Method for producing P2X3 inhibitors

Abstract

The present invention relates to the field of drug synthesis, specifically to a method for preparing a P2X3 inhibitor, 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazol-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)benzamide (I-1), which comprises the steps of: starting from 3-bromo-2-fluoro-5-iodobenzoic acid, substituting iodine for a hydroxy group, and converting the carboxy group into a methyl ester to obtain compound 1C; The present invention discloses a method for preparing the compound I-1, which comprises the steps of: coupling compound 1C with B2(pin)2 to obtain 1D; coupling compound 1D with 2-bromo-5-methylthiazole to obtain 1E; substituting compound 1E with 1F to obtain compound 1H; hydrolyzing 1H with a base to obtain 1I; and condensing compound 1I with 1L to obtain product I-1. The synthetic route provided by the present invention is easy to control the product quality, has a relatively high yield, and is suitable for industrial production. [Formula 1] JPEG2026504260000033.jpg46169

Description

Detailed description of the invention

[0001] This application claims priority to a prior application filed with the China National Intellectual Property Administration on December 22, 2022, with patent application number 2022116671852, titled "Method for Producing a P2X3 Inhibitor." The entire text of the said prior application is incorporated herein by reference.

[0002] [Technical field] The present invention relates to the synthesis process of 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazole-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)benzamide and its intermediates.

[0003] [Background technology] P2X receptors are non-selective ATP-dependent ion channel receptors, or purinergic receptors, that can bind to extracellular ATP primarily derived from damaged or inflamed tissue. These receptors are widely expressed in systems such as the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems, and are involved in various physiological processes including regulation of cardiac rhythm and contractility, regulation of vasotonic tension, regulation of nociception, particularly chronic pain, contraction of the vas deferens during ejaculation, contraction of the bladder during urination, platelet aggregation, macrophage activation, cell apoptosis, and neuron-glial interactions. The P2X receptors include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7, and three heterologous receptors: P2X2 / 3, P2X4 / 6, and P2X1 / 5.

[0004] P2X3 is an isoform of the P2X receptor family and is selectively expressed in dorsal root ganglia, spinal cord, and brain neurons, i.e., small to medium-diameter primary sensory neurons.

[0005] Extensive studies have revealed that activation of P2X3 and P2X2 / 3, expressed in primary sensory neurons, plays a crucial role in acute injury, hyperalgesia, and hypersensitivity in rodents. Many studies have shown that upregulation of P2X3 receptor expression can lead to the development of hyperalgesia and may be involved in pain signaling. P2X3 gene knockout mice exhibit reduced pain responses, and P2X3 receptor antagonists have shown reduced nociception in pain and inflammatory pain models.

[0006] P2X3 receptors are distributed to primary afferent nerves around the airways and can regulate cough. Studies have shown that ATP released from airway injury or inflamed tissue acts on P2X3 receptors in primary neurons, triggering depolarization and action potentials. The transmission of these potentials then triggers a cough impulse, resulting in coughing. P2X3 receptors play a crucial role in cough reflex hypersensitivity, and inhibiting cough reflex hypersensitivity by antagonizing binding to P2X3 receptors can suppress excessive coughing in patients with chronic cough. Furthermore, studies suggest that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary arterial hypertension, or asthma, indicating their potential as novel drugs for treating these conditions.

[0007] P2X3 is associated with an induction channel that controls the bladder capacity reflex, and it has been reported that P2X3 gene knockout mice exhibit a significant decrease in urination frequency and a significant increase in bladder capacity. Therefore, inhibiting the binding of P2X3 receptor antagonists to the P2X3 receptor has therapeutic effects on conditions of urine storage and voiding disorders such as overactive bladder. Thus, P2X3 antagonists may be potential drugs for treating overactive bladder and related diseases.

[0008] P2X3 antagonists show great promise. While therapies such as gabapentin, morphine, and amitriptyline, which are currently commonly used cough medications, or speech-pathology treatments can improve cough in many patients, they are not applicable to all patients. Furthermore, central nervous system drugs such as gabapentin can cause harmful side effects and are not suitable for long-term administration. There is a need to develop clinically long-term-administered drugs for chronic, refractory cough that offer physicians more drug options, and therefore, the development of P2X3 antagonists is of clinical importance.

[0009] [Overview of the prefecture] The present invention provides a method for producing 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazole-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)benzamide and intermediates thereof. The synthetic route provided by the present invention allows for easy control of product quality, has a relatively high yield, and is suitable for industrial production.

[0010] This invention provides a method for producing compound I-1, which is a2) Compound 1I and compound 1L are condensed in a solvent using a condensing agent and a base as shown below to obtain compound I-1.

[0011] [ka]

[0012] Includes steps.

[0013] In one arbitrary embodiment of the present invention, in step a2, the solvent includes, but is not limited to, water, a chloroalkane solvent, an ether solvent, an amide solvent, an aromatic hydrocarbon solvent, an ester solvent, or a mixture of two or more thereof, and is preferably an amide solvent. Of these, the chloroalkane solvent is preferably dichloromethane, chloroform, dichloroethane, or a mixture of two or more thereof, with dichloromethane being more preferred. The ether solvent is preferably tetrahydrofuran, ethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether, or a mixture of two or more thereof, with tetrahydrofuran being more preferred. The amide solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture thereof, with N,N-dimethylformamide being more preferred. The aromatic hydrocarbon solvent is preferably toluene. The ester solvent is preferably ethyl acetate. In one arbitrary embodiment of the present invention, in the method for producing the compound of formula I-1, the solvent is preferably an amide solvent, and more preferably N,N-dimethylformamide.

[0014] In one arbitrary embodiment of the present invention, in step a2, 1L of the compound is its free base or a salt thereof, for example, the hydrochloride salt of 1L of the compound.

[0015] In one arbitrary embodiment of the present invention, in step a2, the condensing agent may be one or more of HOBt / EDCI, T3P, PyBOP, DCC, CDI, or HATU, and the preferred condensing agent is HOBt / EDCI.

[0016] In one arbitrary embodiment of the present invention, in step a2, the base may be DIPEA, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, or pyridine, with DIPEA being the preferred base.

[0017] In one arbitrary embodiment of the present invention, in step a2, the coupling agent is HOBt / EDCI, the base is DIPEA, and the solvent is DMF.

[0018] In an optional embodiment of the present invention, in step a2, the molar ratio of the above intermediate 1I to the condensing agent may be 1:(1 to 5), preferably 1:(1.5 to 2), more preferably 1:1.5.

[0019] In an optional embodiment of the present invention, in step a2, the molar ratio of the above intermediate 1I to the base may be 1:(1 to 5), preferably 1:(2 to 4), more preferably 1:3.

[0020] In an optional embodiment of the present invention, in step a2, the molar ratio of the above intermediate 1I to intermediate 1L may be 1:(1 to 4), preferably 1:(1 to 3), more preferably 1:1.2.

[0021] In an optional embodiment of the present invention, in step a2, the above condensation reaction is carried out under the protection of an inert gas, and the inert gas may be nitrogen gas, helium gas or argon gas.

[0022] In an optional aspect of the present invention, the reaction time of the above condensation reaction may be 1 to 20 hours, for example, 1 to 2 hours.

[0023] In an optional aspect of the present invention, in step a2, after the completion of the above condensation reaction, a post-treatment step may be further included, for example, extracting the reaction solution, centrifuging, drying, recrystallizing, centrifuging and drying.

[0024] In an optional aspect of the present invention, in step a2, the extraction in the post-treatment step comprises: after adding ethyl acetate to the reaction solution, adding a 6% aqueous sodium bicarbonate solution to wash twice, collecting the organic phase, then washing once with a 0.2 M aqueous hydrochloric acid solution until the pH reaches 3 to 4, collecting the organic phase, further washing twice with purified water until the pH becomes neutral, and collecting the organic phase.

[0025] In any embodiment of the present invention, step a2 includes drying the centrifugally separated filtered cake in a blast oven at 55±5°C for 8 hours or more.

[0026] In any embodiment of the present invention, step a2 includes heating and dissolving the dried product in a good solvent, then adding a poor solvent dropwise, cooling, and crystallizing.

[0027] In any embodiment of the present invention, in step a2, the good solvent may be one or more of methanol, anhydrous ethanol, isopropanol, ethyl acetate, and isopropyl acetate, and is preferably anhydrous ethanol.

[0028] In any embodiment of the present invention, in step a2, the poor solvent may be one or more of isopropyl ether, n-heptane, n-hexane, and petroleum ether, preferably n-heptane.

[0029] In any embodiment of the present invention, in step a2, the heating and dissolution temperature of the recrystallized material is 60 to 80°C.

[0030] In any embodiment of the present invention, in step a2, the recrystallization is cooled to 15-25°C.

[0031] The above method for producing compound I-1 may further include a method for producing compound 1I, which is: a1) Compound 1H is hydrolyzed in a solvent in the presence of a basic substance as follows to obtain compound 1I.

[0032] [ka]

[0033] Includes steps.

[0034] In one arbitrary embodiment of the present invention, R 1This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0035] In one arbitrary embodiment of the present invention, in step a1, the solvent is selected from an alcohol-based solvent, water, or a mixed solvent of an alcohol-based solvent and water. Of these, methanol or ethanol is preferred as the alcohol-based solvent.

[0036] In one arbitrary embodiment of the present invention, in the method for producing the compound of formula 1I, the solvent is preferably a mixed solvent of an alcohol-based solvent and water, and more preferably a mixed solvent of methanol and water.

[0037] In one arbitrary embodiment of the present invention, in step a1, the basic substance may be one or more of triethylamine, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, or potassium hydroxide, with lithium hydroxide being the preferred basic substance.

[0038] In one arbitrary embodiment of the present invention, in step a1, R 1 The compound is a methyl group, the basic substance is lithium hydroxide, and the solvent is a mixed solvent of methanol and water.

[0039] In one arbitrary embodiment of the present invention, in step a1, the mixed volume ratio of methanol to water is (1 to 10):1.

[0040] In one arbitrary embodiment of the present invention, in step a1, the molar ratio of compound 1H to the basic substance is 1:(1~5), preferably 1:2.

[0041] In one arbitrary embodiment of the present invention, the reaction time for the hydrolysis reaction in step a1 may be 1 to 20 hours, for example, 1 to 2 hours.

[0042] In any embodiment of the present invention, step a1 may further include a post-treatment step after the completion of the hydrolysis reaction, for example, lowering the temperature of the reaction solution, acidifying it, centrifuging it, washing and drying it to obtain a pure product of compound 1I.

[0043] In any embodiment of the present invention, in step a1, the reaction solution is cooled to 0-20°C in the post-treatment step.

[0044] In any embodiment of the present invention, step a1 includes acidification in the post-treatment step, acidifying the reaction solution to pH 4, maintaining the temperature at 0-20°C for crystallization, acidifying it again to pH 2-3, maintaining the temperature for crystallization, and so on.

[0045] The above method for producing compound 1I may further include a method for producing compound 1H, which is: b3) In a solvent, compound 1E is substituted with 1F in the presence of a base as described below, and after acidification with an acid, compound 1H is obtained.

[0046] [ka]

[0047] Includes steps.

[0048] In one arbitrary embodiment of the present invention, R 1 This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0049] In one arbitrary embodiment of the present invention, in step b3, the solvent is selected from alcohol-based solvents, aromatic hydrocarbon-based solvents, ether-based solvents, amide-based solvents, or a mixture of two or more thereof, preferably a mixture of an ether-based solvent and an amide-based solvent. Of these, the alcohol-based solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon-based solvent is preferably toluene. The ether-based solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof, and tetrahydrofuran is more preferred. The amide-based solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture thereof.

[0050] In one arbitrary embodiment of the present invention, in the method for producing the above formula 1H compound, the solvent is preferably a mixture of an ether-based solvent and an amide-based solvent, and more preferably a mixture of tetrahydrofuran and N,N-dimethylformamide.

[0051] In one arbitrary embodiment of the present invention, in step b3, the base may be one or more of DIPEA, triethylamine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, potassium acetate, sodium hydride, sodium hydroxide, and potassium hydroxide, and is preferably potassium carbonate.

[0052] In one arbitrary embodiment of the present invention, in step b3, the acid may be sulfuric acid, preferably a 20% to 75% aqueous sulfuric acid solution, more preferably a 20% aqueous sulfuric acid solution.

[0053] In one arbitrary embodiment of the present invention, step b3 is performed as described above R 1 The compound is a methyl group, the solvent is a mixture of tetrahydrofuran and N,N-dimethylformamide, the base is potassium carbonate, and the acid is a 20% aqueous sulfuric acid solution.

[0054] In one arbitrary embodiment of the present invention, in step b3, the molar ratio of compound 1E to compound 1F is 1:(1~5), preferably 1:(1.3~1.5), and more preferably 1:1.3.

[0055] In one arbitrary embodiment of the present invention, in step b3, the molar ratio of compound 1E to the base is 1:(1-5), preferably 1:2.

[0056] In one arbitrary embodiment of the present invention, in step b3, the volume ratio of the mixture of tetrahydrofuran and N,N-dimethylformamide is (1 to 10):1.

[0057] In one arbitrary embodiment of the present invention, in step b3, the molar ratio of compound 1E to the acid is 1:(1-5), preferably 1:2.

[0058] In one arbitrary embodiment of the present invention, in step b3, the reaction temperature of the substitution reaction may be 60°C to 75°C, preferably 65°C to 70°C.

[0059] In one arbitrary embodiment of the present invention, in step b3, the acidification temperature is 50 to 70°C, preferably 55 to 65°C.

[0060] In one arbitrary embodiment of the present invention, the reaction time for the hydrolysis reaction in step b3 may be 5 to 20 hours, for example, 12 hours.

[0061] In one arbitrary embodiment of the present invention, step b3 may further include a post-treatment step after the completion of the substitution reaction, for example, lowering the temperature of the reaction solution, allowing it to stand and separate the liquid, extracting, washing, concentrating, recrystallizing, centrifuging, and washing to obtain a wet product of compound 1H.

[0062] In any embodiment of the present invention, step b3 includes heating and dissolving the dried product in a good solvent, then adding a poor solvent dropwise, cooling, and crystallizing.

[0063] In any embodiment of the present invention, in step b3, the good solvent may be one or more of methanol, anhydrous ethanol, isopropanol, ethyl acetate, and isopropyl acetate, and is preferably methanol.

[0064] In any embodiment of the present invention, in step b3, the poor solvent may be one or more of water, isopropyl ether, n-heptane, n-hexane, and petroleum ether, and is preferably water.

[0065] In any embodiment of the present invention, in step b3, the heating and melting temperature of the recrystallized material is 50 to 70°C.

[0066] In any embodiment of the present invention, in step b3, the recrystallization is cooled to 10-20°C.

[0067] In any embodiment of the present invention, step b3 includes adding compound 1E, compound 1F, and a base to a solvent to carry out a first-step reaction, and then adding an acid to the reaction system to acidify it and obtain compound 1H.

[0068] The above method for producing compound 1H may further include a method for producing compound 1E, which is... b2) Compound 1D is coupled with 2-bromo-5-methylthiazole in a solvent in the presence of a palladium catalyst and a base as follows to obtain compound 1E.

[0069] [ka]

[0070] Includes steps.

[0071] In one arbitrary embodiment of the present invention, R 1 This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0072] In one arbitrary embodiment of the present invention, in step b2, the solvent is selected from water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, preferably an ether-based solvent, of which the alcohol-based solvent is preferably methanol, ethanol, or a mixture thereof, the aromatic hydrocarbon-based solvent is preferably toluene, and the ether-based solvent is preferably ethylene glycol dimethyl ether, tetrahydrofuran, or a mixture thereof. In one arbitrary embodiment of the present invention, in the method for producing the compound of formula 1E, the solvent is preferably an ether-based solvent, and more preferably ethylene glycol dimethyl ether.

[0073] In one arbitrary embodiment of the present invention, in step b2, the palladium catalyst may be one or more of Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2, with Pd(OAc)2 being a preferred palladium catalyst.

[0074] In one arbitrary embodiment of the present invention, in step b2, the base may be one or more of the following: KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, Et3N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine, with K2CO3 being a preferred base.

[0075] In one arbitrary embodiment of the present invention, in step b2, the coupling reaction further comprises a phosphine ligand, which may be one or more of PPh3, SPhos, XPhos, 1,1'-bis(diphenylphosphino)ferrocene, and XantPhos, with XantPhos being the preferred phosphine ligand.

[0076] In one arbitrary embodiment of the present invention, in step b2, the above R 1 The base is a methyl group, the solvent is ethylene glycol dimethyl ether, the palladium catalyst is Pd(OAc)2, and the base is K2CO3, and also contains the phosphine ligand XantPhos.

[0077] In one arbitrary embodiment of the present invention, in step b2, the molar ratio of the intermediate 1D to the palladium catalyst is 1:(0.01~0.1), preferably 1:(0.01~0.05), and more preferably 1:0.02.

[0078] In one arbitrary embodiment of the present invention, in step b2, the molar ratio of the intermediate 1D to 2-bromo-5-methylthiazole is 1:(0.5~5), preferably 1:1.

[0079] In one arbitrary embodiment of the present invention, in step b2, the molar ratio of the intermediate 1D to the base is 1:(1~5), preferably 1:(1.5~2), and more preferably 1:1.9.

[0080] In one arbitrary embodiment of the present invention, in step b2, the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1-5), preferably 1:(1-2), and more preferably 1:2.

[0081] In one arbitrary embodiment of the present invention, in step b2, the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas.

[0082] In one arbitrary embodiment of the present invention, in step b2, the reaction temperature of the coupling reaction may be 65°C to 75°C, for example, 70°C.

[0083] In one arbitrary embodiment of the present invention, the reaction time for the coupling reaction in step b2 may be 10 to 30 hours, preferably 14 to 18 hours.

[0084] In one arbitrary embodiment of the present invention, step b2 may further include a post-treatment step after the completion of the coupling reaction, for example, concentrating the reaction solution, acidifying it, extracting it, purifying it using a silica gel column, concentrating it again, distilling it with methanol, recrystallizing it, washing it, and drying it.

[0085] The above method for producing compound 1E may further include a method for producing compound 1D, which is... b1) Compound 1C is coupled with bis(pinacolate)diboron in a solvent in the presence of a palladium catalyst and a base as follows to obtain compound 1D.

[0086] [ka]

[0087] Includes steps.

[0088] In one arbitrary embodiment of the present invention, R 1 This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0089] In one arbitrary embodiment of the present invention, in step b1, the solvent is selected from water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, and is preferably an ether-based solvent. Of these, the alcohol-based solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon-based solvent is preferably toluene. The ether-based solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one arbitrary embodiment of the present invention, in the method for producing the compound of formula 1D, the solvent is preferably an ether-based solvent, and more preferably 1,4-dioxane.

[0090] In one arbitrary embodiment of the present invention, in step b1, the palladium catalyst may be one or more of Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2, with Pd(OAc)2 being a preferred palladium catalyst.

[0091] In one arbitrary embodiment of the present invention, in step b1, the base may be one or more of the following: KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, Et3N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine, with potassium acetate being a preferred base.

[0092] In one arbitrary embodiment of the present invention, in step b1, the coupling reaction further comprises a phosphine ligand, which may be one or more of PPh3, SPhos, XPhos, 1,1'-bis(diphenylphosphino)ferrocene and XantPhos, with XPhos being the preferred phosphine ligand.

[0093] In one arbitrary embodiment of the present invention, step b1 is performed as follows: 1 The compound is a methyl group, the solvent is 1,4-dioxane, the palladium catalyst is Pd(OAc)2, the base is potassium acetate, and the compound also contains the phosphine ligand Xphos.

[0094] In one arbitrary embodiment of the present invention, in step b1, the molar ratio of the intermediate 1C to the palladium catalyst is 1:(0.01~0.1), preferably 1:(0.01~0.05), and more preferably 1:0.01.

[0095] In one arbitrary embodiment of the present invention, in step b1, the molar ratio of the intermediate 1C to bis(pinacolate)diboron is 1:(1~5), preferably 1:1.1.

[0096] In one arbitrary embodiment of the present invention, in step b1, the molar ratio of the intermediate 1C to the base is 1:(1-5), preferably 1:(2-3), and more preferably 1:2.5.

[0097] In one arbitrary embodiment of the present invention, in step b1, the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1-5), preferably 1:(1-2), and more preferably 1:2.

[0098] In one arbitrary embodiment of the present invention, in step b1, the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas.

[0099] In one arbitrary embodiment of the present invention, in step b1, the reaction temperature of the coupling reaction may be 75 to 85°C, for example, 80°C.

[0100] In one arbitrary embodiment of the present invention, the reaction time for the coupling reaction in step b1 may be 2 to 10 hours, preferably 4 hours.

[0101] In one arbitrary embodiment of the present invention, step b1 may further include a post-treatment step after the completion of the coupling reaction, for example, filtering the reaction solution through diatomaceous earth, extracting it, purifying it with a silica gel column, distilling it with n-heptane, recrystallizing it, and drying it.

[0102] The above method for producing compound 1I may further include a method for producing compound 1H, which is: c3) Compound 1K is coupled with 2-bromo-5-methylthiazole in a solvent in the presence of a palladium catalyst and a base as follows to obtain compound 1H.

[0103]

Chem.

[0104] comprising the step.

[0105] In an optional embodiment of the present invention, R 1 is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0106] In an optional embodiment of the present invention, in step c3, the solvent is selected from water, alcoholic solvents, aromatic hydrocarbon solvents, ether solvents, or a mixture of any two or more thereof, preferably a mixture of an ether solvent and water. Among these, the alcoholic solvent is preferably methanol, ethanol, or a mixture thereof; the aromatic hydrocarbon solvent is preferably toluene; the ether solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In an optional embodiment of the present invention, in the method for producing the compound of Formula 1H described above, the solvent is preferably a mixture of an ether solvent and water, more preferably a mixture of 1,4-dioxane and water.

[0107] In an optional embodiment of the present invention, in step c3, the palladium catalyst may be one or more selected from the group consisting of Pd(OAc)2, PdCl2, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2 and Pd(dppf)Cl2, and the preferred palladium catalyst is Pd(dppf)Cl2.

[0108] In one arbitrary embodiment of the present invention, in step c3, the base may be one or more of the following: KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, Et3N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine, with K2CO3 being a preferred base.

[0109] In one arbitrary embodiment of the present invention, in step c3, the above R 1 The base is a methyl group, the solvent is a mixture of 1,4-dioxane and water, the palladium catalyst is Pd(dppf)Cl2, and the base is K2CO3.

[0110] In one arbitrary embodiment of the present invention, in step c3, the molar ratio of the intermediate 1K to the palladium catalyst is 1:(0.01~1), preferably 1:(0.01~0.05), and more preferably 1:0.05.

[0111] In one arbitrary embodiment of the present invention, in step c3, the molar ratio of the intermediate 1K to 2-bromo-5-methylthiazole is 1:(1~5), preferably 1:(1~1.2), and more preferably 1:1.1.

[0112] In one arbitrary embodiment of the present invention, in step c3, the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas.

[0113] In one arbitrary embodiment of the present invention, in step c3, the reaction temperature of the coupling reaction may be 85°C to 95°C, for example, 90°C.

[0114] In one arbitrary embodiment of the present invention, the reaction time for the coupling reaction in step c3 may be 1 to 20 hours.

[0115] In one arbitrary embodiment of the present invention, step c3 may further include a post-treatment step after the completion of the coupling reaction, for example, lowering the temperature of the reaction solution, purifying it using a silica gel column, and concentrating it to obtain a pure product of compound 1H.

[0116] The above method for producing compound 1H may further include a method for producing compound 1K, which is... c2) Compound 1J is coupled with bis(pinacolate)diboron in a solvent in the presence of a palladium catalyst and a base as follows to obtain compound 1K.

[0117] [ka]

[0118] Includes steps.

[0119] In one arbitrary embodiment of the present invention, R 1 This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0120] In one arbitrary embodiment of the present invention, in step c2, the solvent is selected from water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, preferably an ether-based solvent, of which the alcohol-based solvent is preferably methanol, ethanol, or a mixture thereof, the aromatic hydrocarbon-based solvent is preferably toluene, and the ether-based solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one arbitrary embodiment of the present invention, in the method for producing the above formula 1K compound, the solvent is preferably an ether-based solvent, and more preferably 1,4-dioxane.

[0121] In one arbitrary embodiment of the present invention, in step c2, the palladium catalyst may be one or more of Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2, with Pd(dppf)Cl2 being a preferred palladium catalyst.

[0122] In one arbitrary embodiment of the present invention, in step c2, the base may be one or more of the following: KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, Et3N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine, with potassium acetate being a preferred base.

[0123] In one arbitrary embodiment of the present invention, in step c2, the above R 1 The compound is a methyl group, the solvent is 1,4-dioxane, the palladium catalyst is Pd(dppf)Cl2, and the base is potassium acetate.

[0124] In one arbitrary embodiment of the present invention, in step c2, the molar ratio of the intermediate 1J to the palladium catalyst is 1:(0.01~0.1), preferably 1:(0.01~0.05), and more preferably 1:0.05.

[0125] In one arbitrary embodiment of the present invention, in step c2, the molar ratio of the intermediate 1J to bis(pinacolate)diboron is 1:(1~5), preferably 1:(1~1.2), and more preferably 1:1.1.

[0126] In one arbitrary embodiment of the present invention, in step c2, the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas.

[0127] In one arbitrary embodiment of the present invention, in step c2, the reaction temperature of the coupling reaction may be 85°C to 95°C, for example, 90°C.

[0128] In one arbitrary embodiment of the present invention, the reaction time for the coupling reaction in step c2 may be 1 to 20 hours.

[0129] In one arbitrary embodiment of the present invention, step c2 may further include a post-treatment step after the completion of the coupling reaction, for example, lowering the temperature of the reaction solution, purifying it with a silica gel column, and concentrating it to obtain a pure product of compound 1K.

[0130] The above method for producing compound 1K may further include a method for producing compound 1J, which is... c1) In a solvent, compound 1C is substituted with compound 1F in the presence of a base as described below, and after acidification with an acid, compound 1J is obtained.

[0131] [ka]

[0132] Includes steps.

[0133] In one arbitrary embodiment of the present invention, R 1 This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0134] In one arbitrary embodiment of the present invention, in step c1, the solvent is selected from water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, preferably an ether-based solvent, of which the alcohol-based solvent is preferably methanol, ethanol, or a mixture thereof, the aromatic hydrocarbon-based solvent is preferably toluene, and the ether-based solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one arbitrary embodiment of the present invention, in the method for producing the above formula 1J compound, the solvent is preferably an ether-based solvent, and more preferably tetrahydrofuran.

[0135] In one arbitrary embodiment of the present invention, in step c1, the base may be one or more of DIPEA, triethylamine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, potassium acetate, sodium hydride, sodium hydroxide, and potassium hydroxide, and is preferably potassium carbonate.

[0136] In one arbitrary embodiment of the present invention, in step c1, the acid may be sulfuric acid, preferably a 20% to 75% aqueous sulfuric acid solution, more preferably a 20% aqueous sulfuric acid solution.

[0137] In one arbitrary embodiment of the present invention, in step c1, the molar ratio of compound 1C to the acid is 1:(1-5), preferably 1:2.

[0138] In one arbitrary embodiment of the present invention, in step c1, the solvent is tetrahydrofuran, the base is potassium carbonate, and the acid is a 20% aqueous sulfuric acid solution.

[0139] In one arbitrary embodiment of the present invention, in step c1, the molar ratio of compound 1C to compound 1F is 1:(1~5), preferably 1:(1.1~1.3), and more preferably 1:1.2.

[0140] In one arbitrary embodiment of the present invention, in step c1, the molar ratio of compound 1C to the base is 1:(1-5), preferably 1:(1-2), and more preferably 1:(1.5).

[0141] In one arbitrary embodiment of the present invention, in step c1, the reaction temperature of the substitution reaction may be 45°C to 55°C, preferably 50°C.

[0142] In one arbitrary embodiment of the present invention, in step c1, the acidification temperature is 50 to 70°C, preferably 55 to 65°C.

[0143] In one arbitrary embodiment of the present invention, the reaction time for the substitution reaction in step c1 may be 1 to 20 hours.

[0144] In any embodiment of the present invention, step c1 may further include a post-treatment step after the completion of the substitution reaction, for example, lowering the temperature of the reaction solution, acidifying it, extracting it, washing it, drying it, and purifying it using a silica gel column to obtain a pure product of compound 1H.

[0145] In one arbitrary embodiment of the present invention, step c1 includes adding compound 1C, compound 1F, and a base to a solvent to carry out a first-step reaction, and then adding an acid to the reaction system to acidify it, thereby obtaining compound 1H.

[0146] The above method for producing compound 1D or compound 1J may further include a method for producing compound 1C, which is: d2) In the solvent, compound 1B is used in the presence of the catalyst R 1 Compound 1C is obtained by esterifying -OH as shown below.

[0147] [ka]

[0148] Includes steps.

[0149] In one arbitrary embodiment of the present invention, in step d2, the solvent is selected from water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, and is preferably an alcohol-based solvent. Of these, methanol, ethanol, or a mixture thereof is preferred for the alcohol-based solvent. Toluene is preferred for the aromatic hydrocarbon-based solvent. 1,4-dioxane, tetrahydrofuran, or a mixture thereof is preferred for the ether-based solvent. In one arbitrary embodiment of the present invention, in the method for producing the compound of formula 1C, the solvent is preferably an alcohol-based solvent, and methanol is more preferred.

[0150] In one arbitrary embodiment of the present invention, in step d2, the above R 1 -R in OH 1 This is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0151] In one arbitrary embodiment of the present invention, in step d2, the catalyst may be sulfuric acid, phosphoric acid, thionyl chloride, and acetyl chloride, with acetyl chloride being the preferred catalyst.

[0152] In one arbitrary embodiment of the present invention, in step d2, the solvent is methanol, the catalyst is acetyl chloride, and the R 1 -OH is methanol.

[0153] In one arbitrary embodiment of the present invention, in step d2, the molar ratio of compound 1B to catalyst is 1:(0.1~1), preferably 1:(0.5~1), and more preferably 1:1.

[0154] In one arbitrary embodiment of the present invention, in step d2, the reaction temperature of the esterification reaction may be 55°C to 65°C, for example, 60°C.

[0155] In one arbitrary embodiment of the present invention, the reaction time for the esterification reaction in step d2 may be 1 to 20 hours, for example, 4 hours.

[0156] In one arbitrary embodiment of the present invention, step d2 may further include a post-treatment step after the completion of the esterification reaction, for example, lowering the temperature of the reaction solution, slowly adding it to ice water to quench the reaction, centrifuging, and drying to obtain a pure product of compound 1C.

[0157] The above method for producing compound 1C may further include a method for producing compound 1B, which is... d1) In a solvent, compound 1A is subjected to a substitution reaction with water using a cuprous catalyst and an inorganic base as described below to obtain compound 1B.

[0158] [ka]

[0159] Includes steps.

[0160] In one arbitrary embodiment of the present invention, in step d1, the solvent is selected from water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, and is preferably water. Of these, the alcohol-based solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon-based solvent is preferably toluene. The ether-based solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one arbitrary embodiment of the present invention, in the method for producing the compound of formula 1B, the solvent is preferably water.

[0161] In one arbitrary embodiment of the present invention, in step d1, the cuprous catalyst may be one or more of cuprous bromide, cuprous chloride, cuprous iodide, and cuprous oxide, with cuprous oxide being the preferred cuprous catalyst.

[0162] In one arbitrary embodiment of the present invention, in step d1, the inorganic base may be one or more of KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, and NaH, with NaOH being a preferred base.

[0163] In one arbitrary embodiment of the present invention, in step d1, the solvent is water, the cuprous catalyst is cuprous oxide, and the inorganic base is NaOH.

[0164] In one arbitrary embodiment of the present invention, in step d1, the molar ratio of the intermediate 1A to the first copper catalyst is 1:(0.1~2), preferably 1:0.2.

[0165] In one arbitrary embodiment of the present invention, in step d1, the molar ratio of the intermediate 1A to the inorganic base is 1:(1-5), preferably 1:(3-5), and more preferably 1:5.

[0166] In one arbitrary embodiment of the present invention, in step d1, the reaction temperature of the substitution reaction may be 90°C to 100°C, for example, 95°C.

[0167] In one arbitrary embodiment of the present invention, the reaction time for the substitution reaction in step d1 may be 1 to 20 hours, for example, 10 hours.

[0168] In one arbitrary embodiment of the present invention, step d1 may further include a post-treatment step after the completion of the substitution reaction, for example, lowering the temperature of the reaction solution, filtering it with diatomaceous earth, washing it, adjusting the pH with dilute hydrochloric acid to pH=1-3, extracting it, and concentrating it to obtain a pure product of compound 1H.

[0169] [Beneficial effects] The positive and progressive effect of the present invention is to provide a novel method for producing 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazole-2-yl)-N-((R)-1-(2-(trifluoromethyl)pyrimidine-5-yl)ethyl)benzamide and its intermediates. This production method is easy to operate, allows for easy control of product quality, has a relatively high yield, and is suitable for industrial production.

[0170] [Definitions and explanations of terms] In the present invention, the term "C1-C4 alkyl group" refers to a saturated linear or branched alkyl group having 1 to 4 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, and in particular a methyl group or an ethyl group.

[0171] [Table 1]

[0172] By arbitrarily combining the above preferred conditions without deviating from common sense in the field, various relatively suitable examples of the present invention can be obtained.

[0173] The reagents and raw materials used in this invention are all commercially available.

[0174] [Modes for carrying out the invention] The technical proposals of this disclosure will be described in more detail below, in conjunction with specific embodiments. The embodiments described below are merely illustrative and should not be interpreted as limiting the scope of the claims of this disclosure. Any technology realized based on the above-mentioned content of this disclosure falls within the scope of the claims of this disclosure.

[0175] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or may be manufactured by known methods.

[0176] Steps 1 and 2: Production of Intermediate 1C

[0177] [ka]

[0178] 614.0 kg of water was added to a clean 2000 L reaction vessel, and 50.2 kg of sodium hydroxide, 86.55 kg of compound 1A, and 7.13 kg of cuprous oxide were added in five separate additions. The temperature was raised to 95°C, and the reaction was maintained at a constant temperature for 10 hours. Samples were taken and analyzed by HPLC, indicating that the starting materials had reacted almost completely.

[0179] The solution was cooled to 25°C, filtered through 22.5 kg of diatomaceous earth, washed with 50.0 kg of water, and the pH was adjusted to 1-3 with a dilute hydrochloric acid solution (prepared by pouring 185.0 kg of concentrated hydrochloric acid into 400.0 kg of water). 615 kg of ethyl acetate was added for liquid-liquid separation, 353.0 kg of ethyl acetate was added to the aqueous phase for extraction, and the organic phase was combined. The COD of the aqueous phase was measured and, after passing the test, the waste liquid was treated. The organic phase was vacuum concentrated (internal temperature ≤ 55°C, vacuum ≤ -0.07 MPa) until no obvious fractions remained, and then distilled twice with methanol (320.0 kg × 2). A sample was taken and the purity was confirmed to be acceptable by HPLC. 120 kg of methanol was added, and the product was stored in methanol for the next material input. The total weight was 190.0 kg, the content was 29.3%, and the yield was 94.1%.

[0180] 280.0 kg of methanol solution of intermediate 1B from the previous step was added to a clean 2000 L reaction vessel, the temperature was lowered to 0-10°C, 36.0 kg of acetyl chloride (temperature control during material supply process ≤ 40°C) was added dropwise, the temperature was raised to 60°C, and the reaction was allowed to proceed for 4 hours. A sample was taken and analyzed by HPLC, indicating that the reaction was complete under process control, and the reaction was considered complete.

[0181] The mixture was cooled to 25°C, and 275.0 kg of ice water was added. After stirring for 1 hour, it was centrifuged and washed with 185 kg of 33.3% methanol aqueous solution to obtain a wet intermediate 1C. The wet product was sampled and tested for purity by HPLC, and dried in a vacuum drying chamber for 20 hours to obtain 53.6 kg of dried intermediate 1C, with a yield of 91.6%. LC-MS, M / Z (ESI): 248.9 [M+H] + .

[0182] Step 3: Production of Intermediate 1D

[0183] [ka]

[0184] In a dry, clean 2000 L reaction vessel, 560.0 kg of dioxane, 53.5 kg of intermediate 1C, 60.0 kg of bis(pinacolate)diboron, 0.48 kg of Pd(OAc)2, 2.0 kg of Xphos, and 52.0 kg of potassium acetate were added. The mixture was purged three times with argon gas, the temperature was raised to 80°C, and the reaction was maintained at a constant temperature for 4 hours. A sample was taken and the reaction was controlled by HPLC to confirm that the reaction was complete.

[0185] The solution was cooled to 25°C, filtered through 25.0 kg of diatomaceous earth, washed with 150.0 kg of ethyl acetate, and concentrated. 480.0 kg of ethyl acetate and 266 kg of water were added for liquid-liquid separation, the organic phase was passed through a silica gel column, washed with 94.0 kg of ethyl acetate, concentrated, and distilled twice with 75.0 kg × 4 n-heptane. After one crystallization and centrifugation, it was washed once more. A wet intermediate 1D was obtained, sampled, and tested for purity by HPLC. The sample was then placed in a vacuum drying chamber and vacuum-dried at 55-60°C for 16 hours to obtain a dry intermediate 1D, which was a white solid weighing 56.5 kg with a yield of 89.1%. LC-MS, M / Z (ESI): 297.1 [M+H] + .

[0186] Step 4: Production of Intermediate 1E

[0187] [ka]

[0188] 480.0 kg of ethylene glycol dimethyl ether was added to a clean 2000 L reaction vessel, followed by 56.5 kg of intermediate 1D, 32.8 kg of 2-bromo-5-methylthiazole, 107 kg of 47% potassium carbonate aqueous solution, 0.83 kg of Pd(OAc)2, and 4.2 kg of Xantphos. The mixture was purged three times with argon gas, the temperature was raised to 70°C, and the reaction was allowed to proceed for 14-18 hours. A sample was taken and analyzed by HPLC to confirm that the reaction was complete.

[0189] The internal temperature was lowered to 40°C, vacuum concentration was turned on until no obvious fractions remained (jacket temperature ≤ 55°C, vacuum ≤ -0.07 MPa), the temperature was cooled to 25°C, an aqueous citric acid solution (prepared by pouring 72 kg of citric acid into 270 kg of water) was added, 540.0 kg of ethyl acetate was added and liquid-liquid was separated, the aqueous phase was extracted with 110.0 kg of ethyl acetate, the organic phase was combined, the organic phase was filtered through 40.0 kg of silica gel, the filtered cake was washed with 110.0 kg of ethyl acetate, vacuum concentration was turned on until no obvious fractions remained (jacket temperature ≤ 55°C, vacuum ≤ -0.07 MPa), distilled twice with methanol (79.0 kg × 2), distilled until no fractions remained, 100.0 kg of methanol was added, crystallized at 5°C for 2 hours, then centrifuged, and 79 The intermediate 1E was washed with methanol in kg, and a wet product was obtained. After sampling and testing by HPLC to confirm that the purity was acceptable, it was dried in a vacuum drying chamber for 16 hours to obtain 33.4 kg of dried intermediate 1E, with a yield of 65.6%. LC-MS, M / Z (ESI): 268.2 [M+H] + .

[0190] Step 5: Production of intermediate 1H

[0191] [ka]

[0192] In a 100 L glass reaction vessel, 29.5 kg of tetrahydrofuran was added sequentially, followed by 4.15 kg of intermediate 1E, 3.92 kg of N,N-dimethylformamide, 3.07 kg of compound 1F, and 4.29 kg of anhydrous potassium carbonate (fine powder), while stirring. The temperature was raised to 65-70°C, and the reaction was maintained for 12 hours. Sampling was then started, and the reaction was monitored by TLC until the 1E point of the intermediate was no longer visible. After the first stage of the reaction was complete, the reaction solution was cooled to 0-20°C, and 15.25 kg of the prepared 20% sulfuric acid aqueous solution was slowly added dropwise. After the addition was complete, the temperature was raised to 55-65°C. After 3 hours of reaction, sampling was started, and the reaction was monitored by TLC until the 1G point of the intermediate was no longer visible.

[0193] The mixture was cooled to 10-20°C, allowed to stand, and then separated. The upper organic layer was collected, and 18.7 kg of ethyl acetate was added to the lower aqueous phase and stirred. After standing, the mixture was separated again, and the upper organic layer was collected. The two organic phases were combined and added to a saturated sodium bicarbonate aqueous solution. The aqueous phase was washed to a pH of 7-8 (based on the pH value), and the organic phase was washed once with 20.75 kg of purified water. The organic layer was concentrated to dryness under reduced pressure at 50-60°C to obtain the crude product of intermediate 1H (~6.7 kg).

[0194] 6.6 kg of methanol was added to a dry, clean 50 L glass reaction vessel, followed by the addition of the concentrated, dry crude product of intermediate 1H (~6.7 kg). The mixture was heated to 50-70°C, stirred, and clarified. 8.3 kg of purified water was slowly added dropwise at 60-70°C (approximately 1.0 h). After the addition was complete, the heating was stopped, the mixture was cooled to 10-20°C, and crystallization was performed for 1-2 hours. The mixture was centrifuged, rinsed once with the prepared methanol / purified water mixture (3.0 kg / 3.75 kg), and the filtered cake was collected and weighed to obtain 5.455 kg of the wet intermediate 1H. The dry weight loss was measured and directly converted before being added to the next step. LC-MS, M / Z (ESI): 340.1 [M+H] +.

[0195] Step 6 1I Manufacturing

[0196] [ka]

[0197] 32.1 kg of methanol and 5.37 kg of wet intermediate 1H were added to a 100 L glass reaction vessel, the temperature was controlled to 10-30°C, and 10.31 kg of the prepared 13% LiOH·H2O aqueous solution was slowly added dropwise. After reacting at 10-30°C for 2 hours, sampling was started and monitored by TLC until intermediate 1H was completely gone.

[0198] After the reaction was complete, the temperature was lowered to 0-20°C, and 4 M hydrochloric acid was added in several batches. First, the pH was adjusted to 4 (approximately 6.5 kg used), and crystallization was carried out at a constant temperature for 1-2 hours, during which a large amount of white solid precipitated. Next, the remaining 4 M hydrochloric acid was slowly added dropwise to adjust the pH to 2-3, and crystallization was carried out at 10-20°C for 1-2 hours with stirring. The mixture was then centrifuged, and purified water (10.0 kg x 3) was rinsed three times. The wet product of the filtered cake was collected and air-dried at 65±5°C for 8 hours or more to obtain 4.345 kg of dried intermediate 1I. LC-MS, M / Z (ESI): 324.1 [MH] + .

[0199] Step 7: Manufacturing of the finished product

[0200] [ka]

[0201] Under nitrogen gas flow protection, 20.48 kg of DMF and 4.32 kg of intermediate 1I were added to a 100 L glass reaction vessel. The mixture was cooled to 10-25°C, and 2.68 kg of HOBt, 3.80 kg of EDCI, and 3.63 kg of compound (1 L) were added sequentially while stirring. The mixture was cooled again, and 5.14 kg of DIPEA was slowly added dropwise, maintaining the reaction mixture temperature at 5-20°C. After the addition was complete, the reaction was allowed to proceed at 10-30°C. Sampling began after 2 hours, and the reaction was stopped by monitoring with TLC until intermediate 1I was completely eliminated.

[0202] 77.76 kg of ethyl acetate was added to the reaction mixture, and the mixture was washed twice with a 6% aqueous sodium bicarbonate solution (64.8 kg used each time) to collect the organic phase. The mixture was then washed once with a 0.2 M aqueous hydrochloric acid solution to a pH of 3-4, and the organic phase was collected. The mixture was then washed twice more with purified water to a pH of neutral (43.2 kg used each time), and the organic phase was collected. The organic layer was then vacuum concentrated at 50-60°C until a small amount of solvent remained. 40.0 kg of n-heptane was added to a rotary distillation bottle in several batches, and the mixture was transferred to a transfer barrel. The mixture was stirred at 10-30°C for 0.5-2 hours, centrifuged, and the filtered cake was dried in a blast oven at 55±5°C for at least 8 hours to obtain a white to yellow solid. The solid was weighed. 5.64 kg of the dried compound I-1 was obtained, with a yield of 98%.

[0203] 8.68 kg of anhydrous ethanol was added to a 50 L spherical glass reaction vessel, and 2.80 kg of compound I-1 was added while stirring. The mixture was heated to 60-80°C, clarified, filtered, and the filtrate was collected. The filtrate was heated again and clarified. Then, 13.44 kg of n-heptane was slowly added dropwise to the vessel at 60-80°C (for approximately 1.0 h) to precipitate the solid. The temperature was slowly lowered to 15-25°C and stirred for 1-3 hours, then centrifuged, and the filtered cake was collected. The filtered cake was dried in a vacuum oven at 55±5°C for more than 8 hours to obtain 2.53 kg of the finished product. LC-MS, M / Z (ESI): 499.2 [M+H] + . 1H NMR (400 MHz, Chloroform-d) δ9.20 (1H, d, J = 7.2 Hz),9.11 (1H, s),7.74 (1H, dd, J = 5.6, 3.2 Hz),7.70 (1H, dd, J = 2.3, 1.2 Hz),7.19 (1H, dd, J = 5.3, 3.2 Hz),5.26 (1H, p, J = 7.0 Hz),4.80 (1H, d, J = 5.1 Hz),4.29 (1H, qd, J = 6.1, 4.4 Hz),3.71 (1H, m),2.50 (3H, d, J = 1.0 Hz),1.55 (3H, d, J = 7.1 Hz),1.20 (3H, d, J = 6.2 Hz),1.11 (3H, d, J = 6.4 Hz).

[0204] Example 2: Preparation of intermediate 1H

[0205] [ka]

[0206] Step 1: Synthesis of 3-bromo-2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)methyl benzoate (1J)

[0207] [ka]

[0208] 3-Brom-2-fluoro-5-hydroxybenzoate methyl (1C) (30 g, 120 mmol) was placed in a round-bottom flask, compound 1F (22 g, 145 mmol), potassium carbonate (24.97 g, 181 mmol), and tetrahydrofuran (30 mL) were added, and the mixture was refluxed overnight. After TLC analysis confirmed that the starting materials had completely reacted, the reaction mixture was cooled to room temperature. 20% H2SO4 (300 mL) was added to the reaction mixture, and the mixture was heated at 50°C for 6 hours. After LCMS analysis confirmed that the starting materials had completely consumed, the mixture was cooled to room temperature. EA was added for extraction, and the organic phase was collected. The organic phase was washed with saturated sodium bicarbonate (200 mL) solution and dried over anhydrous sodium sulfate. Separation and purification by silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1~3:1) yielded a yellow oily liquid (20.0 g, yield 77%). LC-MS, M / Z (ESI): 321.0 [M+H] + .

[0209] Step 2: Synthesis of 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (1K)

[0210] [ka]

[0211] 50 g, 156 mmol of 3-bromo-2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)methyl benzoate was placed in a three-necked flask containing 500 mL of 1,4-dioxane. Bis(pinacolate)diborone (43.5 g, 171 mmol), Pd(dppf)Cl2 (5.70 g, 7.78 mmol), and potassium acetate (45.8 g, 467 mmol) were added, and the mixture was reacted overnight at 90°C under nitrogen gas protection after being purged three times with nitrogen gas. After being detected by TLC and the starting materials were completely consumed, the mixture was cooled to room temperature and concentrated. It was directly separated and purified by silica gel column (100% ethyl acetate). The oily liquid was concentrated and directly added to the next reaction.

[0212] Step 3: Synthesis of 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(5-methylthiazole-2-yl)methyl(1H) benzoate

[0213] [ka]

[0214] 2-Fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (28.7 g, 78 mmol) was added to a solution of 1,4-dioxane (300 mL) and water (30 mL). Pd(dppf)Cl2 (2.58 g, 3.9 mmol), 2-bromo-5-methylthiazole (15.27 g, 86 mmol), and potassium carbonate (21.5 g, 156 mmol) were added, and the mixture was reacted overnight at 90°C under nitrogen gas protection after being purged three times with nitrogen gas. After detection by TLC and confirmation that the starting materials were completely consumed, the mixture was cooled to room temperature and concentrated. The solution was directly separated and purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1 to 3:1) to obtain a yellow oily liquid (20.0 g, yield 76%). LC-MS, M / Z (ESI): 340.1 [M+H] + .

[0215] The embodiments of the technical proposal described herein have been illustrative. It should be understood that the claims of this disclosure are not limited to the embodiments described above. Any modifications, equivalent substitutions, or improvements made by those skilled in the art, within the spirit and principles of this disclosure, should all be included within the scope of the claims of this application.

Claims

1. A method for producing compound I-1, a2) Compound 1I and compound 1L are condensed in a solvent using a condensing agent and a base as shown below to obtain compound I-1. 【Chemistry 1】 Includes steps, Here, the solvent is selected from water, chloroalkane solvents, ether solvents, amide solvents, aromatic hydrocarbon solvents, ester solvents, or a mixture of two or more of these. 1 L of compound is a free base or a salt thereof. The aforementioned condensing agent is HOBt / EDCI, The base is DIPEA, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine, or pyridine. Manufacturing method.

2. The aforementioned solvent is an amide-based solvent. and / or, 1 L of compound is its free base or the hydrochloride salt of 1 L of compound, and / or, the base is DIPEA, and / or, the molar ratio of intermediate 1I to the condensing agent is 1:(1 to 5), and / or, the molar ratio of intermediate 1I to the base is 1:(1-5), And / or, the molar ratio of intermediate 1I to intermediate 1L is 1:(1-4). The manufacturing method according to claim 1.

3. The solvent is N,N-dimethylformamide, and / or, the molar ratio of the intermediate 1I to the condensing agent is 1:(1.5 to 2), and / or, the molar ratio of the intermediate 1I to the base is 1:(2-4), And / or, the molar ratio of intermediate 1I to intermediate 1L is 1:(1-3), The manufacturing method according to claim 2.

4. The molar ratio of the intermediate 1I to the condensing agent is 1:1.5, and / or, the molar ratio of the intermediate 1I to the base is 1:3, And / or, the molar ratio of intermediate 1I to intermediate 1L is 1:1.2, and / or, the condensation reaction is carried out under the protection of an inert gas, the inert gas being nitrogen gas, helium gas or argon gas, and / or, after the completion of the condensation reaction, the post-treatment step further includes extracting the reaction solution, centrifuging it, drying it, recrystallizing it, centrifuging it again, and drying it again. The manufacturing method according to claim 3.

5. The method for producing compound 1I further includes, a1) Compound 1H is hydrolyzed in a solvent in the presence of a basic substance as follows to obtain compound 1I. 【Chemistry 2】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is an alcohol-based solvent, water, or a mixed solvent of an alcohol-based solvent and water. The basic substance is one or more of the following: triethylamine, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, or potassium hydroxide. The manufacturing method according to claim 1.

6. R １ is a methyl group or an ethyl group, and / or, the solvent is a mixed solvent of an alcohol-based solvent and water. and / or, the basic substance is lithium hydroxide, and / or, the molar ratio of compound 1H to the basic substance is 1:(1-5), And / or, the reaction time for the hydrolysis reaction is 1 to 20 hours. The manufacturing method according to claim 5.

7. The molar ratio of compound 1H to the basic substance is 1:2, and / or, the reaction time of the hydrolysis reaction is 1 to 2 hours. and / or, as a post-treatment step after the completion of the hydrolysis reaction, the reaction solution is cooled, acidified, centrifuged, washed, and dried to obtain a pure product of compound 1I. The manufacturing method according to claim 6.

8. The method for producing compound 1H further comprises, b3) In a solvent, compound 1E is substituted with 1F in the presence of a base as described below, and after acidification with an acid, compound 1H is obtained. 【Transformation 3】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, an amide-based solvent, or a mixture of two or more of these. The base is one or more of DIPEA, triethylamine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, potassium acetate, sodium hydride, sodium hydroxide, and potassium hydroxide. The acid is sulfuric acid. The manufacturing method according to claim 5.

9. R １ is a methyl group or an ethyl group, Step b3 includes the steps of adding compound 1E, compound 1F, and a base to a solvent to carry out the first step reaction, then adding an acid to the reaction system to acidify it, and finally obtaining compound 1H. and / or, the solvent is a mixture of an ether-based solvent and an amide-based solvent. and / or, the base is potassium carbonate, and / or, the acid is a 20% to 75% aqueous sulfuric acid solution. And / or, the molar ratio of compound 1E to compound 1F is 1:(1-5), and / or, the molar ratio of compound 1E to the base is 1:(1-5), and / or, the molar ratio of compound 1E to the acid is 1:(1-5), And / or, the reaction temperature of the substitution reaction is 60°C to 75°C. and / or, the acidification temperature is 50 to 70°C. The manufacturing method according to claim 8.

10. The solvent is a mixture of tetrahydrofuran and N,N-dimethylformamide, And / or, the molar ratio of compound 1E to compound 1F is 1:(1.3 to 1.5), and / or, the volume ratio of the mixture of tetrahydrofuran and N,N-dimethylformamide is (1 to 10):1, And / or, the reaction temperature of the substitution reaction is 65°C to 70°C. and / or, the acidification temperature is 55 to 65°C. The manufacturing method according to claim 9.

11. The acid is a 20% aqueous sulfuric acid solution, And / or, the molar ratio of compound 1E to compound 1F is 1:1.

3. and / or, the molar ratio of compound 1E to the base is 1:2, and / or, the molar ratio of compound 1E to the acid is 1:2, and / or, as a post-treatment step after the completion of the substitution reaction, the reaction solution is cooled, allowed to stand, separated, extracted, washed, concentrated, recrystallized, centrifuged, and washed to obtain a wet product of compound 1H. The manufacturing method according to claim 10.

12. The method for producing compound 1E further includes, b2) In a solvent, compound 1D is coupled with 2-bromo-5-methylthiazole in the presence of a palladium catalyst and a base as follows to obtain compound 1E. 【Chemistry 4】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. The palladium catalyst is one or more of the following: Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2. The base is one or more of the following: KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, Et3N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine. The coupling reaction further comprises a phosphine ligand, which is one or more of PPh3, SPhos, XPhos, 1,1'-bis(diphenylphosphino)ferrocene, and XantPhos. The manufacturing method according to claim 8.

13. R １ is a methyl group or an ethyl group, and / or, the solvent is an ether-based solvent, and / or the palladium catalyst is Pd(OAc) ２ And, and / or the base is K ２ CO ３ And, and / or, the phosphine ligand is XantPhos, And / or, the molar ratio of intermediate 1D to the palladium catalyst is 1:(0.01 to 0.1), And / or, the molar ratio of intermediate 1D to 2-bromo-5-methylthiazole is 1:(0.5-5), And / or, the molar ratio of intermediate 1D to the base is 1:(1-5), and / or, the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1 to 5), and / or, the reaction temperature of the coupling reaction is 65°C to 75°C. And / or, the reaction time of the coupling reaction is 10 to 30 hours. The manufacturing method according to claim 12.

14. The solvent is ethylene glycol dimethyl ether, And / or, the molar ratio of the intermediate 1D to the palladium catalyst is 1:(0.01 to 0.05), And / or, the molar ratio of the intermediate 1D to the base is 1:(1.5-2), and / or, the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1-2), And / or, the reaction time of the coupling reaction is 14 to 18 hours. The manufacturing method according to claim 13.

15. The molar ratio of the intermediate 1D to the palladium catalyst is 1:0.02, And / or, the molar ratio of intermediate 1D to 2-bromo-5-methylthiazole is 1:

1. And / or, the molar ratio of the intermediate 1D to the base is 1:1.

9. and / or, the molar ratio of the palladium catalyst to the phosphine ligand is 1:

2. and / or, the coupling reaction is carried out under the protection of an inert gas, the inert gas being nitrogen gas, helium gas or argon gas, and / or, the reaction temperature of the coupling reaction is 70°C. and / or, after the completion of the coupling reaction, the post-treatment step further includes concentrating the reaction solution, acidifying it, extracting it, purifying it using a silica gel column, concentrating it again, distilling it with methanol, recrystallizing it, washing it, and drying it. The manufacturing method according to claim 14.

16. The method for producing compound 1D further includes, b1) In a solvent, compound 1C is coupled with bis(pinacolate)diboron in the presence of a palladium catalyst and a base as follows to obtain compound 1D. 【Transformation 5】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. The palladium catalyst is one or more of the following: Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2. The base is one or more of the following: KHCO3, NaHCO3, Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, K2CO3, NaOH, KOH, Et3N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine. The coupling reaction further comprises a phosphine ligand, which is one or more of PPh3, SPhos, XPhos, 1,1'-bis(diphenylphosphino)ferrocene, and XantPhos. The manufacturing method according to claim 12.

17. R １ is a methyl group or an ethyl group, and / or, the solvent is an ether-based solvent, and / or the palladium catalyst is Pd(OAc) ２ And, and / or, the base is potassium acetate, and / or, the phosphine ligand is XPhos, And / or, the molar ratio of intermediate 1C to the palladium catalyst is 1:(0.01 to 0.1), And / or, the molar ratio of intermediate 1C to bis(pinacolate)diborone is 1:(1-5), And / or, the molar ratio of intermediate 1C to the base is 1:(1-5), and / or, the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1 to 5), And / or, the reaction temperature of the coupling reaction is 75 to 85°C. And / or, the reaction time of the coupling reaction is 2 to 10 hours. The manufacturing method according to claim 16.

18. The solvent is 1,4-dioxane, And / or, the molar ratio of the intermediate 1C to the palladium catalyst is 1:(0.01 to 0.05), And / or, the molar ratio of intermediate 1C to the base is 1:(2-3), and / or, the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1-2), The manufacturing method according to claim 17.

19. The molar ratio of the intermediate 1C to the palladium catalyst is 1:0.

01. And / or, the molar ratio of the intermediate 1C to bis(pinacolate)diboron is 1:1.

1. And / or, the molar ratio of the intermediate 1C to the base is 1:2.

5. and / or, the molar ratio of the palladium catalyst to the phosphine ligand is 1:

2. and / or, the coupling reaction is carried out under the protection of an inert gas, the inert gas being nitrogen gas, helium gas or argon gas, and / or, the reaction temperature of the coupling reaction is 80°C. And / or, the reaction time of the coupling reaction is 4 hours. and / or, after the coupling reaction is complete, the post-treatment step further includes filtering the reaction solution through diatomaceous earth, extracting it, purifying it with a silica gel column, distilling it with n-heptane, recrystallizing it, and drying it. The manufacturing method according to claim 18.

20. The method for producing compound 1H further comprises, c3) In a solvent, compound 1K is coupled with 2-bromo-5-methylthiazole in the presence of a palladium catalyst and a base as follows to obtain compound 1H. 【Transformation 6】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. The palladium catalyst is one or more of the following: Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2. The aforementioned base is one or more of the following: KHCO₃, NaHCO₃, Na₂CO₃, Ba(OH)₂, K₃PO₄, Cs₂CO₃, K₂CO₃, NaOH, KOH, Et₃N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine. The manufacturing method according to claim 5.

21. R １ is a methyl group or an ethyl group, and / or, the solvent is a mixture of an ether-based solvent and water. and / or the palladium catalyst is Pd(dppf)Cl ２ And, and / or the base is K ２ CO ３ And, And / or, the molar ratio of intermediate 1K to the palladium catalyst is 1:(0.01 to 0.1), And / or, the molar ratio of intermediate 1K to 2-bromo-5-methylthiazole is 1:(1-5), and / or, the reaction temperature of the coupling reaction is 85°C to 95°C. And / or, the reaction time of the coupling reaction is 1 to 20 hours. The manufacturing method according to claim 20.

22. The solvent is a mixture of 1,4-dioxane and water, And / or, the molar ratio of intermediate 1K to the palladium catalyst is 1:(0.01 to 0.05), And / or, the molar ratio of intermediate 1K to 2-bromo-5-methylthiazole is 1:(1-2). The manufacturing method according to claim 21.

23. The molar ratio of intermediate 1K to the palladium catalyst is 1:0.

05. And / or, the molar ratio of intermediate 1K to 2-bromo-5-methylthiazole is 1:1.

1. and / or, the coupling reaction is carried out under the protection of an inert gas, the inert gas being nitrogen gas, helium gas or argon gas, and / or, the reaction temperature of the coupling reaction is 90°C. And / or, the reaction time of the coupling reaction is 1 to 20 hours. and / or, as a post-treatment step after the coupling reaction is completed, the reaction solution is cooled, purified using a silica gel column, and concentrated to obtain a pure product of compound 1H. The manufacturing method according to claim 22.

24. The method for producing compound 1K further includes, c2) Compound 1J is coupled with bis(pinacolate)diboron in the presence of a palladium catalyst and a base in a solvent as follows to obtain compound 1K. 【Transformation 7】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. The palladium catalyst is one or more of the following: Pd(OAc)2, PdCb, Pd(TFA)2, Pd[O2C(CH3)3]2, Pd2(dba)3, PdBr2, and Pd(dppf)Cl2. The aforementioned base is one or more of the following: KHCO₃, NaHCO₃, Na₂CO₃, Ba(OH)₂, K₃PO₄, Cs₂CO₃, K₂CO₃, NaOH, KOH, Et₃N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine, and dicyclohexylamine. The manufacturing method according to claim 20.

25. R １ is a methyl group or an ethyl group, and / or, the solvent is an ether-based solvent, and / or the palladium catalyst is Pd(dppf)Cl ２ And, and / or, the base is potassium acetate, and / or, the reaction temperature of the coupling reaction is 85°C to 95°C. And / or, the reaction time of the coupling reaction is 1 to 20 hours. The manufacturing method according to claim 24.

26. The solvent is 1,4-dioxane, And / or, the molar ratio of the intermediate 1J to the palladium catalyst is 1:(0.01 to 0.05), And / or, the molar ratio of intermediate 1J to bis(pinacolate)diborone is 1:(1 to 1.2). The manufacturing method according to claim 25.

27. ​​The molar ratio of the intermediate 1J to the palladium catalyst is 1:0.

05. And / or, the molar ratio of the intermediate 1J to bis(pinacolate)diboron is 1:1.

1. and / or, the coupling reaction is carried out under the protection of an inert gas, the inert gas being nitrogen gas, helium gas or argon gas, and / or, the reaction temperature of the coupling reaction is 90°C. and / or, as a post-treatment step after the coupling reaction is completed, the reaction solution is cooled, purified using a silica gel column, and concentrated to obtain a pure product of compound 1K. The manufacturing method according to claim 26.

28. The method for producing compound 1J further includes, c1) In a solvent, compound 1C is substituted with compound 1F in the presence of a base as described below, and after acidification with an acid, compound 1J is obtained. 【Transformation 8】 Includes steps, Here, R1 is a C1-C4 alkyl group or a benzyl group. The solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. The base is one or more of DIPEA, triethylamine, pyridine, cesium carbonate, potassium carbonate, potassium phosphate, potassium acetate, sodium hydride, sodium hydroxide, and potassium hydroxide. The acid is sulfuric acid. The manufacturing method according to claim 24.

29. R １ is a methyl group or an ethyl group, and / or, the solvent is an ether-based solvent, and / or, the base is potassium carbonate, and / or, the acid is a 20% to 75% aqueous sulfuric acid solution. and / or, the molar ratio of compound 1C to the acid is 1:(1-5), And / or, the molar ratio of compound 1C to compound 1F is 1:(1-5), and / or, the molar ratio of compound 1C to the base is 1:(1-5), And / or, the reaction temperature of the substitution reaction is 45 to 55°C. and / or, the acidification temperature is 50 to 70°C. And / or, the reaction time for the substitution reaction is 1 to 20 hours. The manufacturing method according to claim 28.

30. The solvent is tetrahydrofuran, and / or, the acid is a 20% aqueous sulfuric acid solution, And / or, the molar ratio of compound 1C to compound 1F is 1:(1.1 to 1.3), and / or, the molar ratio of compound 1C to the base is 1:(1-2), and / or, the acidification temperature is 55 to 65°C. The manufacturing method according to claim 29.

31. The molar ratio of compound 1C to the acid is 1:

2. And / or, the molar ratio of compound 1C to compound 1F is 1:1.

2. And / or, the molar ratio of compound 1C to the base is 1:1.

5. And / or, the reaction temperature of the substitution reaction is 50°C. and / or, as a post-treatment step after the completion of the substitution reaction, the reaction solution is cooled, acidified, extracted, washed, dried, and purified using a silica gel column to obtain a pure product of compound 1H. and / or, step c1 includes the step of adding compound 1C, compound 1F, and a base to a solvent to carry out a first-step reaction, and then adding an acid to the reaction system to acidify it, thereby obtaining compound 1H. The manufacturing method according to claim 30.

32. The method for producing compound 1C further comprises, d2) In the solvent, compound 1B is used in the presence of the catalyst R １ -OH is esterified as shown below to obtain compound 1C. 【Chemistry 9】 Includes steps, Here, the solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. In R1-OH, R1 is a C1-C4 alkyl group or a benzyl group. The catalyst is sulfuric acid, phosphoric acid, thionyl chloride, or acetyl chloride. The manufacturing method according to any one of claims 16 to 19 and 28 to 31.

33. The aforementioned solvent is an alcohol-based solvent. and / or, R １ - R in OH １ is a methyl group or an ethyl group, and / or, the catalyst is acetyl chloride, And / or, the molar ratio of compound 1B to the catalyst is 1:(0.1 to 1), and / or, the reaction temperature of the esterification reaction is 55°C to 65°C. The manufacturing method according to claim 32.

34. The solvent is methanol, R1-OH is methanol, And / or, the molar ratio of compound 1B to the catalyst is 1:(0.5 to 1). The manufacturing method according to claim 33.

35. The molar ratio of compound 1B to the catalyst is 1:

1. and / or, the reaction temperature of the esterification reaction is 60°C. and / or, after the esterification reaction is complete, the post-treatment step further includes lowering the temperature of the reaction solution, quenching the reaction with ice water, centrifuging, and drying to obtain a pure product of compound 1C. The manufacturing method according to claim 34.

36. The method for producing compound 1B further comprises: d1) In a solvent, compound 1A is subjected to a substitution reaction with water using a cuprous catalyst and an inorganic base as described below to obtain compound 1B. 【Chemistry 10】 Includes steps, Here, the solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more of these. The cuprous catalyst is one or more of the following: cuprous bromide, cuprous chloride, cuprous iodide, and cuprous oxide. The inorganic base is one or more of the following: KHCO₃, NaHCO₃, Na₂CO₃, Ba(OH)₂, K₃PO₄, Cs₂CO₃, K₂CO₃, NaOH, KOH, NaH. The manufacturing method according to claim 32.

37. The solvent is water. and / or, the cuprous catalyst is cuprous oxide, and / or, the inorganic base is NaOH, And / or, the molar ratio of intermediate 1A to the first copper catalyst is 1:(0.1 to 2), And / or, the molar ratio of intermediate 1A to the inorganic base is 1:(1 to 5), and / or, the reaction temperature of the substitution reaction is 90°C to 100°C. And / or, the reaction time for the substitution reaction is 1 to 20 hours. The manufacturing method according to claim 36.

38. The molar ratio of the intermediate 1A to the first copper catalyst is 1:0.2, And / or, the molar ratio of intermediate 1A to the inorganic base is 1:(3-5). The manufacturing method according to claim 37.

39. The molar ratio of the intermediate 1A to the inorganic base is 1:

5. and / or, the reaction temperature of the substitution reaction is 95°C. And / or, the reaction time for the substitution reaction is 10 hours. and / or, after the substitution reaction is completed, the post-treatment step further includes lowering the temperature of the reaction solution, filtering it with diatomaceous earth, washing it, adjusting the pH to pH 1-3 with dilute hydrochloric acid, extracting it, and concentrating it to obtain a pure product of compound 1H. The manufacturing method according to claim 38.

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