Industrial preparation of heterocyclic modulators for lipid synthesis

Abstract

A method for preparing compound SGL1 is disclosed, which includes subjecting compound SGL1-SM1 to a hydrolysis reaction under alkaline conditions to obtain compound SGL1-A; subjecting compound SGL1-A to a reaction with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate to obtain compound SGL1-B; subjecting compound SGL1-B to a hydrolysis reaction under alkaline conditions to obtain compound SGL1-C; and subjecting compound SGL1-C to a reaction with compound SGL1-SM2 to obtain compound SGL1.

Description

【Technical Field】 【0001】 Reference to Related Applications This disclosure claims all rights and interests of a patent application for an invention filed with the State Intellectual Property Office of China on June 5, 2023, under application number 202310658687.7 and entitled "INDUSTRIAL PREPARATION OF HETEROCYCLIC MODULATOR FOR LIPID SYNTHESIS", the entire content of which is incorporated herein by reference. 【0002】 This disclosure generally relates to the field of medicinal chemistry, and more specifically, to the field of pharmaceutical synthesis. 【Background Art】 【0003】 Compound SGL1, also known as ASC40 (foreign code: TVB-2640), is a potent and safe oral small molecule inhibitor of selective fatty acid synthase, with the chemical name: 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile, molecular formula: C 【0004】 , , , , , 【0005】 H 31 N5O2, and has the following structural formula: 【Chemical Formula】 <00​​​​​​​​​​​【0006】 In yet another aspect, the disclosure relates to a method for preparing compound SGL1-C, the method comprising subjecting compound SGL1-B to a hydrolysis reaction under alkaline conditions. 【0007】 In yet another embodiment, the disclosure relates to a method for preparing compound SGL1, the method comprising reacting compound SGL1-C with compound SGL1-SM2. 【0008】 In another embodiment, the Disclosure relates to a method for preparing compound SGL1, the method including a method for preparing compound SGL1-A according to the Disclosure, and / or a method for preparing compound SGL1-B according to the Disclosure, and / or a method for preparing compound SGL1-C according to the Disclosure, and / or a method for preparing compound SGL1 according to the Disclosure. 【0009】 In yet another aspect, the disclosure relates to a method for preparing compound SGL1, the method comprising: subjecting compound SGL1-SM1 to a hydrolysis reaction under alkaline conditions to obtain compound SGL1-A; subjecting compound SGL1-A to a reaction with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate to obtain compound SGL1-B; subjecting compound SGL1-B to a hydrolysis reaction under alkaline conditions to obtain compound SGL1-C; and subjecting compound SGL1-C to a reaction with compound SGL1-SM2 to obtain compound SGL1. [Modes for carrying out the invention] 【0010】 detail The following description includes several specific details to provide a full understanding of the various embodiments disclosed. However, those skilled in the art will recognize that the embodiments can still be implemented using other methods, components, materials, etc., without using one or more of these specific details. 【0011】 In this application, unless otherwise required throughout the specification and the appended claims, the words “comprising,” “including,” “containing,” and “having” shall be interpreted as open-ended and inclusive, i.e., “including, but not limited to.” 【0012】 As used in this disclosure and the attached claims, a singular nominal referent without a number includes multiple referents unless the context explicitly indicates otherwise. 【0013】 References throughout this specification to “one embodiment,” “an embodiment,” “in another embodiment,” or “in some embodiments” mean that in at least one embodiment, a specific reference element, structure, or feature associated with that embodiment is included. Therefore, occurrences of the expressions “one embodiment,” “in another embodiment,” or “in some embodiments” in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, specific elements, structures, or features can be combined in any preferred manner in one or more embodiments. 【0014】 Where used in the specification and appended claims of this disclosure, the singular article “one” (corresponding to “a,” “an,” and “the” in English) should be understood to include multiple subjects unless the context explicitly indicates otherwise. Therefore, for example, a reference to “adding an acid to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate” includes either “adding one acid to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate” or “adding two or more acids to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate.” 【0015】 definition Thus, unless otherwise specified, the following terms used in this specification and the appended claims have the following meanings. 【0016】 In the present disclosure, the term "Compound SGL1-A" refers to 5-carbamoyl-4-cyclobutyl-2-methylbenzoic acid and has the following structure: 【Chem.】 【0017】 In the present disclosure, the term "Compound SGL1-B" refers to methyl 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate hydrochloride and has the following structure: 【Chem.】 <> 【0018】 In the present disclosure, the term "Compound SGL1-C" refers to 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid and has the following structure: 【Chem.】 【0019】 In the present disclosure, the term "Compound SGL1-SM1" refers to 5-cyano-4-cyclobutyl-2-methylbenzoic acid and has the following structure: 【Chem.】 【0020】 In the present disclosure, the term "Compound SGL1-SM2" refers to 4-(piperidin-4-yl)benzonitrile and has the following structure: 【Chem.】 【0021】 In this disclosure, the term "compound SGL1" refers to 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazole-3-yl)benzoyl)piperidine-4-yl)benzonitrile, which has the following structure: [ka] 【0022】 In this disclosure, the term “equivalent” refers to the mass ratio of substances when they interact, and is calculated based on the specific reactants specified. 【0023】 In this disclosure, the term "condensing agent" refers to a reaction adjuvant added in a condensation reaction. 【0024】 Detailed description In a first aspect, the disclosure relates to a method for preparing compound SGL1-A, the method comprising subjecting compound SGL1-SM1 to a hydrolysis reaction under alkaline conditions, wherein an aqueous solution of hydrogen peroxide is added to the hydrolysis reaction. 【0025】 In some embodiments, the aqueous solution of hydrogen peroxide that may be used in this disclosure has a concentration of about 20 to 70% by mass. 【0026】 In some embodiments, the amount of aqueous hydrogen peroxide added that may be used in this disclosure is about 7 to 15 equivalents based on compound SGL1-SM1. 【0027】 In some embodiments, the hydrolysis reaction is carried out at approximately 20-30°C. 【0028】 In some embodiments, the hydrolysis reaction is carried out for about 5 to 10 hours. 【0029】 In some embodiments, exemplary examples of alkaline conditions that may be used in a method for preparing compound SGL1-A of the present disclosure include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, or any mixture thereof. 【0030】 In some embodiments, hydrogen peroxide, having oxidizing ability, can readily oxidize oxidizable cyanos to more stable thiocyanate ions (SCN-), thereby preventing hydrolysis of the cyanos to acids, inhibiting the formation of by-products, and improving yield. 【0031】 In some embodiments, the method for preparing the compound SGL1-A of the present disclosure can achieve a scale-up yield of over 90% at the 10 kg level. 【0032】 In another aspect, the disclosure relates to a method for preparing compound SGL1-B, the method comprising subjecting compound SGL1-A to a reaction with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate. 【0033】 In some embodiments, the amount of dimethylaminoacetaldehyde dimethyl acetal added is about 3.0 to 6.0 equivalents, based on compound SGL1-A. 【0034】 In some embodiments, the amount of hydrazine acetate added is 1.5 to 3.0 equivalents, based on compound SGL1-A. 【0035】 In some embodiments, the reaction is carried out at approximately 60-70°C. 【0036】 In some embodiments, compound SGL1-A is subjected to a reaction with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate in the presence of an organic solvent, and the resulting product is purified. 【0037】 In some embodiments, exemplary organic solvents that may be used to purify the product obtained by reacting compound SGL1-A with dimethylaminoacetaldehyde dimethyl acetal and hydrazine acetate include, but are not limited to, methanol, ethanol, isopropanol, methyl tert-butyl ether, n-heptane, isopropyl acetate, acetone, methyl isobutyl ketone, isobutyl acetate, ethyl acetate, or any mixture thereof. 【0038】 In some embodiments, a method for preparing compound SGL1-B further comprises purifying the product obtained by reacting compound SGL1-A with dimethylaminoacetaldehyde dimethyl acetal and hydrazine acetate in the presence of ethyl acetate. 【0039】 In some embodiments, a method for preparing compound SGL1-B further includes adding an acid to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate. 【0040】 In some embodiments, exemplary examples of acids that may be used in the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethyl acetal and hydrazine acetate include, but are not limited to, formic acid, acetic acid, phosphoric acid, hydrochloric acid, maleic acid, fumaric acid, or any mixture thereof. 【0041】 In some embodiments, a method for preparing compound SGL1-B further comprises adding acetic acid to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate. 【0042】 In some embodiments, the amount of acid added to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal is about 4 to 12 equivalents. 【0043】 In some embodiments, the method for preparing compound SGL1-B involves subjecting dimethylaminoacetaldehyde dimethyl acetal (DMA-DMA) and hydrazine acetate to a one-pot process to efficiently construct a five-membered heterocycle. 【0044】 In some embodiments, the method for preparing the compound SGL1-B of the present disclosure can achieve a scale-up yield of over 70% at the 10 kg level. 【0045】 In yet another aspect, the disclosure relates to a method for preparing compound SGL1-C, the method comprising subjecting compound SGL1-B to a hydrolysis reaction under alkaline conditions. 【0046】 In some embodiments, the amount of base added is about 3 to 10 equivalents, based on compound SGL1-B. 【0047】 In some embodiments, exemplary examples of alkaline conditions that may be used in a method for preparing the compound SGL1-C of the present disclosure include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, or any mixture thereof. 【0048】 In some embodiments, compound SGL1-B is subjected to a hydrolysis reaction in the presence of sodium hydroxide. 【0049】 In some embodiments, the hydrolysis reaction is carried out at approximately 20-30°C. 【0050】 In some embodiments, the hydrolysis reaction is carried out for approximately 3 to 20 hours. 【0051】 In some embodiments, the method for preparing the compound SGL1-C of the present disclosure can achieve a scale-up yield of over 70% at the 10 kg level. 【0052】 In yet another embodiment, the disclosure relates to a method for preparing compound SGL1, the method comprising reacting compound SGL1-C with compound SGL1-SM2. 【0053】 In some embodiments, compound SGL1-C is subjected to a reaction with compound SGL1-SM2 in the presence of a coupling agent. 【0054】 In some embodiments, exemplary examples of coupling agents that may be used in the reaction of compound SGL1-C with compound SGL1-SM2 include, but are not limited to, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), propylphosphonic anhydride (T3P), n-butyl phosphate anhydride (T4P), or any mixture thereof. 【0055】 In some embodiments, the reaction of compound SGL1-C with compound SGL1-SM2 is carried out in the presence of n-butyl phosphate anhydride (T4P). 【0056】 In some embodiments, in the reaction of compound SGL1-C with compound SGL1-SM2, the amount of n-butyl phosphate anhydride (T4P) added is at least about 1.5 equivalents based on compound SGL1-C. 【0057】 In some embodiments, compound SGL1-C is subjected to a reaction with compound SGL1-SM2 under alkaline conditions. 【0058】 In some embodiments, the amount of base added is at least 5 equivalents, based on compound SGL1-C. 【0059】 In some embodiments, exemplary examples of alkaline conditions that may be used in a method for preparing compound SGL1 of the present disclosure include, but are not limited to, N,N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine (Py), 4-dimethylaminopyridine (DMAP), 2,6-lutidine, N-methylmorpholine (NMM), potassium carbonate, sodium carbonate, or any mixture thereof. 【0060】 In some embodiments, compound SGL1-C is subjected to a reaction with compound SGL1-SM2 in the presence of diisopropylethylamine (DIEA). 【0061】 In some embodiments, the amount of compound SGL1-SM2 added is approximately 1.05 to 5 equivalents based on compound SGL1-C. 【0062】 In some embodiments, compound SGL1-C is subjected to a reaction with compound SGL1-SM2 at 20-30°C. 【0063】 In some embodiments, compound SGL1-C is subjected to reaction with compound SGL1-SM2 for about 5 to 20 hours. 【0064】 In some embodiments, a method for preparing the compound SGL1 of the present disclosure includes dehydration condensation in the presence of n-butyl phosphate anhydride (T4P) to efficiently complete the preparation of the amide in a yield exceeding 85%. 【0065】 In another aspect, the present disclosure relates to a method for preparing compound SGL1, the method being Methods for preparing compound SGL1-A according to this disclosure, and / or Methods for preparing compound SGL1-B according to this disclosure, and / or Methods for preparing compound SGL1-C according to this disclosure, and / or Method for preparing compound SGL1 according to this disclosure, Includes. 【0066】 In yet another aspect, the present disclosure relates to a method for preparing compound SGL1, the method being: To obtain compound SGL1-A, compound SGL1-SM1 is subjected to a hydrolysis reaction under alkaline conditions. To obtain compound SGL1-B, compound SGL1-A is subjected to a reaction with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate. To obtain compound SGL1-C, compound SGL1-B is subjected to a hydrolysis reaction under alkaline conditions. To obtain compound SGL1, compound SGL1-C is subjected to a reaction with compound SGL1-SM2, Includes. 【0067】 In some embodiments, the method for preparing heterocyclic regulators for lipid synthesis according to the present disclosure can improve yield, reduce impurities, and be suitable for industrial applications. 【0068】 This disclosure will be described in detail below with reference to the following embodiments in order to better understand the various aspects and merits of this application. However, it should be understood that the following embodiments are not restrictive and are used only to illustrate some embodiments of this disclosure. [Examples] 【0069】 All reagents and devices used in the embodiments of this disclosure are conventional and commercially available. 【0070】 for example, [Table 1] [Table 2] 【0071】 Example 1 Preparation of compound SGL1-A [ka] Purified water (6.03 equivalents, 66.33 kg) was added to the reactor, stirring was started, and anhydrous ethanol (2.38 equivalents, 26.18 kg) and sodium hydroxide (0.56 equivalents, 6.16 kg) were added. After the mixture was thoroughly stirred, SGL1-SM1 (1 equivalent, 11 kg) was added, and the reactor was rinsed with purified water (1.05 equivalents, 11.55 kg). An aqueous solution of 30% hydrogen peroxide (3.73, 41.03 kg) was slowly added dropwise. After the addition was complete, the mixture was stirred at a controlled temperature of 25 ± 5 °C for 5 hours, then sampled and sent to HPLC for IPC-1 testing until the reaction reached a baseline. A solution of 20% sodium bisulfite (2.9 equivalents, 31.9 kg) in water (11.5 equivalents, 126.5 kg) was prepared in advance. After the solution reached the standard level, the 20% sodium bisulfite solution was added dropwise to the reactor. The mixture was stirred at 25±10°C for 1 hour and the pH was adjusted to 1-2 using hydrochloric acid. The mixture was stirred at a controlled temperature of 25±10°C for 2 hours and then filtered. The filtered cake was rinsed with purified water (3.04 equivalents, 33.44 kg) to obtain the crude wet product of SGL1-A. Purified water (19.04 equivalents, 209.44 kg) was added to the reactor, stirring was started, the crude wet product of SGL1-A was added, and the reactor walls were washed with purified water (1.00 equivalent, 11 kg). The mixture was heated to a temperature of 35±5°C, held at that temperature for at least 1 hour for reaction, cooled to a temperature of 20±5°C, and centrifuged. The filtered cake was rinsed twice with purified water (3.0 equivalents, 33 kg) to obtain the purified wet product of SGL1-A. The wet product was sampled and sent for IPC-2 analysis. The purified wet product of SGL1-A was transferred to a vacuum dryer with a controlled dryer jacket at a temperature of 55±5°C and dried for 15 hours. The dried product was sampled for IPC-3 testing of KF and LOD (KF ≤ 0.5%, LOD ≤ 2.0%). After the sample reached the criteria, the dried product was cooled and the powder was recovered, thereby obtaining 11.09 kg of dried product of SGL1-A in 93.0% yield. 【0072】 1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H),7.72 (s, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.22 (s, 1H), 3.11 (q, J=5.3 Hz, 1H), 2.45 (s, 3H), 1.97-1.64 (m, 7H) 【0073】 The above Example 1 was repeated using the following process parameters, and the results are shown in Table 1. 【0074】 [Table 3] 【0075】 Example 2 Preparation of compound SGL1-B [ka] Tetrahydrofuran (6.27 equivalents, 68.97 kg) was added to the reactor under nitrogen protection, and stirring was started. Dimethylaminoacetaldehyde dimethyl acetal (DMA-DMA) (1.7173 equivalents, 18.8903 kg) was added to the reactor. SGL1-A (1.0 equivalent, 11 kg) was added to the reactor. After the addition was complete, the reactor walls were washed with tetrahydrofuran (0.903 equivalents, 9.933 kg). The system was heated to a temperature of 65 ± 5 °C and stirred at that temperature for 5 hours, and sampled for IPC-1 testing. In-process control was achieved. The reactor temperature was adjusted to 30 ± 10 °C. Hydrazine acetate (0.596 equivalents, 6.556 kg) was added to the reactor, and acetic acid (1.0724 equivalents, 11.7964 kg) was added dropwise. After the dropwise addition was complete, the mixture was stirred for an additional 30 minutes at a temperature of 30±10°C, then heated to a temperature of 50±5°C and stirred at that temperature for 2 hours before being sampled for IPC-2 testing. 【0076】 After the reaction was complete, the mixture was cooled to a temperature of 30±10°C, purified water (7.245 equivalents, 79.695 kg) was added to the reactor, and the mixture was concentrated to 7 times its volume under reduced pressure at a controlled temperature of ≤50°C, cooled to a temperature of 20±5°C, stirred for 1 hour, then centrifuged and filtered. The filtered cake was washed with purified water (2.092 equivalents, 23.012 kg) to obtain free SGL1-B. This wet product was transferred to a vacuum dryer with a controlled jacket at a temperature of 45-55°C and dried for at least 10 hours, and samples were taken for the IPC-3 test of KF until KF ≤ 2%, to obtain the dried product of free SGL1-B. Under nitrogen protection, ethyl acetate (8.265 equivalents, 90.915 kg) was added to the reactor and stirring was started. The dried product of free SGL1-B was added, and after the addition was complete, the reactor walls were washed with ethyl acetate (0.878 equivalents, 9.658 kg). The mixture was stirred for 10 minutes, heated to a temperature of 60 ± 5°C, stirred at that temperature for 1 hour, and then cooled to a temperature of 25 ± 5°C. The reactor was controlled to a temperature of 20 ± 10°C, and hydrochloric acid (0.51 equivalents, 5.61 kg) was added dropwise. The mixture was stirred at this temperature for 1 hour and then centrifuged. The filtered cake was washed with ethyl acetate (3.571 equivalents, 39.28 kg) to obtain the wet product of SGL1-B. The wet product of SGL1-B was transferred to a vacuum dryer with a jacket controlled to a temperature of 45–55°C and dried for at least 10 hours, and samples were taken for IPC-5 testing of LOD until LOD ≤ 2%. After the sample reached the standard, 10.87 kg of the dried product of SGL1-B was obtained in a yield of 71.6%. 【0077】 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 2H), 8.49 (s, 2H), 7.34 (s, 2H), 3.88 (s, 6H), 3.29 (dd, J=5.6, 4.9 Hz, 2H), 2.78 (s, 6H), 2.50 (s, 6H), 1.96-1.87 (m, 4H), 1.87-1.81 (m, 1H), 1.81-1.76 (m, 5H), 1.75 (d, J=1.7 Hz, 1H), 1.74-1.64 (m, 2H) 【0078】 The above Example 2 was repeated using the following process parameters, and the results are shown in Table 2. 【0079】 [Table 4] 【0080】 Example 3 Preparation of compound SGL1-C [ka] Under nitrogen protection, methanol (3.58 equivalents, 38.66 kg) was added to the reactor and stirring was initiated. Purified water (1.53 equivalents, 16.52 kg) was then added to the reactor, and the reactor temperature was controlled to below 50°C. Sodium hydroxide (0.369 equivalents, 3.99 kg) was then added to the reactor. The mixture was stirred for at least 30 minutes, and then SGL1-B (1.0 equivalent, 10.80 kg) was added. After the addition was complete, the reactor walls were washed with methanol (0.82 equivalents, 8.86 kg). The system was then heated to a temperature of 60 ± 5°C and stirred at that temperature for 3 hours. Samples were taken for IPC-1 testing until SGL1-B ≤ 0.5%. After the sample reached the standard, the reactor was cooled to a temperature of 40±5°C, and purified water (4.77 equivalents, 51.52 kg) was added to the reactor. The mixture was concentrated under reduced pressure to 6 times its volume. The reactor was cooled to a temperature of 20±10°C, and hydrochloric acid was added dropwise while maintaining this temperature. The mixture was adjusted to pH 1-3, stirred at that temperature for 1 hour, and then centrifuged. The filtered cake was rinsed with purified water (5.0 equivalents, 54 kg) to obtain the wet product of SGL1-C. This wet product, having reached the standard, was transferred to a vacuum dryer with a jacket controlled at a temperature of 40-55°C and dried for at least 10 hours. Sampling was performed for the IPC-3 test of KF until KF ≤ 0.5%, thereby obtaining 8.79 kg of dried SGL1-C in 96.6% yield. 【0081】 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.98 (s, 1H), 8.21 (s, 1H), 7.27 (s, 1H), 3.34 (dd, J=5.6, 4.9 Hz, 1H), 2.43 (d, J=16.1 Hz, 6H), 1.98-1.87 (m, 3H), 1.84 (dd, J=7.6,5.3 Hz, 1H), 1.84-1.78 (m,2H), 1.81-1.71 (m, 1H), 1.74-1.66 (m, 1H) 【0082】 The above Example 3 was repeated using the following process parameters, and the results are shown in Table 3. 【0083】 [Table 5] 【0084】 Example 4 Preparation of compound SGL1 [ka] Dichloromethane (6.88 equivalents, 60.54 kg) was added to the reactor under nitrogen protection, and stirring was started. SGL1-C (1.0 equivalent, 8.8 kg) and SGL1-SM2 (0.86 equivalents, 7.6 kg) were added to the reactor. After the addition was complete, the reactor walls were washed with dichloromethane (1.34 equivalents, 11.79 kg), the reactor temperature was adjusted to 15 ± 5 °C, N,N-diisopropylethylamine (2.36 equivalents, 20.77 kg) was added dropwise, and a solution of 50% butyl anhydride in ethyl acetate (4 equivalents, 35.2 kg) was added dropwise. After the dropwise addition was complete, the mixture was allowed to react for 2 hours at room temperature, and then samples were taken for IPC-1 testing until SGL1-C ≤ 2%. After the sample reached the standard, ethyl acetate (9.03 equivalents, 79.46 kg) was added to the reactor, and the mixture was concentrated to 15 times its volume under reduced pressure at 40°C, followed by the addition of purified water (5.06 equivalents, 44.53 kg). The mixture was stirred for 2 hours and then centrifuged. The filtered cake was washed with purified water (1.99 equivalents, 17.51 ​​kg) to obtain wet product 1 of SGL1. Anhydrous ethanol (2.73 equivalents, 24.02 kg) was added to the reactor, stirring was started, and wet product 1 of SGL1 was added. The reactor was heated to a temperature of 78 ± 5°C, and the mixture was brought into the clean area through a precision filter at this temperature. After filtration was complete, purified water (1.74 equivalents, 15.31 kg) was added dropwise, and the mixture was then stirred at this temperature for at least an additional 0.5 hours. The system was cooled to a temperature of 15±10°C within 6 hours, stirred at this temperature for 6 hours, and then centrifuged. The filtered cake was washed with a 1:1 mixed solution of ethanol (0.47 equivalents, 4.14 kg) and purified water (0.47 equivalents, 4.14 kg) to obtain the purified wet product of SGL1, which was sampled for the IPC-2 test. The purified wet product of SGL1 was dried under reduced pressure at 40-55°C for 10 hours, and the sample was sampled for the IPC-3 test of residual solvent by GC until the sample reached the standard, thereby obtaining 13.085 kg of SGL1 in 88.1% yield. 【0085】 1HNMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.55 (s, 1H), 7.47 (d, J=8.0 Hz, 2H), 7.37 (s, 1H), 4.72 (d, J=12.5 Hz, 1H), 4.31 (s, 1H), 3.44 (m, 1H), 3.13 (t, J=12.0 Hz, 1H), 2.90-2.85 (m, 2H), 2.39 (s, 3H), 2.36-2.26 (m, 3H), 2.17 (s, 2H), 2.07-2.00 (m, 2H), 1.89-1.71 (m, 3H), 1.67-1.64 (m, 2H),1.46 (s, 1H). 【0086】 The above Example 4 was repeated using the following process parameters, and the results are shown in Table 4. 【0087】 [Table 6] 【0088】 In this disclosure, relational terms such as “first” and “second” are used solely to distinguish one entity or operation from another, and do not necessarily require or suggest the existence of any actual relationship or order between these entities or operations. 【0089】 As can be understood from the above description, specific embodiments of this disclosure have been described for illustrative purposes only, but various modifications or improvements can be made by those skilled in the art without departing from the spirit and scope of this disclosure. All such modifications or improvements should be included within the scope of the claims attached to this disclosure.

Claims

[Claim 1] A method for preparing compound SGL1-A, comprising subjecting compound SGL1-SM1 to a hydrolysis reaction under alkaline conditions, wherein an aqueous solution of hydrogen peroxide is added to the hydrolysis reaction. [Claim 2] The method according to claim 1, wherein the amount of aqueous solution of hydrogen peroxide added is 7 to 15 equivalents based on the compound SGL1-SM1. [Claim 3] The method according to claim 1 or 2, wherein the hydrolysis reaction is carried out at 20 to 30°C. [Claim 4] A method for preparing compound SGL1-B, comprising subjecting compound SGL1-A to a reaction with dimethylaminoacetaldehyde dimethyl acetal and hydrazine acetate. [Claim 5] The method according to claim 4, wherein the amount of dimethylaminoacetaldehyde dimethylacetal added is 3.0 to 6.0 equivalents based on the compound SGL1-A. [Claim 6] The method according to claim 4 or 5, wherein the amount of hydrazine acetate added is 1.5 to 3.0 equivalents based on the compound SGL1-A. [Claim 7] The method according to any one of claims 4 to 6, wherein the reaction is carried out at 60 to 70°C. [Claim 8] The method according to any one of claims 4 to 7, further comprising purifying the product of the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate using an organic solvent, preferably methanol, ethanol, isopropanol, methyl tert-butyl ether, n-heptane, isopropyl acetate, acetone, methyl isobutyl ketone, isobutyl acetate, ethyl acetate, or any mixture thereof, more preferably ethyl acetate. [Claim 9] The method according to any one of claims 4 to 8, further comprising adding an acid, preferably formic acid, acetic acid, phosphoric acid, hydrochloric acid, maleic acid, fumaric acid, or any mixture thereof, more preferably acetic acid, to the reaction of compound SGL1-A with dimethylaminoacetaldehyde dimethyl acetal and hydrazine acetate. [Claim 10] A method for preparing compound SGL1-C, comprising subjecting compound SGL1-B to a hydrolysis reaction under alkaline conditions. [Claim 11] The method according to claim 10, wherein the amount of base added is 3 to 10 equivalents based on the compound SGL1-B. [Claim 12] The method according to claim 10 or 11, wherein the alkaline conditions are selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, or any mixture thereof, preferably sodium hydroxide. [Claim 13] The method according to any one of claims 10 to 12, wherein the hydrolysis reaction is carried out at 20 to 30°C. [Claim 14] The method according to any one of claims 10 to 13, wherein the hydrolysis reaction is carried out for 3 to 20 hours. [Claim 15] A method for preparing compound SGL1, comprising subjecting compound SGL1-C to a reaction with compound SGL1-SM2. [Claim 16] The reaction is carried out in the presence of a condensing agent, preferably, the condensing agent is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBT), propylphosphonic anhydride (T ３ P), n-butyl phosphate anhydride (T ４ P), or any mixture thereof, more preferably n-butyl phosphate anhydride (T ４ Selected from P), and more preferably n-butyl phosphate anhydride (T ４ The method according to claim 15, wherein the amount of P added is at least 1.5 equivalents based on the compound SGL1-C. [Claim 17] The method according to claim 15 or 16, wherein the reaction is carried out under alkaline conditions, and preferably the amount of base added is at least 5 equivalents based on the compound SGL1-C. [Claim 18] The method according to claim 17, wherein the alkaline condition is selected from N,N-diisopropylethylamine (DIEA), triethylamine (TEA), pyridine (Py), 4-dimethylaminopyridine (DMAP), 2,6-dimethylpyridine, N-methylmorpholine (NMM), potassium carbonate, sodium carbonate, or any mixture thereof, preferably diisopropylethylamine (DIEA). [Claim 19] A method for preparing compound SGL1, The method according to any one of claims 1 to 3, and / or The method according to any one of claims 4 to 9, and / or The method according to any one of claims 10 to 14, and / or The method according to any one of claims 15 to 18, The method, including the method described above. [Claim 20] A method for preparing compound SGL1, To obtain compound SGL1-A, compound SGL1-SM1 is subjected to a hydrolysis reaction under alkaline conditions. To obtain compound SGL1-B, compound SGL1-A is subjected to a reaction with dimethylaminoacetaldehyde dimethylacetal and hydrazine acetate. To obtain compound SGL1-C, compound SGL1-B is subjected to a hydrolysis reaction under alkaline conditions. To obtain the compound SGL1, the compound SGL1-C is subjected to a reaction with the compound SGL1-SM2, The method, including the method described above.

Images