Intermediate for synthesizing nav1.8 inhibitor, preparation method therefor, and use thereof

Abstract

The present invention relates to the pharmaceutical field, and provides an intermediate for synthesizing a Nav1.8 inhibitor, a preparation method therefor, and a use thereof. The present invention provides a compound represented by formula I. The compound can be used for synthesizing a Nav1.8 inhibitor represented by formula (II), and is a novel intermediate for synthesizing the Nav1.8 inhibitor. The compound represented by formula I of the present invention can be readily prepared by means of an amide condensation reaction. A method for preparing the Nav1.8 inhibitor by using the compound represented by formula I as a raw material is characterized by short steps, mild reaction conditions, simple post-treatment and purification, high conversion rate, and suitability for industrial production.

Description

An intermediate for the synthesis of a Nav1.8 inhibitor, its preparation method and uses. Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to an intermediate for the synthesis of Nav1.8 inhibitors, a method for preparing the intermediate, and its uses. Background Technology

[0002] Pain is a complex physiological and psychological activity and one of the most common symptoms in clinical practice. Originally intended as a protective mechanism to alert people to potential dangers, abnormal pain can cause physiological dysfunction, especially chronic pain, which severely impacts people's quality of life. According to a 2019 report (http: / / news.medlive.cn / anes / info-progress / show-153086_201.html), the global prevalence of chronic pain is 12%–30%. In the United States, the number of people suffering from pain has surpassed the number suffering from diabetes, heart disease, and cancer, with annual economic losses due to pain reaching $560 billion–635 billion (https: / / www.physio-pedia.com / Epidemiology_of_Pain); while statistics from China in 2015 show that the pain market reached 20.8 billion RMB (https: / / paindoctor.com / resources / chronic-pain-statistics / ). Currently used analgesics, such as opioid receptor agonists, cyclooxygenase inhibitors, and GABA receptor agonists, either have addictive properties, respiratory depression, gastrointestinal side effects, or cause adverse cardiovascular reactions and central nervous system depression, leaving clinical needs far from being met. Therefore, the pain management market has enormous potential. (Nora D. Volkow, A. Thomas McLellan. Opioid Abuse in Chronic Pain-Misconceptions and Mitigation Strategies. N Engl J Med, 2016, 374(13): 1253-63. Sheng HG, Shao JY, Kir Kland SC, et al. Inhibition of human colon Cancer cell growth by selective inhibition of cyclooxygenase-2. J Chm Invest,1997,99:2254.Janette Brohan,Basavana G.Goudra.The Role of GABA Receptor Agonists in Anesthesia and Sedation.CNSDrugs,2017.)

[0003] Pain encompasses various types. Based on the nature of the stimulus, it can be classified as mechanical pain, thermal pain, and chemical pain; based on the inflammatory cause, it can be classified as inflammatory pain and non-inflammatory pain; based on the nerve location, it can be classified as central nervous system pain, peripheral nervous system pain, and autonomic nervous system pain; and based on the duration of the illness, it can be classified as acute pain and chronic pain. Regardless of the form of pain, sodium ion channels (Navs) are involved.

[0004] Human pain originates from pain receptors located in the peripheral nerve endings throughout the body. These receptors convert mechanical, thermal, cold, and chemical stimuli into nerve impulses, which are then transmitted via afferent nerves to the dorsal root ganglion (DRG), and then via efferent nerves to the central nervous system, thus allowing the perception of pain (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151.). The role of the nerve impulse receptors (NAVs) is to trigger and transmit signals during this process, acting as the primary mediator of the rising limb of the action potential (i.e., nerve impulse) (Mark D. Baker, John N. Wood. Involvement of NAVs). + Channels in pain pathways. TRENDS in Pharmacological Sciences, 2001, 22(1):27-31. Alan L. Goldin. RESURGENCE OF SODIUM CHANNEL RESEARCH. Annu. Rev. Physiol. 2001. 63:871-894.). Therefore, inhibiting NaVs can help relieve and treat pain. However, existing NaVs inhibitors such as lidocaine, carbamazepine, and lamotrigine all have drawbacks such as narrow therapeutic window and large side effects due to their lack of selectivity for NaVs. Therefore, research has turned to selective NaV inhibitors.

[0005] Navs are a class of transmembrane ion channel proteins composed of an α subunit with a molecular weight of 260 kD and a β subunit with a molecular weight of 30–40 kD (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151.). Based on the strength of their inhibitory activity against tetrodotoxin (TTX), Navs subtypes can be divided into two categories: TTX-sensitive (TTX-S), including Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, and Nav1.7; and TTX-resistant (TTX-R), including Nav1.5, Nav1.8, and Nav1.9. Based on existing physiological and pharmacological studies (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99: 1079-1151. Alan L Goldin. RESURGENCE OF SODIUM CHANNEL RESEARCH. Annu. Rev. Physiol. 2001. 63: 871-94. Laura Solé, Michael M. Tamkun. Trafficking mechanisms underlying Nav channel subcellular localization in neurons. Channels, 2020, 14(1), 1-17. Manuel de Lera Ruiz, Richard L. Kraus. Voltage-Gated Sodium Channels: Structure, Function, Pharmacology and Clinical As shown in Table 1, Nav1.1, Nav1.2, and Nav1.3 are mainly distributed in the CNS area and are associated with CNS diseases such as epilepsy and local anesthesia; Nav1.4 is mainly distributed in skeletal muscle, and its inhibitors are used as local anesthetics for myotonia; Nav1.5 is mainly distributed in cardiomyocytes, and its inhibitors are used to treat arrhythmias; Nav1.6 is involved in movement disorders; currently, the main targets related to pain are Nav1.7, Nav1.8, and Nav1.9.Among them, Nav1.7 inhibitors have been most widely studied in the field of pain, but no related clinical trials have been successful to date; there are fewer studies on Nav1.9, and its mechanism of action in pain is not yet fully understood, nor has any evidence of pain efficacy models for related inhibitors been reported; regarding the mechanism of action of Nav1.8, Dib-Hajj et al. (Bennett DL, Clark AJ, Huang J, et al. The Role of Voltage-Gated Sodium Channels in Pain Signaling. Physiol Rev, 2019, 99:1079-1151.) summarized existing research in a 2019 review, believing that Nav1.8 is the main contributor to the rising branch of the action potential, its rapid initiation supports high-frequency discharge, it has a high activation threshold, a slow kinetic process, and blocking Nav1.8 can block the generation of action potential and the transmission of electrical signals; Blair and Bean's research (Blair NT, Bean BP. Roles of tetrodotoxin (TTX)-sensitive Na) + current, TTX-resistant Na + current, and Ca 2+(Currently in the action potentials of nociceptive sensory neurons. J Neurosci 2002,22:10277-10290.) suggests that although both Nav1.8 and Nav1.9 are expressed in DRG, Nav1.8 contributes the most to TTX-R current. In the acute phase of nerve injury, Nav1.8 is downregulated in damaged neurons but upregulated in neighboring undamaged neurons, thereby increasing spontaneous firing. In the chronic phase, crosstalk occurs between damaged and undamaged neurons, leading to upregulation of Nav1.8 in damaged neurons, which further increases and maintains idiopathic firing.In addition to mechanistic studies, the efficacy of Nav1.8 inhibitors in animal models of pain has also been validated: for example, Abbott's A-803467 showed an analgesic effect of more than 50% compared to the model groups in carrageenan, complete Freund's adjuvant (CFA), chronic sciatic nerve compression pain (CCI), spinal nerve ligation pain (SNL), and acute mechanical pain models (Michael F. Jarvis, Prisca Honore, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. PNAS, 2007, 104(20):8520-8525.); and A-803467 showed better efficacy than lidocaine when administered systemically in a streptozotocin (STZ)-induced diabetic neuropathic thermal pain model, while the two were comparable when administered via local plantar injection, but A-803467 maintained its efficacy for a longer period (Mert). T, Gunes Y. Antinociceptive activities of lidocaine and the nav1.8 blocker a803467 in diabetic rats. J Am Assoc Lab Anim Sci. 2012; 51(5):579-585.); Pfizer's PF-01247324 also showed significant pain relief in CFA and SNL models (Payne CE, Brown AR, Theile JW, et al. A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability. Br J Pharmacol. 2015; 172(10):2654-2670.). Most importantly, Vertex's highly selective Nav1.8 inhibitor VX150 has been successful in three pain-related phase II clinical trials. In conclusion, Nav1.8 is a very promising target for treating pain or pain-related diseases.

[0006] Table 1. Overview of Navs subtypes

[0007] Currently, there are not many companies reporting on Nav1.8 inhibitors in development. Internationally, these include Abbott, Pfizer (WO2013114250A1), Gilead (AU2015224425A1), Sumitomo (WO2015008861A1), AbbVie (WO2016149169A1), Raqualia (WO2020138271A1), Merck (WO2020092187A1), Lieber (WO2020014243A1), and Vertex (WO2019014352A1). Domestically, these include Hengrui (WO2020151728A1) and Shanghai Jiyu Pharmaceutical (CN111808019A). Most of the companies' patents did not disclose the specific inhibitory activity of Nav1.8, or the activity was not good. Only Pfizer's PF-04531083 and Vertex's VX-150 and VX-548 entered Phase II clinical trials. PF-04531083 was discontinued because it did not show superior activity to placebo in postoperative toothache. VX-150 was successful in three Phase II clinical trials for inflammatory pain, postoperative acute pain, and neuropathic pain, providing preliminary validation of Nav1.8's role in pain. However, according to Vertex's official report, its development has been discontinued due to unsatisfactory pharmacokinetic (PK) properties, while VX-548 is currently undergoing Phase III clinical trials. Therefore, the development of new Nav1.8 inhibitors remains promising and essential. Summary of the Invention

[0008] The purpose of this invention is to provide an intermediate for the synthesis of Nav1.8 inhibitors, as well as a method for preparing the intermediate and its uses.

[0009] On one hand, the present invention provides a method for preparing a compound of formula (I), the method comprising: reacting a compound of formula (Ia) and a compound of formula (Ib) in a reaction solvent in the presence of a condensing agent and an acid-binding agent to prepare a compound of formula (I).

[0010] in,

[0011] Ring A is benzene, a 5-6 membered heterocyclic group, or a 5-10 membered heteroaryl group, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N or O;

[0012] R1 is a halogen, C 1-5 Alkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Halogenated alkoxy or C 3-6 cycloalkyl;

[0013] Y is a halogen;

[0014] T is benzyl, or has 1, 2, or 3 carbon atoms. 1-3 Alkoxy-substituted benzyl, C 1-3 Alkyl, hydroxyl, or amino;

[0015] n is 0, 1, 2, 3, or 4.

[0016] In some embodiments, ring A is benzene, a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group, or... The 5-6 membered heteroaryl or 5-6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N or O; wherein ring B is benzene, a 5-6 membered heteroaryl or 5-6 membered heterocyclic group, and the 5-6 membered heteroaryl or 5-6 membered heterocyclic group contains 1, 2 or 3 heteroatoms selected from N or O; X is CH or N.

[0017] In some embodiments, ring A is benzene, pyridine, pyrazine, pyridazine, pyrimidine, pyran, tetrahydropyran, furan, or tetrahydrofuran.

[0018] In some implementations, ring A is Where ring B is benzene, pyridine, pyrazine, pyridazine, pyrimidine, pyran, tetrahydropyran, pyrrole, pyrazole, imidazole, pyrrolidine, pyran, tetrahydropyran, cyclopentyl, cyclohexyl, or cycloheptyl; X is CH or N.

[0019] In some implementation schemes, yes

[0020] In some implementation schemes, yes X is CH or N.

[0021] In some implementations, R1 is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, cyclopropyl, or cyclobutyl.

[0022] In some embodiments, R1 is a halogen, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy, or cyclopropyl.

[0023] In some embodiments, T is benzyl, p-methoxybenzyl, o-methoxybenzyl, m-methoxybenzyl, methyl, ethyl, isopropyl, or tert-butyl.

[0024] In some implementations, T is benzyl, methyl, or ethyl.

[0025] In some embodiments, the compound of formula (I) has the structure shown in formula (IIIc), and the preparation method of the compound of formula (IIIc) includes: reacting the compounds of formula (IIIa) and (IIIb) in a reaction solvent in the presence of a condensing agent and an acid-binding agent to prepare the compound of formula (IIIc).

[0026] For the preparation of compounds of formula (I) or (IIIc), in some embodiments, the reaction optionally contains a catalyst, and in some embodiments, the catalyst is N,N-dimethylformamide.

[0027] On the other hand, the present invention provides a specific method for preparing the compound shown in formula (I), the method comprising the following steps:

[0028] Step (i): Add the compound of formula (Ⅰb), catalyst, and condensing agent to the reaction solvent. After the reaction is complete, solution 1 is obtained.

[0029] Step (ii): Add the compound of formula (Ⅰa) and the acid-binding agent to the reaction solvent to obtain solution 2. Add solution 1 to solution 2. After the reaction is complete, the compound of formula (Ⅰ) is obtained.

[0030] In some embodiments, the molar ratio of compound (Ib) to catalyst in step (i) is 1:(0.3–0.6), the molar ratio of compound (Ib) to condensing agent is 1:(1–1.5), the reaction temperature is 10–25°C, and the reaction time is 1–3 h. In some embodiments, the molar ratio of compound (Ia) to compound (Ib) in step (ii) is (1–1.5):1, the molar ratio of acid-binding agent to compound (Ib) is (1.5–2.5):1, the reaction temperature is 0–25°C, and the reaction time is 0.5–3 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0031] In some embodiments, the molar ratio of compound (Ib) to catalyst in step (i) is 1:(0.3–0.6), the molar ratio of compound (Ib) to condensing agent is 1:(1–1.5), the reaction temperature is 10–20°C, and the reaction time is 1–3 h. In some embodiments, the molar ratio of compound (Ia) to compound (Ib) in step (ii) is (1–1.5):1, the molar ratio of acid-binding agent to compound (Ib) is (1.5–2.5):1, the reaction temperature is 15–25°C, and the reaction time is 1–3 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0032] On the other hand, the present invention provides a specific method for preparing a compound of formula (Ⅲc), comprising the following steps:

[0033] Step (i): Add the compound of formula (Ⅲb) and the catalyst to the reaction solvent, then add the condensing agent. After the reaction is complete, solution 1 is obtained.

[0034] Step (ii): Add compound (Ⅲa) and acid-binding agent to the reaction solvent to obtain solution 2. Add solution 1 to solution 2. After the reaction is complete, compound (Ⅲc) is obtained.

[0035] In some embodiments, the molar ratio of compound (Ⅲb) to catalyst in step (i) is 1:(0.3–0.6), the molar ratio of compound (Ⅲb) to condensing agent is 1:(1–1.5), the reaction temperature is 10–25°C, and the reaction time is 1–3 h. In some embodiments, the molar ratio of compound (Ⅲa) to compound (Ⅲb) in step (ii) is (1–1.5):1, the molar ratio of acid-binding agent to compound (Ⅲb) is (1.5–2.5):1, the reaction temperature is 0–25°C, and the reaction time is 0.5–3 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0036] In some embodiments of the preparation method of compound (I) or compound (IIIc), the condensing agent is selected from any one or a mixture of any number of oxaloyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfoxide, or pentanoyl chloride in any proportion; in some embodiments, the condensing agent is oxaloyl chloride and sulfoxide; in some embodiments, the condensing agent is oxaloyl chloride.

[0037] In some embodiments, the acid-binding agent is selected from any one or a mixture of any proportions of Na2CO3, K2CO3, NaOH, KOH, NaHCO3, KHCO3, triethylamine, pyridine, N,N-diisopropylethylamine, N-methylmorpholine, or 4-dimethylaminopyridine; in some embodiments, the acid-binding agent is triethylamine.

[0038] In some embodiments, the reaction solvent is selected from any one or a mixture of any proportions of dichloromethane, tetrahydrofuran, dimethyl sulfoxide, 1,2-dichloroethane, N-methylpyrrolidone, or acetonitrile; in some embodiments, the reaction solvent is dichloromethane.

[0039] On the other hand, the present invention also provides a method for preparing a compound of formula (Ia), wherein the method comprises reacting a compound of formula (Ia-1) and a compound of formula (Ia-2) in a reaction solvent under the presence of a base to prepare a compound of formula (Ia).

[0040] Where Y is F, Cl, or Br; T is benzyl.

[0041] In some implementations, Y is F and T is benzyl.

[0042] In some embodiments, the compound of formula (Ia) has the structure shown in formula (IIIa), and the method for preparing the compound of formula (IIIa) includes reacting a compound of formula E1 with benzyl mercaptan in a reaction solvent in the presence of a base to prepare the compound of formula (IIIa).

[0043] For the preparation of compounds of formula (Ia) or (IIIa), in some embodiments, the base is selected from any one or any mixture of several of Cs2CO3, K2CO3, potassium tert-butoxy, sodium hydroxide, and potassium hydroxide in any proportion, and in some embodiments, the base is Cs2CO3.

[0044] In some embodiments, the reaction solvent is selected from any one or a mixture of any proportions of N,N-diisopropylethylamine, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and 1,3-dimethylimidazolin-2-one. In some embodiments, the reaction solvent is N-methylpyrrolidone.

[0045] In some embodiments, the molar ratio of the compound of formula (Ia-1) to benzyl mercaptan is 1:1 to 2.5, the molar ratio of the compound of formula (Ia-1) to the base is 1:3 to 6, the reaction temperature is 120 to 150°C, and the reaction time is 8 to 12 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0046] In some embodiments, the molar ratio of the E1 compound to benzyl mercaptan is 1:1 to 2.5, the molar ratio of the E1 compound to the alkali is 1:3 to 6, the reaction temperature is 120 to 150°C, and the reaction time is 8 to 12 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0047] On the other hand, the present invention also provides an intermediate compound having the structure shown in formula (I):

[0048] The definitions of rings A, R1, Y, T, and n are the same as before.

[0049] On the other hand, the present invention also provides an intermediate compound with the structure shown in formula (I-1):

[0050] The definitions of R1, X, Y, T, and n are the same as before.

[0051] In some implementations, the intermediate compound is one of the following compounds:

[0052] On the other hand, the present invention also provides the use of the compound of formula (I) as an intermediate in the preparation of Nav1.8 inhibitors, the structure of which is shown in formula (II):

[0053] Among them, the definitions of rings A, R1, and n are the same as before;

[0054] R4 and R5 are each independently selected from H or C. 1-3 alkyl;

[0055] m is 1, 2, 3, 4 or 5;

[0056] R6 is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, hydroxyl, oxo, or cyano groups;

[0057] p is 0, 1, 2 or 3.

[0058] On the other hand, the present invention also provides the use of the compound of formula (I) as an intermediate in the preparation of Nav1.8 inhibitors, the structure of which is shown in formula (II-1):

[0059] The definitions of X, R1, n, R4, and R5 are the same as before;

[0060] R2 and R3 are each independently selected from H or halogens.

[0061] On the other hand, the present invention also provides a method for preparing a compound of formula (IIa), wherein the compound of formula (I) prepared by the method of the present invention is used as a raw material, and reacted with an oxidizing halogenating agent under solvent conditions and in the presence of an acid to obtain a compound of formula (IIa).

[0062] Among them, rings A, Y, R1, T, and n are defined as before, and Rx is chlorine, bromine, or iodine.

[0063] In some embodiments, the compound of formula (IIa) has the structure shown in formula (IIId), wherein the compound of formula (IIId) is reacted with an oxidizing halogenating agent under solvent conditions and in the presence of an acid, using the compound of formula (IIIc) prepared by the aforementioned method as a starting material, to obtain the compound of formula (IIId).

[0064] In some embodiments of the preparation method of compound (IIa) or compound (IIId), the oxidizing halogenator is selected from any one or a mixture of any number of dichlorohydantoin, dibromohydantoin, diiodohydantoin, 1,3-dichloro-5-methyl-5-ethylhydantoin, or sodium hypochlorite in any proportion; in some embodiments, the oxidizing halogenator is dichlorohydantoin; in some embodiments, the solvent is selected from any one or a mixture of any number of acetonitrile, dichloromethane, water, methyl tert-butyl ether, or dichloromethane in any proportion; in some embodiments, the solvent is acetonitrile; in some embodiments, the acid is a C1-C5 fatty acid; in some embodiments, the acid is acetic acid, formic acid, propionic acid, isopropionic acid, butyric acid, isobutyric acid, valeric acid, or isovaleric acid; in some embodiments, the acid is acetic acid.

[0065] In some embodiments, the molar ratio of compound (I) to oxidative halogenating agent is 1:(2-4), the molar ratio of compound (I) to C1-C5 fatty acid is 1:(6-18), the oxidative halogenation reaction temperature is -5 to 35°C, and the reaction time is 1 to 3 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0066] In some embodiments, the molar ratio of the compound of formula (Ⅲc) to the oxidizing halogenating agent is 1:(2-4), the molar ratio of the compound of formula (Ⅲc) to the acid is 1:(6-18), the oxidizing halogenation reaction temperature is -5 to 35°C, and the reaction time is 1 to 3 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0067] On the other hand, the present invention also provides a method for preparing a compound of formula (IIc), using a compound of formula (IIa) prepared by the method of the present invention as a raw material, reacting it with NH(Ra)(Rb) under solvent conditions, and when Ra or Rb is an amino protecting group, undergoing a deprotection reaction to obtain a compound of formula (IIc).

[0068] Ra and Rb are each independently selected from H, methyl, ethyl or amino protecting groups, and the rings A, Y, R1, T, n, Rx, R4 and R5 are defined as before.

[0069] The term "amino protecting group" is used to protect the amino group by means of an easily removable group, so that the amino group remains unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, benzoyl (Bz), tetrahydropyranyl, dimethylimine, tert-butoxycarbonyl, acetyl, benzyl, allyl, benzyloxycarbonyl, p-methylbenzenesulfonyl, p-methoxybenzyl, phthaloyl, etc.

[0070] In some embodiments, the amino protecting group is benzyl, tert-butoxycarbonyl, p-methoxybenzyl, benzyloxycarbonyl, or p-toluenesulfonyl.

[0071] In some embodiments, the NH(Ra)(Rb) is NH3, and in some embodiments, it is added in the form of ammonia.

[0072] In some embodiments, the compound of formula (IIc) has the structure shown in formula (IIIe), and the compound of formula (IIIe) is prepared from the compound of formula (IIId) obtained by the aforementioned method, and reacted with ammonia water under solvent conditions to obtain the compound of formula (IIIe).

[0073] For the preparation of compounds of formula (IIc) or (IIIe), in some embodiments, the solvent is selected from any one or a mixture of any number of acetonitrile, dichloromethane, water, methyl tert-butyl ether, and dichloromethane in any proportion; in some embodiments, the solvent is acetonitrile.

[0074] In some embodiments, the molar ratio of compound (IIa) to compound (IIb) is 1:(1–80), the reaction temperature is -5–5°C, and the reaction time is 1.5–3 h; in other embodiments, the molar ratio of compound (IIa) to compound (IIb) in step (b) is 1:(30–50), the reaction temperature is -5–5°C, and the reaction time is 1.5–3 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0075] In some embodiments, the molar ratio of the compound of formula (Ⅲd) to ammonia is 1:(1-80), the reaction temperature is -5 to 5°C, and the reaction time is 1.5 to 3 hours; in other embodiments, the molar ratio of the compound of formula (Ⅲd) to ammonia is 1:(30-50), the reaction temperature is -5 to 5°C, and the reaction time is 1.5 to 3 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0076] On the other hand, the present invention also provides a method for preparing a compound of formula (II), wherein the compound of formula (IIc) obtained by the preparation method of the present invention is used as a raw material, and reacted with a salt of compound (IId) in the presence of an alkali under solvent conditions to obtain compound (II).

[0077] The definitions of rings A, Y, R1, T, n, R4, R5, R6, m, and p are the same as before.

[0078] In some embodiments, the compound of formula (II) has the structure shown in formula (III), and the compound of formula (III) is further reacted with a salt of the compound of formula (IIIe) in the presence of a base under solvent conditions to give the compound of formula (III).

[0079] In some embodiments of the preparation method of compound (II) or compound (III), the base is selected from any one or a mixture of any number of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, K2CO3, and Cs2CO3 in any proportion; in some embodiments, the base is N,N-diisopropylethylamine. In some embodiments, the solvent is selected from any one or a mixture of any number of N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide in any proportion; in some embodiments, the solvent is N-methylpyrrolidone.

[0080] In some embodiments, the molar ratio of compound (IIc) to alkali is 1:(4-6), the molar ratio of compound (IIc) to salt of compound (IId) is 1:(1.3-1.65), the reaction temperature is 110-150℃, and the reaction time is 7-12 h. In other embodiments, the molar ratio of compound (IIc) to alkali is 1:(4-6), the molar ratio of compound (IIc) to salt of compound (IId) is 1:(1.3-1.6), the reaction temperature is 110-150℃, and the reaction time is 7-10 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0081] In some implementation schemes, the molar ratio of compound (Ⅲe) to alkali is 1:(4-6), the molar ratio of compound (Ⅲe) to salt of compound (Ⅲf) is 1:(1.3-1.65), the reaction temperature is 110-150℃, and the reaction time is 7-12h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0082] On the other hand, the present invention also provides a more specific method for preparing the Nav1.8 inhibitor shown in formula (III), comprising the following steps:

[0083] Wherein, the compound of formula (Ⅲf) is in the form of a salt, preferably a hydrochloride salt.

[0084] In some embodiments, the method for preparing the Nav1.8 inhibitor shown in formula (III) includes the following steps:

[0085] Step (1): Add compound (Ⅲb) and N,N-dimethylformamide to dichloromethane, stir, add oxaloyl chloride, concentrate after the reaction is complete, add dichloromethane with distillation, continue to concentrate, and then add dichloromethane to dissolve to obtain solution 1;

[0086] Compound (Ⅲa) and triethylamine were added to dichloromethane to obtain solution 2. Solution 1 was added to solution 2 and stirred. After the reaction was complete, water was added and stirred. Then n-heptane was added and stirred. After centrifugation, the filter cake was rinsed with water and then rinsed with a mixed solution of dichloromethane and n-heptane. After centrifugation, the filter cake was collected and dried to obtain compound (Ⅲc).

[0087] Step (2): Add compound (Ⅲc) and acetic acid to acetonitrile, add dichlorohydantoin, add water after the reaction is complete, stir, centrifuge, and compound (Ⅲd);

[0088] Step (3): Add ammonia and acetonitrile to the reactor, add compound (Ⅲd), after the reaction is complete, add water, stir to crystallize, centrifuge, slurry the filter cake with acetonitrile, centrifuge, collect the filter cake, and dry-explode to obtain compound (Ⅲe).

[0089] Step (4): Add the compound of formula (IIIe), the salt of the compound of formula (IIIf), and N,N-diisopropylethylamine to N-methylpyrrolidone. After the reaction is complete, reaction solution 1 is obtained. Add reaction solution 1 to water or a mixture of water and ethanol, stir, filter, add the filter cake to dichloromethane, slurry, filter, and dry the filter cake to obtain compound of formula (III).

[0090] In some embodiments, the molar ratio of compound (IIIb) to N,N-dimethylformamide in step (1) is 1:(0.3–0.6), the molar ratio of compound (IIIb) to oxalyl chloride is 1:(1–1.5), the reaction temperature is 10–25°C, and the reaction time is 1–3 h. In some embodiments, the molar ratio of compound (IIIa) to compound (IIIb) in step (1) is (1–1.5):1, the molar ratio of triethylamine to compound (IIIb) is (1.5–2.5):1, the reaction temperature is 0–25°C, and the reaction time is 0.5–3 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0091] In some embodiments, the molar ratio of compound (IIIb) to N,N-dimethylformamide in step (1) is 1:(0.3–0.6), the molar ratio of compound (IIIb) to oxalyl chloride is 1:(1–1.5), the reaction temperature is 10–20°C, and the reaction time is 1–3 h. In some embodiments, the molar ratio of compound (IIIa) to compound (IIIb) in step (1) is (1–1.5):1, the molar ratio of triethylamine to compound (IIIb) is (1.5–2.5):1, the reaction temperature is 15–25°C, and the reaction time is 1–3 h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0092] In some implementations, the volume ratio of dichloromethane to n-heptane in step (1) is 1:(1-3). Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0093] In some implementation schemes, the molar ratio of compound (Ⅲc) to dichlorohydantoin in step (2) is 1:(2-4), the molar ratio of compound (Ⅲc) to acetic acid is 1:(6-18), the oxidative halogenation reaction temperature is -5 to 35°C, and the reaction time is 1 to 3 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0094] In some embodiments, the molar ratio of compound (Ⅲd) to ammonia in step (3) is 1:(1-80), the reaction temperature is -5 to 5°C, and the reaction time is 1.5 to 3 hours; in other embodiments, the molar ratio of compound (Ⅲd) to ammonia in step (3) is 1:(30-50), the reaction temperature is -5 to 5°C, and the reaction time is 1.5 to 3 hours. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0095] In some embodiments, the molar ratio of compound (Ⅲe) to N,N-diisopropylethylamine in step (4) is 1:(4-6), the molar ratio of compound (Ⅲe) to the salt of compound (Ⅲf) is 1:(1.3-1.6), the reaction temperature is 110-150℃, and the reaction time is 7-10h. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0096] In some implementations, in step (4) the water and ethanol mixed solution, the volume ratio of water to ethanol is (7-14):1. Under the above process conditions or parameters, the same or similar technical effects can be achieved.

[0097] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0098] 1. This invention provides the compound shown in formula (Ⅰ), which can be used to synthesize the Nav1.8 inhibitor shown in formula (Ⅱ). It is a new intermediate for the synthesis of Nav1.8 inhibitor. The method for preparing Nav1.8 inhibitor using this intermediate as a raw material is simple, the reaction conditions are mild, the post-processing and purification are simple, and the conversion rate is high.

[0099] 2. The present invention provides a method for preparing the compound shown in formula (Ⅰ), which enables the compound of formula (Ⅰa) and formula (Ⅰb) to undergo amide condensation easily with high yield. Detailed Implementation

[0100] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0101] Terminology Explanation

[0102] Alkyl or alkane are fully saturated straight-chain or branched non-aromatic hydrocarbons. Generally, unless otherwise defined, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also called "lower alkyl groups".

[0103] Furthermore, as used throughout the specification, examples, and claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent that replaces hydrogen on one or more carbons of the hydrocarbon backbone. Unless otherwise specified, such substituents may include, for example, halogens, hydroxyl groups, carbonyl groups (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (such as thioesters, thioacetate, or thioformate), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphonites, amino groups, amide groups, amidines, imines, cyano groups, nitro groups, azides, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic moiety components. Those skilled in the art will understand that, where appropriate, the substituted portion on the hydrocarbon chain may itself be substituted. For example, the substituents of the substituted alkyl group may include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphonite), sulfonyl (including sulfate, sulfonamide, aminosulfonyl and sulfonate), and silyl, as well as substituted and unsubstituted forms of ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylic esters and esters), -CF3, -CN, etc.

[0104] The cycloalkyl group preferably has 3-7 ring carbon atoms and can be in substituted or unsubstituted form. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, or methylcyclopentyl. The cycloalkyl group can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0105] A heteroaryl group is an aromatic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, and is either monocyclic or bicyclic. Monocyclic heteroaryl groups include 5- to 8-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Bicyclic heteroaryl groups include 9- or 10-membered fused-ring heteroaryl groups. Examples of heteroaryl groups include pyrroleyl, thiopheneyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and benzo[a]-fused derivatives of these monocyclic heteroaryl groups, such as indolyl, benzimidazolyl, or benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, or purineyl.

[0106] In the optionally substituted heteroaryl group, the substituent is preferably a lower alkyl group, a lower alkoxy group, a lower alkoxy-lower alkoxy group, an amino group, and is optionally substituted by one or two substituents selected from lower alkyl groups, lower alkenyl groups, and alkyl carbonyl groups, halogenated lower alkyl groups, lower alkoxy-lower alkyl groups, halogens, or nitro groups.

[0107] Heterocyclic groups preferably represent saturated, partially saturated, or unsaturated monocyclic or bicyclic rings containing 4-10 atoms, including 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, they can be carbon or nitrogen-linked, wherein the cyclic nitrogen atom may optionally be substituted by a group selected from lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, and acyl groups, and the cyclic carbon atom may be substituted by lower alkyl, amino-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, lower alkoxy, hydroxyl, or oxo-substituted groups. Examples of heterocyclic groups include pyrrolidinyl, oxazolyl, thiazolyl, piperidinyl, morpholinyl, piperazine, dioxopentyl, or tetrahydropyranyl.

[0108] A haloalkyl group refers to an alkyl group that is substituted with at least one halogen, preferably a halogen-lower alkyl group, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl or pentafluoroethyl.

[0109] Halogens are fluorine, chlorine, bromine or iodine.

[0110] Lower alkoxy groups, especially methoxy, ethoxy, isopropoxy, or tert-butoxy.

[0111] Bn is benzyl.

[0112] PMB is a methoxybenzyl group.

[0113] Catalytic amount refers to the amount of catalyst used in a chemical reaction, and its value is less than one molar equivalent. In some embodiments, the catalytic amount includes, but is not limited to, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, and 0.7 molar equivalents.

[0114] The comparative examples, screening examples, or embodiments of this invention involve the following LCMS (high performance liquid chromatography-mass spectrometry) detection method:

[0115] 1. Instrument: LC / MS (Model: I-Class Plus / QDa)

[0116] 2. Detection method:

[0117] (1) Chromatographic column: Waters ACQUITY UPLC BEH C18 1.7μm 2.1*50mm

[0118] (2) Mobile phase

[0119] (3) Detection methods and chromatographic conditions

[0120] Flow rate: 0.3 mL / min; Column temperature: 35℃; Detection wavelength: 210 nm~400 nm

[0121] gradient:

[0122] Comparative Example 1

[0123] N,N-dimethylformamide (2.0 mL) was added to the reaction tube, and stirring was started. Then, 2-chloroquinoline-3-carboxylic acid (compound (IIIb)) (100.0 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (202.1 mg), and N,N-diisopropylethylamine (124.9 mg) were added sequentially. The mixture was stirred at 20-30 °C for 30 min, and then 4-aminopyridine-2-sulfonic acid ammonium (83.5 mg) was added. The reaction was continued for 15 h. LC-MS analysis showed that the target product, 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide, was not detected.

[0124] Comparative Example 2

[0125] Tetrahydrofuran / dichloromethane (1.0 mL / 1.0 mL) was added to the reaction tube, and stirring was started. 2-chloroquinoline-3-carboxylic acid (compound (IIIb)) (30.0 mg), oxalyl chloride (1.0 mL), and N,N-diisopropylethylamine (112.4 mg) were added sequentially. The mixture was stirred at 20-30 °C for 30 min, and then 4-aminopyridine-2-sulfonic acid ammonium (12.5 mg) was added. The reaction was continued with stirring for 1 h. LC-MS analysis showed that less than 10% of the target product, 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide, was formed.

[0126] Comparative Example 3

[0127] N,N-dimethylformamide (2.0 mL) was added to the reaction tube, and stirring was started. Then, 2-chloroquinoline-3-carboxylic acid (compound (IIIb)) (50.0 mg), cuprous iodide (23.0 mg), N,N,N',N'-tetramethylethylenediamine (28.0 mg), and 4-aminopyridine-2-sulfonic acid (50.1 mg) were added sequentially. The mixture was heated to 110-120 °C and reacted for 39 h. LC-MS analysis showed that the target product, 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide, was not detected.

[0128] Comparative Example 4

[0129] Tetrahydrofuran / dichloromethane (1.0 mL / 1.0 mL) was added to the reaction tube, and stirring was started. 2-Chloroquinoline-3-carboxylic acid (compound (IIIb)) (30.0 mg), oxalyl chloride (1.0 mL), and N,N-diisopropylethylamine (112.4 mg) were added sequentially. The mixture was stirred at 20-30 °C for 30 min, and then 4-aminopyridine-2-sulfonic acid bis-(4-methoxybenzyl)-amide (29.9 mg) was added. The reaction was continued with stirring for 1 h. The target product was detected by LC-MS at less than 10%. The reaction solution was quenched with saturated sodium chloride solution, extracted with ethyl acetate, dried over saturated sodium sulfate solution, concentrated, and separated by thin-layer chromatography. The target product was not obtained after column chromatography.

[0130] Comparative Example 5

[0131] 2-Chloroquinoline-3-carboxylic acid (compound of formula (IIIb)) (100.0 mg), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU) (200.9 mg), 4-aminopyridine-2-sulfonic acid (83.4 mg), and N,N-dimethylformamide (2.0 mL) were added sequentially to a three-necked flask. Stirring was started, and the temperature was lowered to 0–10 °C. N,N-diisopropylethylamine (124.5 mg) was then added, and the mixture was allowed to rise naturally to room temperature with stirring for 15 h. LC-MS analysis showed no detection of the target product.

[0132] Comparative Example 6

[0133] 30.0 mg of 2-chloroquinoline-3-carboxylic acid (compound (IIIb)) and 1 mL of tetrahydrofuran were added sequentially to a three-necked flask. Stirring was started, and the temperature was lowered to 0–10 °C. Oxaloyl chloride (1.0 mL) was added dropwise, and the temperature was naturally raised to 20–30 °C. The reaction solution was concentrated, and tetrahydrofuran (2 mL) was added with distillation to obtain a yellow solid. 30 mg of 4-aminopyridine-2-sulfonic acid bis-(4-methoxybenzyl)-amide was dissolved in 1 mL of dichloromethane. N,N-diisopropylethylamine (112 mg) was added, and the temperature was lowered to 0–10 °C. The above solution of the yellow solid in 1 mL of dichloromethane was then added dropwise, and the temperature was naturally raised to 20–30 °C. The reaction was continued with stirring for 1 h. LC-MS analysis showed that less than 10% of the target product was formed.

[0134] Comparative Example 7

[0135] Comparative Example 7-1: To 2-(4,4-difluoroaza) A solution of 100 mg of quinoline-3-carboxylic acid (1-1-yl)quinoline-3-carboxylic acid in dichloromethane (1.0 mL) was added with 44.5 mg of oxalyl chloride and N,N-dimethylformamide (catalytic amount), and stirred at 25 °C for 10 min. After the starting material disappeared, the solution was concentrated under reduced pressure to remove excess oxalyl chloride and solvent, yielding a yellow oily substance. This oil was dissolved in dichloromethane (1 mL), and then N,N-diisopropylethylamine (127.1 mg) and 2-(benzylthio)pyridine-4-amine (85.77 mg) were added. The solution was stirred overnight at 25 °C. TLC (petroleum ether / ethyl acetate = 5 / 1) analysis was performed, but the target product was not obtained.

[0136] Comparative Example 7-2: To 2-(4,4-difluoroaza) A solution of 1,1-yl)quinoline-3-carboxylic acid (101 mg) in dichloromethane (1.0 mL) was added with oxalyl chloride (44.5 mg) and N,N-dimethylformamide (catalytic amount), and stirred at 25 °C for 10 min. After the starting material disappeared, the solution was concentrated under reduced pressure to remove excess oxalyl chloride and solvent, yielding a yellow oily substance. This oil was dissolved in dichloromethane (1 mL), followed by the addition of triethylamine (303.61 mg) and 2-(benzylthio)pyridine-4-amine (85.1 mg), and stirred at 25 °C for 3.5 h. TLC (petroleum ether / ethyl acetate = 5 / 1) analysis was performed, but the target product was not obtained.

[0137] Screening Example 1

[0138] To a solution of 100 mg of 2-chloro-3-quinolinecarboxylic acid in dichloromethane (2 mL), 91.71 mg of oxaloyl chloride and N,N-dimethylformamide (catalytic amount) were added sequentially. The mixture was stirred at 25 °C for 30 min, concentrated under reduced pressure to remove the solvent, and then dissolved in dichloromethane (2 mL) for later use. To a solution of 125 mg of 2-(benzylthio)pyridine-4-amine in dichloromethane (1 mL), N,N-diisopropylethylamine (124.6 mg) was added. The mixture was cooled to 0–5 °C, and the intermediate solution was slowly added to the above solution. The reaction was carried out at 0–5 °C for 1 h. After 1 h, the starting material disappeared, and the target product LCMS ratio was 73.26%.

[0139] Screening Example 2

[0140] Screening Example 2-1: Add acetic acid (2 ml) and water (2 ml) sequentially to a solution of 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (1.0 g) in acetonitrile (10 mL), and cool to 0-10 °C.

[0141] ① Add dichlorohydantoin (1.0 eq, 0.52 g) to the above solution, stir for 30 min, continue to add dichlorohydantoin (1.0 eq, 0.53 g) to the above solution, stir for 30 min, take a sample, add ammonia water to quench, and the LCMS ratio of the target product is 76.57%;

[0142] ② Continue to add dichlorohydantoin (1.0 eq, 0.46 g) to the above solution, stir for 30 min, take a sample, add ammonia water to quench, and the LCMS ratio of the target product is 78.33%;

[0143] ③ Continue to add dichlorohydantoin (1.0 eq, 0.52 g) to the above solution, stir for 30 min, take a sample and add ammonia water to quench, and the LCMS ratio of the target product is 79.90%.

[0144] Screening Example 2-2: At room temperature, dichloromethane (5 mL), acetic acid (1 mL), water (1 mL), and 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (0.5 g) were added to a reaction flask. The mixture was stirred and then cooled to 0–10 °C. Dichlorohydantoin (0.728 g) was then added, and the reaction was maintained at 0–10 °C for 1 h. The reaction was quenched with ammonia water, and the LCMS ratio of the target product was found to be 79.83%.

[0145] Screening Example 2-3: At room temperature, methyl tert-butyl ether (5 mL), acetic acid (1 mL), water (1 mL), and 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (0.5 g) were added to a reaction flask. The mixture was stirred and then cooled to 0–10 °C. Dichlorohydantoin (0.728 g) was then added, and the mixture was kept at 0–10 °C for 1 h. The reaction was quenched with ammonia water, and the LCMS ratio of the target product was found to be 75.40%.

[0146] Screening Example 2-4: At room temperature, acetic acid (9 mL), water (45 mL), and 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (4.48 g) were added to a reaction flask. Stirring was started, and the temperature was lowered to 0–10 °C. Then, dichlorohydantoin (6.48 g) was added, and the reaction was maintained at 0–10 °C for 1 h. Ammonia was added to quench the reaction, and the LCMS ratio of the target product was measured to be 87.76%. The reaction was continued for another 2 h, and the LCMS ratio of the target product was measured to be 86.74%.

[0147] Screening Example 2-5: At room temperature, acetonitrile (10 mL), acetic acid (2 mL), water (2 mL), and 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (1.00 g) were added to the reaction flask. Stirring was started, and then the temperature was lowered to 0-10 °C. Then, dichlorohydantoin (1.46 g) was added, and the temperature of the reaction solution was raised to 35 °C. After reacting for 2 h, ammonia water was added to quench the reaction. The LCMS ratio of the target product was 77.88%.

[0148] Screening Example 3

[0149] Screening Example 3-1: Water (500 mL) and acetic acid (100 mL) were added to an acetonitrile (250 mL) solution of 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (50 g). The temperature was lowered to 0–5 °C, and dichlorohydantoin (3.0 eq, 72.86 g) was slowly added. After the reaction starter disappeared, ammonia water (2 V, 100 mL) was added under controlled temperature. The reaction was allowed to proceed overnight, and the LCMS ratio of the target product was found to be 86.32%.

[0150] Screening Example 3-2: Acetic acid (4.43 g) was added to an acetonitrile (50 mL) solution of 2-chloroquinoline-3-carboxylic acid (2-benzylaminopyridin-4-yl)-amide (5 g), the temperature was lowered to 0-5 °C, and dichlorohydantoin (3.0 eq, 7.28 g) was slowly added. After the reaction starter disappeared, ammonia water (4 V, 20 mL) was added under controlled temperature. The reaction was carried out for 2 h, and the LCMS ratio of the target product was found to be 86.45%.

[0151] Screening Example 4

[0152] Screening Example 4-1: 0.5 g of 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide (compound (IIIe)) was weighed and dissolved in 2.5 ml of N-methylpyrrolidone. 0.30 g of 4,4-difluoroazacycloheptane (compound (IIIf)) hydrochloride and 0.89 g of N,N-diisopropylethylamine were added sequentially. The mixture was heated to 130 °C and stirred for 11 h. The remaining raw material was 1.81%, and the LCMS ratio of the target product was 91.36%.

[0153] Screening Example 4-2: 15 g of 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide (compound (IIIe)) was weighed and dissolved in 75 ml of N-methylpyrrolidone. 9.92 g of 4,4-difluoroazacycloheptane (compound (IIIf)) hydrochloride and 26.75 g of N,N-diisopropylethylamine were added sequentially. The mixture was heated to 130 °C and stirred for 8 h. The remaining raw material was 0.45%, and the LCMS ratio of the target product was 89.84%.

[0154] Screening Example 4-3: 1 g of 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide (compound (IIIe)) was weighed and dissolved in 10 ml of N-methylpyrrolidone. 0.71 g of 4,4-difluoroazacycloheptane (compound (IIIf)) hydrochloride and 1.60 g of N,N-diisopropylethylamine were added sequentially. The mixture was heated to 130 °C and stirred for 8 h. 0.15% of the raw material remained. The LCMS ratio of the target product was 94.47%.

[0155] Screening Example 4-4: 5 g of 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide (compound (IIIe)) was dissolved in 25 ml of N-methylpyrrolidone. 3.90 g of 4,4-difluoroazacycloheptane (compound (IIIf)) hydrochloride and 8.9 g of N,N-diisopropylethylamine were added sequentially. The mixture was heated to 130 °C and stirred for 9 h. 0.44% of the raw material remained. The LCMS ratio of the target product was 91.94%.

[0156] Screening Example 4-5: 2 g of 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide (compound (IIIe)) was weighed and dissolved in 20 ml of N-methylpyrrolidone. 1.42 g of 4,4-difluoroazacycloheptane (compound (IIIf)) hydrochloride and 3.57 g of N,N-diisopropylethylamine were added sequentially. The mixture was heated to 130 °C and stirred overnight. The remaining raw material was 0.73%, and the LCMS ratio of the target product was 91.41%.

[0157] Example 1

[0158] Example 1-1: N,N-dimethylformamide (0.14 g) was added to a solution of 1.0000 g of 2-chloro-3-quinolinecarboxylic acid in dichloromethane (10 mL), followed by the slow addition of 0.6886 g of sulfoxide. The mixture was stirred at 10–25 °C for 3 hours and concentrated under reduced pressure to obtain a brown solid. This solid was dissolved in dichloromethane (5 mL) and set aside (Solution 1). Then, dichloromethane (5 mL), triethylamine (0.9786 g), and 2-(benzylthio)pyridine-4-amine (1.0951 g) were added to a reaction flask. The temperature was lowered to 0–10 °C, and Solution 1 was added. After the addition was complete, the mixture was stirred at 10–25 °C for 2 hours. Water (5 mL) was added to the reaction flask, and the mixture was stirred for 1 hour. Then, n-heptane (10 mL) was added, and the mixture was stirred for another 1 hour. The mixture was then filtered. The solid was dried and weighed to 1.11 g, with a purity of 68.757% and a yield of 39.04%.

[0159] Examples 1-2: Oxaloyl chloride (29.37 g) and N,N-dimethylformamide (catalytic amount) were added sequentially to a solution of 2-chloro-3-quinolinecarboxylic acid (32.01 g) in dichloromethane (400 mL). The mixture was stirred at 25 °C for 1 h, concentrated under reduced pressure to remove the solvent, and then dissolved in dichloromethane (500 mL) for later use. Triethylamine (31.18 g) was added to a solution of 2-(benzylthio)pyridine-4-amine (40.1 g) in dichloromethane (320 mL). The mixture was cooled to 0–5 °C, and the intermediate solution was slowly added to the above solution. The mixture was reacted at 0–5 °C for 30 min, and then processed to obtain 57.01 g, with a yield of 91%.

[0160] Examples 1-3: Oxaloyl chloride (22.02 g) and N,N-dimethylformamide (catalytic amount) were added sequentially to a solution of 2-chloro-3-quinolinecarboxylic acid (30.01 g) in dichloromethane (300 mL). The mixture was stirred at 25 °C for 2 h, concentrated under reduced pressure to remove the solvent, and then dissolved in dichloromethane (150 mL) for later use. Triethylamine (29.35 g) was added to a solution of 2-(benzylthio)pyridine-4-amine (32.80 g) in dichloromethane (150 mL). The mixture was cooled to 0–5 °C, and the intermediate solution was slowly added to the above solution. The mixture was reacted at 0–5 °C for 2 h, and then processed to obtain 55.1 g, with a yield of 93.95%.

[0161] Example 2

[0162] Add 12.0 L of dichloromethane to reactor 1, start stirring, and add 1200.0 g of 2-chloroquinoline-3-carboxylic acid (compound (IIIb)) and 168.0 g of N,N-dimethylformamide in sequence. Cool the mixture to below 20 °C. Slowly add 878.0 g of oxaloyl chloride dropwise to the system (controlling the rate of gas release). After the addition is complete, continue the reaction at 15 ± 5 °C for 2 h. After the reaction is qualified, concentrate (<50 °C, <-0.07 MPa) until no distillate flows out, and continue to concentrate for 30 min. After concentration, add 6.0 L of dichloromethane with distillation once, concentrate until no distillate flows out, and continue to concentrate for 5 min. Add 6.0 L of dichloromethane again to dissolve and set aside for later use. Label this solution 1.

[0163] Dichloromethane (6.0 L), 2-benzylthio-4-aminopyridine (compound of formula (IIIa)) (1308.0 g.), and triethylamine (1163.0 g.) were added sequentially to reactor 2. Solution 1 was slowly added dropwise to reactor 2 at a controlled temperature of 5±5 °C. After the addition was complete, the temperature was raised to 20±5 °C and the reaction was continued with stirring for 2 h. After the reaction was complete, water (6.0 L) was added to reactor 2 and stirred for 1 h. Then, n-heptane (12.0 L) was added and stirring was continued for 1 h. After centrifugation for 5 min, the filter cake was washed once with water (2.4 L) and once with a dichloromethane:n-heptane = 1:1 (3.6 L) solution. The filter cake was collected by centrifugation for 30 min and dried at 50 °C with forced air to constant weight to obtain the target product. Yield: 93.95%, purity: 99.30%.

[0164] Add acetonitrile (20.0 L) to reactor 1, start stirring, and continue adding acetic acid (4.0 L) and 2-chloroquinoline-3-carboxylic acid-(2-benzylaminopyridine-4)-amide (compound (IIIc)) (2000.0 g). Add dichlorohydantoin (2920.0 g) in batches at -5 to 5 °C, and maintain the temperature at -5 to 5 °C for 1 h. After the reaction is complete, add water (8.0 L), maintain the temperature at 15 to 25 °C, stir for 30 min, and centrifuge for 30-40 min to obtain a white solid 4-[(2-chloroquinoline-3-carbonyl)-amino]-pyridine-2-sulfonyl chloride (compound (IIId)), which is directly added to the next reaction step.

[0165] Ammonia (4.0 L) and acetonitrile (10.0 L) were added to reactor 2. The temperature was controlled at -5 to 5 °C. The above-mentioned off-white solid 4-[(2-chloroquinoline-3-carbonyl)-amino]-pyridine-2-sulfonyl chloride (compound (IIId)) was added in batches. After the addition was complete, the temperature was maintained at -5 to 5 °C for 2 h. H2O (26.0 L) was added to the system, and the mixture was stirred to crystallize for 1 h. After centrifugation for 20-30 min, the filter cake was slurried with acetonitrile (10.0 L) for 1 h and centrifuged for 30-40 min. The filter cake was collected and dried at 50 °C to constant weight to obtain compound (IIIe). The yield of the two-step reaction from compound (IIIc) to compound (IIIe) was 61.79%, and the purity of compound (IIIe) was 97.20%.

[0166] Add N-methylpyrrolidone (5.0 L) to reactor 1, start stirring, and then add 2-chloroquinoline-3-carboxylic acid-(2-sulfonamide-pyridine-4)-amide (compound (IIIe)) (1000.0 g), N,N-diisopropylethylamine (1780.0 g) and 4,4-difluoroazacycloheptane hydrochloride (compound (IIIf)) (710.0 g) in sequence. Heat to 125-135 °C and maintain the temperature for 8 h. Add water / ethanol (14 / 1; 60 L) to reactor 2, start stirring, and then slowly add reaction solution 1 to reactor 2. After the addition is complete, continue stirring for 10 mins and filter. Add dichloromethane (10.0 L) to reactor 1, start stirring, and then add the filter cake to reactor 1. Pulverize for 2 h, filter, and dry the filter cake in a forced-air drying oven at 50 °C. Yield: 88.34%, Purity: 99.30%.

[0167] Example 3

[0168] Example 3-1: N-methylpyrrolidone (0.8 L) was added to reaction vessel 1, and stirring was started. 2-fluoro-4-aminopyridine (compound of formula (E1)) (80.0 g), cesium carbonate (464.6 g) and benzyl mercaptan (141.9 g) were added in sequence. The temperature was raised to 140 °C and the reaction was maintained at this temperature for 10 h. The reaction solution was then cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (0.1 L * 2). The filtrate was collected. The filtrate was diluted with water (4.0 L), then extracted with ethyl acetate (1.0 L x 5), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (0.5 L x 3), and the organic phase was concentrated to obtain a solid. The solid was dissolved in dilute hydrochloric acid (1 M, 2.0 L), washed with ethyl acetate (1.0 L x 2), and the aqueous phase was collected. The pH of the aqueous phase was adjusted to 8-10 with sodium hydroxide solution (1 M, 2.1 L), and then extracted with ethyl acetate (1.0 L x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a solid. Yield: 63.62%, Purity: 97.62%.

[0169] Example 3-2: 1,4-Dioxane (10 mL) was added to the reaction tube, and stirring was started. 2-Chloro-4-aminopyridine (100.0 mg), potassium tert-butoxide (200.4 mg), and benzyl mercaptan (177.1 mg) were added in sequence. After reacting at reflux temperature for 22 h, the reaction solution was analyzed by LC-MS. The product content was 33.50%.

Claims

1. A process for the preparation of a compound of formula (I) ###0001### (I) characterized in that The method comprises: reacting the compound of formula (Ia) and the compound of formula (Ib) in a reaction solvent in the presence of a condensing agent and an acid binding agent to prepare the compound of formula (I), wherein, ring A is benzene, 5-6 membered heterocyclyl, 5-10 membered heteroaryl, the 5-6 membered heterocyclyl or 5-10 membered heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from N or O; R1is halogen, C 1-5 alkyl, C 1-5 haloalkyl, C 1-5 alkoxy, C 1-5 haloalkoxy or C 3-6 cycloalkyl; Y is halogen; T is benzyl, 1, 2 or 3 C 1-3 alkoxy-substituted benzyl, C 1-3 alkyl, hydroxy or amino; n is 0, 1, 2, 3 or 4.

2. The preparation method of the compound shown in formula (I) according to claim 1, characterized in that, Ring A is phenyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl or the 5-6 membered heteroaryl or 5-6 membered heterocyclyl contains 1, 2 or 3 heteroatoms selected from N or O; wherein, ring B is benzene, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, the 5-6 membered heteroaryl or 5-6 membered heterocyclyl contains 1, 2 or 3 heteroatoms selected from N or O; X is CH or N.

3. The preparation method according to claim 1, characterized in that, R1is halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, cyclopropyl or cyclobutyl; preferably R1is halogen, methyl, ethyl, methoxy, ethoxy, halomethyl, haloethyl, halomethoxy or cyclopropyl.

4. The method of claim 1, wherein, T is benzyl, p-methoxybenzyl, o-methoxybenzyl, m-methoxybenzyl, methyl, ethyl, isopropyl or tert-butyl, preferably T is benzyl, methyl or ethyl.

5. The preparation method according to claim 1, characterized in that, The compound of formula (I) has a structure as shown in formula (IIIc), and the method comprises: reacting a compound of formula (IIIa) and a compound of formula (IIIb) in a reaction solvent in the presence of a condensing agent and an acid binding agent to prepare the compound of formula (IIIc), 6. The production method according to claim 1 or 5, characterized by, The reaction optionally contains a catalyst, preferably the catalyst is N,N-dimethylformamide.

7. The production method according to claim 6, characterized by, The method comprises the following steps: Step (i): the compound of formula (Ib), a catalyst and a condensing agent are added into a reaction solvent, and after the reaction is completed, solution 1 is obtained; Step (ii): the compound of formula (Ia) and an acid binding agent are added into a reaction solvent to obtain solution 2, and solution 1 is added into solution 2, and after the reaction is completed, the compound of formula (I) is obtained; Preferably, in step (i), the molar ratio of the compound of formula (Ib) to the catalyst is 1:(0.3-0.6), the molar ratio of the compound of formula (Ib) to the condensing agent is 1:(1-1.5), the reaction temperature is 10-25℃, and the reaction time is 1-3h; In step (ii), the molar ratio of the compound of formula (Ia) to the compound of formula (Ib) is (1-1.5):1, the molar ratio of the acid binding agent to the compound of formula (Ib) is (1.5-2.5):1, the reaction temperature is 0-25℃, and the reaction time is 0.5-3h.

8. The preparation method according to claim 6, characterized in that, The method comprises the following steps: Step (i): the compound of formula (IIIb), a catalyst are added into a reaction solvent, and then a condensing agent is added, and after the reaction is completed, solution 1 is obtained; Step (ii): the compound of formula (IIIa) and an acid binding agent are added into a reaction solvent to obtain solution 2, and solution 1 is added into solution 2, and after the reaction is completed, the compound of formula (IIIc) is obtained; Preferably, in step (i), the molar ratio of the compound of formula (IIIb) to the catalyst is 1:(0.3-0.6), the molar ratio of the compound of formula (IIIb) to the condensing agent is 1:(1-1.5), the reaction temperature is 10-25℃, and the reaction time is 1-3h; In step (ii), the molar ratio of the compound of formula (IIIa) to the compound of formula (IIIb) is (1-1.5):1, the molar ratio of the acid binding agent to the compound of formula (IIIb) is (1.5-2.5):1, the reaction temperature is 0-25℃, and the reaction time is 0.5-3h.

9. The production method according to claim 1 or 5, characterized by, In the reaction, the condensing agent is selected from any one or any mixture of oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, dichlorosulfoxide or pivaloyl chloride in any ratio, preferably oxalyl chloride and dichlorosulfoxide, more preferably oxalyl chloride; Preferably, the acid-binding agent is selected from any one or mixture of any ratio of Na2CO3, K2CO3, NaOH, KOH, NaHCO3, KHCO3, triethylamine, pyridine, N,N-diisopropylethylamine, N-methylmorpholine or 4-dimethylaminopyridine, preferably triethylamine; Preferably, the reaction solvent is selected from any one or mixture of any ratio of dichloromethane, tetrahydrofuran, dimethyl sulfoxide, 1,2-dichloroethane, N-methylpyrrolidone or acetonitrile, preferably dichloromethane.

10. The method of any one of claims 1-9, wherein, The method further comprises a step of preparing the compound of formula (Ia) from a compound of formula (Ia-1) and a compound of formula (Ia-2) in the presence of a base in a reaction solvent: Y is F, Cl or Br; T is benzyl.

11. The method of claim 10, wherein, The compound of formula (Ia) has a structure represented by formula (IIIa), and the method comprises preparing the compound of formula (IIIa) from a compound of formula E1 and benzyl mercaptan in a reaction solvent in the presence of a base, 12. The production method according to claim 10 or 11, characterized by, The base is selected from any one or mixture of any ratio of Cs2CO3, K2CO3, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, preferably Cs2CO3; the reaction solvent is selected from any one or mixture of any ratio of N,N-diisopropylethylamine, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,3-dimethylimidazolidin-2-one, preferably N-methylpyrrolidone.

13. The preparation method according to claim 11, characterized in that, The feeding molar ratio of the E1 compound to benzyl mercaptan is 1:1-2.5, the feeding molar ratio of the E1 compound to base is 1:3-6, the reaction temperature is 120-150℃, and the reaction time is 8-12h.

14. An intermediate compound having the structure of formula (I): ###0002### (I) wherein Ring A, R1, Y, T, n are as defined in claim 1; Preferably, the intermediate compound, which structure is shown as formula (I-1): wherein R1, Y, T, n are as defined in claim 1, and X is as defined in claim 2; More preferably, the intermediate compound is one of the following compounds:

15. Use of the compound of claim 14 as an intermediate in the preparation of a Nav1.8 inhibitor, the structure of which is shown in formula (II): wherein Ring A, R1, n are as defined in claim 1; R4and R5are each independently selected from H or C 1-3 alkyl; m is 1, 2, 3, 4 or 5; R6is halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, hydroxy, oxo, or cyano; p is 0, 1, 2 or 3; Preferably, the Nav1.8 inhibitor structure is as shown in formula (II-1): wherein X, R1, n are as defined in claim 1; R4and R5are each independently selected from H or C 1-3 alkyl; R2 and R3 are each independently selected from H or halogen.

16. A method for preparing a compound of formula (IIa), characterized in that, The compound of formula (IIa) thus obtained is reacted with a reducing agent in the presence of a solvent to obtain the compound of formula (IIb), wherein ring A, Y, R1, T, n are as defined in claim 1, and Rx is chloro, bromo or iodo.

17. The method of claim 16, wherein, The compound of formula (IIa) has a structure as shown in formula (III d), which is prepared from the compound of formula (IIIc) prepared by the method of claim 5, by reacting with an oxidizing halogenating agent in the presence of an acid under solvent conditions to obtain the compound of formula (III d), 18. The method of manufacturing according to claim 16 or 17, characterized in that, The oxidizing halogenating agent is selected from any one or mixture of any ratio of dichloro-hydantoin, dibromo-hydantoin, diiodo-hydantoin, 1,3-dichloro-5-methyl-5-ethyl-hydantoin or sodium hypochlorite, preferably dichloro-hydantoin; the solvent is selected from any one or mixture of any ratio of acetonitrile, dichloromethane, water, methyl tert-butyl ether, dichloromethane, preferably acetonitrile; the acid is C1-C5 aliphatic acid, preferably acetic acid.

19. The method of claim 17, wherein, The feeding molar ratio of the compound of formula (IIIc) to the oxidizing halogenating agent is 1:(2-4), and the feeding molar ratio of the compound of formula (IIIc) to the acid is 1:(6-18), the oxidizing halogenating reaction temperature is -5-35℃, and the reaction time is 1-3h.

20. A process for the preparation of a compound of formula (lie) ###00022### (lie) characterized in that, The compound of formula (IIc) is prepared by reacting the compound of formula (IIa) prepared according to the method of claim 16, with NH(Ra)(Rb) under solvent conditions and, when Ra or Rb is an amino protecting group, by deprotection, to give the compound of formula (IIc), wherein Ra and Rb are each independently selected from H, methyl, ethyl or an amino protecting group, ring A, Y, R1, n are as defined in claim 1, Rx is chloro, bromo or iodo, and R4, R5 are as defined in claim 15.

21. The method of claim 20, wherein, The compound of formula (lie) has a structure as shown in formula (Illc), which is prepared from the compound of formula (Ill d) obtained in the method of claim 17, by reacting with ammonia in a solvent to obtain the compound of formula (Illc), 22. The method of manufacturing according to claim 20 or 21, wherein, The solvent is selected from any one or mixture of any ratio of acetonitrile, dichloromethane, water, methyl tert-butyl ether, dichloromethane, preferably acetonitrile.

23. The preparation method according to claim 21, characterized in that, The feeding molar ratio of the compound of formula (IIId) to ammonia is 1:(1-80), the reaction temperature is -5-5℃, and the reaction time is 1.5-3h. Preferably, the molar ratio of the compound of formula (III d) to ammonia water is 1:(30-50), the reaction temperature is -5-5℃, and the reaction time is 1.5-3h.

24. A process for the preparation of a compound of formula (II) ###00019### (II) characterized in that, The compound of formula (IIc) prepared according to the method of claim 20 is reacted with a salt of a compound of formula (IId) in the presence of a base under solvent conditions to give a compound of formula (II), wherein, ring A, Y, R1, n are defined as in claim 1, and R4, R5, R6, m, p are defined as in claim 15.

25. The method of claim 24, wherein, The compound of formula (II) has a structure as shown in formula (III), which is prepared by further reacting the compound of formula (IIIe) prepared by the method of claim 21 with a salt of the compound of formula (III f) in the presence of a base under solvent conditions to obtain the compound of formula (III), 26. The method of manufacturing according to claim 24 or 25, wherein, The base is selected from any one or any mixture of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, K2CO3, Cs2CO3, and preferably is N,N-diisopropylethylamine; and the solvent is selected from any one or any mixture of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and preferably is N-methylpyrrolidone.

27. The method of claim 25, wherein, The molar ratio of the compound of formula (III e) to the base is 1:(4-6), and the molar ratio of the compound of formula (III e) to the salt of the compound of formula (III f) is 1:(1.3-1.65), the reaction temperature is 110-150℃, and the reaction time is 7-12h.

27. A method of preparing a Navl.8 inhibitor of formula (III) comprising the steps of: The compound of formula (III f) is in the form of a salt, and preferably is a hydrochloride.

28. The method of claim 27, wherein: The method comprises the following steps, Step (1): the compound of formula (III b), N,N-dimethylformamide are added into dichloromethane, stirred, oxalyl chloride is added, after the reaction is completed, concentrated, dichloromethane is added for distillation, continuously concentrated, dichloromethane is added for dissolution to obtain solution 1; The compound of formula (III a), triethylamine are added into dichloromethane to obtain solution 2, solution 1 is added into solution 2, stirred, after the reaction is completed, water is added, stirred, n-heptane is added, stirred, centrifuged, the filter cake is washed with water, then washed with a mixed solution of dichloromethane and n-heptane, centrifuged, the filter cake is collected, dried to obtain the compound of formula (III c); Step (2): the compound of formula (III c) and acetic acid are added into acetonitrile, dichloro hydrazine is added, after the reaction is completed, water is added, stirred, centrifuged, the compound of formula (III d); Step (3): ammonia water and acetonitrile are added into a reaction kettle, the compound of formula (III d) is added, after the reaction is completed, water is added, stirred, crystallized, centrifuged, the filter cake is pulped with acetonitrile, centrifuged, the filter cake is collected, dried to obtain the compound of formula (III e); Step (4): the compound of formula (III e), the salt of the compound of formula (III f), N,N-diisopropylethylamine are added into N-methylpyrrolidone, after the reaction is completed, reaction liquid 1 is obtained, reaction liquid 1 is added into water or a mixed solution of water and ethanol, stirred, filtered, the filter cake is added into dichloromethane, pulped, filtered, the filter cake is dried to obtain the compound of formula (III); Preferably, in step (1), the molar ratio of the compound of formula (III b) to N,N-dimethylformamide is 1:(0.3-0.6), the molar ratio of the compound of formula (III b) to oxalyl chloride is 1:(1-1.5), the reaction temperature is 10-25℃, and the reaction time is 1-3h. Preferably, in step (1), the molar ratio of the compound of formula (IIIa) to the compound of formula (IIIb) is (1-1.5):1, the molar ratio of triethylamine to the compound of formula (IIIb) is (1.5-2.5):1, the reaction temperature is 0-25°C, and the reaction time is 0.5-3h; Preferably, in step (1), the volume ratio of dichloromethane to n-heptane is 1:(1-3). Preferably, in step (2), the molar ratio of the compound of formula (IIIc) to dichloro hydantoin is 1:(2-4), the molar ratio of the compound of formula (IIIc) to acetic acid is 1:(6-18), the reaction temperature is -5-35°C, and the reaction time is 1-3h; Preferably, in step (3), the molar ratio of the compound of formula (IIId) to ammonia is 1:(1-80), the reaction temperature is -5-5°C, and the reaction time is 1.5-3h; Preferably, in step (3), the molar ratio of the compound of formula (IIId) to ammonia is 1:(30-50). Preferably, in step (4), the molar ratio of the compound of formula (IIIe) to N,N-diisopropyl ethylamine is 1:(4-6), the molar ratio of the salt of the compound of formula (IIIe) to the compound of formula (III f) is 1:(1.3-1.6), the reaction temperature is 110-150°C, and the reaction time is 7-10h; Preferably, in step (4), in the mixed solution of water and ethanol, the volume ratio of water to ethanol is (7-14):1.

Images