Methods 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 from a prior patent application bearing patent application number 2022116671852 and entitled "Method for Preparing a P2X3 Inhibitor," filed with the State Intellectual Property Office of China on December 22, 2022, the entire text of which is incorporated herein by reference.

[0002] [Technical field] The present invention relates to a process for the synthesis of 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 and intermediates thereof.

[0003] [Background technology] P2X receptors are nonselective ATP-gated ion channel receptors, i.e., purinergic receptors, that can bind extracellular ATP, primarily derived from injured or inflamed tissues. These receptors are widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems, and are involved in various physiological processes, such as regulating cardiac rhythm and contractile force, vascular tone, nociception (especially chronic pain), contraction of the vas deferens during ejaculation, bladder contraction during urination, platelet aggregation, macrophage activation, cell apoptosis, and neuron-glia interactions. 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, which is selectively expressed in dorsal root ganglia of nerve terminals, spinal cord and brain neurons, ie, small to medium diameter primary sensory neurons.

[0005] A large amount of research has revealed that activation of P2X3 and P2X2 / 3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia, and hypersensitivity in rodents. Many studies have revealed that upregulation of P2X3 receptor expression leads to the formation of hyperalgesia and may be involved in pain signaling. P2X3 gene knockout mice show reduced pain responses, and P2X3 receptor antagonists have shown the effect of reducing nociception in pain and inflammatory pain models.

[0006] P2X3 is distributed in primary afferent nerves around the airway and can regulate coughing. Research has 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 triggers the urge to cough, resulting in coughing. P2X3 receptors play an important role in cough reflex hypersensitivity, and antagonizing P2X3 receptor binding can inhibit cough reflex hypersensitivity and thus excessive coughing in patients with chronic cough. Furthermore, research has suggested that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary arterial hypertension, and asthma, suggesting that P2X3 antagonists may also be promising new drugs for the treatment of these diseases.

[0007] P2X3 is involved in the channel that controls the bladder volume reflex, and it has been reported that P2X3 gene knockout mice have a significantly reduced urination frequency and a significantly increased bladder volume.Therefore, the inhibition of the binding of P2X3 receptor antagonists to P2X3 receptors has the effect of treating diseases of urine storage and urination disorder such as overactive bladder.Therefore, P2X3 antagonists may be potential drugs for treating related diseases such as overactive bladder.

[0008] P2X3 antagonists show great promise. Although currently commonly used cough medications, such as gabapentin, morphine, and amitriptyline, or treatment with speech pathology, can improve cough in many patients, they are not applicable to all patients, and centrally acting drugs such as gabapentin may cause adverse side effects and are not suitable for long-term administration. Therefore, there is a need to develop a clinically viable drug for chronic refractory cough that can be administered for a long period of time, which will provide doctors with a drug option. Therefore, the development of P2X3 antagonists is of great clinical significance.

[0009] [Summary of the Invention] The present invention provides a method for preparing 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 and an intermediate thereof. The synthetic route provided by the present invention is easy to control product quality, has a relatively high yield, and is suitable for industrial production.

[0010] The present invention provides a method for preparing compound I-1, which comprises: a2) In a solvent, compound 1I and compound 1L are subjected to a condensation reaction in the presence of a condensing agent and a base as follows to obtain compound I-1:

[0011] [ka]

[0012] Includes steps.

[0013] In one 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 any two or more thereof, preferably an amide solvent. Among these, the chloroalkane solvent is preferably dichloromethane, chloroform, dichloroethane, or a mixture of any two or more thereof, more preferably dichloromethane. The ether solvent is preferably tetrahydrofuran, ethyl ether, 1,4-dioxane, anisole, methyl tert-butyl ether, or a mixture of any two or more thereof, more preferably tetrahydrofuran. The amide solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture thereof, more preferably N,N-dimethylformamide. The aromatic hydrocarbon solvent is preferably toluene. The ester solvent is preferably ethyl acetate. In one embodiment of the present invention, in the method for producing the compound of formula I-1, the solvent is preferably an amide solvent, more preferably N,N-dimethylformamide.

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

[0015] In one optional 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 optional embodiment of the present invention, in step a2, the base may be DIPEA, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine or pyridine, and the preferred base is DIPEA.

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

[0018] In one optional embodiment of the present invention, in step a2, the molar ratio of the 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 one optional embodiment of the present invention, in step a2, the molar ratio of the intermediate 1I to the base may be 1:(1 to 5), preferably 1:(2 to 4), more preferably 1:3.

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

[0021] In one optional embodiment of the present invention, in step a2, the 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 one embodiment of the present invention, the reaction time for the condensation reaction may be 1 to 20 hours, for example, 1 to 2 hours.

[0023] In one optional embodiment of the present invention, step a2 may further include a post-treatment step after the completion of the condensation reaction, such as extracting the reaction solution, centrifuging, drying, recrystallizing, centrifuging and drying.

[0024] In one optional embodiment of the present invention, in step a2, the extraction in the post-treatment step includes adding ethyl acetate to the reaction solution, washing twice with a 6% aqueous sodium bicarbonate solution, collecting the organic phase, washing once with a 0.2 M aqueous hydrochloric acid solution until the pH is 3 to 4, collecting the organic phase, and further washing twice with purified water until the pH is neutral, and collecting the organic phase.

[0025] In one optional embodiment of the present invention, in step a2, the drying in the post-treatment step comprises drying the centrifuged filter cake in a blast oven at 55±5° C. for 8 hours or more.

[0026] In one optional embodiment of the present invention, in step a2, the recrystallization includes dissolving the dried product in a good solvent under heating, adding a poor solvent dropwise, lowering the temperature, and crystallizing.

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

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

[0029] In one embodiment of the present invention, in step a2, the temperature for heating and dissolving the recrystallization is 60 to 80°C.

[0030] In one optional embodiment of the present invention, in step a2, the temperature of the recrystallization is lowered to 15 to 25°C.

[0031] The above-mentioned 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 optional embodiment of the present invention, R 1is a C1-C4 alkyl group or a benzyl group, for example, a methyl group or an ethyl group.

[0035] In one embodiment of the present invention, in step a1, the solvent is selected from the group consisting of an alcoholic solvent, water, and a mixture of an alcoholic solvent and water, and the alcoholic solvent is preferably methanol or ethanol.

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

[0037] In one optional 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, lithium hydroxide or potassium hydroxide, and the preferred basic substance is lithium hydroxide.

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

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

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

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

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

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

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

[0045] The above-mentioned method for producing compound 1I may further include a method for producing compound 1H, which is b3) Compound 1E is subjected to a substitution reaction with 1F in the presence of a base in a solvent as follows, and after acidification with an acid, compound 1H is obtained:

[0046] [ka]

[0047] Includes steps.

[0048] In one 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.

[0049] In one embodiment of the present invention, in step b3, the solvent is selected from alcohol solvents, aromatic hydrocarbon solvents, ether solvents, amide solvents, or a mixture of any two or more thereof, preferably a mixture of an ether solvent and an amide solvent. Among these, the alcohol 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, more preferably tetrahydrofuran. The amide solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, or a mixture thereof.

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

[0051] In one optional 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, preferably potassium carbonate.

[0052] In one optional 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 embodiment of the present invention, in step b3, 1 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 optional embodiment of the present invention, in step b3, the molar ratio of compound 1E to compound 1F is 1:(1 to 5), preferably 1:(1.3 to 1.5), more preferably 1:1.3.

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

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

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

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

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

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

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

[0062] In one optional embodiment of the present invention, in step b3, the recrystallization includes dissolving the dried product in a good solvent under heating, adding a poor solvent dropwise, lowering the temperature, and crystallizing.

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

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

[0065] In one optional embodiment of the present invention, in step b3, the temperature for heating and dissolving the recrystallization is 50 to 70°C.

[0066] In one optional embodiment of the present invention, in step b3, the temperature of the recrystallization is lowered to 10 to 20°C.

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

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

[0069] [ka]

[0070] Includes steps.

[0071] In one 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.

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

[0073] In one optional 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, and a preferred palladium catalyst is Pd(OAc)2.

[0074] In one optional embodiment of the present invention, in step b2, the base may be one or more of KHCO, NaHCO, NaCO, Ba(OH), KPO, CsCO, KCO, NaOH, KOH, EtN, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, and the preferred base is KCO.

[0075] In one optional 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, and a preferred phosphine ligand is XantPhos.

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

[0077] In one 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), more preferably 1:0.02.

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

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

[0080] In one optional 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), more preferably 1:2.

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

[0082] In one optional 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 optional embodiment of the present invention, in step b2, the reaction time of the coupling reaction may be 10 to 30 hours, and preferably 14 to 18 hours.

[0084] In an optional embodiment of the present invention, step b2 may further include post-treatment steps after the completion of the coupling reaction, such as concentrating the reaction solution, acidifying it, extracting, purifying it through a silica gel column, concentrating it, distilling it with methanol, recrystallizing it, washing it, and drying it.

[0085] The above-mentioned method for producing compound 1E may further include a method for producing compound 1D, which is: b1) In a solvent, compound 1C is subjected to a coupling reaction with bis(pinacolato)diboron in the presence of a palladium catalyst and a base as follows to obtain compound 1D:

[0086] [ka]

[0087] Includes steps.

[0088] In one 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.

[0089] In one embodiment of the present invention, in step b1, the solvent is selected from water, an alcoholic solvent, an aromatic hydrocarbon solvent, an etheric solvent, or a mixture of any two or more thereof, preferably an etheric solvent. Among them, the alcoholic solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon solvent is preferably toluene. The etheric solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one embodiment of the present invention, in the method for preparing the compound of formula 1D, the solvent is preferably an etheric solvent, more preferably 1,4-dioxane.

[0090] In one optional 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, and a preferred palladium catalyst is Pd(OAc)2.

[0091] In one optional embodiment of the present invention, in step b1, the base may be one or more of KHCO, NaHCO, NaCO, Ba(OH), KPO, CsCO, KCO, NaOH, KOH, EtN, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, with the preferred base being potassium acetate.

[0092] In one optional 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 preferred.

[0093] In one embodiment of the present invention, in step b1, 1 is a methyl group, the solvent is 1,4-dioxane, the palladium catalyst is Pd(OAc)2, the base is potassium acetate, and the phosphine ligand Xphos is included.

[0094] In one 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), more preferably 1:0.01.

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

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

[0097] In one optional 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), more preferably 1:2.

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

[0099] In one optional 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 optional embodiment of the present invention, in step b1, the reaction time of the coupling reaction may be 2 to 10 hours, and preferably 4 hours.

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

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

[0103] [ka]

[0104] Includes steps.

[0105] In one 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 one embodiment of the present invention, in step c3, the solvent is selected from water, an alcoholic solvent, an aromatic hydrocarbon solvent, an etheric solvent, or a mixture of any two or more thereof, preferably a mixture of an etheric solvent and water. Among them, the alcoholic solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon solvent is preferably toluene. The etheric solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one embodiment of the present invention, in the method for producing a compound of Formula 1H, the solvent is preferably a mixture of an etheric solvent and water, more preferably a mixture of 1,4-dioxane and water.

[0107] In one optional embodiment of the present invention, in step c3, 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, and a preferred palladium catalyst is Pd(dppf)Cl2.

[0108] In one optional embodiment of the present invention, in step c3, the base may be one or more of KHCO, NaHCO, NaCO, Ba(OH), KPO, CsCO, KCO, NaOH, KOH, EtN, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, and the preferred base is KCO.

[0109] In one embodiment of the present invention, in step c3, 1 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 embodiment of the present invention, in step c3, the molar ratio of the intermediate 1K to the palladium catalyst is 1:(0.01 to 1), preferably 1:(0.01 to 0.05), more preferably 1:0.05.

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

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

[0113] In one optional 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 optional embodiment of the present invention, in step c3, the reaction time of the coupling reaction may be 1 to 20 hours.

[0115] In an optional embodiment of the present invention, step c3 may further include a post-treatment step after the completion of the coupling reaction, such as cooling 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) In a solvent, compound 1J is subjected to a coupling reaction with bis(pinacolato)diboron in the presence of a palladium catalyst and a base as follows to obtain compound 1K:

[0117] [ka]

[0118] Includes steps.

[0119] In one 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.

[0120] In one embodiment of the present invention, in step c2, the solvent is selected from water, an alcoholic solvent, an aromatic hydrocarbon solvent, an etheric solvent, or a mixture of any two or more thereof, preferably an etheric solvent, wherein the alcoholic solvent is preferably methanol, ethanol, or a mixture thereof, the aromatic hydrocarbon solvent is preferably toluene, and the etheric solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one embodiment of the present invention, in the method for preparing a compound of Formula 1K, the solvent is preferably an etheric solvent, more preferably 1,4-dioxane.

[0121] In one optional 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, and a preferred palladium catalyst is Pd(dppf)Cl2.

[0122] In one optional embodiment of the present invention, in step c2, the base may be one or more of KHCO, NaHCO, NaCO, Ba(OH), KPO, CsCO, KCO, NaOH, KOH, EtN, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, with the preferred base being potassium acetate.

[0123] In one embodiment of the present invention, in step c2, 1 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 optional 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), more preferably 1:0.05.

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

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

[0127] In one optional 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 optional embodiment of the present invention, in step c2, the reaction time of the coupling reaction may be 1 to 20 hours.

[0129] In an optional embodiment of the present invention, step c2 may further include a post-treatment step after the completion of the coupling reaction, such as cooling the reaction solution, purifying it using a silica gel column, and concentrating it to obtain a pure product of compound 1K.

[0130] The above-mentioned method for producing compound 1K may further include a method for producing compound 1J, which is: c1) In a solvent, compound 1C is subjected to a substitution reaction with compound 1F in the presence of a base as follows, and after acidification with an acid, compound 1J is obtained:

[0131] [ka]

[0132] Includes steps.

[0133] In one 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.

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

[0135] In one optional 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, preferably potassium carbonate.

[0136] In one optional 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 optional embodiment of the present invention, in step c1, the molar ratio of compound 1C to acid is 1:(1-5), preferably 1:2.

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

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

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

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

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

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

[0144] In one embodiment of the present invention, step c1 may further include a post-treatment step after the completion of the substitution reaction, such as cooling the reaction solution, acidifying it, extracting, washing, drying, and purifying it on a silica gel column to obtain a pure product of compound 1H.

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

[0146] The above-mentioned method for producing Compound 1D or Compound 1J may further include a method for producing Compound 1C, which is: d2) In a solvent, compound 1B is reacted with R 1 -OH to give compound 1C.

[0147] [ka]

[0148] Includes steps.

[0149] In one embodiment of the present invention, in step d2, the solvent is selected from water, an alcoholic solvent, an aromatic hydrocarbon solvent, an etheric solvent, or a mixture of any two or more thereof, preferably an alcoholic solvent. Among them, the alcoholic solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon solvent is preferably toluene. The etheric solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one embodiment of the present invention, in the method for producing a compound of formula 1C, the solvent is preferably an alcoholic solvent, more preferably methanol.

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

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

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

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

[0154] In one optional 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 optional embodiment of the present invention, in step d2, the reaction time of the esterification reaction may be 1 to 20 hours, for example, 4 hours.

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

[0157] The above-mentioned 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 in the presence of a copper(I) catalyst and an inorganic base to obtain compound 1B as follows:

[0158] [ka]

[0159] Includes steps.

[0160] In one embodiment of the present invention, in step d1, the solvent is selected from water, alcoholic solvents, aromatic hydrocarbon solvents, etheric solvents, or a mixture of any two or more thereof, preferably water. Among them, the alcoholic solvent is preferably methanol, ethanol, or a mixture thereof. The aromatic hydrocarbon solvent is preferably toluene. The etheric solvent is preferably 1,4-dioxane, tetrahydrofuran, or a mixture thereof. In one embodiment of the present invention, in the method for producing the compound of formula 1B, the solvent is preferably water.

[0161] In one optional 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 the preferred cuprous catalyst being cuprous oxide.

[0162] In one optional embodiment of the present invention, in step d1, the inorganic base may be one or more of KHCO, NaHCO, NaCO, Ba(OH), KPO, CsCO, KCO, NaOH, KOH, NaH, and the preferred base is NaOH.

[0163] In one optional 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 optional embodiment of the present invention, in step d1, the molar ratio of the intermediate 1A to the cuprous catalyst is 1:(0.1-2), preferably 1:0.2.

[0165] In one optional 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), more preferably 1:5.

[0166] In one optional 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 optional embodiment of the present invention, in step d1, the reaction time of the substitution reaction may be 1 to 20 hours, for example, 10 hours.

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

[0169] [Beneficial effects] A positive and progressive effect of the present invention is to provide a novel method for preparing 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 and an intermediate thereof. The method is simple in operation, easy to control product quality, has a relatively high yield, and is suitable for industrial production.

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

[0171] [Table 1]

[0172] By arbitrarily combining the above-mentioned preferable conditions without departing from the common knowledge in the art, each relatively preferable example of the present invention can be obtained.

[0173] All reagents and raw materials used in the present invention are commercially available.

[0174] [Mode for Carrying Out the Invention] The technical solutions of the present disclosure will be described in more detail below in conjunction with specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present disclosure. Any technology realized based on the above content of the present disclosure is included within the scope of the claims of the present disclosure.

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

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

[0177] [ka]

[0178] 614.0 kg of water was added to a clean 2000 L reactor, and 50.2 kg of sodium hydroxide, 86.55 kg of compound 1A, and 7.13 kg of cuprous oxide were added in five portions. The mixture was heated to 95°C and reacted for 10 hours. Sampling was performed and HPLC analysis showed that the raw materials had almost completely reacted.

[0179] The mixture was cooled to 25°C, filtered through 22.5 kg of diatomaceous earth, washed with 50.0 kg of water, and adjusted to pH 1-3 with dilute hydrochloric acid (prepared by adding 185.0 kg of concentrated hydrochloric acid to 400.0 kg of water). 615 kg of ethyl acetate was added and the mixture was separated. 353.0 kg of ethyl acetate was added to the aqueous phase for extraction. The combined organic phases were analyzed for COD and, if acceptable, were then disposed of. The organic phase was concentrated under vacuum (internal temperature ≤ 55°C, vacuum ≤ -0.07 MPa) until no significant fractions remained. The organic phase was then distilled twice with methanol (320.0 kg × 2). After sampling and testing for purity by HPLC, 120 kg of methanol was added. The product was stored in methanol for the next feed. The total weight was 190.0 kg, the content was 29.3%, and the yield was 94.1%.

[0180] 280.0 kg of the methanol solution of intermediate 1B from the previous step was added to a clean 2000 L reactor, 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 carried out for 4 hours. Sampling was carried out and the reaction was analyzed by HPLC. Process control showed that the reaction was complete, and the reaction was completed.

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

[0182] Step 3 Preparation of intermediate 1D

[0183] [ka]

[0184] A dry and clean 2000 L reactor was charged with 560.0 kg of dioxane, 53.5 kg of intermediate 1C, 60.0 kg of bis(pinacolato)diboron, 0.48 kg of Pd(OAc)2, 2.0 kg of Xphos, and 52.0 kg of potassium acetate. The reactor was purged with argon gas three times, heated to 80°C, and reacted at this temperature for 4 hours. Sampling was carried out and the reaction mixture was analyzed by HPLC for process control, confirming that the reaction was complete.

[0185] The mixture 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 and the layers were separated. The organic phase was loaded onto a silica gel column, washed with 94.0 kg of ethyl acetate, concentrated, and distilled twice with 75.0 kg x 4 of n-heptane, crystallized once, centrifuged, and washed once more. The wet product of intermediate 1D was obtained, sampled, and tested for purity by HPLC. It was then placed in a vacuum drying box and vacuum dried at 55-60°C for 16 hours to obtain the dried product of intermediate 1D, an off-white solid, 56.5 kg, in an 89.1% yield. LC-MS, M / Z (ESI): 297.1 [M+H] + .

[0186] Step 4 Preparation of Intermediate 1E

[0187] [ka]

[0188] A clean 2000 L reactor was charged with 480.0 kg of ethylene glycol dimethyl ether, 56.5 kg of intermediate 1D, 32.8 kg of 2-bromo-5-methylthiazole, 107 kg of 47% aqueous potassium carbonate solution, 0.83 kg of Pd(OAc)2, and 4.2 kg of Xantphos. The mixture was purged with argon gas three times, heated to 70°C, and reacted for 14-18 hours. Sampling was performed and the reaction was confirmed to be complete by HPLC.

[0189] The internal temperature was lowered to 40°C, and vacuum concentration (jacket temperature ≦55°C, vacuum ≦-0.07 MPa) was turned on until no clear distillates remained. The temperature was then lowered to 25°C, and a citric acid solution (72 kg of citric acid was poured into 270 kg of water) was added. 540.0 kg of ethyl acetate was added and the mixture was separated. The aqueous phase was extracted with 110.0 kg of ethyl acetate. The organic phases were combined, filtered through 40.0 kg of silica gel, and the filter cake was washed with 110.0 kg of ethyl acetate. Vacuum concentration (jacket temperature ≦55°C, vacuum ≦-0.07 MPa) was turned on until no clear distillates remained. 100.0 kg of methanol was added, and the mixture was crystallized at 5°C for 2 hours. After centrifugation, the 79.0 kg of methanol was added. The wet product of intermediate 1E was obtained by washing with 1 kg of methanol, and the wet product was sampled and tested by HPLC to determine that the purity was acceptable. The wet product was then dried in a vacuum drying cabinet 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 Preparation of intermediate 1H

[0191] [ka]

[0192] To a 100 L glass reactor, 29.5 kg of tetrahydrofuran was added, 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) in this order with stirring. The mixture was heated to 65-70°C and incubated for 12 h. After this, sampling was initiated and TLC monitoring was continued until the 1E point of the starting intermediate was no longer visible. After completion of the first-stage reaction, the reaction mixture was cooled to 0-20°C and 15.25 kg of the prepared 20% aqueous sulfuric acid solution was slowly added dropwise. After the addition was complete, the mixture was heated to 55-65°C. After 3 h of reaction, sampling was initiated and TLC monitoring was continued until the 1G point of the intermediate was no longer visible.

[0193] The temperature was lowered to 10-20°C, and the mixture was allowed to stand for separation. The upper organic layer was collected. 18.7 kg of ethyl acetate was added to the lower aqueous phase, which was stirred and allowed to stand for separation. The upper organic layer was collected. The two organic phases were combined and added to a saturated aqueous solution of sodium bicarbonate, and washed until the aqueous layer reached a pH of 7-8 (based on the pH value). 20.75 kg of purified water was added to the organic phase for one wash. 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] A dry, clean 50 L glass reactor was charged with 6.6 kg of methanol, followed by the crude product of Intermediate 1H (approximately 6.7 kg) concentrated to dryness. The mixture was heated to 50-70°C and stirred to clarify. At 60-70°C, 8.3 kg of purified water was slowly added dropwise (requiring approximately 1.0 h). After the addition was complete, the heating was stopped, the temperature was lowered to 10-20°C, and crystallization was allowed to continue for 1-2 hours. After centrifugation and rinsing once with the prepared methanol / purified water mixed solvent (3.0 kg / 3.75 kg), the filter cake was collected and weighed to obtain 5.455 kg of wet product of Intermediate 1H. The dry weight loss was measured and converted directly to ethanol before being used in the next step. LC-MS, M / Z (ESI): 340.1 [M+H] +.

[0195] Step 6: Manufacture of 1I

[0196] [ka]

[0197] A 100 L glass reactor was charged with 32.1 kg of methanol and 5.37 kg of wet intermediate 1H, and the temperature was controlled at 10-30°C. 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 the mixture was monitored by TLC until intermediate 1H was completely consumed.

[0198] After the reaction was completed, the temperature was lowered to 0-20°C, and 4 M hydrochloric acid was added in several portions to adjust the pH to 4 (usage amount: approximately 6.5 kg). The mixture was kept at the same temperature for 1-2 hours to crystallize, resulting in the precipitation of a large amount of white solid. The remaining 4 M hydrochloric acid was then added dropwise to adjust the pH to 2-3, and the mixture was kept at the same temperature for 1-2 hours to crystallize, followed by stirring and centrifugation. The wet filter cake was collected and 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 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 reactor, and the temperature was lowered to 10-25°C. With stirring, 2.68 kg of HOBt, 3.80 kg of EDCI, and 3.63 kg of Compound 1L were added in that order. The temperature was lowered, and 5.14 kg of DIPEA was slowly added dropwise, maintaining the reaction temperature at 5-20°C. After the addition was complete, the reaction was continued at 10-30°C. Sampling began after 2 hours, and the reaction was stopped after monitoring by TLC until Intermediate 1I was no longer present.

[0202] 77.76 kg of ethyl acetate was added to the reaction mixture, which was then washed twice with 6% aqueous sodium bicarbonate (64.8 kg each time). The organic phase was then collected. This was followed by another wash with 0.2 M aqueous hydrochloric acid until the pH reached 3-4, and the organic phase was then collected. This was followed by two washes with purified water until the pH reached neutral (43.2 kg each time). The organic phase was then collected and concentrated under vacuum at 50-60°C until a small amount of solvent remained. Then, 40.0 kg of n-heptane was added to the rotary evaporator in several portions. The mixture was transferred to a transfer barrel and stirred at 10-30°C for 0.5-2 h. Then, the mixture was centrifuged. The filter cake was dried in a blast oven at 55±5°C for 8 h or more to obtain a pale yellow solid. The resulting mixture was weighed. 5.64 kg of dried compound I-1 was obtained, representing a 98% yield.

[0203] A 50 L spherical glass reactor was charged with 8.68 kg of absolute ethanol, and 2.80 kg of compound I-1 was added with stirring. The mixture was heated to 60-80°C to clarify the reaction, filtered, and the filtrate was collected. After the filtrate was heated again to clarify the reaction, 13.44 kg of n-heptane was slowly added dropwise to the reactor at 60-80°C (requiring approximately 1.0 h) to precipitate a solid. The temperature was slowly lowered to 15-25°C, and the mixture was stirred for 1-3 h. The mixture was then centrifuged and the filter cake was collected. The filter cake was dried in a vacuum oven at 55±5°C for at least 8 h 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 methyl 3-bromo-2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)benzoate (1J)

[0207] [ka]

[0208] Methyl 3-bromo-2-fluoro-5-hydroxybenzoate (1C) (30 g, 120 mmol) was placed in a round-bottom flask, and compound 1F (22 g, 145 mmol), potassium carbonate (24.97 g, 181 mmol), and tetrahydrofuran (30 mL) were added. The mixture was refluxed overnight. After the starting materials were completely reacted as determined by TLC, 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 the starting materials were completely consumed as determined by LCMS, 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) and dried over anhydrous sodium sulfate. The residue was purified using a silica gel column (petroleum ether:ethyl acetate (V / V) = 10:1 to 3:1) to give a yellow oily liquid (20.0 g, 77% yield). LC-MS, M / Z (ESI): 321.0 [M+H] + .

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

[0210] [ka]

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

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

[0213] [ka]

[0214] Methyl 2-fluoro-5-(((2S,3R)-3-hydroxybutan-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (28.7 g, 78 mmol) was added to a solution of 1,4-dioxane (300 mL) and water (30 mL), and 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. The mixture was purged with nitrogen gas three times and reacted under nitrogen gas protection at 90 °C overnight. After complete consumption of the starting material as determined by TLC, the mixture was cooled to room temperature and concentrated. The product 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 above is an illustrative description of the embodiments of the technical solution of the present disclosure. It should be understood that the scope of the claims of the present disclosure is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present disclosure should be included within the scope of the claims of the present application.

Claims

1. A method for producing compound I-1, comprising the steps of: a2) In a solvent, compound 1I and compound 1L are subjected to a condensation reaction in the presence of a condensing agent and a base as follows to obtain compound I-1: 【Chemistry 1】 Including steps, Manufacturing method.

2. The organic solvent may be selected from 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, and more preferably N,N-dimethylformamide; and / or said compound 1L is a free base or a salt thereof, for example, the hydrochloride salt of compound 1L; And / or the condensing agent is HOBt / EDCI, T ３ P, PyBOP, DCC, CDI or HATU, the preferred condensing agent is HOBt / EDCI; and / or the base may be DIPEA, sodium bicarbonate, potassium carbonate, cesium carbonate, triethylamine or pyridine, the preferred base being DIPEA; and / or the molar ratio of the intermediate 1I to the condensing agent may be 1:(1-5), preferably 1:(1.5-2), more preferably 1:1.5; and / or the molar ratio of intermediate 1I to base may be 1:(1-5), preferably 1:(2-4), more preferably 1:3; and / or the molar ratio of Intermediate 1I to Intermediate 1L may be 1:(1-4), preferably 1:(1-3), more preferably 1:1.2; and / or the condensation reaction is carried out under protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas; And / or, after the condensation reaction is completed, the process may further include a post-treatment step, such as extracting the reaction solution, centrifuging, drying, recrystallizing, centrifuging and drying. The method of claim 1.

3. The method may further include a method for preparing Compound 1I, a1) Compound 1H is hydrolyzed in a solvent in the presence of a basic substance as follows to obtain Compound 1I: 【Chemistry 2】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 1 to 2.

4. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is an alcoholic solvent, water, or a mixed solvent of an alcoholic solvent and water, preferably a mixed solvent of an alcoholic solvent and water, more preferably a mixed solvent of methanol and water; and / or the basic substance may be one or more of triethylamine, potassium tert-butoxide, sodium tert-butoxide, lithium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide or potassium hydroxide, the preferred basic substance being lithium hydroxide; and / or the molar ratio of compound 1H to the basic substance is 1:(1-5), preferably 1:2; and / or the reaction time of the hydrolysis reaction may be 1 to 20 hours, for example, 1 to 2 hours; and / or may further comprise a post-treatment step after the completion of the hydrolysis reaction, for example, cooling the reaction solution, acidifying it, centrifuging it, washing it, and drying it to obtain a pure product of Compound 1I. The method of claim 3.

5. The method may further include a method for preparing compound 1H, b3) Compound 1E is subjected to a substitution reaction with 1F in the presence of a base in a solvent as follows, and after acidification with an acid, compound 1H is obtained: 【Transformation 3】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 3 to 4.

6. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, an amide solvent, or a mixture of any two or more thereof, preferably a mixture of an ether solvent and an amide solvent, more preferably a mixture of tetrahydrofuran and N,N-dimethylformamide; and / or 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, preferably potassium carbonate; and / or the acid may be sulfuric acid, preferably 20% to 75% aqueous sulfuric acid, more preferably 20% aqueous sulfuric acid; and / or the molar ratio of compound 1E to compound 1F is 1:(1-5), preferably 1:(1.3-1.5), more preferably 1:1.3; and / or the molar ratio of compound 1E to base is 1:(1-5), preferably 1:2; and / or the volume ratio of tetrahydrofuran to N,N-dimethylformamide is (1 to 10):1; and / or the molar ratio of compound 1E to acid is 1:(1-5), preferably 1:2; and / or the reaction temperature of the substitution reaction may be 60°C to 75°C, preferably 65°C to 70°C; and / or the temperature of the acidification is between 50 and 70°C, preferably between 55 and 65°C; and / or may further include a post-treatment step after the completion of the substitution reaction, such as cooling the reaction solution, allowing it to stand for liquid separation, extraction, washing, concentration, recrystallization, centrifugation, and washing to obtain a wet product of Compound 1H; Preferably, step b3 comprises the steps of adding compound 1E, compound 1F and a base to a solvent to carry out a first-stage reaction, and then adding an acid to the reaction system to acidify it, and then obtaining compound 1H. The method of claim 5.

7. The method may further include a method for preparing compound 1E, b2) In a solvent, compound 1D is subjected to a coupling reaction with 2-bromo-5-methylthiazole in the presence of a palladium catalyst and a base as follows to obtain compound 1E: 【Chemistry 4】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 5 to 6.

8. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of any two or more thereof, preferably an ether-based solvent, more preferably ethylene glycol dimethyl ether; and / or the palladium catalyst is Pd(OAc) ２ , PdCb, Pd(TFA) ２ , Pd[O ２ C(CH ３ ) ３ ] ２ , Pd ２ (dba) ３ , PdBr ２ and Pd(dppf)Cl ２ The preferred palladium catalyst is Pd(OAc) ２ and and / or the base is KHCO ３ , NaHCO ３ , Na ２ CO ３ , Ba(OH) ２ , K. ３ P.O. ４ , Cs ２ CO ３ , K. ２ CO ３ , NaOH, KOH, Et ３ The base may be one or more of N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, with the preferred base being K ２ CO ３ and and / or the coupling reaction further comprises a phosphine ligand, the phosphine ligand being PPh ３ , SPhos, XPhos, 1,1′-bis(diphenylphosphino)ferrocene, and XantPhos, with the preferred phosphine ligand being XantPhos; and / or the molar ratio of the intermediate 1D to the palladium catalyst is 1:(0.01-0.1), preferably 1:(0.01-0.05), more preferably 1:0.02; and / or the molar ratio of the intermediate 1D to 2-bromo-5-methylthiazole is 1:(0.5-5), preferably 1:1; and / or the molar ratio of the intermediate 1D to the base is 1:(1-5), preferably 1:(1.5-2), more preferably 1:1.9; and / or the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1-5), preferably 1:(1-2), more preferably 1:2; and / or the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas; and / or the reaction temperature of the coupling reaction may be 65°C to 75°C, for example 70°C; and / or the reaction time of the coupling reaction may be 10 to 30 hours, preferably 14 to 18 hours; and / or, after the completion of the coupling reaction, the process may further include a post-treatment step, such as concentrating the reaction solution, acidifying, extracting, purifying with a silica gel column, concentrating, distilling with methanol, recrystallizing, washing and drying. The method of claim 7.

9. The method may further include a method for preparing compound 1D, b1) In a solvent, compound 1C is subjected to a coupling reaction with bis(pinacolato)diboron in the presence of a palladium catalyst and a base as follows to obtain compound 1D: 【Transformation 5】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 7 to 8.

10. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is water, an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, or a mixture of any two or more thereof, preferably an ether solvent, more preferably 1,4-dioxane; and / or the palladium catalyst is Pd(OAc) ２ , PdCb, Pd(TFA) ２ , Pd[O ２ C(CH ３ ) ３ ] ２ , Pd ２ (dba) ３ , PdBr ２ and Pd(dppf)Cl ２ The preferred palladium catalyst is Pd(OAc) ２ and and / or the base is KHCO ３ , NaHCO ３ , Na ２ CO ３ , Ba(OH) ２ , K. ３ P.O. ４ , Cs ２ CO ３ , K. ２ CO ３ , NaOH, KOH, Et ３ N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, the preferred base being potassium acetate; and / or the coupling reaction further comprises a phosphine ligand, the phosphine ligand being PPh ３ , SPhos, XPhos, 1,1′-bis(diphenylphosphino)ferrocene and XantPhos, with the preferred phosphine ligand being XPhos; and / or the molar ratio of the intermediate 1C to the palladium catalyst is 1:(0.01-0.1), preferably 1:(0.01-0.05), more preferably 1:0.01; and / or the molar ratio of intermediate 1C to bis(pinacolato)diboron is 1:(1-5), preferably 1:1.1; and / or the molar ratio of the intermediate 1C to the base is 1:(1-5), preferably 1:(2-3), more preferably 1:2.5; and / or the molar ratio of the palladium catalyst to the phosphine ligand is 1:(1-5), preferably 1:(1-2), more preferably 1:2; and / or the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas; and / or the reaction temperature of the coupling reaction may be 75 to 85°C, for example 80°C; and / or the reaction time of the coupling reaction may be 2 to 10 hours, preferably 4 hours; and / or, after the completion of the coupling reaction, the process may further include a post-treatment step, for example, filtering the reaction solution with diatomaceous earth, extracting, purifying with a silica gel column, distilling with n-heptane, recrystallizing, and drying. The method of claim 9.

11. The method may further include a method for preparing compound 1H, c3) In a solvent, compound 1K is subjected to a coupling reaction with 2-bromo-5-methylthiazole in the presence of a palladium catalyst and a base as follows to obtain compound 1H: 【Transformation 6】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 1 to 2.

12. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is water, an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, or a mixture of any two or more thereof, preferably a mixture of an ether solvent and water, more preferably a mixture of 1,4-dioxane and water; and / or the palladium catalyst is Pd(OAc) ２ , PdCb, Pd(TFA) ２ , Pd[O ２ C(CH ３ ) ３ ] ２ , Pd ２ (dba) ３ , PdBr ２ and Pd(dppf)Cl ２ and the preferred palladium catalyst is Pd(dppf)Cl ２ and and / or the base is KHCO ３ , NaHCO ３ , Na ２ CO ３ , Ba(OH) ２ , K. ３ P.O. ４ , Cs ２ CO ３ , K. ２ CO ３ , NaOH, KOH, Et ３ The base may be one or more of N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, with the preferred base being K ２ CO ３ and and / or the molar ratio of the intermediate 1K to the palladium catalyst is 1:(0.01-0.1), preferably 1:(0.01-0.05), more preferably 1:0.05; and / or the molar ratio of the intermediate 1K to 2-bromo-5-methylthiazole is 1:(1-5), preferably 1:(1-2), more preferably 1:1.1; and / or the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas; and / or the reaction temperature of the coupling reaction may be 85°C to 95°C, for example 90°C; and / or the reaction time of the coupling reaction may be 1 to 20 hours; and / or may further comprise 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 1H. The method of claim 11.

13. The method may further include a method for preparing Compound 1K, c2) In a solvent, compound 1J is subjected to a coupling reaction with bis(pinacolato)diboron in the presence of a palladium catalyst and a base as follows to obtain compound 1K: 【Transformation 7】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 11 to 12.

14. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is water, an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, or a mixture of any two or more thereof, preferably an ether solvent, more preferably 1,4-dioxane; and / or the palladium catalyst is Pd(OAc) ２ , PdCb, Pd(TFA) ２ , Pd[O ２ C(CH ３ ) ３ ] ２ , Pd ２ (dba) ３ , PdBr ２ and Pd(dppf)Cl ２ and the preferred palladium catalyst is Pd(dppf)Cl ２ and and / or the base is KHCO ３ , NaHCO ３ , Na ２ CO ３ , Ba(OH) ２ , K. ３ P.O. ４ , Cs ２ CO ３ , K. ２ CO ３ , NaOH, KOH, Et ３ N, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, LiHMDS, NaHMDS, potassium acetate, sodium tert-pentoxide, n-butyllithium, diethylamine and dicyclohexylamine, the preferred base being potassium acetate; and / or the molar ratio of the intermediate 1J to the palladium catalyst is 1:(0.01-0.1), preferably 1:(0.01-0.05), more preferably 1:0.05; and / or the molar ratio of the intermediate 1J to bis(pinacolato)diboron is 1:(1-5), preferably 1:(1-1.2), more preferably 1:1.1; and / or the coupling reaction is carried out under the protection of an inert gas, which may be nitrogen gas, helium gas, or argon gas; and / or the reaction temperature of the coupling reaction may be 85°C to 95°C, for example 90°C; and / or the reaction time of the coupling reaction may be 1 to 20 hours; and / or may further comprise 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. The method of claim 13.

15. The method may further include a method for preparing compound 1J, c1) Compound 1C is subjected to a substitution reaction with compound 1F in the presence of a base in a solvent as follows, and after acidification with an acid, compound 1J is obtained: 【Transformation 8】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 13 to 14.

16. R １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the solvent is water, an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, or a mixture of any two or more thereof, preferably an ether solvent, more preferably tetrahydrofuran; and / or 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, preferably potassium carbonate; and / or the acid may be sulfuric acid, preferably 20% to 75% aqueous sulfuric acid, more preferably 20% aqueous sulfuric acid; and / or the molar ratio of compound 1C to the acid is 1:(1-5), preferably 1:2; and / or the molar ratio of compound 1C to compound 1F is 1:(1-5), preferably 1:(1.1-1.3), more preferably 1:1.2; and / or the molar ratio of compound 1C to base is 1:(1-5), preferably 1:(1-2), more preferably 1:1.5; and / or the reaction temperature of the substitution reaction may be 45°C to 55°C, preferably 50°C; and / or the temperature of the acidification is between 50 and 70°C, preferably between 55 and 65°C; and / or the reaction time of the substitution reaction may be 1 to 20 hours; and / or, after the substitution reaction is completed, the method may further include a post-treatment step, such as cooling the reaction solution, acidifying it, extracting, washing, drying, and purifying it with a silica gel column to obtain a pure product of compound 1H; Preferably, step c1 comprises the steps of adding compound 1C, compound 1F and a base to a solvent to carry out a first-stage reaction, and then adding an acid to the reaction system to acidify it, and then obtaining compound 1H. The method of claim 15.

17. The method may further include a method for preparing compound 1C, d2) In a solvent, compound 1B is reacted with R １ -OH to give compound 1C. 【Chemistry 9】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 9, 10, 15 and 16.

18. the solvent is water, an alcohol-based solvent, an aromatic hydrocarbon-based solvent, an ether-based solvent, or a mixture of two or more thereof, preferably an alcohol-based solvent, more preferably methanol; and / or the R １ R in —OH １ is C １ -C ４ an alkyl group or a benzyl group, for example, a methyl group or an ethyl group; and / or the catalyst may be sulfuric acid, phosphoric acid, thionyl chloride and acetyl chloride, the preferred catalyst being acetyl chloride; and / or the solvent is methanol, the catalyst is acetyl chloride, and the R １ -OH is methanol, and / or the molar ratio of the compound 1B to the catalyst is 1:(0.1-1), preferably 1:(0.5-1), more preferably 1:1; and / or the reaction temperature of the esterification reaction may be 55°C-65°C, for example 60°C; and / or may further include a post-treatment step after the esterification reaction is completed, such as 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 method of claim 17.

19. The method may further include a method for preparing compound 1B, d1) In a solvent, compound 1A is subjected to a substitution reaction with water in the presence of a copper(I) catalyst and an inorganic base, to obtain compound 1B as follows: 【Chemistry 10】 The method is characterized in that it includes the steps of: The manufacturing method according to any one of claims 17 to 18.

20. the solvent is water, an alcohol solvent, an aromatic hydrocarbon solvent, an ether solvent, or a mixture of two or more thereof, and is preferably water; and / or the cuprous catalyst may be one or more of cuprous bromide, cuprous chloride, cuprous iodide, and cuprous oxide, with the preferred cuprous catalyst being cuprous oxide; and / or the inorganic base is KHCO ３ , NaHCO ３ , Na ２ CO ３ , Ba(OH) ２ , K. ３ P.O. ４ , Cs ２ CO ３ , K. ２ CO ３ , NaOH, KOH, NaH, with the preferred inorganic base being NaOH; and / or the molar ratio of the intermediate 1A to the cuprous catalyst is 1:(0.1-2), preferably 1:0.2; and / or the molar ratio of the intermediate 1A to the inorganic base is 1:(1-5), preferably 1:(3-5), more preferably 1:5; and / or the reaction temperature of the substitution reaction may be 90°C to 100°C, for example 95°C; and / or the reaction time of the substitution reaction may be 1 to 20 hours, for example, 10 hours; and / or 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 through diatomaceous earth, washing it, adjusting the pH to pH = 1 to 3 with dilute hydrochloric acid, extracting it, and concentrating it to obtain a pure product of compound 1H. The method of claim 19.

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