptom, or condition, including any objective or subjective parameters such as relief; mitigation; reduction of symptoms or making the injury, symptom, or condition more tolerable for the patient; slowing the rate of degeneration or decline; making the final stages of degeneration less debilitating; or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters and may include the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0136] "Administration" refers to oral administration to a subject, as a suppository, local contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal or subcutaneous administration, intrathecal administration, or implantation of a slow-release device such as a small osmotic pump.

[0137] "Patient" or "subject" means an organism that suffers from or is susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, horses, and other non-mammal animals. In some embodiments, the patient is a human.

[0138] "Therapeutic effective amount" means the amount of a compound or pharmaceutical composition that can be used to treat or improve an identified disease or condition, or to exhibit detectable therapeutic or inhibitory effects. The exact amount will depend on the purpose of treatment and will be determined by someone skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dose Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmatia, 20th ed., 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0139] "Glucocorticoid receptor" ("GR") refers to one of the families of intracellular receptors that specifically bind to cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner & Muller, *Journal of Molecular Endocrinology*, October 1, 2005, 35 283-292). Glucocorticoid receptor is also known as cortisol receptor. The term includes isotypes of GR, recombinant GR, and mutant GR.

[0140] The cortisol receptor is a glucocorticoid receptor (GR), particularly type II GR, which specifically binds to cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol, 1 October 2005, 35 283-292).

[0141] "Mineralocorticoid receptor" (MR) refers to type I glucocorticoid receptor (GR I) activated by aldosterone in humans.

[0142] "Glucocorticoid receptor modulator" (GMM) refers to any compound that modulates any biological response related to the binding of glucocorticoid receptors to agonists. As used herein, with respect to GMM, the glucocorticoid receptor can be a GR or both. For example, GMMs acting as agonists such as dexamethasone increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (a hepatocellular carcinoma cell line from the human liver; ECACC, UK). GMMs acting as antagonists such as mifepristone inhibit the agonist-induced increase in tyrosine aminotransferase (TAT) activity in HepG2 cells. TAT activity can be measured as listed in the literature A. Ali et al., *Journal of Medicinal Chemistry*, 2004, 47, 2441-2452.

[0143] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits or relates to any biological response involving the binding of glucocorticoid receptors to agonists. As used herein, with respect to GRA, the glucocorticoid receptor can be GR or both. Therefore, GR antagonists can be identified by measuring the ability of a compound to inhibit the action of dexamethasone. TAT activity can be measured as listed in the literature A. Ali et al., *Journal of Medicinal Chemistry*, 2004, 47, 2441-2452. Inhibitors are IC50 inhibitors. 50 Compounds with a half-maximal inhibitory concentration (MCC) of less than 10 μmol. See Example 1 of U.S. Patent 8,685,973, the entire contents of which are hereby incorporated by reference.

[0144] "Modulate" and "modulating" are used in their ordinary, common sense sense, referring to the act of changing or altering one or more properties. "Modulation" is the process of changing or altering one or more properties. For example, when applied to the effect of a modulator on a target protein, regulation refers to altering the properties or function of the target molecule or the amount of the target molecule by increasing or decreasing it.

[0145] "Regulator" refers to a composition that increases or decreases the level or function of a target molecule or the physical state of a molecular target.

[0146] "Antagonism" refers to the inhibition of agonist binding at receptor molecules or the suppression of receptor-agonist signaling. Receptor antagonists inhibit or attenuate agonist-mediated responses, such as gene expression.

[0147] An "antagonist" is a substance that can detectably reduce the expression or activity of a given gene or protein. Compared to a control without an antagonist, the antagonist can inhibit expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or less. In some embodiments, inhibition is 1.5, 2, 3, 4, 5, 10, or more times the expression or activity in the absence of an antagonist.

[0148] "Inhibition," "inhibits," and "inhibitors" refer to compounds or methods that prohibit specific actions or functions.

[0149] "Disorder" or "condition" refers to a condition or health status of a patient or subject who can be treated with the glucocorticoid receptor modulator of the present invention. In some embodiments, examples of disorder or condition include, but are not limited to, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and weight gain induced by antipsychotic drugs.

[0150] Fatty liver disease refers to a disease or pathological condition caused at least in part by abnormal lipid deposition in the liver. Fatty liver disease includes, for example, alcoholic fatty liver disease, non-alcoholic fatty liver disease, and acute fatty liver of pregnancy. Fatty liver disease can be, for example, macrovesicular steatosis or microvesicular steatosis.

[0151] Nonalcoholic fatty liver disease (NAFLD) is a type of fatty liver disease that occurs when fat accumulates in the liver (steatodegeneration) due to causes other than excessive alcohol consumption. NAFLD is considered to encompass a range of disease activities caused by the accumulation of fat in the liver (hepatic steatosis). Most people with NAFLD have few or no symptoms. Patients may complain of fatigue, malaise, and discomfort in the upper right quadrant of the abdomen. Mild jaundice may occur, though rare. More commonly, NAFLD is diagnosed after abnormal liver function tests during routine blood tests. By definition, alcohol consumption exceeding 20 g / day (approximately 25 ml / day of net ethanol) does not include this condition.

[0152] Nonalcoholic steatohepatitis (NASH) refers to the most extreme form of NAFLD. NAFLD can develop into nonalcoholic steatohepatitis (NASH), a condition characterized by steatosis combined with inflammation and fibrosis (steatohepatitis). NASH is a progressive disease. Over a 10-year period, up to 20% of NASH patients will develop cirrhosis, and 10% will die from liver disease-related deaths.

[0153] Substance use disorder refers to the compulsive use of a substance despite the adverse or harmful consequences of such use. Substance use disorders may involve impaired control (e.g., overuse of the substance or use for longer periods than originally planned), social barriers (e.g., failure to fulfill primary responsibilities at work, school, or home), dangerous use (e.g., repeated use of the substance in a manner harmful to the body), and pharmacological criteria (e.g., tolerance or withdrawal). Although substance use disorder may have previously been referred to as addiction, since… Diagnostic and Statistical Manual of Mental Disorders Manual of Mental Disorders, 5th Edition (DSM-5) Since the publication of (hereinafter “DSM-V”), terms such as “addiction” and “addict” have been replaced by the terms “substance use disorder” (instead of “addiction”) and “person with substance use disorder” (instead of “addict”). A person with substance use disorder may be described as having a substance use disorder associated with a specific substance; prior to the publication of DSM-V, such a person may have been described as “addicted to” that substance. For example, if a person has a substance use disorder associated with a stimulant, then prior to the publication of DSM-V, that person may have been described as “addicted to” that stimulant.

[0154] The term "substance" as used in phrases such as "substance use disorder related to the substance" and "substance use disorder associated with the substance" refers to a substance that a patient craves or compulsively uses despite the adverse or harmful consequences of its use. Therefore, such a "substance" is a substance used, ingested, or otherwise administered (including self-administered) by a person suffering from a substance use disorder associated with that substance. The terms "addictive substance" and "abuse substance" may have previously been used to refer to such substances, which may have previously been referred to as "addictive substances" (e.g., prior to the publication of DSM-V).

[0155] A person with a substance use disorder is someone who has a substance use disorder related to a specific substance (or, in some cases, more than one specific substance). Such a substance can be a drug, or alcohol, or cigarettes, or other substances that a person may consume (ingest). For example, such a substance can be alcohol, stimulants, opioids, or other substances.

[0156] III. Method for preparing Formula I from Formula IIb-1

[0157] This invention provides a method for preparing compounds of formula J or pharmaceutically acceptable salts thereof:

[0158]

[0159] The method includes:

[0160] (a) Formation of compounds including formula IIb:

[0161]

[0162] The first reaction mixture of sulfonyl chloride:

[0163] The compound of formula J is prepared in a yield of at least 60% and a purity of at least 98%.

[0164] in

[0165] X 1 It is -CH= or -N=;

[0166] HX is an acid solvate; and

[0167] The subscript n is from 1 to 4.

[0168] In some embodiments, X of formula J 1 It is -CH=.

[0169] This invention provides a method for preparing compounds of formula I, namely (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone (Rellacore):

[0170]

[0171] Methods for compounds of formula Ia, namely (R)-(1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone:

[0172]

[0173] Compounds of formula I (Rellacolan; CORT125134) and formula Ia are described in PCT Publication No. WO 2013 / 177559 and U.S. Patent No. 8,859,774.

[0174] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0175]

[0176] The method includes:

[0177] (a) Formation of compounds including formula IIb:

[0178]

[0179] The first reaction mixture of 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0180]

[0181] The compound of formula I is prepared in a yield of at least 60% and a purity of at least 98%.

[0182] in

[0183] HX is an acid solvate; and

[0184] The subscript n is from 1 to 4.

[0185] In some embodiments, HX is HCl, HBr,

[0186]

[0187] Where R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl.

[0188] In some embodiments, the compound of formula IIb may have the following structure:

[0189]

[0190] The subscript n is from 1 to 4.

[0191] In some embodiments, the compound of formula IIb may have the following structure:

[0192]

[0193] The subscript n is from 1 to 4.

[0194] In some embodiments, the compound of formula IIb may have the following structure:

[0195]

[0196] Where R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and the subscript n is 1 to 4.

[0197] In some embodiments, the compound of formula IIb may have the following structure:

[0198]

[0199] The subscript n is from 1 to 4.

[0200] In some embodiments, the compound of formula IIb may have the following structure:

[0201]

[0202] Where R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and the subscript n is 1 to 4.

[0203] In some embodiments, the compound of formula IIb may have the following structure:

[0204]

[0205] Where R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and the subscript n is 1 to 4.

[0206] A. Preparation of Formula I from Formula IIb-1

[0207] In some embodiments, HX is HBr. Compounds of Formula I can be prepared from compounds of Formula IIb-1:

[0208]

[0209] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0210]

[0211] The method includes:

[0212] (a) Formation of compounds including formula IIb-1:

[0213]

[0214] The first reaction mixture of 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0215]

[0216] To prepare compounds of formula I with a yield of at least 60% and a purity of at least 98%, wherein the compounds of formula I contain less than 1% (w / w) of the compounds of formula X-5:

[0217]

[0218] And the subscript n is from 1 to 4.

[0219] The subscript n can be 1, 1.5, 2, 2.5, 3, 3.5, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of formula IIb-1 has the following structure:

[0220]

[0221] In some embodiments, the first reaction mixture further comprises a nonnucleophilic amine base. Any suitable nonnucleophilic amine base may be used in the first reaction mixture. In some embodiments, the nonnucleophilic amine base comprises trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMAN), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinine ring, 4-pyrrolylpyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or mixtures thereof. In some embodiments, the nonnucleophilic amine base comprises triethylamine.

[0222] The first reaction mixture may contain any suitable solvent. For example, the solvent may be an organic solvent, including, but not limited to, ethyl acetate, isopropyl acetate, and n-butyl acetate. In some embodiments, the first reaction mixture further includes a first solvent. In some embodiments, the first solvent contains ethyl acetate, isopropyl acetate, or n-butyl acetate. In some embodiments, the first reaction mixture further includes isopropyl acetate.

[0223] The sulfonyl chloride used in the first reaction mixture can be present in any suitable molar ratio to the compound of formula IIb-1. For example, the sulfonyl chloride can be present in a molar ratio of 1.0 to 3.0 to the compound of formula IIb-1, or in molar ratios of 1.0 to 2.5, 1.0 to 2.0, 1.0 to 1.5, 1.1 to 2.4, or 1.2 to 2.3 to the compound of formula IIb-1. In some embodiments, the sulfonyl chloride is present in a molar ratio of 1.2 to 2.3 to the compound of formula IIb-1. The sulfonyl chloride can be present in molar ratios of 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, or 2.3 to the compound of formula IIb-1. In some embodiments, the sulfonyl chloride can be present in a molar ratio of about 1.2 to the compound of formula IIb-1.

[0224] Compounds of Formula I can be prepared in any suitable yield. For example, compounds of Formula I can be prepared in yields of at least 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least 95%. In some embodiments, compounds of Formula I can be prepared in yields of at least 60%.

[0225] Compounds of Formula I can be prepared at any suitable purity. For example, compounds of Formula I can be prepared at a purity of at least 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 96%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 97%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 98%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 99%.

[0226] Compounds of Formula I can be prepared in any acceptable amount of compounds of Formula X-4:

[0227]

[0228] For example, compounds of formula I containing less than 5% (w / w) or 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of formula X-4 can be prepared. In some embodiments, compounds of formula I containing less than 0.5% (w / w) of formula X-4 can be prepared. In some embodiments, compounds of formula I containing less than 0.3% (w / w) of formula X-4 can be prepared. In some embodiments, compounds of formula I containing less than 0.1% (w / w) of formula X-4 can be prepared.

[0229] Compounds of Formula I can be prepared using any acceptable amount of Formula X-5. For example, compounds of Formula I containing less than 5% (w / w) or 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of Formula X-5 can be prepared. In some embodiments, compounds of Formula I containing less than 1% (w / w) of Formula X-5 can be prepared. In some embodiments, compounds of Formula I containing less than 0.75% (w / w) of Formula X-5 can be prepared. In some embodiments, a compound of formula I containing less than 0.5% (w / w) of a compound of formula X-5 can be prepared. In some embodiments, a compound of formula I containing less than 0.2% (w / w) of a compound of formula X-5 can be prepared.

[0230] Compounds of Formula I can be prepared in any acceptable amount of compounds of Formula X-6:

[0231]

[0232] For example, compounds of Formula I containing less than 5% (w / w) or 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of Formula X-6 can be prepared. In some embodiments, compounds of Formula I containing less than 0.25% (w / w) of Formula X-6 can be prepared. In some embodiments, compounds of Formula I containing less than 0.2% (w / w) of Formula X-6 can be prepared. In some embodiments, compounds of Formula I containing less than 0.1% (w / w) of Formula X-6 can be prepared.

[0233] Compounds of Formula I can be prepared using 1,4-dibromopentane in amounts less than 10 ppm. For example, compounds of Formula I can be prepared using 1,4-dibromopentane in amounts less than 10 ppm, or less than 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm. In some embodiments, compounds of Formula I can be prepared using 1,4-dibromopentane in amounts less than 8 ppm. In some embodiments, compounds of Formula I can be prepared using 1,4-dibromopentane in amounts less than 6 ppm. In some embodiments, compounds of Formula I can be prepared using 1,4-dibromopentane in amounts less than 4 ppm.

[0234] The compound of formula I can be prepared by using methyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 10 ppm:

[0235]

[0236] For example, the compound of formula I can be prepared using methyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 10 ppm, or less than 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm. In some embodiments, the compound of formula I can be prepared using methyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 8 ppm. In some embodiments, the compound of formula I can be prepared using methyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 6 ppm. In some embodiments, the compound of formula I can be prepared using methyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 4 ppm.

[0237] The compound of formula I can be prepared by using ethyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 10 ppm:

[0238]

[0239] For example, the compound of formula I can be prepared using ethyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 10 ppm, or less than 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm. In some embodiments, the compound of formula I can be prepared using ethyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 8 ppm. In some embodiments, the compound of formula I can be prepared using ethyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 6 ppm. In some embodiments, the compound of formula I can be prepared using ethyl 1-methyl-1H-pyrazole-4-sulfonate in amounts less than 4 ppm.

[0240] The compound of formula I can be prepared by using isopropyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 10 ppm:

[0241]

[0242] For example, the compound of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonate isopropyl ester in amounts less than 10 ppm, or less than 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm. In some embodiments, the compound of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonate isopropyl ester in amounts less than 8 ppm. In some embodiments, the compound of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonate isopropyl ester in amounts less than 6 ppm. In some embodiments, the compound of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonate isopropyl ester in amounts less than 4 ppm.

[0243] The compounds of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonyl chloride in a concentration of less than 10 ppm:

[0244]

[0245] For example, compounds of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonyl chloride in amounts less than 10 ppm, or less than 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm. In some embodiments, compounds of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonyl chloride in amounts less than 8 ppm. In some embodiments, compounds of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonyl chloride in amounts less than 6 ppm. In some embodiments, compounds of formula I can be prepared using 1-methyl-1H-pyrazole-4-sulfonyl chloride in amounts less than 4 ppm.

[0246] In some embodiments, a method for preparing a compound of formula I includes:

[0247] (a) Formation of a first reaction mixture comprising a compound of formula IIb-1, triethylamine, and 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0248]

[0249] The compound of formula I is prepared in the presence of sulfonyl chloride in a molar ratio of about 1.2 to the compound of formula IIb-1, with a yield of at least 60% and a purity of at least 98%, wherein the compound of formula I contains less than 1% (w / w) of the compound of formula X-5.

[0250]

[0251] In some embodiments, the method for preparing a compound of formula I further includes, after step (a):

[0252] (a1) The first reaction mixture is mixed with water at a pH of 4 to 5 to form a first organic phase and a first aqueous phase;

[0253] (a2) The first organic phase is mixed with water and sodium chloride, wherein the water has a pH of 5 to 6; and

[0254] (a3) Mix the first organic phase and silica gel.

[0255] The organic phase may contain any suitable organic solvent. In some embodiments, the first organic phase contains a first solvent.

[0256] Any suitable silicone can be used in the method of the present invention. Representative silicone includes, but is not limited to, 200-300 mesh silicone, or 60-80 mesh, 80-120 mesh, 100-200 mesh, etc. In some embodiments, the silicone is 200-300 mesh silicone.

[0257] B. Formula IIb-1 is prepared from formula IIa.

[0258] Compounds of formula IIb-1 can be prepared by a variety of methods. In some embodiments, compounds of formula IIb-1 are prepared by the following steps:

[0259] (b) Formation of compounds including formula IIa:

[0260]

[0261] The second reaction mixture with gaseous HBr forms a compound of formula IIb-1 having the following structure:

[0262]

[0263] Gaseous HBr can exist at any suitable partial pressure.

[0264] The second reaction mixture may also contain a second solvent. The second solvent can be any suitable solvent, including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene. In some embodiments, the second reaction mixture further includes a second solvent. In some embodiments, the second solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene. In some embodiments, the second reaction mixture further includes toluene.

[0265] Compounds of Formula I can be prepared from compounds of Formula IIa. Compounds of Formula IIa correspond to intermediate 29 of U.S. Patent No. 8,859,974, namely (R)-1-(4-chlorophenyl)-4a-(4-(trifluoromethyl)pyridinyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylic acid tert-butyl ester. Compounds of Formula IIa can also be named (R)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)pyridinyl)-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylic acid tert-butyl ester. In some embodiments, compounds of Formula I are prepared by the following steps:

[0266] (b) Formation of compounds including formula IIa:

[0267]

[0268] The second reaction mixture with gaseous HBr forms a compound of formula IIb-1 having the following structure:

[0269]

[0270] (a) Formation of compounds including formula IIb-1:

[0271] The first reaction mixture of triethylamine and 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0272]

[0273] The sulfonyl chloride is present in a molar ratio of about 1.2 to the compound of formula IIb-1;

[0274] (a1) The first reaction mixture is mixed with water at a pH of 4 to 5 to form a first organic phase and a first aqueous phase;

[0275] (a2) The first organic phase is mixed with water and sodium chloride, wherein the water has a pH of 5 to 6; and

[0276] (a3) A first organic phase and silica gel are mixed to prepare a compound of formula I in a yield of at least 60% and a purity of at least 98%, wherein the compound of formula I contains less than 1% (w / w) of a compound of formula X-5:

[0277]

[0278] C. Preparation of Formula IIa from Formula III

[0279] Compounds of formula IIa can be prepared by any suitable method. In some embodiments, compounds of formula IIa are prepared by:

[0280] (c) Formation of compounds including Grignard reagents and Formula III:

[0281]

[0282] The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0283]

[0284] The compound of formula IIa is prepared in a molar ratio of pyridine to the compound of formula III of 1.0 to 1.5, and in a molar ratio of Grignard reagent to the compound of formula III of 1.5 to 1.7.

[0285] Further examples of the preparation of compounds of formula IIa are described in section IV below.

[0286] In some embodiments, a method for preparing a compound of formula I includes:

[0287] (c) Formation of compounds including iPrMgBr, 2-methyltetrahydrofuran, toluene, and formula III:

[0288]

[0289] The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0290]

[0291] The compound of formula IIa is prepared in a molar ratio of pyridine to the compound of formula III of about 1.4, and in a molar ratio of Grignard reagent to the compound of formula III of about 1.65.

[0292]

[0293] (c1) Add acetic acid and water to the third reaction mixture to form a post-treatment mixture;

[0294] (c2) Distillation post-processing of the mixture to form an intermediate mixture comprising a compound of formula IIa, 2-methyltetrahydrofuran in a concentration of less than 100 ppm and water in a concentration of less than 0.5% (w / w);

[0295] (b) A second reaction mixture comprising an intermediate mixture and gaseous HBr is formed to form a compound of formula IIb-1 having the following structure:

[0296]

[0297] (a) Formation of a first reaction mixture comprising a compound of formula IIb-1, triethylamine, and 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0298]

[0299] The compound of formula I is prepared in a molar ratio of sulfonyl chloride to the compound of formula IIb-1 of about 1.2, with a yield of at least 60% and a purity of at least 98%, wherein the compound of formula I contains less than 1% (w / w) of the compound of formula X-5.

[0300]

[0301] In some embodiments, a method for preparing a compound of formula I includes the following step (a):

[0302] (a1) The first reaction mixture is mixed with water at a pH of 4 to 5 to form a first organic phase and a first aqueous phase;

[0303] (a2) The first organic phase is mixed with water and sodium chloride, wherein the water has a pH of 5 to 6; and

[0304] (a3) Mix the first organic phase and silica gel.

[0305] Purification of compounds of formula I (D.)

[0306] Compounds of Formula I can be purified by a variety of methods. In some embodiments, the present invention provides a method for purifying compounds of Formula I or pharmaceutically acceptable salts thereof:

[0307]

[0308] The method includes:

[0309] (a) Use

[0310] (i) a first fluid mixture comprising at least 95% (v / v) water, 0.05% (v / v) to 0.2% (v / v) formic acid, and 1% (v / v) to 5% (v / v) acetonitrile.

[0311] (ii) a second fluid mixture comprising water at a content of 45% (v / v) to 55% (v / v), formic acid at a content of 0.01% (v / v) to 0.1% (v / v), and acetonitrile at a content of 45% (v / v) to 55% (v / v), and

[0312] (iii) A third mobile phase comprising 5% (v / v) to 15% (v / v) water, 0.005% (v / v) to 0.02% (v / v) formic acid, and at least 85% (v / v) acetonitrile is eluted by high-performance liquid chromatography (HPLC) using a C18 column to elute compounds of formula I.

[0313] To form an elution mixture comprising a compound of formula I with a purity of at least 98% and a compound of formula X-5 with a content of less than 0.75% (w / w):

[0314]

[0315] (a1) Extracting the compound of formula I from the elution mixture into ethyl acetate to form an extraction mixture;

[0316] (a2) The extraction mixture was mixed with methyl tert-butyl ether (MTBE) under vacuum to form an MTBE mixture comprising less than 5% (v / v) ethyl acetate;

[0317] (d) Filtering the MTBE mixture through a filter to form a filtered MTBE mixture, the filtered MTBE mixture comprising:

[0318] Compounds of formula I,

[0319] Compounds of formula X-5 with a content of less than 0.5% (w / w)

[0320] Compounds of formula X-4 with a content of less than 0.3% (w / w):

[0321]

[0322] Compounds of formula X-6 with a content of less than 0.25% (w / w):

[0323]

[0324] (e) Add the filtered MTBE mixture to heptane to form a precipitated compound of formula I, wherein the precipitated compound of formula I includes 1,4-dibromopentane in an amount of less than 20 ppm.

[0325] (f) Dissolving the precipitated compound of formula I in methanol to form a methanol mixture; and

[0326] (g) Adding a methanol mixture to water to precipitate the purified compound of formula I, wherein the purified compound of formula I has a purity of at least 99%, and includes

[0327] Compounds of formula X-5 with a content of less than 0.5% (w / w)

[0328] 1,4-Dibromopentane at a concentration of less than 6 ppm

[0329] 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 6 ppm:

[0330]

[0331] 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 6 ppm:

[0332]

[0333] Any suitable filter can be used in the purification method of the present invention. For example, the filter can be a cartridge filter. In some embodiments, the filter can be a CUNO cartridge filter.

[0334] In some embodiments, the purified compound of formula I has a purity of at least 99% and includes 1,4-dibromopentane in an amount of less than 8 ppm.

[0335] In some embodiments, the purified compound of formula I has a purity of at least 99% and further comprises less than 20 ppm of methyl bromide and less than 20 ppm of 2-bromopropane. In some embodiments, the purified compound of formula I has a purity of at least 99% and further comprises less than 8 ppm of methyl bromide and less than 8 ppm of 2-bromopropane. In some embodiments, the purified compound of formula I has a purity of at least 99% and comprises less than 8 ppm of methyl bromide, less than 8 ppm of 2-bromopropane, and less than 8 ppm of 1,4-dibromopentane.

[0336] In some embodiments, the purified compound of formula I has a purity of at least 99%, and includes a compound of formula X-4 in an amount of less than 0.1% (w / w).

[0337] Compounds of formula X-5 with a content of less than 0.2% (w / w)

[0338] Compounds of formula X-6 with a content of less than 0.2% (w / w)

[0339] 1,4-Dibromopentane at a concentration of less than 4 ppm

[0340] 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 4 ppm, and

[0341] 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 4 ppm.

[0342] In some embodiments, the purified compound of formula I has a purity of at least 99%, and further includes

[0343] Ethyl 1-methyl-1H-pyrazole-4-sulfonate at a concentration of less than 6 ppm:

[0344]

[0345] Isopropyl 1-methyl-1H-pyrazole-4-sulfonate at a concentration of less than 6 ppm:

[0346]

[0347] In some embodiments, the purified compound of formula I has a purity of at least 99%, and further includes

[0348] Compounds of formula X-4 with a content of less than 0.1% (w / w)

[0349] Compounds of formula X-5 with a content of less than 0.2% (w / w)

[0350] Compounds of formula X-6 with a content of less than 0.2% (w / w)

[0351] Methyl bromide with a content of less than 4 ppm,

[0352] 2-bromopropane with a content of less than 4 ppm,

[0353] 1,4-Dibromopentane at a concentration of less than 4 ppm

[0354] 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 4 ppm

[0355] 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 4 ppm

[0356] Ethyl 1-methyl-1H-pyrazole-4-sulfonate with a content of less than 4 ppm, and

[0357] Isopropyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 4 ppm.

[0358] The compound of formula I purified by the above method can be prepared by the above method.

[0359] IV. Method for preparing Formula IIA from Formula III

[0360] Compounds of formula IIa can be prepared by any suitable method. In some embodiments, the present invention provides a method for preparing compounds of formula IIa:

[0361]

[0362] The method includes the following steps:

[0363] (c) Formation of compounds including Grignard reagents and Formula III:

[0364]

[0365] The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0366]

[0367] The compound of formula IIa is prepared in a molar ratio of pyridine to the compound of formula III of 1.0 to 1.5, and in a molar ratio of Grignard reagent to the compound of formula III of 1.5 to 1.7.

[0368] The Grignard reagent can be any suitable Grignard reagent. In some embodiments, the Grignard reagent includes iPrMgCl or iPrMgBr. In some embodiments, the Grignard reagent includes iPrMgBr.

[0369] The Grignard reagent may be present in any suitable molar ratio to the compound of Formula III. For example, the Grignard reagent may be present in a molar ratio of 1.0 to 2.0, or 1.1 to 1.9, 1.2 to 1.8, 1.3 to 1.8, 1.4 to 1.7, 1.5 to 1.7, or 1.6 to 1.7 to the compound of Formula III. In some embodiments, the Grignard reagent may be present in a molar ratio of 1.5 to 1.7 to the compound of Formula III. The Grignard reagent may be present in a molar ratio of about 1.5, or about 1.55, 1.60, 1.65, 1.70, or about 1.75 to the compound of Formula III. In some embodiments, the Grignard reagent may be present in a molar ratio of about 1.65 to the compound of Formula III.

[0370] Pyridine may be present in any suitable ratio to the compound of Formula III. For example, pyridine may be present in a molar ratio of 1.0 to 2.0, 1.0 to 1.9, 1.0 to 1.8, 1.0 to 1.7, 1.0 to 1.6, 1.0 to 1.5, 1.1 to 1.5, 1.2 to 1.5, or 1.3 to 1.5 to the compound of Formula III. In some embodiments, pyridine may be present in a molar ratio of 1.0 to 1.5 to the compound of Formula III. Pyridine may be present in a molar ratio of about 1.0, or about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or about 2.0 to the compound of Formula III. In some embodiments, pyridine may be present in a molar ratio of about 1.4 to the compound of Formula III.

[0371] The third reaction mixture may also contain a third solvent. The third solvent can be any suitable solvent, including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the third reaction mixture further includes a third solvent. In some embodiments, the third solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the third reaction mixture further includes 2-methyltetrahydrofuran and toluene.

[0372] In some embodiments, the method for preparing the compound of formula IIa further comprises: (c1) adding acid and water to a third reaction mixture to form a post-treatment mixture; and (c2) distilling the post-treatment mixture to form an intermediate mixture comprising the compound of formula IIa, 2-methyltetrahydrofuran in a concentration of less than 200 ppm and water in a concentration of less than 0.5% (w / w).

[0373] The acid in step (c1) can be any suitable acid. In some embodiments, the acid includes formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or mixtures thereof. In some embodiments, the acid includes acetic acid.

[0374] The intermediate mixture may contain any amount less than 200 ppm of 2-methyltetrahydrofuran. For example, the intermediate mixture may contain less than 200 ppm, or less than 190 ppm, 180 ppm, 170 ppm, 160 ppm, 150 ppm, 140 ppm, 130 ppm, 120 ppm, 110 ppm, 100 ppm, 90 ppm, 80 ppm, 70 ppm, 60 ppm, or less than 50 ppm of 2-methyltetrahydrofuran. In some embodiments, the intermediate mixture may contain less than 100 ppm of 2-methyltetrahydrofuran.

[0375] In some embodiments, a method for preparing a compound of formula IIa includes:

[0376] (c) Formation of compounds including iPrMgBr, 2-methyltetrahydrofuran, toluene, and formula III:

[0377]

[0378] The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0379]

[0380] The compound of formula IIa is prepared in a molar ratio of pyridine to the compound of formula III of about 1.4, and in a molar ratio of Grignard reagent to the compound of formula III of about 1.65.

[0381]

[0382] (c1) Add acetic acid and water to the third reaction mixture to form a post-treatment mixture; and

[0383] (c2) The mixture is post-distilled to form an intermediate mixture comprising a compound of formula IIa, 2-methyltetrahydrofuran in a concentration of less than 100 ppm and water in a concentration of less than 0.5% (w / w).

[0384] V. Method for preparing formula J from formula IIb-2

[0385] In some embodiments, HX is

[0386]

[0387] in

[0388] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0389] The subscript n is from 1 to 4.

[0390] In some embodiments, a method for preparing a compound of formula J or a pharmaceutically acceptable salt thereof:

[0391]

[0392] include:

[0393] (a) Formation of compounds including formula IIb-2:

[0394]

[0395] The fourth reaction mixture with sulfonyl chloride:

[0396]

[0397] The compound of formula J is prepared in a yield of at least 75% and a purity of at least 98%, wherein...

[0398] X 1 It is -CH= or -N=;

[0399] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0400] The subscript n is from 1 to 4.

[0401] In some embodiments, a method for preparing a compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0402]

[0403] include:

[0404] (a) Formation of compounds including formula IIb-2:

[0405]

[0406] The fourth reaction mixture with 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride:

[0407]

[0408] The compound of formula Ia is prepared in a yield of at least 75% and a purity of at least 98%, wherein

[0409] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0410] The subscript n is from 1 to 4.

[0411] In some embodiments, the compound of formula I contains less than 1% (w / w) of the compound of formula X-5a:

[0412]

[0413] Compounds of formula I can be prepared from compounds of formula IIb-2:

[0414]

[0415] A. Preparation of formula J from formula IIb-2

[0416] In some embodiments, the present invention provides a method for preparing a compound of formula J or a pharmaceutically acceptable salt thereof:

[0417]

[0418] The method includes:

[0419] (a) Formation of compounds including formula IIb-2:

[0420]

[0421] The fourth reaction mixture with sulfonyl chloride:

[0422]

[0423] The compound of formula J is prepared in a yield of at least 75% and a purity of at least 98%.

[0424] in

[0425] X 1 It is -CH= or -N=;

[0426] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0427] The subscript n is from 1 to 4.

[0428] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0429]

[0430] The method includes:

[0431] (a) Formation of compounds including formula IIb-2:

[0432]

[0433] The fourth reaction mixture with 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0434]

[0435] The compound of formula I is prepared in a yield of at least 75% and a purity of at least 98%.

[0436] in

[0437] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0438] The subscript n is from 1 to 4.

[0439] In some embodiments, the present invention provides a method for preparing a compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0440]

[0441] The method includes:

[0442] (a) Formation of compounds including formula IIb-2:

[0443]

[0444] The fourth reaction mixture with 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride:

[0445]

[0446] The compound of formula Ia is prepared in a yield of at least 75% and a purity of at least 98%.

[0447] in

[0448] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0449] The subscript n is from 1 to 4.

[0450] In some embodiments, R 1 It is C 1-2 Alkyl, C 1-2 Halogenated alkyl, phenyl, or 4-methylphenyl. In some embodiments, R 1 It is methyl, ethyl, -CF3, phenyl, or 4-methylphenyl. In some embodiments, R 1 It is a methyl group.

[0451] The subscript n can be 1, 2, 3, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of formula IIb-2 has the following structure:

[0452]

[0453] In some embodiments, the fourth reaction mixture further comprises a nonnucleophilic amine base. Any suitable nonnucleophilic amine base may be used in the fourth reaction mixture. In some embodiments, the nonnucleophilic amine base comprises trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMAN), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinine ring, 4-pyrrolylpyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or mixtures thereof. In some embodiments, the nonnucleophilic amine base comprises triethylamine.

[0454] The fourth reaction mixture may contain any suitable solvent. For example, the solvent may be an organic solvent, including, but not limited to, ethyl acetate, isopropyl acetate, and n-butyl acetate. In some embodiments, the fourth reaction mixture further includes a fourth solvent. In some embodiments, the fourth solvent comprises ethyl acetate, isopropyl acetate, n-butyl acetate, or mixtures thereof. In some embodiments, the fourth reaction mixture further includes ethyl acetate.

[0455] The sulfonyl chloride used in the fourth reaction mixture can be present in any suitable molar ratio to the compound of formula IIb-2. For example, the sulfonyl chloride can be present in a molar ratio of 0.5 to 2.0 to the compound of formula IIb-2, or in molar ratios of 0.5 to 1.5, 0.6 to 1.4, 0.7 to 1.3, 0.8 to 1.2, or 0.9 to 1.1 to the compound of formula IIb-2. In some embodiments, the sulfonyl chloride is present in a molar ratio of 0.5 to 1.5 to the compound of formula IIb-2. The sulfonyl chloride can be present in a molar ratio of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 to the compound of formula IIb-2. In some embodiments, the sulfonyl chloride can be present in a molar ratio of about 1.0 to the compound of formula IIb-2.

[0456] Compounds of formula J, I, or Ia can be prepared in any suitable yield. For example, compounds of formula J, I, or Ia can be prepared in yields of at least 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least 95%. In some embodiments, compounds of formula J, I, or Ia can be prepared in a yield of at least 75%.

[0457] Compounds of Formula I can be prepared in any suitable yield. For example, compounds of Formula I can be prepared in yields of at least 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or at least 95%. In some embodiments, compounds of Formula I can be prepared in yields of at least 75%.

[0458] Compounds of formula J, I, or Ia can be prepared at any suitable purity. For example, compounds of formula J, I, or Ia can be prepared at a purity of at least 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%. In some embodiments, compounds of formula J, I, or Ia can be prepared at a purity of at least 96%. In some embodiments, compounds of formula J, I, or Ia can be prepared at a purity of at least 97%. In some embodiments, compounds of formula J, I, or Ia can be prepared at a purity of at least 98%. In some embodiments, compounds of formula J, I, or Ia can be prepared at a purity of at least 99%.

[0459] Compounds of Formula I can be prepared at any suitable purity. For example, compounds of Formula I can be prepared at a purity of at least 90%, or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 96%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 97%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 98%. In some embodiments, compounds of Formula I can be prepared at a purity of at least 99%.

[0460] In some embodiments, the method for preparing compounds of formula J, I, or Ia further includes the following steps:

[0461] (a1) Add methanol to the fourth reaction mixture; and

[0462] (a2) Add water to the fourth reaction mixture to precipitate the compound of formula J, formula I or formula Ia.

[0463] In some embodiments, the method for preparing a compound of formula I further includes the following steps:

[0464] (a1) Add methanol to the fourth reaction mixture; and

[0465] (a2) Add water to the fourth reaction mixture to precipitate the compound of formula I.

[0466] In some embodiments, a method for preparing compounds of formula I from compounds of formula IIb-2 includes the following steps:

[0467] (a) Formation of compounds including formula IIb-2

[0468]

[0469] A fourth reaction mixture of triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0470]

[0471] The sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2;

[0472] (a1) Add methanol to the fourth reaction mixture; and

[0473] (a2) Add water to the fourth reaction mixture to precipitate the compound of formula I, in a yield of at least 75% and a purity of at least 98%.

[0474] Compounds of Formula I can be prepared in any acceptable amount of Formula X-5:

[0475]

[0476] For example, compounds of formula I containing less than 5% (w / w) or 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of formula X-5 can be prepared. In some embodiments, compounds of formula I containing less than 1% (w / w) of formula X-5 can be prepared.

[0477]

[0478] In some embodiments, a compound of formula I containing less than 0.75% (w / w) of a compound of formula X-5 can be prepared. In some embodiments, a compound of formula I containing less than 0.5% (w / w) of a compound of formula X-5 can be prepared. In some embodiments, a compound of formula I containing less than 0.2% (w / w) of a compound of formula X-5 can be prepared.

[0479] In some embodiments, the compound of formula Ia contains less than 1% (w / w) of the compound of formula X-5a:

[0480]

[0481] B. Preparation of formula IIb-2 from formula IIa

[0482] Compounds of formula IIb-2 can be prepared from compounds of formula IIa. In some embodiments, the present invention provides a method for preparing compounds of formula IIb-2:

[0483]

[0484] The method includes:

[0485] (b) Formation of compounds including formula IIa:

[0486]

[0487] The fifth reaction mixture of sulfonic acid according to the following formula:

[0488]

[0489] To form compounds of formula IIb-2,

[0490] in

[0491] R 1 It is C 1-6 Alkyl, C 1-10 Halogenated alkyl, phenyl, or 4-methylphenyl; and

[0492] The subscript n is from 1 to 4.

[0493] The subscript n can be 1, 2, 3, or 4. In some embodiments, the subscript n is 1. In some embodiments, the subscript n is 2. In some embodiments, the subscript n is 3. In some embodiments, the subscript n is 4. In some embodiments, the compound of formula IIb-2 has the following structure:

[0494]

[0495] The fifth reaction mixture may contain any suitable solvent. In some embodiments, the fifth reaction mixture contains a fifth solvent. The fifth solvent may contain, but is not limited to, pentane, hexane, heptane, benzene, toluene, diethyl ether, tetrahydrofuran, acetone, ethyl acetate, acetonitrile, dichloromethane, and chloroform. In some embodiments, the fifth solvent contains acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), methanol, ethanol, diethyl ether, methyl tert-butyl ether (MTBE), toluene, or combinations thereof. In some embodiments, the fifth reaction mixture contains acetonitrile.

[0496] C. Preparation of Formula IIa from Formula III

[0497] Compounds of formula IIa can be prepared by a variety of methods. In some embodiments, compounds of formula IIa can be prepared by the following steps:

[0498] (c) Formation of compounds including Grignard reagents and Formula III:

[0499]

[0500] The sixth reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0501]

[0502] The compound of formula IIa is prepared in a molar ratio of pyridine to the compound of formula III of 2.8 to 3.2, and in a molar ratio of Grignard reagent to the compound of formula III of 2.8 to 3.3.

[0503] The Grignard reagent can be any suitable Grignard reagent. In some embodiments, the Grignard reagent includes iPrMgCl or iPrMgBr. In some embodiments, the Grignard reagent includes iPrMgCl.

[0504] The Grignard reagent can be present in any suitable molar ratio to the compound of Formula III. For example, the Grignard reagent can be present in a molar ratio of 2.0 to 4.0, or 2.5 to 3.5, 2.6 to 3.4, 2.7 to 3.3, 2.8 to 3.3, 2.8 to 3.2, 2.9 to 3.2, or 2.9 to 3.1 to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.8 to 3.3 to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of 2.9 to 3.2 to the compound of Formula III. The Grignard reagent can be present in a molar ratio of about 2.90, or about 2.95, 3.00, 3.05, 3.10, 3.15, or about 3.20 to the compound of Formula III. In some embodiments, the Grignard reagent can be present in a molar ratio of about 3.05 to the compound of Formula III.

[0505] Pyridine can be present in any suitable ratio to the compound of Formula III. For example, pyridine can be present in a molar ratio of 2.0 to 4.0, or 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 to the compound of Formula III. In some embodiments, pyridine can be present in a molar ratio of 2.8 to 3.2 to the compound of Formula III. Pyridine can be present in a molar ratio of about 2.5, or about 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or about 3.5 to the compound of Formula III. In some embodiments, pyridine can be present in a molar ratio of about 3.0 to the compound of Formula III.

[0506] The sixth reaction mixture may also contain a sixth solvent. The sixth solvent can be any suitable solvent, including, but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the sixth reaction mixture further includes a sixth solvent. In some embodiments, the sixth solvent can be tetrahydrofuran, 2-methyltetrahydrofuran, toluene, xylene, or combinations thereof. In some embodiments, the sixth reaction mixture further includes 2-methyltetrahydrofuran and toluene.

[0507] In some embodiments, the method for preparing a compound of formula IIa further comprises: (c1) adding acid and water to a sixth reaction mixture to form a post-treatment mixture; and (c2) distilling the post-treatment mixture to form an intermediate mixture comprising a compound of formula IIa.

[0508] The acid in step (c1) can be any suitable acid. In some embodiments, the acid includes formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or mixtures thereof. In some embodiments, the acid includes acetic acid.

[0509] In some embodiments, the sixth reaction mixture further comprises an intermediate mixture containing compounds of formula IIa.

[0510] In some embodiments, a method for preparing a compound of formula IIb-2 includes the following steps:

[0511] (c) Formation of compounds including tetrahydrofuran, toluene, iPrMgCl, and formula III:

[0512]

[0513] The sixth reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0514]

[0515] The pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and the Grignard reagent is present in a molar ratio of 3.05 to the compound of formula III.

[0516] (c1) Add acetic acid and water to the sixth reaction mixture to form a post-treatment mixture;

[0517] (c2) Distillation post-processing of the mixture to form an intermediate mixture comprising compounds of formula IIa:

[0518]

[0519] (b) Formation of a mixture including intermediates,

[0520] The fifth reaction mixture of acetonitrile and methanesulfonic acid forms a compound of formula IIb-2:

[0521]

[0522] In some embodiments, the present invention provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof:

[0523]

[0524] The method includes:

[0525] (c) Formation of compounds including tetrahydrofuran, toluene, iPrMgCl, and formula III:

[0526]

[0527] The sixth reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0528]

[0529] The pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and the Grignard reagent is present in a molar ratio of 3.05 to the compound of formula III.

[0530] (c1) Add acetic acid and water to the sixth reaction mixture to form a post-treatment mixture;

[0531] (c2) Distillation post-processing of the mixture to form an intermediate mixture comprising compounds of formula IIa:

[0532]

[0533] (b) Formation of a mixture including intermediates,

[0534] The fifth reaction mixture of acetonitrile and methanesulfonic acid forms a compound of formula IIb-2:

[0535]

[0536] (a) Formation of a fourth reaction mixture comprising a compound of formula IIb-2, triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride:

[0537]

[0538] The sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2;

[0539] (a1) Add methanol to the fourth reaction mixture; and

[0540] (a2) Add water to the reaction mixture to precipitate the compound of formula I, in a yield of at least 75% and a purity of at least 98%.

[0541] In some embodiments, the present invention provides a method for preparing a compound of formula Ia or a pharmaceutically acceptable salt thereof:

[0542]

[0543] The method includes:

[0544] (c) Formation of compounds including tetrahydrofuran, toluene, iPrMgCl, and formula III:

[0545]

[0546] The sixth reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine:

[0547]

[0548] The pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and the Grignard reagent is present in a molar ratio of about 3.05 to the compound of formula III.

[0549] (c1) Add acetic acid and water to the sixth reaction mixture to form a post-treatment mixture;

[0550] (c2) Distillation post-processing of the mixture to form an intermediate mixture comprising compounds of formula IIa:

[0551]

[0552] (b) Formation of a mixture including intermediates,

[0553] The fifth reaction mixture of acetonitrile and methanesulfonic acid forms a compound of formula IIb-2:

[0554]

[0555] (a) Formation of a fourth reaction mixture comprising a compound of formula IIb-2, triethylamine, ethyl acetate, and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride:

[0556]

[0557] The sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2;

[0558] (a1) Add methanol to the fourth reaction mixture; and

[0559] (a2) Add water to the reaction mixture to precipitate the compound of form Ia in a yield of at least 75% and a purity of at least 98%.

[0560] VI. Low-impurity compositions

[0561] This invention provides compositions of Formula I having low impurity content. In some embodiments, this invention provides a composition comprising:

[0562] Compounds of formula I with a content of at least 99% (w / w):

[0563]

[0564] One or more impurities in a content of 0.01% (w / w) to 1% (w / w).

[0565] The composition of Formula I may contain one or more impurities present in a total amount of 0.01% (w / w) to 1% (w / w). In some embodiments, the impurity comprises at least one of the following:

[0566] Compounds of formula X-4 with a content of less than 0.5% (w / w):

[0567]

[0568] Compounds of formula X-5 with a content of less than 0.2% (w / w):

[0569]

[0570] Compounds of formula X-6 with a content of less than 0.1% (w / w):

[0571]

[0572] Impurities present in a composition of a compound of Formula I may comprise less than 1% (w / w) of a compound of Formula X-4. For example, a composition of a compound of Formula I may comprise less than 1.0% (w / w) or less than 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of a compound of Formula X-4. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.5% (w / w) of a compound of Formula X-4. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.3% (w / w) of a compound of Formula X-4. In some embodiments, a composition comprising a compound of formula I may contain less than 0.1% (w / w) of a compound of formula X-4.

[0573] Impurities present in a composition of a compound of Formula I may comprise less than 1% (w / w) of a compound of Formula X-5. For example, a composition comprising a compound of Formula I may contain less than 1.0% (w / w) or less than 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of a compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 1% (w / w) of a compound of Formula X-5. In some embodiments, a composition comprising a compound of Formula I may contain less than 0.75% (w / w) of a compound of Formula X-5. In some embodiments, a composition comprising a compound of formula I may contain less than 0.5% (w / w) of a compound of formula X-5. In some embodiments, a composition comprising a compound of formula I may contain less than 0.2% (w / w) of a compound of formula X-5.

[0574] Impurities present in a composition comprising a compound of formula I may contain less than 1.0% (w / w) or less than 0.9% (w / w), 0.8% (w / w), 0.75% (w / w), 0.7% (w / w), 0.6% (w / w), 0.5% (w / w), 0.4% (w / w), 0.3% (w / w), 0.25% (w / w), 0.2% (w / w), or less than 0.1% (w / w) of a compound of formula X-6. In some embodiments, a composition comprising a compound of formula I may contain less than 0.25% (w / w) of a compound of formula X-6. In some embodiments, a composition comprising a compound of formula I may contain less than 0.2% (w / w) of a compound of formula X-6. In some embodiments, a composition comprising a compound of formula I may contain less than 0.1% (w / w) of a compound of formula X-6.

[0575] In some embodiments, the impurities include: a compound of formula X-4 in a content of less than 0.1% (w / w); a compound of formula X-5 in a content of less than 0.15% (w / w); and a compound of formula X-6 in a content of less than 0.1% (w / w).

[0576] Impurities present in compositions comprising compounds of formula I may include methyl 1-methyl-1H-pyrazole-4-sulfonate in amounts of less than 10 ppm.

[0577]

[0578] For example, a composition comprising a compound of formula I may contain methyl 1-methyl-1H-pyrazole-4-sulfonate impurity in amounts less than 10 ppm, or less than 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm. In some embodiments, a composition comprising a compound of formula I may contain methyl 1-methyl-1H-pyrazole-4-sulfonate impurity in amounts less than 8 ppm. In some embodiments, a composition comprising a compound of formula I may contain methyl 1-methyl-1H-pyrazole-4-sulfonate impurity in amounts less than 6 ppm. In some embodiments, a composition comprising a compound of formula I may contain methyl 1-methyl-1H-pyrazole-4-sulfonate impurity in amounts less than 4 ppm.

[0579] Impurities present in compositions including compounds of formula I may contain less than 10 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride.

[0580]

[0581] For example, a composition comprising a compound of formula I may contain less than 10 ppm, or less than 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, or less than 4 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. In some embodiments, a composition comprising a compound of formula I may contain less than 8 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. In some embodiments, a composition comprising a compound of formula I may contain less than 6 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride. In some embodiments, a composition comprising a compound of formula I may contain less than 4 ppm of 1-methyl-1H-pyrazole-4-sulfonyl chloride.

[0582] In some embodiments, the impurities further include: 1-methyl-1H-pyrazole-4-sulfonyl chloride in a concentration of less than 4 ppm; and methyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 4 ppm. In some embodiments, the impurities further include: 1-methyl-1H-pyrazole-4-sulfonyl chloride in a concentration of less than 4 ppm; methyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 4 ppm; ethyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 4 ppm; and isopropyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 4 ppm.

[0583] Compositions comprising compounds of formula I may also contain one or more of the following impurities:

[0584] Compounds with formula XD with a content of less than 0.40% (w / w):

[0585]

[0586] Compounds with formula XE with a content of less than 0.40% (w / w):

[0587]

[0588] Compounds with the formula XF with a content of less than 0.30% (w / w):

[0589]

[0590] In some embodiments, a composition comprising a compound of formula I may further contain one or more of the following impurities:

[0591] Compounds with formula XD with a content of less than 0.40% (w / w):

[0592]

[0593] Compounds with formula XE with a content of less than 0.40% (w / w):

[0594]

[0595] In some embodiments, the composition comprising the compound of formula I may further contain less than 0.30% (w / w) of a compound having formula XF:

[0596]

[0597] In some embodiments, the present invention provides the following composition:

[0598] Compounds of formula Ia with a content of at least 99% (w / w):

[0599]

[0600] One or more impurities present in a concentration of 0.01% (w / w) to 1% (w / w). In some embodiments, the impurity comprises at least one of the following:

[0601] Compounds of formula X-4a with a content of less than 0.5% (w / w):

[0602]

[0603] Compounds of formula X-5a with a content of less than 0.2% (w / w):

[0604]

[0605] Compounds of formula X-6a with a content of less than 0.1% (w / w):

[0606]

[0607] In some embodiments, the impurities include: a compound of formula X-4a in a content of less than 0.1% (w / w); a compound of formula X-5a in a content of less than 0.15% (w / w); and a compound of formula X-6a in a content of less than 0.1% (w / w).

[0608] In some embodiments, the impurity further comprises one or more of the following: 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride in a concentration of less than 4 ppm; methyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in a concentration of less than 4 ppm; ethyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in a concentration of less than 4 ppm; and isopropyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in a concentration of less than 4 ppm. In some embodiments, the impurity further comprises: 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride in a concentration of less than 4 ppm; methyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in a concentration of less than 4 ppm; ethyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in a concentration of less than 4 ppm; and isopropyl 2-methyl-2H-1,2,3-triazole-4-sulfonate in a concentration of less than 4 ppm.

[0609] In some embodiments, the impurities further include:

[0610] Compounds of formula X-Da with a content of less than 0.40% (w / w)

[0611]

[0612] Compounds of formula X-Ea with a content of less than 0.40% (w / w)

[0613]

[0614] VII. Crystal form of formula IIb

[0615] The present invention also provides crystal forms of compounds of formula IIb.

[0616] A.(R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid

[0617] In some embodiments, the present invention provides a crystal form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid:

[0618]

[0619] The feature is that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 18.2°2-θ±0.2°2-θ, 18.3°2-θ±0.2°2-θ, and 19.7°2-θ±0.2°2-θ.

[0620] In some embodiments, XRPD further includes peaks at approximately 9.9°²-θ ± 0.2°²-θ, 16.5°²-θ ± 0.2°²-θ, and 17.6°²-θ ± 0.2°²-θ. In some embodiments, XRPD further includes peaks at approximately 5.0°²-θ ± 0.2°²-θ, 14.5°²-θ ± 0.2°²-θ, 17.9°²-θ ± 0.2°²-θ, 19.0°²-θ ± 0.2°²-θ, 20.8°²-θ ± 0.2°²-θ, 22.9°²-θ ± 0.2°²-θ, 23.4°²-θ ± 0.2°²-θ, and 25.3°²-θ ± 0.2°²-θ. In some embodiments, XRPD includes peaks at approximately 5.0°2-θ±0.2°2-θ, 9.9°2-θ±0.2°2-θ, 14.5°2-θ±0.2°2-θ, 16.5°2-θ±0.2°2-θ, 17.6°2-θ±0.2°2-θ, 17.9°2-θ±0.2°2-θ, 18.2°2-θ±0.2°2-θ, 18.3°2-θ±0.2°2-θ, 19.0°2-θ±0.2°2-θ, 19.7°2-θ±0.2°2-θ, 20.8°2-θ±0.2°2-θ, 22.9°2-θ±0.2°2-θ, 23.4°2-θ±0.2°2-θ, and 25.3°2-θ±0.2°2-θ. In some embodiments, the crystal form is characterized in that the XRPD pattern is substantially as shown in the figure. Figure 2 As shown.

[0621] In some embodiments, the crystal form is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic start at approximately 167°. In some embodiments, the crystal form is characterized by a DSC thermogram that is substantially as follows: Figure 3 As shown.

[0622] B.(R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone oxalic acid

[0623] In some embodiments, the present invention provides a crystal form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone oxalic acid:

[0624]

[0625] The feature is that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 6.1°2-θ±0.2°2-θ, 8.4°2-θ±0.2°2-θ, 10.6°2-θ±0.2°2-θ, and 15.6°2-θ±0.2°2-θ.

[0626] In some embodiments, the XRPD further includes peaks at approximately 12.3°2-θ±0.2°2-θ, 13.0°2-θ±0.2°2-θ, and 25.3°2-θ±0.2°2-θ. In some embodiments, the XRPD further includes peaks at approximately 16.2°2-θ±0.2°2-θ, 17.1°2-θ±0.2°2-θ, 18.2°2-θ±0.2°2-θ, 19.9°2-θ±0.2°2-θ, 21.7°2-θ±0.2°2-θ, 22.9°2-θ±0.2°2-θ, 23.7°2-θ±0.2°2-θ, and 24.6°2-θ±0.2°2-θ. In some embodiments, the XRPD further includes approximately 6.1°²-θ±0.2°²-θ, 8.4°²-θ±0.2°²-θ, 10.6°²-θ±0.2°²-θ, 12.3°²-θ±0.2°²-θ, 13.0°²-θ±0.2°²-θ, 15.6°²-θ±0.2°²-θ, 16.2°²-θ±0.2°²-θ, and 1... Peaks at 7.1°2-θ±0.2°2-θ, 18.2°2-θ±0.2°2-θ, 19.9°2-θ±0.2°2-θ, 21.7°2-θ±0.2°2-θ, 22.9°2-θ±0.2°2-θ, 23.7°2-θ±0.2°2-θ, 24.6°2-θ±0.2°2-θ, and 25.3°2-θ±0.2°2-θ. In some embodiments, the crystal form is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially as shown in the image. Figure 5 As shown.

[0627] In some embodiments, the crystal form is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic start at approximately 168°. In some embodiments, the crystal form is characterized by a DSC thermogram that is substantially as follows: Figure 6 As shown.

[0628] C.(R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone hydrochloride

[0629] In some embodiments, the present invention provides a crystal form of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-hydrochloric acid:

[0630]

[0631] The feature is that the X-ray powder diffraction (XRPD) pattern has peaks at approximately 15.3°2-θ±0.2°2-θ, 22.0°2-θ±0.2°2-θ, 23.1°2-θ±0.2°2-θ and 24.5°2-θ±0.2°2-θ.

[0632] In some embodiments, XRPD further includes peaks at approximately 7.0°2-θ±0.2°2-θ, 13.5°2-θ±0.2°2-θ, 14.8°2-θ±0.2°2-θ, 17.7°2-θ±0.2°2-θ, 18.3°2-θ±0.2°2-θ, 19.2°2-θ±0.2°2-θ, 23.5°2-θ±0.2°2-θ, and 25.2°2-θ±0.2°2-θ. In some embodiments, XRPD further includes peaks at approximately 8.1°2-θ±0.2°2-θ, 11.5°2-θ±0.2°2-θ, 21.2°2-θ±0.2°2-θ, 26.9°2-θ±0.2°2-θ, 27.2°2-θ±0.2°2-θ, 28.1°2-θ±0.2°2-θ, 30.1°2-θ±0.2°2-θ, and 32.4°2-θ±0.2°2-θ. In some embodiments, the XRPD includes approximately 7.0°²-θ±0.2°²-θ, 8.1°²-θ±0.2°²-θ, 11.5°²-θ±0.2°²-θ, 13.5°²-θ±0.2°²-θ, 14.8°²-θ±0.2°²-θ, 15.3°²-θ±0.2°²-θ, 17.7°²-θ±0.2°²-θ, 18.3°²-θ±0.2°²-θ, 19.2°²-θ±0.2°²-θ, and 21.2°²-θ±0.2°²-θ. Peaks at 2°2-θ, 22.0°2-θ±0.2°2-θ, 23.1°2-θ±0.2°2-θ, 23.5°2-θ±0.2°2-θ, 24.5°2-θ±0.2°2-θ, 25.2°2-θ±0.2°2-θ, 26.9°2-θ±0.2°2-θ, 27.2°2-θ±0.2°2-θ, 28.1°2-θ±0.2°2-θ, 30.1°2-θ±0.2°2-θ, and 32.4°2-θ±0.2°2-θ. In some embodiments, the crystal form is characterized by an X-ray powder diffraction (XRPD) pattern that is substantially as shown in the image. Figure 8 As shown.

[0633] In some embodiments, the crystal form is characterized by a differential scanning calorimetry (DSC) thermogram having an endothermic start at approximately 215°. In some embodiments, the crystal form is characterized by a DSC thermogram that is substantially as follows: Figure 9 As shown.

[0634] VIII. Composition

[0635] In some embodiments, the present invention provides a pharmaceutical composition comprising the low-impurity composition of the present invention and a pharmaceutically acceptable excipient.

[0636] The low-impurity compositions of the present invention can be prepared and administered in various oral, parenteral, and topical dosage forms. Oral formulations include tablets, pills, powders, sugar-coated pills, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, etc., suitable for patient ingestion. The low-impurity compositions of the present invention can also be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, duodenal, or intraperitoneal administration. In addition, the compounds described herein can be administered by inhalation, for example, nasal administration. Furthermore, the low-impurity compositions of the present invention can be administered percutaneously. The compounds of formula I of the present invention (e.g., steroid inhalers, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995) can also be administered via intraocular, intravaginal, and rectal routes (including suppositories, inhalers, powders, and aerosol formulations). Therefore, the present invention also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and / or excipients and compounds of formula I.

[0637] For the preparation of pharmaceutical compositions from the low-impurity compositions of the present invention, a pharmaceutically acceptable carrier may be solid or liquid. Solid form formulations include powders, tablets, pills, capsules, pouches, suppositories, and dispersible granules. The solid carrier may be one or more substances that may also be used as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials. Technical details regarding formulation and administration are well described in scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington's”).

[0638] In powder form, the carrier is a finely ground solid that is mixed with the finely ground active ingredient. In tablet form, the active ingredient is mixed with a carrier having the desired binding properties and additional excipients as needed in appropriate proportions and compressed into the desired shape and size.

[0639] Powders, capsules, and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. The term "formulation" refers to a formulation comprising an active compound having an encapsulating material as a carrier, which provides a capsule in which the active component, with or without other excipients, is surrounded and thus bound to the carrier. Similarly, capsules and tablets are also included. Tablets, powders, capsules, pills, capsules, and tablets can be used as solid dosage forms suitable for oral administration.

[0640] Suitable solid excipients are carbohydrate or protein fillers that include, but are not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starches from corn, wheat, rice, potatoes, or other plants; cellulose, such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; and gums, including gum arabic and gum tragali; and proteins, such as gelatin and collagen. Disintegrants or solubilizers, such as cross-linked polyvinylpyrrolidone, agar, alginate, or salts thereof, such as sodium alginate, may be added if desired.

[0641] The sugar-coated core is provided with a suitable coating, such as a concentrated sugar solution, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or sugar-coated core coating for product identification or characterization of the amount (i.e., dosage) of the active compound. The pharmaceutical formulations of the present invention may also be used orally in push-fit capsules, for example, made of gelatin, and in soft-seal capsules made of gelatin and a coating such as glycerin or sorbitol. Push-fit capsules may contain a compound of formula I mixed with a filler or binder (such as lactose or starch), a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the compound of formula I may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol with or without a stabilizer.

[0642] To prepare the suppositories, a low-melting-point wax (such as a mixture of fatty acid glycerides or cocoa butter) is first melted and the active ingredients are uniformly dispersed within it by stirring. The molten, homogeneous mixture is then poured into a standard-sized mold and allowed to cool and solidify.

[0643] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid formulations can be formulated as solutions in aqueous polyethylene glycol solutions.

[0644] It also includes solid formulations intended to be converted into liquid formulations for oral administration shortly before use. These liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0645] Oil suspensions can be prepared by suspending a compound of Formula I in a vegetable oil (such as peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (such as liquid paraffin), or a mixture thereof. The oil suspension may contain a thickener, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as glycerin, sorbitol, or sucrose, may be added to provide palatable oral preparations. These preparations may be preserved by adding antioxidants such as ascorbic acid. As an example of an injectable oil-based medium, see Minto, *Journal of Pharmacology and Experimental Therapy*, 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil or mineral oil, or a mixture thereof, as described above. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth; naturally occurring phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of these metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents, as in formulations of syrups and elixirs. Such formulations may also contain modifiers, preservatives, or colorants.

[0646] The compounds of Formula I of the present invention can be delivered transdermally via a local route and formulated into applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jelly, coatings, powders, and aerosols.

[0647] Compounds of Formula I and compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be administered via intradermal injection as slowly released subcutaneously containing drug-containing microspheres (see Rao, *J. Biomater Sci. Polym. Ed.* 7: 623-645, 1995); as biodegradable and injectable gel formulations (see, for example, Gao, *Pharm. Res.* 12: 857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, *J. Pharm. Pharmacol.* 49: 669-674, 1997). Both perdermal and intradermal routes provide sustained delivery for weeks or months.

[0648] In some embodiments, formulations of the Formula I compounds of the present invention can be delivered using liposomes fused to or endocytosed by cell membranes, i.e., using ligands linked to the liposomes or directly to oligonucleotides that bind to cell surface membrane protein receptors, thereby leading to endocytosis. By using liposomes, particularly those with ligands on their surface that are specific to target cells or otherwise preferentially targeted to specific organs, GR regulators can be delivered in vivo to target cells. (See, for example, Al-Muhammed, *Journal of Microencapsulation* 13:293-306, 1996; Chonn, *Curr. Opin. Biotechnol.* 6:698-708, 1995; Ostro, *Am. J. Hosp. Pharm.* 46:1576-1587, 1989).

[0649] Pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate amounts of the active ingredient. A unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, and powder in vials or ampoules. Similarly, a unit dosage form itself can be a capsule, tablet, sachets, or lozenge, or can be any of these in appropriate packaged form.

[0650] The amount of active ingredient in a unit dose formulation can vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1,000 mg, and most commonly from 10 mg to 500 mg, depending on the specific application and the potency of the active ingredient. For example, the dose can be 50 mg or 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. If desired, the composition may also contain other compatible therapeutic agents.

[0651] The dosing regimen also takes into account well-known pharmacokinetic parameters in the field, namely absorption rate, bioavailability, metabolism, clearance, etc. (see, for example, Hidalgo-Aragones (1996), Journal of Steroid Biochemistry and Molecular Biology). Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Conception 54:59-69; Johnson (1995) Journal of Pharmaceutical Science 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) European Journal of Clinical Pharmacology 24:103-108; the most recent being Remington (see above). Existing technology allows clinicians to determine the dosing regimen for each individual patient, GR and / or MR modulator, and the disease or condition being treated.

[0652] The formulation of a compound of Formula I can be administered once or multiple times, depending on the dose and frequency required and tolerated by the patient. The formulation should provide an adequate amount of active agent to effectively treat the disease state. Thus, in one embodiment, the daily dose of a pharmaceutical formulation of a compound of Formula I for oral administration is about 0.5 mg to about 30 mg per kilogram of body weight per day. In an alternative embodiment, the dose used is about 1 mg to about 20 mg per kilogram of body weight per patient per day. Lower doses can be used compared to oral administration, particularly when the drug is applied to anatomically concealed sites (such as cerebrospinal fluid (CSF) spaces), into the bloodstream, into body cavities, or into the lumens of organs. Significantly higher doses can be used in topical administration. Practical methods for preparing formulations containing a compound of Formula I for parenteral administration are known or obvious to those skilled in the art and are described in more detail in publications such as the aforementioned Remington. See also Nieman, “Receptor-Mediated Antistero Action,” Agarwal et al., editors, DeGruyter, New York (1987).

[0653] The compounds described herein can be used in combination with each other, in combination with other active agents known to be effective in modulating glucocorticoid receptors, or in combination with adjuvants that may be ineffective on their own but may contribute to the efficacy of the active agents.

[0654] In some embodiments, co-administration involves applying one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Co-administration includes applying the two active agents simultaneously, nearly simultaneously (e.g., within approximately 1, 5, 10, 15, 20, or 30 minutes between each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition comprising the two active agents. In some embodiments, the active agents can be formulated individually. In some embodiments, the active agents and / or adjuvants can be linked or conjugated to each other.

[0655] After a pharmaceutical composition comprising a compound of Formula I of the present invention is formulated in one or more acceptable carriers, it can be placed in a suitable container and labeled for the treatment of a specified condition. For the administration of compounds of Formula I, such labeling will include, for example, instructions regarding the dosage, frequency, and method of administration.

[0656] In some embodiments, the compositions of the present invention can be used for parenteral administration, such as intravenous (IV) administration or administration into body cavities or organ cavities. Formulations for administration will generally comprise a solution of the composition of the present invention dissolved in one or more pharmaceutically acceptable carriers. Additionally, sterile fixative oils can routinely be used as solvents or suspension media. For this purpose, any mild fixative oil containing synthetic monoglycerides or diglycerides can be used. Additionally, fatty acids such as oleic acid can also be used to prepare injectable formulations. These solutions are sterile and generally free of unwanted substances. These formulations can be sterilized using conventional, well-known sterilization techniques. Formulations may contain pharmaceutically acceptable excipients close to physiological conditions, such as pH adjusters and buffers, tonic modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these formulations can vary widely and will be selected based on the specific route of administration chosen and the patient's needs, primarily based on fluid volume, viscosity, body weight, etc. For IV administration, the formulation can be a sterile injectable formulation, such as a sterile injectable aqueous or oil suspension. Such suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions of 1,3-butanediol.

[0657] In some embodiments, formulations of the compositions of the present invention can be delivered using liposomes fused to or endocytosed with cell membranes, i.e., using ligands linked to the liposomes or directly linked to oligonucleotides that bind to cell surface membrane protein receptors, thereby leading to endocytosis. By using liposomes, particularly those with ligands on their surface that are specific to target cells or otherwise preferentially targeted to specific organs, the compositions of the present invention can be delivered and concentrated in target cells in vivo. (See, for example, Al-Muhammed, *Journal of Microencapsulation* 13:293-306, 1996; Chonn, *Curr. Opin. Biotechnol.* 6:698-708, 1995; Ostro, *Am. J. Hosp. Pharm.* 46:1576-1587, 1989).

[0658] IX. Methods and Uses

[0659] In some embodiments, the present invention provides a method for treating a disorder or condition by modulating glucocorticoid receptors, the method comprising administering a therapeutically effective amount of either the low-impurity composition of the present invention or a pharmaceutical composition of the present invention to a subject requiring such treatment, thereby treating the disorder or condition.

[0660] In some embodiments, the present invention provides a method for treating a disorder or condition by antagonizing glucocorticoid receptors, the method comprising administering to a subject requiring such treatment an effective amount of either the low-impurity composition of the present invention or any of the pharmaceutical compositions of the present invention.

[0661] In some embodiments, the disorder or condition is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by excessive cortisol due to adrenal disorders, addiction, psychosis, anorexia, cachexia, post-traumatic stress disorder, postoperative fracture, GR-related metabolic disorders, major psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, weight gain caused by antipsychotic drugs, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neurological disorders in premature infants.

[0662] In some embodiments, the method includes administering one or more second agents (e.g., therapeutic agents). In some embodiments, the method includes administering a therapeutically effective amount of one or more second agents (e.g., therapeutic agents). In some embodiments, the second agent is an agent known to be used to modulate glucocorticoid receptors. In some embodiments, the second agent is an agent for treating amyotrophic lateral sclerosis (ALS), obesity, diabetes, cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Cushing's syndrome, Cushing's disease, cancer, liver disease, osteoporosis, muscle weakness, disorders caused by excessive cortisol due to adrenal disorders, addiction, psychosis, anorexia, cachexia, post-traumatic stress disorder, postoperative fracture, GR-related metabolic disorders, major psychotic depression, mild cognitive impairment, dementia, hyperglycemia, stress disorders, weight gain caused by antipsychotic drugs, delirium, cognitive impairment in patients with depression, postpartum psychosis, postpartum depression, and neurological disorders in premature infants. In some embodiments, the second agent is an agent for treating major psychotic depression, stress disorder, or weight gain induced by antipsychotic drugs. In some embodiments, the second agent is an agent for treating non-alcoholic fatty liver disease and / or non-alcoholic steatohepatitis. In some embodiments, the second agent is an agent for treating addiction disorders. In some embodiments, the second agent is an agent for treating cancer. In some embodiments, the second agent is an anticancer agent. In some embodiments, the second agent is a chemotherapeutic agent.

[0663] In some embodiments, any of the low-impurity compositions of the present invention or any of the pharmaceutical compositions of the present invention can be used in a method of treating disorders or conditions by modulating glucocorticoid receptors.

[0664] In some embodiments, any of the low-impurity compositions of the present invention or any of the pharmaceutical compositions of the present invention can be used in a method of treating disorders or conditions by antagonizing glucocorticoid receptors.

[0665] In some embodiments, any of the low-impurity compositions of the present invention or any of the pharmaceutical compositions of the present invention can be used to manufacture a medicament for treating disorders or conditions by modulating glucocorticoid receptors.

[0666] In some embodiments, any of the low-impurity compositions of the present invention or any of the pharmaceutical compositions of the present invention can be used to manufacture a medicament for treating disorders or conditions by antagonizing glucocorticoid receptors.

[0667] X. Example

[0668] The following abbreviations are used for the following methods:

[0669] ACN Acetonitrile aq Water-based atm Atmospheric pressure Boc tert-butoxycarbonyl DIPEA Diisopropylethylamine eq or equiv equivalent FA Formic acid g gram HDPE High-density polyethylene IPAC Isopropyl acetate Kg kilogram L Lift M Moore mbar millibar 2-MeTHF 2-Methyltetrahydrofuran mins minute mL milliliters MTBE Methyl tert-butyl ether nm nanometer NMR Nuclear magnetic resonance share ppm parts per million r.t. room temperature THF Tetrahydrofuran μm micrometer wt / wt Weight / Weight

[0670] X-ray powder diffraction (XRPD) was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Isothermal samples were analyzed in transmission mode and held between low-density polyethylene films. The XRPD program used included the following parameters: (1) range 3–40°2θ, (2) step size 0.013°, (3) counting time 99 seconds, and (4) run time approximately 22 minutes. XRPD modes were sorted using HighScore Plus 2.2c software.

[0671] Differential scanning calorimetry (DSC) analysis was performed on a Perkin Elmer Jade differential scanning calorimeter. Precisely weighed samples were placed in rolled-up aluminum pans. Each sample was heated to a maximum of 300°C at a rate of 10°C / min under nitrogen atmosphere. Indium was used as a calibration standard. The temperature was reported to the nearest 0.01 degrees at the start of the transition.

[0672] The reaction steps of this invention can be performed 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, about four hours, about six hours, about eight hours, about ten hours, about twelve hours, about fourteen hours, about sixteen hours, about eighteen hours, about twenty hours, about twenty-two hours, or about twenty-four hours. In some embodiments, the reaction time can last for about one day, about two days, about three days, about four days, about five days, about six days, about one week, or about more than one week.

[0673] The reaction steps of this invention can be carried out 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 this 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 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.

[0674] Example 1. (R)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)pyridinyl)-1,4,4a,5,7,8-hexahydro- Preparation of 6H-pyrazolo[3,4-g]isoquinoline-6-carboxylic acid tert-butyl ester

[0675]

[0676] Add 0.7–0.8 parts of 2-bromo-4-(trifluoromethyl)pyridine to 6.8 parts of toluene. Cool the solution to -5°C to 5°C under nitrogen. Add 1.3–1.5 parts of the reagent, i.e., isopropyl magnesium bromide (3.0 M 2-Me-THF solution), to the solution while maintaining the batch temperature at -5°C to 5°C. The Grignard reaction occurs at -5°C to 5°C for ≥6 hours until the reaction is complete (HPLC, ≤15% 2-bromo-4-(trifluoromethyl)pyridine).

[0677] Add 1.0 part of a solution of (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 (compound 9) in 7.0 parts of toluene, while maintaining the batch temperature at -5°C to 5°C. Warm the reaction mixture to 15°C to 25°C and maintain this temperature for at least 12 hours, continuing until the coupling reaction is complete (HPLC, ≤1.0% of compound 9 remaining).

[0678] The reaction was quenched by adding 0.28 parts of acetic acid to 10 parts of water. The solution was stirred and then allowed to settle. The aqueous phase was discarded, and the organic phase was washed with 12 parts of hydrochloric acid aqueous solution. The aqueous phase was discarded, and the organic phase was washed with 12 parts of water. The aqueous phase was discarded. The product was dried by azeotropic distillation at ≤50°C (KF, ≤0.1% water; HPLC, ≤20 ppm 2-MeTHF). The product was separated in toluene (5% w / w–8% w / w) to give 1.1–1.3 parts (90%–100% molar yield). The characterization data of the title compound matched those of intermediate 29 of U.S. Patent No. 8,859,774.

[0679] Example 2. (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8- Preparation of hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone (Rellacolan) Preparation Method I

[0680]

[0681] The target compound was prepared using the following steps.

[0682] Preparation of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone trihydrobromic acid

[0683]

[0684] Add 1.0 part of a toluene solution of the product from Example 1 to the container. Add 1.0-1.2 parts of hydrogen bromide gas at a temperature of -5°C to 5°C until the reaction is complete (HPLC, ≤1.0% of the product from Example 1 remaining). Transfer the mixture to a filter desiccator and wash with at least 2.6 parts of toluene at a temperature of -5°C to 5°C.

[0685] The solid was dried at -5°C to 10°C under vacuum / nitrogen for at least 24 hours, and samples were taken every 12-24 hours (GC, retaining ≤25% toluene). The tri-hydrobromic acid compound was isolated, yielding 1.1-1.3 parts (85%-100% molar yield).

[0686] Preparation of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0687] Add 1.0 part of the tri-hydrobromic acid intermediate from step 2 to 7.8 parts of isopropyl acetate at -5°C to 5°C. Add 0.3 parts of pyrazolesulfonyl chloride and 1.2 parts of triethylamine, and continue stirring for at least 3 hours until the reaction is complete (HPLC, ≤2% of tri-hydrobromic acid intermediate remaining). Wash the organic phase with at least 8.8 parts of water at 15°C–25°C. Then wash the organic phase with 3.7 parts of HCl / water solution (adjusted to pH 4–5). Then wash the organic phase with 13 parts of NaCl / water solution (adjusted to pH 5–6).

[0688] Add 0.3 parts silica gel to the organic solution. Filter the solution and wash with at least 1.2 parts isopropyl acetate. Concentrate the mother liquor under vacuum at ≤50°C and perform solvent exchange in acetone (GC, ≤10% isopropyl acetate). Separate crude ryracolan (target 40% w / w) in acetone to obtain 0.6–0.8 parts (70%–90% molar yield) of crude ryracolan. Characterization data for the crude ryracolan match those of Example 18 of U.S. Patent No. 8,859,774.

[0689] Example 3. (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8- Purification of hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone

[0690] The product of Example 2 was purified using the following method.

[0691] Preparative HPLC purification

[0692] An HPLC column was packed with isopropanol using a C18 pressure pack. The chromatographic resin was specifically designed for rayochrome production, and the packaged column was reused multiple times within each product batch. Usage tests were performed to determine the collection time for the product fractions within the elution parameters given in Table 2.

[0693] Equilibrate the packaged column with 1–2 column volumes of mobile phase A. Load crude ryracolan (1.0 kg–1.5 kg) in solution onto the column at a rate of 3 L / min. Using a gradient from mobile phase B to mobile phase C, elute the product from the column at a flow rate of 4.5 L / min over 100 min. Fractionate the column eluent into multiple collection vessels according to the established use test collection time. After column fractionation, wash the column with buffer C at a flow rate of 6.5 L / min for 10 min to regenerate the packaged material.

[0694] The column equilibration, loading, elution, fractionation, and column washing processes were then repeated to obtain additional fractions. The eluted fractions in the collection vessel were sampled and tested for ryracolan purity and related substances. Eluted fractions meeting the process acceptance criteria (HPLC: ≥98.0% purity, ≤0.6% of Formula X-5, ≤0.20% of single impurities) were identified as product fractions and combined.

[0695] Table 1. Composition of reversed-phase chromatography solutions

[0696]

[0697] Table 2. Reversed-phase chromatography process parameters

[0698]

[0699] MTBE / Heptane Purification

[0700] Following preparative HPLC purification, the ryracolan fraction was further purified as described below. A solution of ryracolan in ACN:FA:water was saturated with sodium chloride and extracted with a total of ≥45 parts ethyl acetate. The ethyl acetate solution was washed with ≥30 parts NaCl / water solution. The organic phase was concentrated under vacuum at ≤50°C (KF, ≤1%) to a concentration of 3 to 5 parts ryracolan in ethyl acetate. Solvent exchange was performed by concentrating the solution of ryracolan in MTBE at ≤50°C under vacuum to ≥11 parts by volume of MTBE solution (GC, ≤5% ethyl acetate). The ryracolan solution was filtered through a CUNO cartridge filter (HPLC, ≤0.30 of formula X-5, ≤0.20 of formula X-6, ≤0.15 of formula X-4, ≤0.10% unknown impurities).

[0701] At 30°C to 40°C, a solution of rilatoklan in MTBE was slowly added to 10 parts heptane, and the solution was cooled to -5°C to 5°C to precipitate rilatoklan. The rilatoklan precipitate was collected and washed with ≥2 parts heptane. The wet filter cake was dried at ≤50°C for ≥4 hours (GC, ≤15% MTBE, ≤15% heptane, ≤4 ppm methyl bromide, ≤4 ppm 2-bromopropane, ≤4 ppm 1,4-dibromopentane). The purified rilatoklan was isolated and purified to give 0.60–0.90 parts (60%–90% molar yield) of purified rilatoklan.

[0702] Methanol solvent washing

[0703] The purified ryracolan was dissolved in 13.6 parts of methanol. The methanol solution was concentrated under vacuum at ≤50°C to ≥9 parts by volume of MTBE solution of ryracolan (GC, ≤300 ppm MTBE, ≤300 ppm heptane). The solution was slowly added to 15 parts of water through a 0.22 μm inline filter to precipitate ryracolan. The ryracolan precipitate was collected by filtration and washed with at least 5 parts of water (HPLC, ≤4 ppm 1-methyl-1H-pyrazole-4-sulfonyl chloride, ≤4 ppm 1-methyl-1H-pyrazole-4-sulfonate methyl ester, ≤4 ppm 1-methyl-1H-pyrazole-4-sulfonate ethyl ester, ≤4 ppm 1-methyl-1H-pyrazole-4-sulfonate isopropyl ester, ≤50 ppm formic acid). Then, the ryracolan (KF, ≤1.1%; GC, ≤4500 ppm isopropyl acetate, ≤4500 ppm acetone, ≤370 ppm acetonitrile, ≤4500 ppm ethyl acetate, ≤2700 ppm methanol, ≤5000 ppm heptane, ≤5000 ppm MTBE) was dried under vacuum.

[0704] Example 4. (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8- Preparation of hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone (Rellacolan) Preparation Method II

[0705]

[0706] The target compound was prepared using the following steps.

[0707] Step 1. Preparation of (R)-1-(4-fluorophenyl)-4a-(4-(trifluoromethyl)pyridinyl)-1,4,4a,5,7,8-hexahydro-6H-pyrazolo[3,4-g]isoquinoline-6-carboxylic acid tert-butyl ester

[0708]

[0709] Compound 9

[0710] Step 1 involves the addition of 2-bromo-4-(trifluoromethyl)pyridine (3.0 equivalents) to (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 (compound 9; 1.0 equivalents) via halogen-metal exchange using the Grignard reagent iPrMgCl (3.05 equivalents). During post-treatment, the intermediate hemiacetal is converted to a ketone, and the product of Step 1 is isolated as a solution in toluene and used directly in the next step.

[0711] 1. The reactor is inertized by vacuum purging with nitrogen.

[0712] 2. Using the remaining vacuum, toluene (40.0 kg) is added to the reactor via the solvent addition line.

[0713] 3. Vigorously stir the contents of the reactor for at least 5 minutes.

[0714] 4. Discharge the reactor contents to a suitable waste receiver via the bottom outlet valve.

[0715] 5. Set up the reactor for distillation and place it under complete vacuum. Ensure the reactor is visually dry.

[0716] 6. (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 (compound 9; 7.2 kg) was introduced into the reactor through a manhole.

[0717] 7. Inject nitrogen gas into the reactor.

[0718] 8. Using the remaining vacuum, add toluene (31.2 kg) into the reactor via the solvent addition line and start the stirrer.

[0719] 9. Stir the contents of the reactor at 25°C for at least 5 minutes to dissolve compound 9.

[0720] 10. Stop stirring and transfer the reactor contents to a clean, plastic-lined drum after tare weight.

[0721] 11. Using the remaining vacuum, add toluene (6.2 kg) into the reactor via the solvent addition line.

[0722] 12. Stir the contents of the reactor for at least 5 minutes.

[0723] 13. Stop stirring and transfer the reactor contents to the plastic drum used in step 10.

[0724] 14. Using the remaining vacuum, add toluene (40.0 kg) into the reactor via the solvent addition line.

[0725] 15. Stir the contents of the reactor for at least 2 minutes.

[0726] 16. Stop stirring and drain the reactor contents into a large tank for disposal via the bottom outlet valve.

[0727] 17. Using the remaining vacuum, add toluene (100 kg) into the reactor via the solvent addition line.

[0728] 18. Purge the reactor three times with nitrogen pressure.

[0729] 19. 2-Bromo-4-(trifluoromethyl)pyridine (11.56 kg) was loaded under vacuum via a reagent addition line.

[0730] 20. Cool the contents of the reactor to 0°C.

[0731] 21. Charge approximately 20% of isopropyl magnesium chloride / THF (26.4 kg) into the reactor over at least 20 minutes via the reagent addition line, while maintaining the batch temperature below 5°C.

[0732] 22. Allow the contents of the reactor to age at 0°C for at least 2 hours.

[0733] 23. Samples were taken from the reactor to determine the conversion of 2-bromo-4-(trifluoromethyl)pyridine to debromination (achieving 89% conversion, as determined at 254 nm).

[0734] 24. Over a period of at least 20 minutes, fill the reactor with the contents of the plastic-lined drum containing the toluene solution of compound 9 from steps 10 and 13 via the reagent addition line, while maintaining the batch temperature below 5°C.

[0735] 25. Heat the contents of the reactor to 20°C.

[0736] 26. Allow the contents of the reactor to age at 20°C for at least 1 hour.

[0737] 27. Samples were taken from the reactor to determine the reaction conversion of compound 9 to the product of step 1 (100% conversion was achieved at 210 nm).

[0738] 28. Cool the contents of the reactor to 0°C.

[0739] 29. Add acetic acid (5.06 kg) to the reactor via the solvent addition line over at least 20 minutes. Throughout the addition process, ensure that the batch temperature is maintained below 10°C.

[0740] 30. Heat the contents of the reactor to 20°C.

[0741] 31. Samples were taken from the reactor to determine the reaction profile and the LCAP of the product from step 1 (82.2% was detected at 210 nm).

[0742] 32. Allow the contents of the reactor to age at 22°C for at least 12 hours.

[0743] 33. Fill a visually clean large container with 132.2 kg of purified water and prepare a 1 M hydrochloric acid solution by adding 37% hydrochloric acid (14.2 kg).

[0744] 34. Using the remaining vacuum, fill the reactor with half the contents (73.2 kg) of the 1 M hydrochloric acid tank via the solvent addition line.

[0745] 35. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle.

[0746] 36. Drain the lower water layer into a large cleaning bucket after tare.

[0747] 37. Using the remaining vacuum, add the remaining 1M hydrochloric acid (73.2 kg) into the reactor via the solvent addition line.

[0748] 38. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle.

[0749] 39. Drain the lower water layer into a large cleaning bucket after tare.

[0750] 40. Add sodium bicarbonate (1.3 kg) to a 75 L container, then add purified water (42.7 kg) to the container and mix until dissolved to produce a 3 wt% sodium bicarbonate solution.

[0751] 41. Using the residual vacuum, fill the reactor with the contents of a large drum containing 3 wt% sodium bicarbonate solution (44.0 kg) via the solvent addition line.

[0752] 42. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle.

[0753] 43. Drain the lower water layer into a large cleaning bucket after tare.

[0754] 44. Fill a large, visually clean container with 100 kg of purified water.

[0755] 45. Using the remaining vacuum, add 72 kg of purified water from step 44 into the reactor via the solvent addition line.

[0756] 46. ​​Stir the reactor contents for at least 15 minutes, then stop stirring and allow the two-phase mixture to settle.

[0757] 47. Drain the lower water layer into a large cleaning bucket after tare.

[0758] 48. Configure the reactor for distillation.

[0759] 49. Keep the reactor contents below 45°C and distill under reduced pressure to achieve a final volume of approximately 72L.

[0760] 50. Cool the contents of the reactor to 20°C.

[0761] 51. The organic layer from the reactor is transferred to a visually clean blue HDPE (high-density polyethylene) lined drum via a 10μm cartridge filter.

[0762] 52. Remove the sample from the large container to determine the weight percentage based on the product from step 1, and determine the reaction profile by HPLC (weight percentage determined to be 13.99%).

[0763] 53. The actual yield was determined to be 99.54%.

[0764] The characterization data of the title compound match the characterization data of intermediate 29 of U.S. Patent No. 8,859,774.

[0765] Step 2. Preparation of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid

[0766]

[0767] Step 2 involves Boc deprotection using methanesulfonic acid (4.5 equivalents) and subsequent crystallization of the reaction mixture starting with 0.25 mol% of the step 2 triMSA salt seed crystals to separate the product into triMSA salts.

[0768] 1. The reactor is inertized by vacuum purging with nitrogen.

[0769] 2. Using the remaining vacuum, add the product solution from step 1 (70 kg, 8.90 kg calibration) into the reactor via the solvent addition line and the in-line filter, and start the stirrer.

[0770] 3. The reactor is inertized by partial vacuum purging (-300 mbar to -400 mbar).

[0771] 4. Keep the reactor contents below 40°C and distill under reduced pressure to achieve a final volume of approximately 18L.

[0772] 5. Using the remaining vacuum, add acetonitrile (71 kg) into the reactor via the solvent addition line.

[0773] 6. Keep the reactor contents below 40°C and distill under reduced pressure to achieve a final volume of approximately 18L.

[0774] 7. Using the remaining vacuum, add acetonitrile (14 kg) into the reactor via the solvent addition line.

[0775] 8. Cool the contents of the reactor to 22°C.

[0776] 9. Remove the sample from the reactor. 1 H NMR analysis of toluene content (result: 1.135 wt / wt).

[0777] 10. Cool the contents of the reactor to 0°C.

[0778] 11. Using the remaining vacuum, add methanesulfonic acid (7.1 kg) to the reactor via the reagent addition line (within at least 15 minutes) while maintaining the batch temperature below 10°C.

[0779] 12. Using the remaining vacuum, add acetonitrile (2 kg) into the reactor via the reagent addition line.

[0780] 13. The reactor is inertized by partial vacuum purging (-300 mbar to -400 mbar).

[0781] 14. Slowly warm the reactor contents to 22°C over at least 20 minutes.

[0782] 15. Add 30g of the product seed crystals from step 2 into the reactor.

[0783] 16. Allow the contents of the reactor to age at 22°C for at least 3 hours.

[0784] 17. Remove the sample from the reactor. Examine the LCAP (liquid chromatography area percentage) of the free base from the product of step 2 relative to the product of step 1 (Result: >99%).

[0785] 18. Using a dosing pump, charge isopropyl acetate (39 kg) into the reactor over a period of at least 30 minutes via the solvent addition line.

[0786] 19. Allow the contents of the reactor to age at 22°C for at least 1 hour.

[0787] 20. Remove the sample (approximately 30-50 mL) from the reactor. Filter the slurry and examine the concentration of free alkali from step 2 in the liquid using HPLC (result: 5.8 mg / mL).

[0788] 21. Stop the agitator, then drain the reactor contents into a pressure filter and collect the liquid in a plastic-lined tank.

[0789] 22. Using the dosing pump, add tetrahydrofuran (24 kg) to the reactor via the solvent addition line and start the stirrer.

[0790] 23. Stop the agitator, then drain the contents into the pressure filter via the bottom outlet valve of the reactor, and collect the liquid in a plastic-lined tank.

[0791] 24. Add tetrahydrofuran (24 kg) to the pressure filter via a spray ball and collect the liquid in a plastic-lined drum.

[0792] 25. Dehydrate the solids on a pressure filter under a nitrogen flow.

[0793] 26. Transfer the solids from the pressure filter to a visually clean tray and place it in the tray dryer.

[0794] 27. Place the dryer under vacuum and set the minimum nitrogen purging.

[0795] 28. Set the dryer to 40°C and dry the solid for at least 18 hours.

[0796] 29. Cool the dryer to 20°C, then return it to atmospheric pressure.

[0797] 30. Transfer the solids from the dryer to a clean, tare-free double-bag antistatic polyethylene liner with two desiccant bags between the liners, and place the liner into a small white HDPE bucket.

[0798] 31. Amount separated: 9.6 kg of Step 2 triMSA salt, 60.5 wt% of Step 2 free base, yield 79.1%.

[0799] Table 3. XRPD of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone tri-methanesulfonic acid

[0800]

[0801]

[0802]

[0803] Step 3. Preparation of (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone

[0804]

[0805] The triMSA salt and triethylamine (4.1 eq.) from step 2 in ethyl acetate were reacted with 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.0 eq.). Once the reaction was confirmed to be complete by HPLC, excess sulfonyl chloride was removed by reaction with a scavenger (N-methylpiperazine, 0.25 eq). The reaction was then post-treated by washing with 1M HCl followed by washing with water. The solvent was exchanged for methanol, and ryracoran was precipitated as an amorphous solid by slow addition to water at ambient temperature.

[0806] 1. Inertize the reactor with nitrogen gas.

[0807] 2. Charge the product from step 2 (tri-MSA salt) (0.779 kg, 0.474 kg correction (free base)) into the reactor.

[0808] 3. Use a dosing pump to add ethyl acetate (10.08 kg) to the reactor and stir.

[0809] 4. The reactor is inertized by partial vacuum purging (-300 mbar to -400 mbar).

[0810] 5. Cool the contents of the reactor to -5°C.

[0811] 6. Using a dosing pump, load triethylamine (0.443 kg) over at least 5 minutes while maintaining the batch temperature at 5°C.

[0812] 7. Allow the contents of the reactor to age at -5°C for at least 5 minutes.

[0813] 8. Add 0.198 kg of 1-methyl-1H-pyrazole-4-sulfonyl chloride to a clean, tare-free HDPE drum, and add 2.012 kg of ethyl acetate to the same drum.

[0814] 9. Ensure the contents of the container are thoroughly mixed to ensure complete dissolution.

[0815] 10. Using the dosing pump (within at least 5 minutes), fill the bulk container into the reactor via the solvent addition line while maintaining the batch temperature below 5°C.

[0816] 11. Ethyl acetate (1.0 kg) is charged into the reactor via the dosing pump set from step 10.

[0817] 12. Warm the reactor contents to 20°C over at least 15 minutes.

[0818] 13. Allow the contents of the reactor to age at 20°C for at least 4 hours.

[0819] 14. The sample was removed from the reactor and analyzed by HPLC to check the LCAP of ryracoran relative to step 2 (free base). The result was 99.1% at 243 nm.

[0820] 15. Use a dosing pump to charge N-methylpiperazine (26.7 g) into the reactor.

[0821] 16. Allow the contents of the reactor to age at 20°C for at least 14 hours.

[0822] 17. The sample was removed from the reactor and analyzed by HPLC to determine the consumption of 1-methyl-1H-pyrazole-4-sulfonyl chloride. Result: No sulfonyl chloride was detected.

[0823] 18. Pour 7.0 kg of purified water into a visually clean 25 L black anti-static container, then add 0.77 kg of concentrated hydrochloric acid to generate a 1.0 M HCl solution.

[0824] 19. Add 3.93 kg of 1.0 M HCl solution to the reactor via the solvent addition line.

[0825] 20. Stir the reactor contents for at least 5 minutes, then stop the agitator and allow the two-phase mixture to settle.

[0826] 21. Drain the lower water layer into a 200L plastic-lined tank via the bottom outlet valve.

[0827] 22. Add 3.88 kg of 1.0 M HCl solution to the reactor via the solvent addition line.

[0828] 23. Stir the reactor contents for at least 5 minutes, then stop the agitator and allow the two-phase mixture to settle.

[0829] 24. Drain the lower water layer into a 200L plastic-lined tank via the bottom outlet valve.

[0830] 25. Using the dosing pump, add purified water (3.92 kg) via the solvent addition line and start the stirrer.

[0831] 26. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle.

[0832] 27. Drain the lower water layer into a 200L plastic-lined tank via the bottom outlet valve.

[0833] 28. Using the dosing pump, add purified water (3.91 kg) via the solvent addition line and start the stirrer.

[0834] 29. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle.

[0835] 30. Drain the lower water layer into a 200L plastic-lined tank via the bottom outlet valve.

[0836] 31. Using the dosing pump, add purified water (3.92 kg) via the solvent addition line and start the stirrer.

[0837] 32. Stir the reactor contents for at least 5 minutes, then stop stirring and allow the two-phase mixture to settle.

[0838] 33. Drain the lower water layer into a 200L plastic-lined tank via the bottom outlet valve.

[0839] 34. Discharge the reactor contents into a clean, tare-weighted 25L drum (discharge mass, 12.31Kg).

[0840] 35. The sample was removed from the large container and analyzed to determine the assay yield of ryracoran (Result: 644.30 g, 103.1%).

[0841] 36. Assemble the in-line filter and connect the Whatman filter outlet to the rotary evaporator.

[0842] 37. Using the remaining vacuum, transfer the contents of the 25L drum through a Whatman filter to the rotary evaporator.

[0843] 38. Concentrate the ryracolan solution from step 37 to a final volume of approximately 1.5 L.

[0844] 39. Add methanol (6.16 kg) to the rotary evaporator.

[0845] 40. Concentrate the ryracolan solution from step 39 to a final volume of approximately 3.0 L.

[0846] 41. Take out the sample and pass through 1 1H NMR analysis of the remaining ethyl acetate level (result: 1.87% wt / wt ethyl acetate).

[0847] 42. Transfer the rilatin solution from step 40 into a clean, detasseled 5L Schott bottle.

[0848] 43. Using a dosing pump, add methanol (4.0 kg) to the reactor via the solvent addition line and stir for at least 5 minutes.

[0849] 44. Transfer the reactor contents to clean plastic-lined drums labeled as waste.

[0850] 45. Using the dosing pump, add 11.68 kg of purified water into the reactor via the solvent addition line, and start the stirrer.

[0851] 46. ​​With rapid agitation (>90 rpm), use a dosing pump to fill the reactor with the contents of a 5L Schott bottle containing rilatin solution over at least 30 minutes via the reagent addition line (use agitation of approximately 160 rpm during NB addition. After addition is complete, reduce the agitation speed to approximately 50 rpm).

[0852] 47. Stir the contents of the reactor at 20°C for at least 12 hours.

[0853] 48. Remove the sample from the reactor, filter it, and analyze it by HPLC to check the concentration of rilacin in the liquid.

[0854] 49. Stop the agitator, drain the reactor contents into the filter, and collect the liquid in a tare-lined plastic drum.

[0855] 50. Using a dosing pump, add 2.34 kg of purified water to the reactor via the solvent addition line.

[0856] 51. Stir the contents of the reactor at 20°C for at least 5 minutes.

[0857] 52. Stop the agitator, drain the reactor contents into the filter, and collect the liquid in a tare-lined plastic drum.

[0858] 53. Dehydrate the filter cake in the filter using nitrogen gas for at least 10 minutes.

[0859] 54. Transfer the solids from the filter to a visually clean tray and place it in the tray dryer.

[0860] 55. Turn on the dryer and set the temperature to 50℃.

[0861] 56. Dry the solid in a desiccator under vacuum by purging with nitrogen for at least 15 hours.

[0862] 57. Transfer the solids from the dryer to a clean, tare-free double-bag antistatic polyethylene liner with two desiccant bags between the liners, and place the liner into an HDPE drum.

[0863] 58. Yield: 606g, 97.0%.

[0864] The characterization data of the title compound match the characterization data of Example 18 of U.S. Patent No. 8,859,774.

[0865] Example 5. Purity Overview

[0866] Determine the impurity profiles of the compounds in Examples 3 and 4.

[0867] Table 4. Impurities

[0868]

[0869] ND = Not detected (LOD = 0.02%); LOQ = 0.05%

[0870] Table 5. Other impurities

[0871]

[0872] ND = Not detected (LOD = 1 ppm); LOQ = 1.5 ppm - 4 ppm

[0873] Example 6. (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a- Preparation of 4-(trifluoromethyl)pyridin-2-yl)methyl ketone oxalic acid

[0874]

[0875] Approximately 180 mg of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone was dissolved in acetonitrile to form a stock solution. Oxalic acid was dissolved separately in acetonitrile and added to the stock solution in an equimolar amount. The resulting oily substance was allowed to crystallize. The crystals were then washed with 5 mL of acetonitrile using a Buchner funnel and flask. The crystals were then dried under a nitrogen stream for 3 hours using a Buchner funnel and flask.

[0876] Table 6. XRPD of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone oxalic acid

[0877]

[0878]

[0879] Example 7. (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a- Preparation of tri-(4-(trifluoromethyl)pyridin-2-yl)methyl ketone hydrochloric acid

[0880]

[0881] The Boc deprotection and crystallization procedure from scheme 5 is described below.

[0882] 1. Add 1 (16.0 g, 95.1 wt%, 28.05 mmol, 1.0 eq.) and MeCN (80 mL, 5 vol.) to a container and cool to 0 °C.

[0883] 2. Add HCl (3M, in CPME, 36.8 mL, 112.2 mmol, 4.0 eq.) over 2 minutes while maintaining the internal temperature below 10°C.

[0884] 3. The reaction mixture was warmed to room temperature and aged for 20 hours. The conversion rate was 98%, as determined by HPLC LCAP (FFCAM method).

[0885] 4. Add DIPEA (2.0 mL, 11.7 mmol, 0.4 eq.) at room temperature over 30 seconds.

[0886] 5. Inoculate the reaction mixture with 2·HCl (about 5 mg) and age it at room temperature for 20 minutes.

[0887] 6. Using a syringe pump, add DIPEA (7.1 mL, 44.4 mmol, 1.5 eq.) over 45 minutes at room temperature and then age for another 30 minutes. The fluid loss was 19.9 mg / mL, as determined by HPLC.

[0888] 7. Add IPAC (96 mL, 6 vol.) as an antisolvent within 1 hour, and age the slurry at room temperature for 16 hours. The liquid loss was 8.2 mg / mL, as determined by HPLC.

[0889] 8. Cool the slurry to -20℃ and age for 2 hours. The liquid loss of 2 was 7.8 mg / mL, as determined by HPLC.

[0890] 9. The slurry was filtered under N2, dehydrated with MeCN (16 mL, 1 vol.), and dried under vacuum at 40 °C for 16 h to obtain 2·HCl as a white crystalline solid, with a separation yield of 72% (9.57 g, 99.6 LCAP purity, 93.3 wt%, relative to 2). The mother liquor contained 13% of the 2·HCl in the determined yield.

[0891] Table 7. XRPD of (R)-(1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone hydrochloride

[0892]

[0893]

[0894] Example 8. [(4aR)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-6-[(2-methyl-2H-1,2,3-triazole- Preparation of 4-yl)sulfonyl]-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl][4-(trifluoromethyl)-2-pyridyl] methyl ketone

[0895]

[0896] The target compound was prepared using the following steps.

[0897] The triMSA salt from step 2 was suspended in ethyl acetate and cooled to 0°C, then triethylamine (4.1 eq.) was added to form a solution, followed by the addition of 2-methyl-2H-1,2,3-triazol-4-sulfonyl chloride (1.0 eq.). Once the reaction was confirmed to be complete by HPLC, excess sulfonyl chloride was removed by reaction with a scavenger (N-methylpiperazine, 0.25 eq). The reaction was then post-treated by washing with 1M hydrochloric acid aqueous solution followed by washing with 3% (w / w) sodium bicarbonate aqueous solution. The solvent was replaced with ethanol, and the title compound was precipitated from a mixture of ethanol, acetone, and water as an amorphous solid. The title compound was separated by filtration, washed with water, and dried under vacuum at high temperature.

[0898] 1. Rinse the container with ethyl acetate and dry it under vacuum.

[0899] 2. Add the MSA salt from step 2 [12.81 kg (7.81 kg corrected)] and ethyl acetate (161.6 kg) to the container and cool the contents to 0°C.

[0900] 3. Over 10 minutes, add triethylamine (7.32 kg) to the container, maintain the batch temperature <5°C, and rinse the line with ethyl acetate.

[0901] 4. Allow the contents to age at <5℃> for 1 hour.

[0902] 5. Load 47.0 kg (3.20 kg correction) of ethyl 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride into the container and maintain the batch temperature.

[0903] 6. Warm the contents to 20°C within 25 minutes and age at this temperature for 2 hours.

[0904] 7. The conversion rate was analyzed by HPLC.

[0905] 8. Fill the container with N-methylpiperazine (0.44 kg) within 5 minutes.

[0906] 1. Allow this batch to age at 20°C for 16 hours.

[0907] 9. Add 1.0M HCl solution (129.3 kg) to the container, allow the two-phase mixture to settle, and drain the aqueous layer. Repeat this step again.

[0908] 10. Pour 1.0M HCl solution (64.6kg) into the container, allow the two-phase mixture to settle, and drain the water layer.

[0909] 11. Pour 3 wt% sodium bicarbonate solution (65.3 kg) into the container, allow the two-phase mixture to settle, and drain the water layer.

[0910] 12. Pour 64.0 kg of purified water into the container, allow the two-phase mixture to settle, and drain the water layer. Repeat this step again.

[0911] 13. Displace the solution of the title compound into two large containers.

[0912] 14. Fill the second container with the title compound solution through an inline filter and concentrate it from approximately 190 L to 38 L under reduced pressure, maintaining the batch temperature below 45°C.

[0913] 15. Pour ethanol (151.3 kg) into the container and concentrate the stream from approximately 230 L to 38 L under reduced pressure, maintaining the batch temperature below 45°C.

[0914] 16. Transfer the title compound solution to a clean, plastic-lined drum.

[0915] 17. Fill the container with purified water (230.6 kg) through the in-line filter.

[0916] 18. Pour the title compound solution into the container within 30 minutes. Allow the slurry to age for 30 minutes to ensure it does not stick.

[0917] 19. Filter the slurry and wash the filter cake with purified water (37.9 kg).

[0918] 20. Dehydrate the wet filter cake under a nitrogen flow.

[0919] 21. Dry the wet filter cake in a vacuum oven at 40°C.

[0920] The title compound was isolated as a grayish-white solid. Overall yield: 9.810 kg (94.6% yield). The characterization data of the title compound matched the characterization data of Example 11CE of U.S. Patent No. 8,859,774.

[0921] Although the foregoing invention has been described in detail by illustration and example for clarity of understanding, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated herein by reference in its entirety as if it were incorporated individually by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A method for preparing a compound of formula J or a pharmaceutically acceptable salt thereof: （J） The method includes: (a) Formation of compounds including formula IIb: (IIb), The first reaction mixture of the non-nucleophilic amine base, the first solvent, and the sulfonyl chloride: To prepare compounds of formula J in a yield of at least 60% and a purity of at least 98%. in X 1 It is -CH= or -N=; HX is an acid solvate, which is HBr or ; Where R 1 It is C 1-6 alkyl; The subscript n is 3; The non-nucleophilic amine base includes trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinine ring, 4-pyrrolylpyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or mixtures thereof; and The first solvent comprises ethyl acetate, isopropyl acetate, or n-butyl acetate.

2. The method according to claim 1, used for preparing compounds of formula I or pharmaceutically acceptable salts thereof: （I） The method includes: (a) Formation of compounds comprising formula IIb: (IIb), The first reaction mixture of the nonnucleophilic amine base, the first solvent, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， To prepare compounds of formula I with a yield of at least 60% and a purity of at least 98%. in HX is the acid solvate, which is HBr or ;and The subscript n is 3.

3. The method according to claim 2, wherein HX is HBr.

4. The method according to claim 3, used for preparing the compound of formula I or a pharmaceutically acceptable salt thereof: （I） The method includes: (a) Formation of compounds including formula IIb-1: (IIb-1), and The first reaction mixture of the nonnucleophilic amine base, the first solvent, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， To prepare compounds of formula I with a yield of at least 60% and a purity of at least 98%, wherein the compounds of formula I contain less than 1% w / w of compounds of formula X-5: （X-5）， And the subscript n is 3.

5. The method according to claim 4, wherein the nonnucleophilic amine base comprises triethylamine.

6. The method according to claim 4, wherein the 1-methyl-1H-pyrazole-4-sulfonyl chloride is present in a molar ratio of 1.2 to 2.3 with the compound of formula IIb-1.

7. The method of claim 4, further comprising, after step (a): (a1) The first reaction mixture is mixed with water of pH 4 to 5 to form a first organic phase and a first aqueous phase; (a2) The first organic phase is mixed with water and sodium chloride, wherein the water has a pH of 5 to 6; and (a3) Mix the first organic phase and silica gel.

8. The method according to claim 4, wherein the compound of formula IIb-1 is prepared by the following steps: (b) Formation of compounds including formula IIa: (IIa), The second reaction mixture with gaseous HBr forms a compound of formula IIb-1 having the following structure: 。 9. The method according to claim 4, wherein the compound of formula I is prepared by the following steps: (b) Formation of compounds including formula IIa: (IIa), The second reaction mixture with gaseous HBr forms a compound of formula IIb-1 having the following structure: ;and (a) Formation of compounds comprising formula IIb-1: The first reaction mixture of triethylamine, the first solvent, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， The 1-methyl-1H-pyrazole-4-sulfonyl chloride is present in a molar ratio of about 1.2 to the compound of formula IIb-1; (a1) The first reaction mixture is mixed with water of pH 4 to 5 to form a first organic phase and a first aqueous phase; (a2) The first organic phase is mixed with water and sodium chloride, wherein the water has a pH of 5 to 6; as well as (a3) The first organic phase and silica gel are mixed to prepare the compound of formula I in a yield of at least 60% and a purity of at least 98%, wherein the compound of formula I contains less than 1% w / w of the compound of formula X-5: （X-5）。 10. The method according to claim 8, wherein the compound of formula IIa is prepared by: (c) Formation of compounds including Grignard reagents and Formula III: (III), and The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine: ， The 2-bromo-4-(trifluoromethyl)pyridine is present in a molar ratio of 1.0 to 1.5 with the compound of formula III, and the Grignard reagent is present in a molar ratio of 1.5 to 1.7 with the compound of formula III, to prepare the compound of formula IIa.

11. The method of claim 10, wherein the Grignard reagent comprises iPrMgCl or iPrMgBr.

12. The method of claim 10, wherein the Grignard reagent comprises iPrMgBr.

13. The method of claim 10, wherein the third reaction mixture further comprises a third solvent comprising tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or xylene.

14. The method of claim 13, wherein the third solvent comprises 2-methyltetrahydrofuran and toluene.

15. The method of claim 10, further comprising the following steps: (c1) Adding acid and water to the third reaction mixture to form a post-treatment mixture; and (c2) Distill the post-treatment mixture to form an intermediate mixture comprising the compound of formula IIa, 2-methyltetrahydrofuran in a concentration of less than 100 ppm and water in a concentration of less than 0.5% w / w.

16. The method of claim 15, wherein the acid comprises formic acid, acetic acid, propionic acid, butyric acid, hexanoic acid, octanoic acid, trifluoroacetic acid, or a mixture thereof.

17. The method of claim 15, wherein the acid comprises acetic acid.

18. The method of claim 17, wherein the method for preparing the compound of formula I comprises: (c) Formation of compounds comprising iPrMgBr, 2-methyltetrahydrofuran, toluene, and the compound of formula III: (III), and The third reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine: ， The 2-bromo-4-(trifluoromethyl)pyridine is present in a molar ratio of about 1.4 to the compound of formula III, and the Grignard reagent is present in a molar ratio of about 1.65 to the compound of formula III to prepare the compound of formula IIa: (IIa); (c1) Add acetic acid and water to the third reaction mixture to form the post-treatment mixture; (c2) Distill the post-treatment mixture to form an intermediate mixture comprising a compound of formula IIa, a compound of 2-methyltetrahydrofuran in an amount of less than 100 ppm, and water in an amount of less than 0.5% w / w; (b) Forming a second reaction mixture comprising the intermediate mixture and gaseous HBr to form a compound of formula IIb-1 having the following structure: ;as well as (a) Forming the first reaction mixture comprising the compound of formula IIb-1, triethylamine, a first solvent, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， The compound of formula I is prepared in a molar ratio of 1-methyl-1H-pyrazole-4-sulfonyl chloride to the compound of formula IIb-1 of about 1.2, with a yield of at least 60% and a purity of at least 98%, wherein the compound of formula I contains less than 1% w / w of the compound of formula X-5. （X-5）。 19. The method of claim 18, wherein the method further comprises the step (a): (a1) The first reaction mixture is mixed with water of pH 4 to 5 to form a first organic phase and a first aqueous phase; (a2) The first organic phase is mixed with water and sodium chloride, wherein the water has a pH of 5 to 6; as well as (a3) Mix the first organic phase and silica gel.

20. A method for purifying a compound of formula I or a pharmaceutically acceptable salt thereof: （I） The method includes: (a) Use (i) A first flow mixture comprising water at a concentration of at least 95% v / v, formic acid at a concentration of 0.05% v / v to 0.2% v / v, and acetonitrile at a concentration of 1% v / v to 5% v / v. (ii) A second flow mixture comprising water at a concentration of 45% v / v to 55% v / v, formic acid at a concentration of 0.01% v / v to 0.1% v / v, and acetonitrile at a concentration of 45% v / v to 55% v / v, and (iii) The compound of Formula I is eluted by high-performance liquid chromatography (HPLC) using a third mobile phase comprising water in a concentration of 5% v / v to 15% v / v, formic acid in a concentration of 0.005% v / v to 0.02% v / v, and acetonitrile in a concentration of at least 85% v / v. To form an elution mixture comprising a compound of formula I with a purity of at least 98% and a compound of formula X-5 with a content of less than 0.75% w / w: （X-5）； (a1) Extracting the compound of Formula I from the elution mixture into ethyl acetate to form an extraction mixture; (a2) The extraction mixture is mixed with methyl tert-butyl ether (MTBE) under vacuum to form an MTBE mixture comprising less than 5% v / v ethyl acetate; (d) Filtering the MTBE mixture through a filter to form a filtered MTBE mixture, the filtered MTBE mixture comprising: The compound of formula I, Compounds of formula X-5 in amounts less than 0.5% w / w, Compounds of formula X-4 with a content of less than 0.3% w / w: (X-4), and Compounds of formula X-6 with a content of less than 0.25% w / w: （X-6）； (e) The filtered MTBE mixture is added to heptane to form a precipitated compound of formula I, wherein the precipitated compound of formula I comprises 1,4-dibromopentane in an amount of less than 20 ppm. (f) Dissolving the precipitated compound of formula I in methanol to form a methanol mixture; and (g) Add the methanol mixture to water to precipitate the purified compound of formula I, wherein the purified compound of formula I has a purity of at least 99% and comprises... Compounds of formula X-5 in amounts less than 0.5% w / w, 1,4-Dibromopentane at a concentration of less than 6 ppm, 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 6 ppm: ,and 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 6 ppm: 。 21. The method of claim 20, wherein the purified compound of formula I has a purity of at least 99% and comprises 1,4-dibromopentane in an amount of less than 4 ppm.

22. The method of claim 20, wherein the purified compound of formula I has a purity of at least 99%, and further comprises... Methyl bromide at a concentration of less than 20 ppm, and 2-Bromopropane with a content of less than 20 ppm.

23. The method of claim 20, wherein the purified compound of formula I has a purity of at least 99%, and comprises... Methyl bromide at a concentration of less than 8 ppm, 2-bromopropane at a concentration of less than 8 ppm, and 1,4-Dibromopentane in a concentration of less than 4 ppm.

24. The method of claim 20, wherein the purified compound of formula I has a purity of at least 99%, and comprises... Compounds of formula X-4 in amounts less than 0.1% w / w, Compounds of formula X-5 in amounts less than 0.2% w / w, Compounds of formula X-6 in amounts less than 0.2% w / w, 1,4-Dibromopentane at a concentration of less than 4 ppm, 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 4 ppm, and 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 4 ppm.

25. The method of claim 20, wherein the purified compound of formula I has a purity of at least 99%, and further comprises... Ethyl 1-methyl-1H-pyrazole-4-sulfonate at a concentration of less than 6 ppm: ,and Isopropyl 1-methyl-1H-pyrazole-4-sulfonate at a concentration of less than 6 ppm: 。 26. The method of claim 20, wherein the purified compound of formula I has a purity of at least 99%, and comprises... Compounds of formula X-4 in amounts less than 0.1% w / w, Compounds of formula X-5 in amounts less than 0.2% w / w, Compounds of formula X-6 in amounts less than 0.2% w / w, Methyl bromide at a concentration of less than 4 ppm, 2-bromopropane with a content of less than 4 ppm, 1,4-Dibromopentane at a concentration of less than 4 ppm, 1-Methyl-1H-pyrazole-4-sulfonyl chloride at a concentration of less than 4 ppm 1-Methyl-1H-pyrazole-4-sulfonate methyl ester with a content of less than 4 ppm Ethyl 1-methyl-1H-pyrazole-4-sulfonate at a content of less than 4 ppm, and Isopropyl 1-methyl-1H-pyrazole-4-sulfonate in a concentration of less than 4 ppm.

27. The method according to any one of claims 20 to 26, wherein the compound of formula I is prepared by the method according to any one of claims 4 to 19.

28. The method of claim 1, wherein... HX is ， in R 1 It is C 1-6 alkyl.

29. The method according to claim 28, used for preparing a compound of formula J or a pharmaceutically acceptable salt thereof: （J） The method includes: (a) Formation of compounds including formula IIb-2: (IIb-2), The fourth reaction mixture of non-nucleophilic amine base, fourth solvent, and sulfonyl chloride: ， Compounds of formula J are prepared in a yield of at least 75% and a purity of at least 98%. in X 1 It is -CH= or -N=; R 1 It is C 1-6 alkyl; The subscript n is 3; The non-nucleophilic amine base includes trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), N,N-dimethylisopropylamine (DIMPA), 1-ethylpiperidine, N-methylmorpholine, N-methylpyrrolidine, pyridine, N,N-dimethylaniline, N,N-diethylaniline, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine (DMAP), quinine ring, 4-pyrrolylpyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), or mixtures thereof; and The fourth solvent includes ethyl acetate, isopropyl acetate, or n-butyl acetate.

30. The method of claim 29, used for preparing a compound of formula Ia or a pharmaceutically acceptable salt thereof: (I), The method includes: (a) Formation of a compound comprising formula IIb-2: (IIb-2), The fourth reaction mixture of the nonnucleophilic amine base, the fourth solvent, and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride: ， To prepare compounds of formula Ia in a yield of at least 75% and a purity of at least 98%. in R 1 It is C 1-6 Alkyl; and The subscript n is 3.

31. The method of claim 30, wherein the compound of formula Ia contains less than 1% w / w of the compound of formula X-5a: (X-5a)。 32. The method of claim 29, used for preparing compounds of formula I or pharmaceutically acceptable salts thereof: （I） The method includes: (a) Formation of compounds including formula IIb-2: (IIb-2), The fourth reaction mixture of the non-nucleophilic amine base, the fourth solvent, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， To prepare compounds of formula I with a yield of at least 75% and a purity of at least 98%. in R 1 It is C 1-6 Alkyl; and The subscript n is 3.

33. The method according to any one of claims 29 to 32, wherein R 1 It is C 1-2 alkyl.

34. The method according to any one of claims 29 to 32, wherein R 1 It is methyl or ethyl.

35. The method according to any one of claims 29 to 32, wherein R 1 It is a methyl group.

36. The method according to any one of claims 29 to 32, wherein the nonnucleophilic amine base comprises triethylamine.

37. The method according to any one of claims 29 to 32, wherein the fourth solvent comprises ethyl acetate.

38. The method according to any one of claims 29 to 32, wherein the sulfonyl chloride, 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride or 1-methyl-1H-pyrazole-4-sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2.

39. The method according to any one of claims 29 to 32, further comprising the following steps: (a1) Add methanol to the fourth reaction mixture; and (a2) Add water to the fourth reaction mixture to precipitate the compound of formula I.

40. The method of claim 32, further comprising the steps of: (a) Formation of a compound comprising formula IIb-2 ， The fourth reaction mixture of triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， The 1-methyl-1H-pyrazole-4-sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2; (a1) Add methanol to the fourth reaction mixture; as well as (a2) Add water to the fourth reaction mixture to precipitate the compound of formula I, with a yield of at least 75% and a purity of at least 98%.

41. The method of claim 32, wherein the compound of formula I contains less than 1% w / w of the compound of formula X-5: （X-5）。 42. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof: （I） The method includes: (c) Formation of compounds including tetrahydrofuran, toluene, iPrMgCl, and formula III: (III), and The sixth reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine: ， The 2-bromo-4-(trifluoromethyl)pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and the Grignard reagent is present in a molar ratio of about 3.05 to the compound of formula III. (c1) Add acetic acid and water to the sixth reaction mixture to form a post-treatment mixture; (c2) Distilling the post-processed mixture to form an intermediate mixture comprising compounds of formula IIa: (IIa); (b) Forming a mixture comprising the intermediates, The fifth reaction mixture of acetonitrile and methanesulfonic acid forms a compound of formula IIb-2: (IIb-2); (a) Formation of a fourth reaction mixture comprising the compound of formula IIb-2, triethylamine, ethyl acetate, and 1-methyl-1H-pyrazole-4-sulfonyl chloride: ， The 1-methyl-1H-pyrazole-4-sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2; (a1) Add methanol to the fourth reaction mixture; as well as (a2) Add water to the reaction mixture to precipitate the compound of formula I, with a yield of at least 75% and a purity of at least 98%.

43. A method for preparing a compound of formula Ia or a pharmaceutically acceptable salt thereof: (I), The method includes: (c) Formation of compounds including tetrahydrofuran, toluene, iPrMgCl, and formula III: (III), and The sixth reaction mixture of 2-bromo-4-(trifluoromethyl)pyridine: ， The 2-bromo-4-(trifluoromethyl)pyridine is present in a molar ratio of about 3.0 to the compound of formula III, and the Grignard reagent is present in a molar ratio of about 3.05 to the compound of formula III. (c1) Add acetic acid and water to the sixth reaction mixture to form a post-treatment mixture; (c2) Distilling the post-processed mixture to form an intermediate mixture comprising compounds of formula IIa: (IIa); (b) Forming a mixture comprising the intermediates, The fifth reaction mixture of acetonitrile and methanesulfonic acid forms a compound of formula IIb-2: (IIb-2); (a) Formation of a fourth reaction mixture comprising the compound of formula IIb-2, triethylamine, ethyl acetate, and 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride: ， The 2-methyl-2H-1,2,3-triazole-4-sulfonyl chloride is present in a ratio of about 1.0 to the compound of formula IIb-2; (a1) Add methanol to the fourth reaction mixture; as well as (a2) Add water to the reaction mixture to precipitate the compound of formula Ia, with a yield of at least 75% and a purity of at least 98%.

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