Method for preparing WEE1 inhibitor compounds

Abstract

Processes are provided for making WEE1 inhibitors of formula (1A) useful in the treatment of conditions characterized by excessive cell proliferation, such as cancer. In some embodiments, processes are provided for making intermediate compounds of formula (3), formula (5), and formula (6) defined herein.

Description

[Technical Field]

[0001] (Incorporation by referencing any priority application) In the application data sheet filed with this application, all applications that confirm a foreign or domestic priority claim, including U.S. Provisional Patent Application No. 63 / 037,766 filed on June 11, 2020, are incorporated herein by reference pursuant to 37 CFR 1.57.

[0002] (Field of invention) This application relates to a method for producing a compound that is a WEE1 inhibitor, which is used to treat diseases characterized by excessive cell proliferation, such as cancer. [Background technology]

[0003] WEE1 kinase plays a role in cell cycle arrest at the G2-M checkpoint for DNA repair before mitosis initiation. Normal cells repair damaged DNA during G1 arrest. Cancer cells often lack the G1-S checkpoint and rely on a functional G2-M checkpoint for DNA repair. WEE1 is overexpressed in various cancer types.

[0004] International Publication No. 2019 / 173082 discloses various WEE1 inhibitors and methods for producing them, including the synthetic route shown in Figure 1 for producing the following racemic compound (1).

[0005] [ka]

[0006] International Publication No. 2019 / 173082 also shows that racemic compound (1) can be divided by SFC chromatography as shown in Figure 1 to form the following enantiomers (1A) and (1B).

[0007] [ka]

[0008] The method described in International Publication No. 2019 / 173082 for preparing such enantiomers (1A) and (1B) represents a significant advance in the art. However, in practice, this method has been found to be difficult to scale up, and at least in part due to the presence of multiple reaction steps and the use of SFC chromatography for the separation of enantiomers, the overall yield is low. For example, the racemic starting compound (1-1) used to prepare compound (1) is difficult to obtain from commercial sources. This is described in International Publication No. 2019 / 173082 as being prepared in low overall yield by a multi-step reaction scheme as shown in Figure 2. A further problem relates to the requirement that the chiral product be highly enantiopure. Thus, in the art of preparing enantiomers (1A) and (1B), further progress is still needed.

Summary of the Invention

Problems to be Solved by the Invention

[0009] Currently, several improvements that are much more practical for scale-up and production compared to the method described in International Publication No. 2019 / 173082 have been developed in the method for preparing the WEE1 inhibitor of formula (1A).

Means for Solving the Problems

[0010] One embodiment provides a compound of formula (3) that is useful in the production of a WEE1 inhibitor of formula (1A), as shown, for example, in Figures 4A and 4B.

[0011] Another embodiment provides a method for preparing a compound of formula (3), which method comprises reacting a compound of formula (3-1) with a compound of formula (3-2) under Ullman coupling reaction conditions effective to form the compound of formula (3), as shown, for example, in FIGS. 3A and / or 3B. In various embodiments, the variable X in formula (3-1) is Cl, Br, or I.

[0012] Another embodiment provides a method for preparing a compound of formula (1A), which method comprises oxidizing a compound of formula (3) under reaction conditions effective to form an oxidation intermediate, as shown, for example, in FIGS. 4A and / or 4B, and reacting the oxidation intermediate with an amine compound of formula (4-1) under Ullman reaction conditions effective to form the compound of formula (1A).

[0013] Another embodiment provides a method for preparing a compound of formula (5), which method comprises reacting a compound of formula (5-1) with acetic anhydride under reaction conditions effective to form an acetyl intermediate of formula (5-2), as shown, for example, in FIGS. 5A and 5B, and reacting the acetyl intermediate of formula (5-2) with a hydroxide base under reaction conditions effective to form the compound of formula (5). In various embodiments, the variable X in formula (5-1), formula (5-2), and formula (5) is Cl, Br, or I.

[0014] Another embodiment provides a method for preparing a compound of formula (6), which method comprises reacting a compound of formula (5) with an oxidizing agent under oxidation reaction conditions effective to form the compound of formula (6), as shown, for example, in FIGS. 6A and 6B. In various embodiments, the variable X in formula (5) and formula (6) is Cl, Br, or I. [[ID=...]] [[ID=...]]

[0015] [[ID=...]] These and other embodiments are described in more detail below.

Brief Description of the Drawings

[0016] [Figure 1]The conventional method for preparing compounds of formula (1A) and formula (1B) using compound (1-1) as a starting material is shown. [Figure 2] The conventional method for preparing the compound of formula (1-1) is shown below. [Figure 3A] One embodiment of a method for preparing the compound of formula (3) is shown. [Figure 3B] One embodiment of a method for preparing the compound of formula (3) is shown. [Figure 4A] One embodiment of a method for preparing the compound of formula (1A) is shown. [Figure 4B] One embodiment of a method for preparing the compound of formula (1A) is shown. [Figure 5A] One embodiment of a method for preparing the compound of formula (5) is shown. [Figure 5B] One embodiment of a method for preparing the compound of formula (5) is shown. [Figure 6A] One embodiment of a method for preparing the compound of formula (6) is shown. [Figure 6B] One embodiment of a method for preparing the compound of formula (6) is shown. [Figure 7A] One embodiment of a method for preparing the compound of formula (7) is shown. This is one embodiment of the compound of formula (6) where the variable X is Cl. [Figure 7B] One embodiment of a method for preparing the compound of formula (7) is shown. The compound of formula (7-7) is one embodiment of the compound of formula (5) where the variable X is Cl. [Figure 8A] One embodiment of a method for preparing the compound of formula (1A) using the compound of formula (7) as a starting material is shown. [Figure 8B] One embodiment of a method for preparing the compound of formula (1A) using the compound of formula (7) as a starting material is shown. [Figure 9] This provides a typical X-ray powder diffraction (XRPD) pattern of compound 3. [Figure 10] A representative DSC thermogram of compound 3 is provided. [Figure 11] A representative TGA thermogram of compound 3 is provided. [Modes for carrying out the invention]

[0017] One embodiment provides a compound of the following formula (3).

[0018] [ka]

[0019] The compound of formula (3) is a useful enantiomer in the production of the WEE1 inhibitor of formula (1A), as shown in Figures 4A and 4B. In various embodiments, the compound of formula (3) has an enantiomer excess (ee) of at least about 85%, 90%, 95%, or 97%. As indicated by the value, it is highly enantiopic.

[0020] The compound of formula (3) can be prepared by various methods. For example, one embodiment provides a method for preparing the compound of formula (3), which involves reacting the compound of formula (3-1) with the compound of formula (3-2) under Ullmann coupling reaction conditions effective for forming the compound of formula (3).

[0021] [ka]

[0022] In various embodiments, the variable X in formula (3-1) is Cl, Br, or I. For example, in one embodiment, the variable X in formula (3-1) is Cl. Those skilled in the art will recognize in this context that the term “Ullmann coupling reaction conditions” refers to a copper-mediated amination reaction that forms a carbon-nitrogen (CN) bond between the pyridinyl ring of the compound of formula (3-1) and the secondary amine of the compound of formula (3-2), as shown in Figure 3A. Those skilled in the art are aware of the various Ullmann coupling reaction conditions that use copper-mediated amination to form a new CN bond by coupling an amine with an aryl or alkenyl electrophile in the presence of copper and a base. Those skilled in the art can easily adapt such known Ullmann coupling reaction conditions for use in the preparation of compound (3) using the routine experiments led by this disclosure.

[0023] In various embodiments, the Ullmann coupling reaction conditions involve reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of copper salt and / or Cu(0). Suitable copper salts include CuI, CuBr, CuCl, and combinations thereof. A suitable source of Cu(0) is elemental copper. The copper salt or Cu(0) may be used in combination with inorganic salts such as NaI, NaBr, NaCl, KI, KBr, KCl, or combinations thereof. In one embodiment, the Ullmann coupling reaction conditions involve reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of CuI and optionally an effective amount of NaI.

[0024] In various embodiments, the Ullmann coupling reaction conditions involve reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of polar aprotic solvent. Various polar aprotic solvents can be used. For example, in one embodiment, the polar aprotic solvent includes dioxane, anisole, 1,2-dimethoxyethane (Glyme), diethylene glycol dimethyl ether (DiGlyme), dimethylacetamide, 1-methylpyrrolidine-2-one, or a combination thereof. In one embodiment, the polar aprotic solvent consists of or contains anisole.

[0025] In various embodiments, the Ullmann coupling reaction conditions involve reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of chelate ligand. Various chelate ligands known to those skilled in the art can be used. In one embodiment, the chelate ligand includes trans-N,N-dimethylcyclohexane-1,2-diamine, N,N-dimethylethane-1,2-diamine, 2,2'-bipyridyl, N,N'-dibenzylethane-1,2-diamine, trans-1,2-diaminocyclohexane, or a combination thereof. For example, in one embodiment, the chelate ligand includes trans-N,N-dimethylcyclohexane-1,2-diamine.

[0026] In various embodiments, the Ullmann coupling reaction conditions involve reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of inorganic base. Various inorganic bases known to those skilled in the art may be used. In one embodiment, the inorganic base includes K2CO3, K3PO4, Cs2CO3, Na2CO3, or a combination thereof. For example, in one embodiment, the inorganic base includes K2CO3.

[0027] In various embodiments, Ullmann coupling reaction conditions include reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of polar aprotic solvent, a chelate ligand, a copper salt, an inorganic base, and optionally an iodide salt. For example, in one embodiment, the Ullmann coupling reaction conditions include the presence of an effective amount of polar aprotic solvent, a chelate ligand, CuI, NaI, and an inorganic base. Figure 5B shows an example of such Ullmann coupling reaction conditions.

[0028] In various embodiments, the Ullmann coupling reaction conditions include reacting the compound of formula (3-1) and the compound of formula (3-2) together for a reaction time ranging from 2 to 40 hours. In one embodiment, the Ullmann coupling reaction conditions include a reaction time ranging from 4 to 36 hours, for example, a reaction time of about 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36 hours, or a reaction time within a range defined by an endpoint selected from any two of the aforementioned reaction time values.

[0029] In various embodiments, the Ullmann coupling reaction conditions include reacting the compound of formula (3-1) and the compound of formula (3-2) together at a high reaction temperature. In one embodiment, the Ullmann coupling reaction conditions include a reaction temperature in the range of about 70°C to about 150°C, for example, a reaction temperature of about 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, or 150°C, or a reaction temperature within a range defined by an endpoint selected from any two of the aforementioned reaction temperature values.

[0030] In various embodiments, the method for preparing the compound of formula (3) is as shown in Figure 3A and / or Figure 3B.

[0031] In some embodiments, the solid form of compound 3 may be characterized by one or more peaks in an X-ray powder diffraction pattern, selected from the following:

[0032] [Table 1]

[0033] In some embodiments, the solid form of compound 3 may be characterized by one or more peaks in the XRPD pattern, which may be selected from peaks in the ranges of 8.8° to about 8.4°²θ, 11.7° to about 11.3°²θ, 17.5° to about 17.1°²θ, and 23.4° to about 23.0°²θ. In some embodiments, the solid form of compound 3 is The X-ray powder diffraction pattern may be characterized by one or more peaks, which can be selected from approximately 8.6°2θ±0.2°2θ, approximately 11.5°2θ±0.2°2θ, approximately 17.3°2θ±0.2°2θ, and approximately 23.2°2θ±0.2°2θ. In some embodiments, the solid form of compound 3 may exhibit an X-ray powder diffraction pattern as shown in Figure 9.

[0034] In some embodiments, the solid form of compound 3 may be characterized by endothermic activity in the range of about 135°C to about 145°C. In some embodiments, the solid form of compound 3 may be characterized by a differential scanning calorimetry (DSC) thermogram that includes an exothermic peak at about 140°C. In some embodiments, the solid form of compound 3 may have the differential scanning calorimetry (DSC) thermogram shown in Figure 10.

[0035] In some embodiments, the solid form of compound 3 may have a weight loss percentage in the range of about 0% to about 2% when heated from about 40°C to about 150°C. In some embodiments, the solid form of compound 3 may have a weight loss percentage of about 0% when heated from about 40°C to about 150°C. In some embodiments, the solid form of compound 3 may be characterized by the TGA curve shown in Figure 11.

[0036] Another embodiment provides a method for preparing the compound of formula (1A), the method being: The compound of formula (3) is oxidized under reaction conditions effective for forming an oxidation intermediate, The method includes reacting an oxidation intermediate with an amine compound of formula (4-1) under reaction conditions effective for forming the compound of formula (1A).

[0037] [ka]

[0038] In various embodiments, effective reaction conditions for forming an oxidation intermediate include oxidizing the compound of formula (3) by reacting it with an effective amount of an oxidizing agent. Isolation of the oxidation intermediate (not shown in Figure 4A or Figure 4B) is unnecessary, and those skilled in the art can infer its existence or presence from their knowledge of the reaction conditions.

[0039] Various oxidizing agents known to those skilled in the art may be used. In various embodiments, the oxidizing agent is selected from oxone, m-chloroperbenzoic acid (MCPBA), H2O2, Na2WO4, NaOCl, cyanuric acid, NaIO4, RuCl3, O2, or a combination thereof. In one embodiment, the oxidizing agent is oxone, MCPBA, or a combination thereof. In one embodiment, the oxidizing agent is oxone. In one embodiment, the oxidizing agent is MCPBA.

[0040] In various embodiments, effective reaction conditions for forming an oxidation intermediate include oxidizing the compound of formula (3) in the presence of an effective amount of organic solvent. Various organic solvents effective in dissolving the compound of formula (3) and the oxidizing agent can be used. In one embodiment, the solvent is , low boiling point chlorinated C such as chloroform or dichloromethane (DCM) 1~3 It is a hydrocarbon. In some embodiments, the solvent includes water, ethanol, 1-methyl-2-pyrrolidone, dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, bis(2-butoxyethyl) ether, bis(2-ethoxyethyl) ether, bis(2-methoxyethyl) ether, dioxane, or a combination thereof.

[0041] In various embodiments, effective reaction conditions for forming an oxidation intermediate include reaction times ranging from 30 minutes to 60 hours. In some embodiments, effective reaction conditions for forming an oxidation intermediate include reaction times ranging from 30 minutes to 48 hours, for example, reaction times of about 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, or 48 hours, or reaction times within a range defined by an endpoint selected from any two of the aforementioned reaction time values.

[0042] In various embodiments, effective reaction conditions for forming an oxidation intermediate include relatively low reaction temperatures. In one embodiment, effective reaction conditions for forming an oxidation intermediate include reaction temperatures in the range of about -25°C to about 25°C, for example, reaction temperatures of about -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, or 25°C, or reaction temperatures within a range defined by an endpoint selected from any two of the aforementioned reaction temperature values.

[0043] In various embodiments, effective reaction conditions for reacting an oxidation intermediate with an amine compound of formula (4-1) to form a compound of formula (1A) include the presence of an effective amount of base (e.g., an organic or inorganic base). Various bases known to those skilled in the art may be used. In one embodiment, the base is an inorganic base. For example, in one embodiment, the inorganic base is selected from K2CO3, Na2CO3, NaHCO3, NaOAc, or a combination thereof. In one embodiment, the base is an organic base, such as an organic base containing a tertiary amine. For example, in one embodiment, the organic base includes N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or a combination thereof.

[0044] In various embodiments, effective reaction conditions for forming the compound of formula (1A) include reaction times ranging from 2 minutes to 40 hours. In some embodiments, effective reaction conditions for forming the compound of formula (1A) include reaction times ranging from 4 hours to 36 hours, for example, reaction times of about 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36 hours, or reaction times within a range defined by an endpoint selected from any two of the aforementioned reaction time values.

[0045] In various embodiments, effective reaction conditions for forming the compound of formula (1A) include relatively moderate reaction temperatures. In one embodiment, effective reaction conditions for forming the compound of formula (1A) include reaction temperatures in the range of about 0°C to about 50°C, for example, reaction temperatures of about 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or reaction temperatures within a range defined by an endpoint selected from any two of the aforementioned reaction temperature values.

[0046] In various embodiments, the method for preparing the compound of formula (1A) is as shown in Figure 4A and / or Figure 4B.

[0047] Other embodiments provide methods and compounds useful for producing compounds of formula (3-1). For example, one embodiment provides a method for producing the following compound of formula (5), which is: Under reaction conditions effective for forming the acetyl intermediate of the following formula (5-2), the following formula ( 5-1) The reaction of the compound with acetic anhydride, This includes reacting the acetyl intermediate of formula (5-2) with a hydroxide base under reaction conditions effective for forming the compound of formula (5).

[0048] [ka]

[0049] In various embodiments, the variable X in formulas (5-1), (5-2), and (5) is Cl, Br, or I. In one embodiment, X is Cl. Isolation of the acetyl intermediate of formula (5-2) is unnecessary, and those skilled in the art can infer its existence or presence from their knowledge of the reaction conditions.

[0050] In various embodiments, effective reaction conditions for forming the acetyl intermediate of formula (5-2) include reacting the compound of formula (5-1) with acetic anhydride in the presence of an effective amount of organic solvent. Various organic solvents effective in dissolving the compound of formula (5-1) and acetic anhydride can be used. In various embodiments, the organic solvent may be acetonitrile (CH3CN), dioxane, toluene, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), DCM, 1,2-dichloroethane (1,2-DCE), C 1~6 The alcohol (e.g., methanol, ethanol) or a combination thereof is included. In one embodiment, effective reaction conditions for forming the compound of formula (5) are acetonitrile, C 1~6 The method involves reacting a compound of formula (5-1) with acetic anhydride in the presence of an organic solvent containing an alcohol or a combination thereof. For example, in one embodiment, the organic solvent is ethanol, etc. 1~6 It contains alcohol. In another embodiment, the organic solvent contains acetonitrile. In yet another embodiment, the acetic anhydride reactant is used in excess to function as a solvent, either alone or in combination with the organic solvent.

[0051] In various embodiments, effective reaction conditions for forming the acetyl intermediate of formula (5-2) include a reaction time in the range of 30 minutes to 12 hours. In some embodiments, effective reaction conditions for forming the acetyl intermediate of formula (5-2) include a reaction time in the range of 30 minutes to 10 hours, for example, a reaction time of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, or a reaction time within a range defined by an endpoint selected from any two of the aforementioned reaction time values.

[0052] In various embodiments, effective reaction conditions for forming the acetyl intermediate of formula (5-2) include relatively moderate reaction temperatures. In one embodiment, effective reaction conditions for forming the acetyl intermediate of formula (5-2) include reaction temperatures in the range of about 60°C to about 130°C, for example, reaction temperatures of about 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, or 130°C, or reaction temperatures within a range defined by an endpoint selected from any two of the aforementioned reaction temperature values.

[0053] In some embodiments, the acetyl intermediate of formula (5-2) is not isolated, but instead reacted in situ with a hydroxide base under reaction conditions effective for forming the compound of formula (5). Various hydroxide bases known to those skilled in the art may be used. In various embodiments, The hydroxide base is selected from LiOH, NaOH, KOH, Mg(OH)2, Ca(OH)2, and combinations thereof. For example, in one embodiment, the hydroxide base includes LiOH.

[0054] In various embodiments, effective reaction conditions for forming the compound of formula (5) include acetonitrile (CH3CN), C 1~6 The method comprises reacting an acetyl intermediate of formula (5-2) with a hydroxide base in the presence of an aqueous solvent containing an alcohol (e.g., methanol, ethanol, or isopropanol), or a combination thereof. For example, in one embodiment, the aqueous solvent is aqueous C such as aqueous ethanol. 1~6 Contains alcohol.

[0055] In various embodiments, effective reaction conditions for forming the compound of formula (5) include reaction times ranging from 1 to 30 hours. In some embodiments, effective reaction conditions for forming the compound of formula (5) include reaction times ranging from 2 to 24 hours, for example, reaction times of about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours, or reaction times within a range defined by an endpoint selected from any two of the aforementioned reaction time values.

[0056] In various embodiments, effective reaction conditions for forming the compound of formula (5) include relatively moderate reaction temperatures. In one embodiment, effective reaction conditions for forming the compound of formula (5) include reaction temperatures in the range of about 0°C to about 50°C, for example, reaction temperatures of about 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, or reaction temperatures within a range defined by an endpoint selected from any two of the aforementioned reaction temperature values.

[0057] In various embodiments, the method for preparing the compound of formula (5) is as shown in Figure 5A and / or Figure 5B.

[0058] In various embodiments, the compound of formula (5) is a useful intermediate for producing another intermediate compound of formula (6). For example, one embodiment provides a method for producing the compound of formula (6), which involves reacting the following compound of formula (5) with an oxidizing agent under oxidation reaction conditions effective for forming the compound of formula (6).

[0059] [ka]

[0060] In various embodiments, the variable X in equations (5) and (6) is Cl, Br, or I. For example, in one embodiment, the variable X is Cl.

[0061] Various oxidizing agents can be used to form the compound of formula (6). In various embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include oxidizing the compound of formula (5) with an effective amount of an oxidizing agent selected from NaOCl, NaOBr, KOCl, KOBr, Ca(OCl)2, and combinations thereof.

[0062] In various embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include mixing the compound of formula (5) and an oxidizing agent together in a solvent. Various organic solvents effective in dissolving the compound of formula (5) and the oxidizing agent can be used. In one embodiment, the solvent is chloroform or a low-boiling point chlorinated C such as dichloromethane (DCM). 1~3 It is a hydrocarbon. In other embodiments, the solvent is water. In some embodiments, the solvent includes water, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, toluene, methyl tert-butyl ether, 2-methyltetrahydrofuran, or a combination thereof.

[0063] In various embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include mixing the compound of formula (5) and an oxidizing agent together in the presence of an effective amount of inorganic base. Various inorganic bases known to those skilled in the art can be used. Examples of suitable inorganic bases include K2CO3, Na2CO3, and NaHCO3. In one embodiment, the inorganic base includes NaHCO3.

[0064] Effective oxidation reaction conditions for forming the compound of formula (6) may also include the presence of one or more other additives in an effective amount to promote the reaction. In various embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include mixing the compound of formula (5) and the oxidizing agent together in the presence of an effective amount of (2,2,6,6-tetramethylpiperidine-1-yl)oxidanil (TEMPO). In some embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include mixing the compound of formula (5) and the oxidizing agent together in the presence of an effective amount of an inorganic salt. Examples of suitable inorganic salts include LiCl, LiBr, NaCl, NaBr, KCl, KBr, and combinations thereof. In some embodiments, the inorganic salt includes NaBr.

[0065] In various embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include reaction times ranging from 1 minute to 6 hours. In some embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include reaction times ranging from 2 minutes to 4 hours, for example, reaction times of about 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours, or reaction times within a range defined by an endpoint selected from any two of the aforementioned reaction time values.

[0066] In various embodiments, effective oxidation reaction conditions for forming the compound of formula (6) include relatively low reaction temperatures. In one embodiment, effective oxidation reaction conditions for forming the compound of formula (6) include reaction temperatures in the range of about -25°C to about 25°C, for example, reaction temperatures of about -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, or 25°C, or reaction temperatures within a range defined by an endpoint selected from any two of the aforementioned reaction temperature values.

[0067] In various embodiments, the method for preparing the compound of formula (6) is as shown in Figures 6A and / or 6B.

[0068] The compound of formula (5) used to prepare the compound of formula (6) can be prepared as shown in Figures 7A and / or 7B. Those skilled in the art will recognize in Figures 7A and 7B that the compound of formula (7-7) is an example of the compound of formula (5) where X is Cl. The compound of formula (6) is useful for preparing the compounds of formula (3-1), such as compound (8-1) where X is Cl, as shown in Figures 8A and 8B. Those skilled in the art will understand that Figures 7A, 7B, 8A, and 8B illustrate other aspects of the present disclosure, including exemplary reaction conditions and embodiments for preparing the compound of formula (1A) and the compound of formula (3).

[0069] Unless otherwise specified, the term "crystalline" and related terms as used herein shall not be used when describing a substance, component, product, or form. The product, or form, is substantially crystalline, as determined, for example, by X-ray diffraction. (See, e.g., Remington’s Pharmaceutical Sciences, 20 th ed., Lippincott Williams & Wilkins, Philadelphia Pa., 173 (2000); The United States Pharmacopeia, 37 th ed., 503-509 (2014).)

[0070] Where used herein, unless otherwise specified, the terms “about” and “approximately” indicate that, when used in relation to numerical values ​​or ranges of values ​​provided to characterize a particular solid form, such as a specific temperature or temperature range (e.g., describing melting, dehydration, desolvation, or glass transition temperature), mass change (e.g., mass change as a function of temperature or humidity), solvent or water content (e.g., mass or percentage), or peak position (e.g., in analysis by IR or Raman spectroscopy or XRPD), the value or range of values ​​may be deviated to a extent that would be reasonable to a person skilled in the art, while still describing the solid form. Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared spectroscopy (IR), Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility tests, and dissolution tests. In some embodiments, the terms “about” and “approximately,” when used in this context, indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the enumerated value or range of values. In the context of molar ratios, “about” and “approximately” indicate that a numerical value or range of values ​​may vary within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the enumerated value or range of values.Since the peak values ​​of X-ray powder diffraction patterns can vary from machine to machine or from sample to sample, the cited values ​​should not be interpreted as absolute, but rather understood to have an acceptable variability of ±0.2 degrees 2 theta (°20) or more. For example, in some embodiments, the XRPD peak position values ​​may vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak. [Examples]

[0071] Further embodiments, which do not limit the scope of the claims, are disclosed in more detail in the following embodiments.

[0072] [ka]

[0073] [ka]

[0074] (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (compound 8-1):(R)-N-(3-methyl-1-(pyrrolidine-1-yl)butan-2-yl)-P,P-diphenylphosphineamide (1276.7 g, 3.580 mol) was suspended in n-heptane (10 L, 5V) under N2 in a 100 L glass container. The suspension was cooled to an internal temperature of -65°C. 1.0 M diethylzinc in n-heptane (47.76 L, 47.76 mol) was added via a peristaltic pump at an average rate of 0.47 L / min. The total addition time was 100 minutes at a target internal temperature of -52 ± 5°C. The solution was then stirred at -65°C for 45 minutes. BF3·OEt2 (169.5 g, 1.19 mol) was added over 10 minutes at a target internal temperature of -67.5 ± 2.5°C. The mixture was stirred at -65°C for 60 minutes until the reaction product became a slurry. 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridine-7-one (compound 7, 2000 g, 11.94 mol) in DCM (20 L, 10 V) was added via a peristaltic pump at a rate of 0.24 L / min. The total addition time was 90 minutes, and the internal temperature was raised to -65 ± 5°C. -The temperature was maintained at -°C. The solution was stirred at -65°C for 4 hours. The temperature was slowly raised to 20°C over 17 hours, and completion of the reaction was determined by HPLC. The reaction mixture was transferred to another container containing saturated NH4Cl (100 L, 5V) that had been initially cooled to -5°C. The internal temperature of the quench was maintained between 10 and 25°C. The mixture was filtered, and the residue was washed with 4 L of DCM. The aqueous phase was separated, and the organic layer was washed with water (10 L, 5V). The combined aqueous phase was extracted with MTBE (10 L, 5V). The combined organic layer was concentrated and dried. 2 L of MTBE was added, and the mixture was evaporated to remove the DCM. The dark-colored oil was taken into MTBE (5 L, 2.5 V), passed through a silica plug (10 kg, 5 wt), and washed with n-heptane / MTBE in the following proportions: (10:1, 33 L), (7.5:1, 34 L), (5:1, 54 L), (3:1, 40 L), and (2:1, 45 L). The eluent was concentrated under vacuum to obtain 2.1 kg of compound 8-1 as oil. The compound was diluted with n-heptane (2 L, 1 V) and heated to 60°C until all solids were dissolved. The mixture was slowly cooled to 30°C and seed crystals (1 wt%) were added. The slurry was then cooled to 10°C and stirred for 1 hour. The solid was filtered and dried under N2 flow for 16 hours. Compound 8-1 (1.7 kg, purity 99.8%, 92.9% ee) was obtained as a beige solid in a yield of 72%. 1 H NMR (400MHz, CDCl3) δ7.50(d, J=7.9Hz, 1H), 7.17(d, J=8.1Hz, 1H), 2.99-2.90(m, 1H), 2.82-2.71(m, 1H), 2.33(ddd, J=4.3, 8 .7, 13.4Hz, 1H), 2.19(ddd, J=6.8, 9.0, 13.5Hz, 1H), 2.04-1.89(m, 1H), 1.81(qd, J=7.3, 14.1Hz, 1H), 0.94(t, J=7.5Hz, 3H), 13 C NMR(101MHz,CDCl3)δ=166.90,150.07,135.67,134.94,123.10,81.98,36.03,32.37,26.47,8.13;LCMS(APCI)198.1[M+H] +Chiral analysis was performed by LC-MS using a Lux Cellulose-4 column (4.6 × 150 mm) with CH3CN / water 0.1% formic acid at a rate of 1.2 mL / min. Under these conditions, compound 8-1 eluted as peak 1 (t1 = 8.16 min), and the enantiomer eluted as peak 2 (t1 = 8.54 min).

[0075] (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 3): Compound 8-1 (800 g, 4.05 mol), CuI (153.9 g, 0.81 mol), NaI (1215.2 g, 8.11 mol), K2CO3 (1397.5 g, 10.13 mol), and 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound (3-2), 899.2 g, 4.05 mol), and anisole (13.6 L, 17V) were added to a 20 L reactor. The reactor was flushed with N2 for 30 minutes. Trans-N,N'-dimethylcyclohexane-1,2-diamine (230.1 g, 1.62 mol) was added to the reactor. The reaction mixture was stirred at 130°C for 20 hours, and completion was determined by HPLC. The reaction mixture was cooled to 25°C for 2 hours and filtered. The filtered cake was washed with anisole (1600 mL, 2V) and MTBE (2400 mL, 3V). The combined filtrate was washed with a mixture of 7.2 kg of NaCl in 36 L of concentrated NH3 (12 L x 3). The organic layer was concentrated to 4V. The crude solution was slowly transferred at 25°C to a stirred solution of MTBE (2400 mL, 3V) and n-heptane (21.6 L, 27V). The flask containing the crude solution was rinsed with 800 mL of anisole. Compound 3 (5 wt% seed crystal) was added. The mixture was stirred at 25°C for 1 hour, then cooled to 0°C for 1 hour while stirring. The solid was filtered, washed with n-heptane (5V), and dried in a vacuum oven at 45°C for 16 hours to obtain the product, compound 3 (1300 g, purity 96.6%, 93.5% ee), in 80.8% yield.

[0076] Compound 3 (900 g) was dissolved in iPrOH (9 L, 10V) and stirred at 70°C for 1 hour. The solution was cooled at a rate of 10°C every 30 minutes. Racemic compound 3 (0.45 g, 0.05 wt%) was added at 35°C. The solution was stirred at 35°C for 16 hours. The solution was filtered and the mother liquor was concentrated to 2.7 L (3V). The mixture was stirred at 70°C until the solid dissolved, then cooled to 45°C, and compound 3 (9 g, 1 wt%) was added. The suspension was cooled to 35°C, and water was added dropwise (9 L, 10V). The slurry was stirred at 25°C for 1 hour, then filtered. The solid was dried in a vacuum oven at 45°C to obtain concentrated compound 3 (502 g, purity 99.1%, 97.1% ee) in 55.8% yield. 1 H NMR(400MHz,DMSO-d6)δ 9.01(s,1H),7.90(d,J=8.1Hz,1H),7.69(d,J=8.1Hz,1H),5.73-5.63(m,1H),5.07(s,1H),5.02-4.97(m,1H),4.88-4.79(m,2H),4.64(dd,J =6.1,16.1Hz,1H),3.01-2.92(m,1H),2.82-2.71(m,1H),2.54(s,3H), 2.27-2.15(m,1H),2.02(m,1H),1.93-1.83(m,1H),1.77-1.64(m,1H), 0.87(t,J=7.5Hz,3H); 13 C NMR(101MHz,DMSO-d6)δ 175.6,166.2,159.3,157.9,154.4,146.6,135.4,135.1,131.9,118.4,117 .9,103.9,80.7,45.9,36.5,31.4,26.2,13.9,8.3;LCMS(APCI)384.0[M+H] + Chiral analysis was performed by HPLC using a Chiralpak ID column (4.6 × 250 mm) with elution at 1.0 mL / min using 0.1% DEA hexane:ethanol (45:55). Under these conditions, the enantiomer eluted as peak 1 (t1 = 5.62 min), and the product, compound 3, eluted as peak 2 (t1 = 9.96 min).

[0077] (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-2-yl)-6-((4-(4-methylpiperazine-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 1A): Compound 3 (750 g, 1.96 mol, 96.8% ee) and DCM (7.5 L, 10 V) were added to a 20 L reactor. The headspace was purged with N2. The suspension was cooled to -5°C, and 85% mCPBA (595.3 g, 2.93 mol) was added to the reaction mixture in 6 portions every 15 minutes. The reaction mixture was stirred at -5°C for 1 hour, and completion of the first reaction was determined by HPLC. DIPEA (1011.1 g, 2.82 mol) was added to the reaction mixture over 30 minutes. Then, 4-(4-methylpiperazin-1-yl)aniline (compound 4-1) (329.8 g, 2.05 mol) was added over 45 minutes. The reaction mixture was stirred at 10-15°C for 7 hours, and completion was determined by HPLC. Saturated Na2SO3 (3750 mL, 5V) was added to the reaction mixture. The temperature was maintained at 10-15°C. The layers were separated, and the aqueous layer was extracted with DCM (3.75 L x 3, 5V x 3). The combined organic layers were washed with 20% K3PO4 (3.75 L, 5V) and water (3.75 L, 5V). The organic layers were concentrated to 4-5V, and iPrOH (1500 mL, 2.5V) was added. This was repeated twice to remove DCM. iPrOH (1500 mL, 2.5V) was added to obtain a total volume of 5.6 L (7.5V). The suspension was heated to 70°C until all solids were dissolved. The mixture was then cooled to 40°C for 1 hour. Seed crystals of compound 1A (3.75 g, 0.5 wt%) were added to the mixture at 40°C. The mixture was then cooled to 25°C for 1 hour and stirred at 25°C for 16 hours. The solids were removed by filtration and washed with n-heptane (7.5 L, 10V). The solids were dried at 25°C under N2 flash for 16 hours to obtain compound 1A (740 g, purity 99.3%, 97.1% ee) in 62% yield.

[0078] [ka]

[0079] [ka]

[0080] 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (compound 7-4): Benzylamine (compound 7-1) (125.0 kg, 1167 mol), cyclopentanone (97.50 kg, 1159 mol), magnesium sulfate (140.0 kg, 1163 mol), and toluene (600 kg, 5.5 V) were added to a 1500 L reactor under N2 conditions. The mixture was stirred at 25-30°C for 18 hours. More than 90% of the benzylamine was consumed by HPLC. The reaction product was filtered, and the filter cake was rinsed with toluene (200 kg, 1.8 V). The filtrate was cooled to 0-10°C with stirring. Triethylamine (120.0 kg, 1186 mol) was added to the reactor with stirring at 0-10°C. Next, while maintaining the temperature at 0-10°C, acetic anhydride (121.2 kg, 1187 mol) was added to the reactor via a peristaltic pump. The reaction mixture was stirred at 20-25°C for 16 hours. The imine intermediate (compound 7-2) was consumed by >95% by HPLC. The mixture was transferred to a 5000 L reactor. The organic layer was washed with water (500 L x 2). Toluene was vaporized at 55-60°C under vacuum. It was removed by distillation. 200 L of toluene was added and removed by distillation. DMF (500 kg) was added to the reactor and the temperature was adjusted to -10 to 0°C. POCl3 (446.3 kg, 2910 mol) was added to the reactor via a peristaltic pump while maintaining the temperature at 5 to 15°C. The reaction mixture was stirred at 25°C for 1 hour, then heated to 105°C for 12 hours. The mixture was cooled to 25°C and water (500 kg) was added dropwise to the mixture at 25°C. The pH was adjusted to 5 by adding 30% NaOH solution (875 kg) to the reactor. MTBE (1500 kg) was added to the reactor and the mixture was stirred for 30 minutes. The layers were separated and the organic layer was filtered through Celite (20 kg). The filtered cake was rinsed with MTBE (300 kg). The filtrate was washed with water (500 kg x 2) and the solvent was removed at 50°C under vacuum. Water (500 kg) was added, and the temperature was maintained at 20-30°C while 36% HCl (250 kg) was added. The reaction mixture was stirred for 30 minutes and extracted with n-heptane (500 kg x 2). The pH was adjusted to 10-12 by adding 30% NaOH solution while maintaining the temperature at 20-30°C. The solid was recovered by filtration and washed with water (300 kg). This process was repeated four times, starting with 125 kg of benzylamine, to obtain 345 kg of crude 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine. 165 kg of crude 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine was dissolved in n-heptane (1500 kg) and heated at 110°C for 2 hours on decolorized carbon (10 kg). The mixture was cooled to 50°C, filtered, and dried at 50°C under vacuum. Next, the solid was slurryed in ethanol (150 kg) and water (650 kg) at 20-25°C for 30 minutes. The solid was removed by filtration and dried at 45°C for 24 hours to obtain 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (125 kg, purity 99.4%) as a yellow solid. 180 kg of crude 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine was treated in the same manner as the 165 kg batch to obtain 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (compound 7-4) (260 kg, purity 99.3%) as a yellow solid with an overall yield of 28%. 1H NMR(CDCl3,400MHz)δ 7.45(d,J=7.8Hz,1H),7.0-7.2(m,1H),3.00(t,J=7.8Hz,2H,),2.91(t,J=7.5Hz,2H,),2.15(quin,J=7.6Hz,2H); 13 C NMR(CDCl3,101MHz)δ 166.5,149.1,135.7,134.5,121.1,34.0,30.0,23.2;LCMS(APCI)154.0[M+H] + .

[0081] 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (compound 7-7): 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (compound 7-4) (125.0 kg, 817.0 mol), DCM (576 kg), and phthalic anhydride (242.5 kg, 1637 mol) were added to a 3000 L reactor at 25°C with stirring. 30% hydrogen peroxide (302.5 kg, 2696 mol) was added to the reactor. The reaction mixture was heated to 40°C and stirred for 18 hours, and the completion of the reaction was determined by HPLC. 50% Na2SO3 solution (500 kg) was added to the reaction mixture at 25°C and stirred for 3 hours. Then, 12% Na2CO3 solution (2500 kg) was added to adjust the pH to 8-10. The layers were separated, and the aqueous layer was extracted with DCM (750 kg x 3). The combined organic layers were concentrated at 40°C under vacuum. MTBE (375 kg) was added, and the mixture was concentrated to remove the DCM. The crude residue was slurryed at 25°C for 3 hours using MTBE (143.7 kg) and n-heptane (350 kg). The solid was removed by filtration, and the mixture was dried at 30°C under vacuum for 18 hours to obtain 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (125 kg, purity 99.8%) as an off-white solid. This process was repeated for 135 g batches of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine to obtain 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (compound 7-5) (258 kg, purity 99.8%) as an off-white solid in 93% yield.

[0082] Acetic anhydride (387 kg, 760.6 mol) was added to a 3000 L reactor at 25-30°C, and then heated to 80-95°C with stirring. 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (compound 7-5) (129 kg, 760.6 mol) was dissolved in CH3CN (516 kg) in a 1000 L reactor. This solution was then added to the 3000 L reactor over 4 hours at a temperature of 80-95°C. The reaction mixture was stirred at 80-95°C for 3 hours, and completion was determined by HPLC. CH3CN was removed by distillation, and the residue was dissolved in DCM (1238 kg), followed by a 13% Na2CO3 solution (1935 kg) to adjust the pH to 8-9. The layers were separated, and the aqueous layer was extracted with DCM (774 kg). The combined organic layers were concentrated.

[0083] Ethanol (412.8 kg), water (322.5 kg), and LiOH (45.15 kg, 1075 mol) were added to the crude residue at 25°C with stirring. The reaction mixture was stirred at 25°C for 8 hours, and completion was determined by HPLC. 3N HCl solution (312.4 kg) was added to this solution to adjust the pH to 1. The mixture was filtered, and the residue was washed with ethanol (103.3 kg) and water (129 kg). 30% NaOH solution (154.8 kg) was added to the mixture to adjust the pH to 9. DCM (774 kg) was added, and the mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was extracted with DCM (774 kg and 387 kg). The combined organic layers were stirred with decolorized charcoal (26 kg) at 40°C for 1 hour. The mixture was cooled, filtered, and DCM was removed. MTBE (290 kg) was added, and then concentrated to remove DCM. The crude residue was dissolved in MTBE (50 kg) and stirred at 20-30°C for 2 hours. The product was precipitated by stirring at 0-5°C for 1 hour. The solid was removed by filtration, rinsed with MTBE (50 kg), and dried at 20-30°C under vacuum for 12 hours to obtain 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (45 kg, purity 98%) as an off-white solid. The chemical reaction was repeated with a second 129 kg batch of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-1-oxide to generally obtain 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (compound 7-7) (147 kg, purity 98%) as an off-white solid in 58% yield. 1 H NMR(CDCl3,400MHz)δ 7.5-7.6(m,1H),7.20(d,J=7.9Hz,1H,),5.20(t,J=6.7Hz,1H),2.9-3.1(m,2H),2.7-2.9(m,1H),2.5-2.6(m,1H),2.0-2.2(m,1H); 13 C NMR(CDCl3,101MHz)δ 165.4,150.1,135.8,135.2,123.2,74.3,32.8,26.9;LCMS(APCI)170.0[M+H] + .

[0084] 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridine-7-one (compound 7): 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol (compound 7-7) (73.5 kg, 434.9 mol), NaHCO3 (75.5 kg, 874.9 mol), NaBr (7.35 kg, 714.3 mol), TEMPO (0.36 kg, 2.3 mol), and DCM (955.5 kg) were added to a 3000 L reactor while stirring at 25-30°C. The reaction mixture was cooled to -15-0°C while stirring, and 10% NaOC (326.7 kg, 438.5 mol) was added dropwise to the reaction mixture. The temperature was maintained at -10-5°C during the addition. The reaction mixture was stirred at -10-5°C for 30 minutes, and completion was determined by HPLC. 5% Na2SO3 solution (385.9 kg) was added to the reactants at 25-30°C with stirring. The reactants were stirred for 30 minutes, and the mixture was filtered. The filtered cake was washed with DCM (147 kg). The layers were separated, and the aqueous layer was extracted with DCM (488.7 kg). The combined organic layers were concentrated at 40°C under vacuum. Isopropanol (146 kg) was added to the mixture and concentrated to remove residual DCM. The crude residue was slurryed with MTBE (183.95 kg) and isopropanol (117.6 kg) at 50-55°C for 2 hours, and then cooled to 10-20°C. The solid was removed by filtration and washed with MTBE (110.25 kg) to obtain 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridine-7 -one (71.5 kg, wet) was obtained as a pale green solid. The chemical reaction was repeated using a second 73.5 kg batch of 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-ol to obtain 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridine-7-one (70 kg, wet) from the second batch as a pale green solid. The 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridine-7-one from the 71.5 kg batch and the 70 kg batch were combined and ground using MTBE (600 kg) at 20-30°C for 2.5 hours. The substance was filtered and dried at 50-55°C under vacuum to obtain 2-chloro-5,6-dihydro-7H-cyclopenta[b]pyridine-7-one (compound 7) (121 kg, purity 99.6%) as an off-white solid in 82% yield. 1 H NMR(CDCl3,400MHz)δ 7.86(td,J=0.8,8.2Hz,1H),7.49(d,J=8.1Hz,1H),3.1-3.2(m,2H),2.7-2.9(m,2H); 13 C NMR(CDCl3,101MHz)δ 203.3,154.2,153.0,148.4,137.8,128.5,35.1,23.0;LCMS(APCI)168.0[M+H] + .

[0085] [ka]

[0086] Tert-butyl(1,3-dioxoisoindolin-2-yl)carbamate:tert-butylhydrazine carboxylate (100 kg, 756.6 mol) was dissolved in dry toluene (1040 kg) in a 3000 L reactor. Phthalic anhydride (106.5 kg, 719 mol) was added to the reactor to obtain a suspension. The reaction mixture was then stirred at 100-115°C for 6 hours while removing water using a Dean-Stark apparatus. Completion of the reaction was determined by HPLC based on the consumption of phthalic anhydride. The reaction mixture was stirred at 20-30°C for 12 hours to form a white precipitate. The precipitate was removed by filtration and washed with n-hexane (75 kg x 2). The compound was dried at 25-35°C under vacuum to obtain tert-butyl(1,3-dioxoisoindorin-2-yl)carbamate (170 kg, purity 98.3%) as a white solid in 86% yield. 1 H NMR(DMSO-d6,300MHz)δ 9.85(s,1H),7.98-7.90(m,4H),1.44(s,9H);MS(ESI)207.1[M+H] + .

[0087] tert-butylallyl(1,3-dioxoiisoindorin-2-yl)carbamate: tert-butyl(1,3-dioxoiisoindorin-2-yl)carbamate (149.5 kg, 572 mol) was suspended in CH3CN (1500 kg) in a 3000 L reactor at 15-25°C. Then, K2CO3 (317 kg, 2,294 mol) and Me3N were added. + BnCl -(10.6 kg, 57.2 mol) was added to the reactor to obtain a yellow suspension. Allyl bromide (103.6 kg, 858 mol) was added to the reactants. The mixture was heated at 50-55°C for 6 hours with stirring. During the reaction, the mixture became a white suspension. After 6 hours, tert-butyl(1,3-dioxoisoindorin-2-yl)carbamate was consumed by HPLC. The reactants were cooled to 25-30°C and filtered. The filtered cake was washed with toluene (100 L). The filtrate was concentrated, and the crude material was taken up with toluene (600 L) and water (600 L). The layers were separated, and the aqueous layer was extracted with toluene (300 L). The combined organic layers were dried with (Na2SO4) and concentrated to 100 L. Hexane (500 L) was added, and the mixture was concentrated. This was repeated to remove toluene. The residue was then ground with hexane (300 L). The solid was recovered by filtration and dried at 25°C under vacuum to obtain tert-butyl(1,3-dioxoisoindorin-2-yl)carbamate (150 kg, purity 99%) as a white solid in 87% yield. 1 H NMR(DMSO-d6,300MHz)δ 8.02-7.93(m,4H),5.93-5.78(m,1H),5.26(dd,J=17.1,0.9Hz,1H),5.17- 5.10(m,1H),4.18(d,J=6.6Hz,2H),1.46&1.25(s,9H);MS(ESI)247.2[M+H] + .

[0088] tert-butyl1-allylhydrazine-1-carboxylate: tert-butylallyl(1,3-dioxoisoindorin-2-yl)carbamate (179.5 kg, 594 mol) was suspended in IPA (900 L) in a 3000 L reactor at 15-25°C. Ethane-1,2-diamine (250 kg, 4167 mol) was added dropwise to the reactor at 10-25°C, and the reaction was stirred at 15-25°C for 16 hours. Completion was determined by HPLC. The mixture was concentrated to 450 L, and water (1200 L) was added. The mixture was extracted with MTBE (600 L x 4), the combined organic layers were dried (Na2SO4), and the solvent was removed to obtain tert-butyl1-allylhydrazine-1-carboxylate (94 kg, purity 99%) as a light brown oil in 92% yield. 1 H NMR(DMSO-d6,300MHz)δ 5.86-5.74(m,1H),5.11(brs,1H),5.09-5.06(m,1H),4.47(brs,2H),3.89-3.81(m,2H),1.40(s,9H).

[0089] 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one:ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (121.8 kg, 524.7 mol) was heated in a 3000 L reactor with THF (6 It was dissolved in 15 kg. Tert-butyl 1-allylhydrazine-1-carboxylate (99 kg, 574.2 mol) and DIPEA (168.3 kg, 1312 mol) were added to obtain a clear solution. The reaction mixture was stirred at 70-75°C for 16 hours, and the reaction solution turned yellow. Completion was determined by HPLC, and the reaction mixture was cooled to 25°C. The reaction mixture was diluted with water (8V) and extracted with RINKAN (5V x 2). The combined organic layers were washed with 1N HCl (5V x 6). The organic layers were dried (Na2SO4) and concentrated to obtain ethyl 4-(2-allyl-2-(tert-butoxycarbonyl)hydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate (190 kg, purity 98.6%) as a brown oil.

[0090] Ethyl 4-(2-allyl-2-(tert-butoxycarbonyl)hydrazinyl)-2-(methylthio)pyrimidine-5-carboxylate (190 kg, 516 mol) was dissolved in DCM (380 L) in a 3000 L reactor at 20°C. The reaction mixture was cooled to -5°C, and TFA (588 kg, 5160 mol) was added dropwise to the mixture at approximately -5 to 0°C. The mixture was then stirred at 25°C for 1 hour, and then at 45 to 50°C for 1 hour. Completion of the reaction was determined by HPLC. The reaction mixture was then cooled to 0 to 5°C, and while maintaining the temperature at 0 to 15°C, 40% NaOH solution (4V) was added dropwise to the reaction mixture over 6 hours. At pH > 11, the reaction mixture became a slurry. MeOH (5V) was added, and the reaction mixture was stirred at 25°C for 5 hours, and completion of the reaction was determined by HPLC. The reaction mixture was concentrated to remove MeOH and DCM. 3N HCl (12V) was added to the residue at 0-10°C to adjust the pH to <1. The solution turned yellow and a solid was formed. The solid was recovered by filtration and washed with water (2V). The crude solid was suspended in water (4V) and heated at 65-70°C for 2 hours. The mixture was cooled to 35°C and filtered. The hot water washing was repeated three times. The substance was dried at 50-55°C under vacuum for 48 hours to obtain 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one (compound 3-2) (100 kg, purity 99%) as a yellow solid in 88% yield. 1 H NMR(DMSO-d6,400MHz)δ 12.72(br s,1H),8.66(s,1H),5.8-6.0(m,1H),5.0-5.2(m,2H),4.38(td,J=1.4,5.3Hz,2H,),2.5-2.5(m,3H);MS(ESI)223.1[M+H] + .

[0091] [ka]

[0092] (R)-2-amino-3-methyl-1-(pyrrolidine-1-yl)butan-1-one hydrochloride: D-valine (78 kg, 665.8 mol), NaHCO3 (111.92 kg, 1332.2 mol), and BOC2O (145.17 kg, 665.8 mol) were added to a 3000 L reactor containing THF (830 kg) and water (935 kg). The mixture was heated to 60-65°C with stirring for 14 hours. Completion of the reaction was determined by HPLC. The mixture was concentrated at 45°C under vacuum. The residue was dissolved in DCM (933 kg) and cooled to 5°C. 20% NaHSO4 aqueous solution (896 kg) was added to the mixture to adjust the pH to 3. The mixture was stirred for 30 minutes and the layers were separated. The aqueous layer was extracted with DCM (930 kg). The combined organic layers were washed with water (468 kg) and used in the next step.

[0093] A solution of (tert-butoxycarbonyl)-D-valine (665.8 mol) in DCM (1863 kg) was added to a 3000 L reactor and stirred at 20°C. HOBT (98.96 kg, 732.4 mol) and EDCI (153.2 kg, 799.2 mol) were added over 1 hour, and the mixture was cooled to 0°C. While maintaining the temperature between 0 and 11°C, pyrrolidine (118.4 kg, 1664.8 mol) was added over 3 hours. The reaction mixture was stirred at 11°C for 16 hours, and completion of the reaction was determined by HPLC. 10% citric acid (500 kg) was added, and the mixture was stirred for 30 minutes. The layers were separated, and the organic layer was washed with 0.5 N NaOH (490 kg) and water (480 kg) and dried (MgSO4). The DCM layer was used directly in the next step.

[0094] A solution of tert-butyl(R)-(3-methyl-1-oxo-1-(pyrrolidine-1-yl)butan-2-yl)carbamate (665.8) in DCM (1863 kg) was added to a 3000 L reactor and cooled to 5°C. 4 M HCl in dioxane (945 kg, 3600 mol) was added to the reaction mixture. The reaction mixture was stirred at 15°C for 12 hours and analyzed by HPLC. The completion of the reaction was determined by this. The reaction mixture was concentrated at 45°C under vacuum. THF (180 kg) was added, and then the mixture was concentrated and removed under vacuum to remove residual DCM. THF (450 kg) was added, and the residue was stirred at 25°C for 17 hours. The mixture was centrifuged to obtain (R)-2-amino-3-methyl-1-(pyrrolidine-1-yl)butan-1-one hydrochloride (115.8 kg, purity 98%) as a white solid in 81% yield. 1 H NMR(400MHz,CDCl3):δ 8.43(s,3H),4.19(s,1H),3.86-3.82(m,1H),3.64-3.57(m,1H),3.43- 3.38(m,2H),2.34-2.30(m,1H),2.03-1.82(m,4H),1.16-1.14(m,6H). MS(ESI)171.2[M+H] + .

[0095] (R)-N-(3-methyl-1-(pyrrolidine-1-yl)butan-2-yl)-P,P-diphenylphosphinamide: Under N2 conditions, (R)-2-amino-3-methyl-1-(pyrrolidine-1-yl)butan-1-one hydrochloride (46 kg, 222.53 mol) was added to a 2000 L reactor containing THF (409 kg). 1 M BH3 in THF (382.8 kg, 445.12 mol) was added to the reaction. The temperature rose to 38°C during the addition. The reaction was stirred at 65°C for 16 hours, and completion of the reaction was determined by HPLC. The reaction was cooled to 30°C, and MeOH (91.2 kg) was added to the solution over 2 hours. The mixture was concentrated at 45°C under vacuum. DCM (184 kg) and water (138 kg) were added to the residue, followed by the addition of 2 M NaOH (162.89 kg) to adjust the pH to 10. The layers were separated, and the aqueous layer was extracted with DCM (184 kg). The combined organic layers were dried (MgSO4). The DCM layer was filtered and used directly in the next step.

[0096] A solution of (R)-3-methyl-1-(pyrrolidine-1-yl)butan-2-amine (222.53 mol) in DCM (368 kg) was added to a 1000 L reactor under N2 conditions, followed by the addition of TEA (52.04 kg, 514.28 mol). The solution was cooled to 0°C, and diphenylphosphinate chloride (60.1 kg, 253.98 mol) was added over 2.5 hours. The reaction mixture was stirred for 1 hour, and completion was determined by HPLC. 10% NaHCO3 (120 L) was added over 1 hour, and the reaction mixture was stirred for 30 minutes. The organic layer was separated and washed with 10% NaHCO3 (120 L) and brine (120 L). The organic layer was concentrated at 30°C under vacuum. n-heptane (52 L) was added to the residue and removed under vacuum to remove residual DCM. n-heptane (89 L) was added and the mixture was stirred for 1 hour. The mixture was centrifuged to obtain a white solid, which was then suspended in MTBE (67 kg) and stirred for 1 hour. The solid was removed by centrifugation. At this point, the substance was combined with another second batch of (R)-N-(3-methyl-1-(pyrrolidine-1-yl)butan-1-one hydrochloride)-P,P-diphenylphosphinamide synthesized from 46 kg of (R)-2-amino-3-methyl-1-(pyrrolidine-1-yl)butan-1-one hydrochloride. The combined batch was added to MTBE (20 L) and n-heptane (200 L) and stirred for 2 hours. The mixture was centrifuged to obtain the product (R)-N-(3-methyl-1-(pyrrolidine-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (94.3 kg, purity 99.2%, chiral purity 99.9%) as a white solid in 59% yield. 1 H NMR(400MHz,DMSO-d6):δ 7.86-7.75(m,4H),7.53-7.45(m,6H),4.85-4.80(m,1H),2.96-2.90(m,1H),2.50-2.41(m,2H),2.29(s,4H) ),1.89-1.82(m,1H),1.58(s,4H),0.85(d,J=7.20Hz,3H),0.81(d,J=6.80Hz,3H);MS(ESI)357.3[M+H];[α] D 20 =+10.6(c 1.00,THF);l-isomer[α] D20 We reported on =-9.2(c1.00,THF).

[0097] [ka]

[0098] (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidine-3-one Compound 1A: Compound 3 (7.00 kg, 18.25 mol, 96.8% ee) and isopropanol (70.0 L, 10V) were added to a 500 L reactor. The headspace was purged with N2 and the solution was cooled to -10 to 0°C. While maintaining the reaction temperature at -10 to 0°C, oxone (9.52 kg, 15.52 mol) dissolved in water (70.0 L, 10V) was slowly added to the mixture over 5 hours. After complete addition, the mixture was stirred at the same temperature for a further 2.5 hours, and completion was determined by HPLC. NaHCO3 aqueous solution (6.30 kg, 7.49 mol dissolved in water (56.0 L, 8V)) was added to the mixture over 2 hours at -5±5°C until the pH reached 7-8. While maintaining the same temperature, DCM (78.0 kg, 8.4V) was added, and the mixture was stirred for 1 hour. After confirming that the pH of the aqueous phase was 7-8, Na2S2O3 aqueous solution (4.55 kg of Na2S2O3·H2O (18.31 mol) dissolved in water (35.0 L, 5V)) was added over 4 hours at -5±5°C. The aqueous layer was tested with KI starch paper to confirm quenching of all oxidizing agents. The two-phase mixture was filtered, and the filter cake was washed with DCM (19.0 kg, 2V). The phases were separated, and the organic layer was filtered through diatomaceous earth (10.0 kg, 1.4 ×). The diatomaceous earth was washed with DCM (19.0 kg, 2 V), and 4-(4-methylpiperazine-1-yl)aniline (compound 4-1) (3.25 kg, 17.30 mol) was added. The organic layer was concentrated to 8-10 V, and iPrOH (35.0 L, 5 V) was added. This mixture was concentrated to 10 V under reduced pressure at ≤70°C. The mixture was heated to 80 ± 5°C and stirred for at least 12 hours, and completion was determined by HPLC. The mixture was cooled to 25 ± 5°C, and an aqueous K2CO3 solution (dissolved in water (21 L, 3 V), 0.63 kg, 0.46 mol) was added. The pH was adjusted to 8-10. DCM (70.0 L, 10 V) was added, and the mixture was stirred for 30 minutes, then allowed to stand for 1 hour. The phases were separated, and water was added to the organic layer. The mixture was stirred for 30 minutes, then left to stand for 1 hour. DCM (14.0 L, 2V) was added. The phases were separated, and the organic layer was filtered through a micropouous filter and flushed with DCM (7.0 L, 1V). The combined organic layers were concentrated to 4-5V under reduced pressure. IPA (35.0 L, 5V) was added, and the mixture was concentrated to 4-5V under reduced pressure (3 times). IPA (17.5 L, 2.5V) was added, and the mixture was heated to 70±5°C until completely dissolved. The reactor temperature was cooled to 40±5°C over 3 hours, and seed crystals of compound 1A (35.0 g, 0.5 wt%) were added. The slurry was stirred at that temperature for a further 1 hour, then cooled to 0±5°C over 4 hours. The mixture was stirred at 0±5°C for 16 hours. The solid was isolated by filtration, washed with IPA (17.5 L, 2.5 V), washed with n-heptane (70.0 L, 10 V), and dried in a vacuum oven controlled at 45 ± 5°C with a small amount of nitrogen flow for at least 8 hours (rotating every 4-5 hours). Drying was stopped when the sample LOD was less than 15% to obtain compound 1A (7.23 kg, purity 99.3%, 97.1% ee) in yield 62%.

[0099] Recrystallization was performed based on the weight of the dry cake. Acetone (23.17 L, 3.2 V), compound 1A (7.24 kg, 1.0 equivalent), and purified water (5.80 L, 0.8 V) were added to a 300 L reactor and heated to 50°C until the solid was completely dissolved. The solution was passed through a microporous inline filter and transferred to a clean 300 L reactor, and the reactor and filter unit were rinsed with acetone:purified water (v:v=4:1, 7.24 L, 1 V). The solution was stirred for 30 minutes and then cooled to 33°C over 1 hour. Seed crystals of compound 1A (65.0 g, (1-LOD) × 1 wt%, LOD=12%) were added all at once at 33°C. The mixture was stirred at 33°C for 5.5 hours. Purified water (21.7 L, 3V) was slowly added to the reactor over 5.5 hours, followed by additional purified water (43.4 L, 6V) over 2.1 hours. The slurry was cooled to 4°C over 2 hours, then stirred for 8.5 hours. The product was filtered and rinsed with acetone:purified water (v:v=4 / 10, 14.5 L, 2V). The filtered cake was placed in a vacuum oven controlled at 20°C and left under vacuum with slight sweeping of N2 for 16 hours, followed by 16 hours at 40°C to obtain compound 1A (5.98 kg, purity 100.00%, chiral purity 99.6%, yield 62.2%) as a yellow solid.

[0100] Characterization Method XRPD parameters For XRPD analysis, a PANalytical Empyrean X-ray powder diffractometer was used.

[0101] [Table 2]

[0102] DSC parameters [Table 3]

[0103] TGA parameters [Table 4]

[0104] Furthermore, although the above text is described in some detail with figures and examples for clarity and understanding, it will be understood by those skilled in the art that numerous and varied modifications can be made without departing from the spirit of this disclosure. Therefore, it should be clearly understood that the forms disclosed herein are merely illustrative and are not intended to limit the scope of this disclosure, but rather encompass all modifications and alternative forms that are in line with the true scope and spirit of the invention.

Claims

1. A crystalline solid of the following formula (3), 【Chemistry 1】 It has an enantiomer excess (EE) of at least 95%, The crystalline solid is characterized by peaks in an X-ray powder diffraction pattern, the peaks of which include 8.6°²θ±0.2°²θ, 11.5°²θ±0.2°²θ, 17.3°²θ±0.2°²θ, and 23.2°²θ±0.2°²θ.

2. A method for producing a crystalline solid according to claim 1, Reacting the compound of formula (5) with an oxidizing agent under oxidation reaction conditions effective for forming the compound of formula (6) below, 【Chemistry 2】 The compound of formula (6) is used to prepare the compound of formula (3-1). The method includes reacting the compound of formula (3-1) with the compound of formula (3-2) under Ullmann coupling reaction conditions effective for forming the crystalline solid of formula (3), 【Transformation 3】 In the formula, X is Cl, Br, or I. A method comprising reacting a compound of formula (3-1) and a compound of formula (3-2) together in the presence of a chelate ligand and NaI, wherein the chelate ligand includes trans-N,N-dimethylcyclohexane-1,2-diamine, N,N-dimethylethane-1,2-diamine, 2,2'-bipyridyl, N,N'-dibenzoylethane-1,2-diamine, trans-1,2-diaminocyclohexane, or a combination thereof.

3. The method according to claim 2, wherein the method for producing the compound of formula (3-1) comprises using the compound of formula (6) and (R)-N-(3-methyl-1-(pyrrolidine-1-yl)butan-2-yl)-P,P-diphenylphosphinamide for producing the compound of formula (3-1).

4. The method according to claim 2 or 3, wherein the Ullmann coupling reaction conditions further include reacting the compound of formula (3-1) and the compound of formula (3-2) together in the presence of an effective amount of polar aprotic solvent, CuI, and an inorganic base.

5. The polar aprotic solvent includes dioxane, anisole, 1,2-dimethoxyethane (glycym), diethylene glycol dimethyl ether (diglym), dimethylacetamide, 1-methylpyrrolidine-2-one, or a mixture thereof. The inorganic base is K ２ CO ３ _K ３ PO ４ , Cs ２ CO ３ Na ２ CO ３ The method according to claim 4, including, or a combination thereof.

6. The method according to any one of claims 3 to 5, wherein the Ullmann coupling reaction conditions include a reaction time in the range of 4 hours to 36 hours and a reaction temperature in the range of 70°C to 150°C.

7. A method for producing the compound of the following formula (1A), The crystalline solid of formula (3) described in claim 1 is oxidized under reaction conditions effective for forming an oxidation intermediate, A method comprising reacting the oxidation intermediate with an amine compound of the following formula (4-1) under reaction conditions effective for forming the compound of formula (1A). 【Chemistry 4】

8. The reaction conditions effective for forming the aforementioned oxidation intermediate are oxone and m-chloroperbenzoate. acid (MCPBA), H ２ O ２ Na ２ WO ４ NaCl, cyanuric acid, NaIO ４ RuCl ３ O ２ The method according to claim 7, comprising oxidizing the crystalline solid of formula (3) by reacting it with an effective amount of an oxidizing agent selected from acid (MCPBA), H

9. The method according to claim 7 or 8, wherein the reaction conditions effective for forming the oxidation intermediate include oxidizing the crystalline solid of formula (3) in the presence of an effective amount of organic solvent.

10. The method according to any one of claims 7 to 9, wherein the reaction conditions effective for forming the oxidation intermediate include a reaction temperature in the range of -25°C to 25°C.

11. The method according to any one of claims 7 to 10, wherein the reaction conditions effective for forming the compound of formula (1A) include a reaction temperature in the range of 0°C to 50°C.

12. The method according to any one of claims 7 to 11, wherein the reaction conditions effective for forming the compound of formula (1A) include the presence of an effective amount of base.

13. Furthermore, the compound of formula (5-1) is reacted with acetic anhydride under reaction conditions effective for forming the acetyl intermediate of formula (5-2), This includes reacting the acetyl intermediate of formula (5-2) with a hydroxide base under reaction conditions effective for forming the compound of formula (5), 【Transformation 5】 In the formula, X is Cl, Br, or I. The hydroxide bases mentioned above are LiOH, NaOH, KOH, and Mg(OH) ２ Ca(OH) ２ The method according to any one of claims 2 to 6, selected from, and mixtures thereof.

14. The method according to claim 13, wherein X is Cl.

15. The method according to claim 13 or 14, wherein the reaction conditions effective for forming the acetyl intermediate of formula (5-2) include reacting the compound of formula (5-1) with acetic anhydride in the presence of an effective amount of an organic solvent.

16. The method according to any one of claims 13 to 15, wherein the reaction conditions effective for forming the acetyl intermediate of formula (5-2) include a reaction temperature in the range of 60°C to 130°C.

17. The reaction conditions effective for forming the compound of formula (5) are C １～６ The method according to any one of claims 13 to 16, comprising reacting the acetyl intermediate of formula (5-2) with the hydroxide base in the presence of an aqueous solvent containing an alcohol.

18. The method according to any one of claims 13 to 17, wherein the reaction conditions effective for forming the compound of formula (5) include a reaction temperature in the range of 0°C to 50°C.

19. The method according to any one of claims 2 to 6 or 13 to 18, wherein X is Cl.

20. The oxidation reaction conditions effective for forming the compound of formula (6) are: the compound of formula (5) is treated with NaOCl, NaOBr, KOCl, KOBr, Ca(OCl) ２ The method according to claim 19, comprising oxidizing with an effective amount of an oxidizing agent selected from a mixture thereof.

21. The method according to claim 19 or 20, wherein the oxidation reaction conditions effective for forming the compound of formula (6) include mixing the compound of formula (5) and the oxidizing agent together in the presence of an effective amount of (2,2,6,6-tetramethylpiperidine-1-yl)oxidanil (TEMPO).

22. The method according to any one of claims 19 to 21, wherein the oxidation reaction conditions effective for forming the compound of formula (6) include mixing the compound of formula (5) and the oxidizing agent together in the presence of an effective amount of inorganic base.

23. The method according to any one of claims 19 to 22, wherein the oxidation reaction conditions effective for forming the compound of formula (6) include mixing the compound of formula (5) and the oxidizing agent together in the presence of an effective amount of an inorganic salt selected from LiCl, LiBr, NaCl, NaBr, KCl, KBr, and mixtures thereof.

24. The method according to any one of claims 19 to 23, wherein the oxidation reaction conditions effective for forming the compound of formula (6) include a reaction temperature in the range of -25°C to 25°C and a reaction time in the range of 2 minutes to 4 hours.

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