Process for the preparation of heterocyclic compounds and intermediates thereof

Abstract

The application provides a preparation method of an imidazopyridine compound shown as formula IV and intermediates thereof shown as formula I or formula II. The imidazopyridine compound shown as formula IV can antagonize P2X3 receptors and has the effects of inhibiting cough and analgesia.

Description

[0001] Priority information

[0002] This application claims priority and benefits to patent application No. 202110090536.7, filed with the China National Intellectual Property Administration on January 22, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to methods for preparing heterocyclic compounds and intermediates thereof; in particular, this invention relates to methods for preparing imidazopyridine compounds and intermediates thereof. Background Technology

[0004] The P2X receptor is a non-selective ATP-gated ion channel receptor, also known as a purinergic receptor, that binds to extracellular ATP, primarily derived from damaged or inflamed tissues. This receptor is widely expressed in the nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, and endocrine systems, and participates in various physiological processes, including regulation of heart rate and contractility, regulation of vascular tone, regulation of nociception, especially chronic pain, vas deferens contraction during ejaculation, bladder contraction during urination, platelet aggregation, macrophage activation, apoptosis, and neuron-glial interactions. The aforementioned 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.

[0005] P2X3 is a subtype of the P2X receptor family that is selectively expressed in dorsal root ganglia of nerve endings, spinal cord, and brain neurons, specifically in small to medium diameter primary sensory neurons.

[0006] Numerous studies have shown that activation of P2X3 and P2X2 / 3 expressed in primary sensory neurons plays a crucial role in acute injury, hyperalgesia, and hypersensitivity responses in rodents. Many studies have demonstrated that upregulation of P2X3 receptor expression can lead to hyperalgesia and participate in pain signaling. P2X3 knockout mice exhibit reduced pain responses, and P2X3 receptor antagonists have shown a role in reducing nociception in pain and inflammatory pain models.

[0007] P2X3 receptors are distributed in primary afferent nerves surrounding the airway and regulate cough. Studies have shown that ATP released from damaged or inflamed airway tissue acts on P2X3 receptors in primary neurons, triggering depolarization and action potentials. These potentials transmit cough impulses, initiating a cough. Preclinical and clinical data strongly demonstrate the important role of P2X3 receptors in cough reflex hypersensitivity, leading to chronic cough. By antagonizing binding to P2X3 receptors, cough reflex hypersensitivity can be inhibited, thereby suppressing excessive coughing in patients with chronic cough.

[0008] P2X3 has been reported to be involved in the afferent pathway controlling the bladder capacity reflex; P2X3 knockout mice exhibit significantly reduced urination frequency and significantly increased bladder capacity. Therefore, inhibiting the binding of P2X3 receptor antagonists to the P2X3 receptor has therapeutic potential for conditions involving urinary storage and voiding disorders, such as overactive bladder. Thus, P2X3 antagonists may be potential drugs for treating overactive bladder and related diseases.

[0009] In addition, studies have shown that P2X3 antagonists can treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, or asthma, so P2X3 antagonists are expected to become new drugs for the treatment of these diseases.

[0010] P2X3 antagonists have shown great promise in multiple disease areas, therefore, the development of P2X3 antagonists is of great clinical significance. Summary of the Invention

[0011] This invention provides a method for preparing imidazopyridine compounds and their intermediates. The preparation method of this invention features mild conditions, stable processes, and simple operation, making it suitable for scale-up and industrial production.

[0012] This invention provides an intermediate as shown in Formula I or Formula II:

[0013]

[0014] in,

[0015] The R 1 Selected from PG 1 or

[0016] The R 2 Selected from halogen, carboxyl or

[0017] The R 2a Selected from C1-C6 alkyl or benzyl groups;

[0018] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl;

[0019] X is selected from H or Br.

[0020] In a preferred embodiment of the present invention, when R 2 When the halogen is halogen, the halogen is Br or I, preferably Br.

[0021] In a preferred embodiment of the present invention, the R 2a It is a C1-C6 alkyl group; preferably, the R 2a It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0022] In a preferred embodiment of the present invention, the intermediate as described above, represented by Formula II, is selected from any of the following intermediates:

[0023]

[0024] in,

[0025] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl;

[0026] The R 2 Selected from halogen, carboxyl or

[0027] The R 2a It has the definition described above.

[0028] The present invention also provides a method for preparing an intermediate as shown in Formula II-1, which includes the following steps:

[0029] Step 1: Under the action of an amino metal compound or an alkyl metal compound, an intermediate as shown in Formula I is prepared by reacting the intermediate shown in Formula I with a compound shown in Formula 1;

[0030]

[0031] in,

[0032] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl;

[0033] The R 2 Selected from halogen, carboxyl or

[0034] The R 2a It has the definition described above.

[0035] In step 1, the amino metal compound is lithium diisopropylamino, lithium bistrimethylsilylamino, potassium bistrimethylsilylamino, sodium bistrimethylsilylamino, preferably lithium diisopropylamino or lithium bistrimethylsilylamino.

[0036] In step 1, the alkyl metal compound is a methyl Grignard reagent, an ethyl Grignard reagent, an isopropyl Grignard reagent, or an alkyl lithium compound, preferably methyl lithium or n-butyl lithium.

[0037] In step 1, when the R 2 When the substance is halogen, the reaction is carried out under the action of an amino metal compound.

[0038] In step 1, when the R 2 For carboxyl or The reaction is carried out under the action of an amino metal compound or an alkyl metal compound.

[0039] In step 1, the reaction can be carried out in an organic solvent, which includes, but is not limited to, diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably tetrahydrofuran.

[0040] In step 1, the reaction temperature is -80 to 0°C, preferably -10 to 0°C or -80 to -60°C.

[0041] In step 1, the molar ratio of the compound shown in Formula I to the compound shown in Formula 1 in the reaction is 1:1 to 1:1.6, preferably 1:1 to 1.2 or 1:1.5 to 1:1.6, and more preferably 1:1.2 or 1:1.5.

[0042] In step 1, the reaction time is 2 to 4 hours, preferably 3 hours.

[0043] In step 1, when the reaction is carried out under the action of an alkyllithium compound, the reaction further includes a stabilizer, wherein the stabilizer is N,N,N',N'-tetramethylethylenediamine.

[0044] The present invention also provides a method for preparing an intermediate as shown in Formula I, the method for preparing an intermediate as shown in Formula I includes the following steps;

[0045] Step 2: The intermediate shown in Formula I is prepared by reacting the intermediate shown in Formula I-2 with the compound shown in Formula 2 under the action of an organic base and a condensing agent.

[0046]

[0047] Wherein, the PG1 It is selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

[0048] In step 2, the reaction temperature is 20–25°C.

[0049] In step 2, the organic base is N,N-diisopropylethylamine.

[0050] In step 2, the condensing agent is 1-propylphosphonic anhydride.

[0051] In step 2, the molar ratio of the intermediate shown in Formula I-2 to the compound shown in Formula 2 is 1:1 to 1:2, preferably 1:1.2.

[0052] In step 2, the molar ratio of the intermediate shown in Formula I-2 to the organic base compound is 1:2 to 4, preferably 1:2.8 to 3.2, and more preferably 1:3.

[0053] In step 2, the molar ratio of the intermediate as shown in Formula I-2 to the condensing agent is 1:1 to 1:2, preferably 1:1.5.

[0054] In step 2, the reaction time is 14 to 18 hours, preferably 16 hours.

[0055] In step 2, the reaction is carried out in dichloromethane.

[0056] According to an embodiment of the present invention, the method for preparing the intermediate shown in Formula I further includes a method for preparing the intermediate shown in Formula I-2, wherein the method for preparing the intermediate shown in Formula I-2 includes the following steps:

[0057] Step 3: Prepare the intermediate shown in Formula I-1 by reducing the compound shown in Formula 3;

[0058]

[0059] Step 4: Under the action of an inorganic base, the intermediate shown in Formula I-1 is hydrolyzed to prepare the intermediate shown in Formula I-2;

[0060]

[0061] Wherein, the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl.

[0062] In step 3, the reaction also includes hydrogen gas.

[0063] In step 3, the reaction also includes palladium on carbon.

[0064] In step 3, the reaction temperature is 20–25°C.

[0065] In step 3, the pressure of hydrogen gas in the reaction is 0.8 to 1.2 atmospheres, preferably 1 atmosphere.

[0066] In step 3, the mass ratio of palladium on carbon to compound 3 is 1:18 to 1:22, preferably 1:20.

[0067] In step 3, the reaction time is 22 to 26 hours, preferably 24 hours.

[0068] In step 4, the inorganic base is selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide, preferably lithium hydroxide.

[0069] In step 4, the reaction temperature is 20–25°C.

[0070] In step 4, the molar ratio of the intermediate shown in Formula I-1 to the inorganic base is 1:1 to 1:4, preferably 1:2.

[0071] In step 4, the reaction time is 14 to 18 hours, preferably 16 hours.

[0072] In step 4, the reaction is carried out in methanol.

[0073] The present invention also provides a method for preparing an intermediate as shown in Formula II-1A, wherein the intermediate as shown in Formula II-1A is prepared from the intermediate as shown in Formula II-1, and the method for preparing the intermediate as shown in Formula II-1A includes the following steps;

[0074] Step 5: Under the action of a catalyst and an organic base, the intermediate shown in Formula II-1 is reacted with carbon monoxide and the compound shown in Formula 4 to obtain the intermediate shown in Formula II-1A.

[0075]

[0076] in,

[0077] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl;

[0078] The R 2 It is a halogen;

[0079] The R 2a It has the definition described above.

[0080] In step 5, the catalyst is a transition metal catalyst, which includes palladium, ruthenium, iron, cobalt, nickel, and rhodium catalysts, preferably palladium catalysts.

[0081] Preferably, the palladium catalyst comprises tetra(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride, 1,1-bis(diphenylphosphine)ferrocene palladium chloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, tris(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium, 1,4-bis(diphenylphosphinebutane)palladium dichloride, and more preferably, the palladium metal catalyst is 1,1-bis(diphenylphosphine)ferrocene palladium chloride.

[0082] In step 5, the organic base includes, but is not limited to, triethylamine or N,N-diisopropylethylamine, preferably triethylamine.

[0083] In step 5, the reaction is carried out under pressure in carbon monoxide at a pressure of 40-50 psi, preferably 45 psi.

[0084] In step 5, the reaction temperature is 55-65℃.

[0085] In step 5, the reaction time is 22 to 26 hours, preferably 24 hours.

[0086] The present invention also provides a method for preparing an intermediate as shown in Formula II-1A, the method for preparing an intermediate as shown in Formula II-1A comprising the following steps;

[0087] Step 6: Under the action of a base, the intermediate shown in Formula II-1 is reacted with the compound shown in Formula 5 to obtain the intermediate shown in Formula II-1A;

[0088]

[0089] in,

[0090] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl;

[0091] The R 2 It is a carboxyl group;

[0092] The R 2a It has the definition described above.

[0093] In step 6, the molar ratio of the intermediate shown in Formula II-1 to the compound shown in Formula 5 is 1:1 to 1:2, preferably 1:1.5.

[0094] In step 6, the reaction temperature is 20–25°C.

[0095] In step 6, the alkali is sodium bicarbonate.

[0096] In step 6, the reaction is carried out in N,N-dimethylformamide.

[0097] In step 6, the reaction time is 22 to 26 hours, preferably 24 hours.

[0098] The present invention also provides a method for preparing an intermediate as shown in Formula II-2, wherein the intermediate as shown in Formula II-2 is prepared from an intermediate as shown in Formula II-1A, and the method for preparing the intermediate as shown in Formula II-2 includes the following steps:

[0099] Step 7: Remove the intermediate protecting group PG as shown in Formula II-1A 1 The deprotected product is obtained; the deprotected product is reacted with a compound as shown in Formula 6 under the action of a base to obtain an intermediate as shown in Formula II-2.

[0100]

[0101] in,

[0102] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl;

[0103] The R 2a It has the definition described above.

[0104] In step 7, the molar ratio of the intermediate shown in Formula II-1A to the compound shown in Formula 6 is 1:1 to 1:2, preferably 1:1.5.

[0105] In step 7, the removal of the intermediate protecting group PG as shown in Formula II-1A is performed. 1 The process is carried out in the presence of hydrochloric acid.

[0106] In step 7, the removal of the intermediate protecting group PG as shown in Formula II-1A is performed. 1 It is carried out in the reaction with hydrogen gas.

[0107] In step 7, the reaction temperature is 20–25°C.

[0108] In step 7, the base includes, but is not limited to, triethylamine or N,N-diisopropylethylamine, preferably triethylamine.

[0109] In step 7, the deprotection reaction is carried out in 1,4-dioxane.

[0110] In step 7, the reaction time for deprotection is 2 to 4 hours, preferably 3 hours.

[0111] In step 7, the deprotected product reacts with the compound shown in Formula 6 under the action of a base in dichloromethane.

[0112] In step 7, the reaction time of the deprotected product with the compound shown in Formula 6 under the action of alkali is 10 to 14 hours, preferably 12 hours.

[0113] The present invention also provides a method for preparing an intermediate as shown in Formula II-3, wherein the intermediate as shown in Formula II-3 is prepared from an intermediate as shown in Formula II-2, and the method for preparing the intermediate as shown in Formula II-3 includes the following steps:

[0114] Step 8: React the intermediate shown in Formula II-2 with a brominating agent to obtain the intermediate shown in Formula II-3;

[0115]

[0116] Among them, R 2a It has the definition described above.

[0117] In step 8, the brominating agent includes N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide, or liquid bromine, preferably liquid bromine.

[0118] In step 8, the molar ratio of the intermediate as shown in Formula II-2 to the brominizing agent is 1:1 to 1:3, preferably 1:1.2.

[0119] In step 8, the reaction is carried out in dichloromethane.

[0120] In step 8, the reaction temperature is 20–25°C.

[0121] In step 8, the reaction time is 0.5 to 2 hours, preferably 1 hour.

[0122] The present invention also provides a method for preparing an intermediate as shown in Formula III, wherein the intermediate as shown in Formula III is prepared from an intermediate as shown in Formulas II-3, and the method for preparing the intermediate as shown in Formula III includes the following steps:

[0123] Step 9: The intermediate shown in Formula II-3 is reacted with the compound shown in Formula 7 to obtain the intermediate shown in Formula III;

[0124]

[0125] in,

[0126] The R 2a It has the definition described above.

[0127] In step 9, the molar ratio of the intermediate shown in Formula II-3 to the compound shown in Formula 7 in the reaction is 1:1 to 1:3, preferably 1:2.

[0128] In step 9, the reaction can be carried out in a conventional organic solvent, including but not limited to acetonitrile, dimethyl sulfoxide, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, n-propanol or n-butanol, preferably acetonitrile.

[0129] In step 9, the reaction temperature is 110–130°C, preferably 120°C.

[0130] In step 9, the reaction time is 22 to 26 hours, preferably 24 hours.

[0131] The present invention also provides a method for preparing an imidazopyridine compound as shown in Formula IV, the method comprising the following steps:

[0132] Step 10: React the intermediate shown in Formula III with methylamine to obtain the compound shown in Formula IV;

[0133]

[0134] in,

[0135] The R 2a It has the definition described above.

[0136] In step 10, the molar ratio of the intermediate as shown in Formula III to methylamine is 1:4 to 1:6, preferably 1:5.

[0137] In step 10, the reaction temperature is 20–25°C.

[0138] In step 10, the reaction is carried out in methanol.

[0139] In step 10, the reaction time is 4 to 6 hours, preferably 5 hours.

[0140] The present invention also provides a method for preparing an intermediate as shown in Formula 3, the method for preparing an intermediate as shown in Formula 3 includes the following steps;

[0141] Step 11: React the intermediate shown in Formula 3-1 with the Des Martin oxidant to obtain the intermediate shown in Formula 3-2; react the intermediate shown in Formula 3-2 with the compound shown in Formula 8 to obtain the intermediate shown in Formula 3.

[0142]

[0143] in,

[0144] The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl.

[0145] In step 11, the molar ratio of the intermediate shown in Formula 3-1 to the Des Martin oxidant is 1:1 to 2, preferably 1:1.2.

[0146] In step 11, the reaction temperature of the intermediate shown in Formula 3-1 with the Des Martin oxidant is 20-25°C.

[0147] In step 11, the reaction time of the intermediate shown in Formula 3-1 with the Des Martin oxidant is 1 to 3 hours, preferably 2 hours.

[0148] In step 11, the intermediate shown in Formula 3-1 reacts with the Des Martin oxidant in dichloromethane.

[0149] In step 11, the molar ratio of the intermediate shown in Formula 3-2 to compound 8 is 1:1 to 1:2, preferably 1:1.1.

[0150] In step 11, the reaction temperature of the intermediate shown in Formula 3-1 with compound 8 is 20-25°C.

[0151] In step 11, the reaction time between the intermediate shown in Formula 3-1 and compound 8 is 14 to 18 hours, preferably 16 hours.

[0152] In step 11, the intermediate shown in Formula 3-1 reacts with the Des Martin oxidant in dichloromethane.

[0153] Terms and Definitions

[0154] Unless otherwise stated, the terms and definitions used in this application, including those set forth in the specification and claims, are as follows.

[0155] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to describe chemical bonds, which are points where a portion or a substituent is connected to a core or skeletal structure.

[0156] The term "C1-C6 alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2 or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0157] The term "alkyl metal compound" refers to an organic compound formed by direct bonding between a metal atom and an alkyl carbon atom. The alkyl group includes, but is not limited to, alkyl or cycloalkyl groups, such as C1-C6 alkyl groups. The metal atom includes, but is not limited to, potassium, sodium, lithium, magnesium, or aluminum. Alkyl metal compounds include, but are not limited to, Grignard reagents and alkyllithium compounds.

[0158] The term "amino metal compound" refers to a compound formed by the combination of a metal atom and an amino group through covalent or coordinate bonds. The "amino" refers to primary (i.e., –NH2), secondary (i.e., –NRH), and tertiary (i.e., –NRR) amines. The R includes, but is not limited to, C1-C6 alkyl, cycloalkyl, or silyl groups. The metal atom includes, but is not limited to, potassium, sodium, lithium, or magnesium. The amino metal compound includes, but is not limited to, lithium diisopropylamino, lithium bis(trimethylsilylamino), potassium bis(trimethylsilylamino), sodium bis(trimethylsilylamino), sodium amino, potassium amino, and lithium amino.

[0159] The terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0160] The term "catalyst" refers to any substance or reagent that can influence, induce, increase, or promote the reactivity or reaction of a compound.

[0161] The term "transition metal catalyst" refers to any metal having electrons in its d orbitals, such as metals selected from Groups 3-12 of the periodic table or the lanthanides. Catalysts that can be used in the methods of the present invention include atoms, ions, salts, or complexes of transition metals from Groups 8-11 of the periodic table. "Groups 3-12 of the periodic table" refers to the periodic table groups numbered according to the IUPAC method. Thus, transition metals from Groups 8-11 include iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, and gold. Such catalysts include, but are not limited to, CuI, CuCl, CuBr, CuBr2, Cu2Cl2, Cu2O, Cu, Pd2(dba)2, Pd / C, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(C6H5)3]4, NiCl2[P(C6H5)]2, and Ni(COD)2.

[0162] The term "R" 2a "-I" refers to the presence of R. 2a Iodine reagent.

[0163] In this application, "optional" or "optionally" means that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted and unsubstituted aryl groups. Detailed Implementation

[0164] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0165] Unless otherwise specified, the structures of the compounds in this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are in units of 10⁻¹⁰. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0166] The abbreviations of this invention are defined as follows:

[0167] M: Molar concentration, such as 1M hydrochloric acid, which represents a 1 mol / L hydrochloric acid solution.

[0168] DIPEA: Also written as DIEA, diisopropylethylamine, i.e., N,N-diisopropylethylamine.

[0169] DMF: N,N-dimethylformamide

[0170] DCM: Dichloromethane

[0171] Et3N: Triethylamine

[0172] Dess-Martin: Oxidant

[0173] T3P: 1-Propylphosphoanhydride

[0174] LDA: Lithium diisopropylamino

[0175] n-BuLi: n-Butyllithium

[0176] TMEDA: N,N,N',N'-Tetramethylethylenediamine

[0177] NaHCO3: Sodium bicarbonate

[0178] THF: Tetrahydrofuran

[0179] Pd(dppf)Cl2: 1,1-bis(diphenylphosphine)ferrocene palladium chloride

[0180] LC-MS: Liquid chromatography-mass spectrometry

[0181] TLC: Thin-layer chromatography

[0182] Preparation 1: Preparation of intermediate (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A)

[0183]

[0184] The synthetic route for target intermediate A is shown below:

[0185]

[0186] Step 1: Synthesis of (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2)

[0187]

[0188] In a 2L three-necked flask, (R)-2-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (A-1) (107 g, 491 mmol) and dichloromethane (1 L) were added. The reaction temperature was adjusted to 0–5 °C, and Dess-Martin reagent (250 g, 590 mmol) was slowly added in portions while maintaining the reaction temperature at 0–5 °C. The reaction was stirred at 0–5 °C for 0.5 h. The reaction temperature was then adjusted to 20–25 °C and stirring was continued for 2 h. TLC showed that the starting material had reacted completely. The reaction solution was slowly poured into a saturated sodium bicarbonate solution (1 L) and stirred for 0.5 h. After filtration and separation, the organic phase was collected. The organic phase was washed with a saturated sodium bicarbonate solution (1 L × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2) (100 g, 95% yield).

[0189] Step 2: Synthesis of (S)-2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylic acid tert-butyl ester (A-3)

[0190]

[0191] (R)-2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2) (100 g, 460 mmol) and dichloromethane (1 L) were added to a 2 L three-necked flask. The reaction temperature was adjusted to 20-25 °C, and methoxyformylmethylenetriphenylphosphine (171 g, 511 mmol) was slowly added in portions while maintaining the reaction temperature at 20-25 °C. The reaction was continued at 20-25 °C with stirring for 16 h. TLC showed that the starting material had reacted completely. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain colorless oily (S)-2-(3-methoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylic acid tert-butyl ester (A-3) (65 g, yield 51.6%).

[0192] 1 H NMR(400MHz,Chloroform-d)δ6.83(ddd,J=15.9,4.2,1.0Hz,0.76H),6.16–6.07(m,1H),5.87(dt,J=11.8,1.2Hz,0.24H) ,4.18–3.80(m,4H),3.74(s,1.0Hz,3H),3.64–3.53(m,1H),3.05–2.85(m,1H),2.75–2.55(m,1H),1.47(t,J=1.6Hz,9H).

[0193] Step 3: Synthesis of (S)-2-(3-methoxy-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A-4)

[0194]

[0195] In a 2L single-necked flask, (S)-2-(3-methoxy-3-oxopropyl-1-en-1-yl)morpholine-4-carboxylic acid tert-butyl ester (A-3) (65 g, 240 mmol) and methanol (650 mL) were added. The reaction system was purged with nitrogen three times. Pd / C (3.25 g) was added, and the reaction system was purged with hydrogen three times. The reaction temperature was adjusted to 20-25 °C and stirred for 24 h at 1 atm under a hydrogen atmosphere. TLC showed that the starting material reacted completely. The reaction system was purged with nitrogen three times, and the resulting methanol solution of (S)-2-(3-methoxy-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A-4) (65.5 g, 100% yield) was used directly for the next step.

[0196] 1 H NMR(400MHz,Chloroform-d)δ3.90–3.65(m,3H),3.59(s,3H),3.44–3.33(m,1H),3.33–3.22(m,1H),2. 83(t,J=13.2Hz,1H),2.50(t,J=22.0Hz,1H),2.45–2.24(m,2H),1.78–1.61(m,2H),1.40–1.36(m,9H).

[0197] Step 4: Synthesis of (S)-3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (A-5)

[0198]

[0199] Add a methanol (650 mL) solution of (S)-2-(3-methoxy-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A-4) (65.5 g, 240 mmol) to a 2 L three-necked flask, add 65 mL of water, adjust the reaction temperature to 20-25 °C, slowly add lithium hydroxide monohydrate (20.1 g, 479 mmol) while maintaining the reaction temperature at 20-25 °C, and continue stirring at 20-25 °C for 16 h. Methanol was concentrated under reduced pressure, 400 mL of water was added, the aqueous phase was washed with ethyl acetate (200 mL × 2), the temperature of the aqueous phase was adjusted to 0-5℃, the pH was adjusted to 4-5 with 4M HCl aqueous solution under stirring, the aqueous phase was extracted with dichloromethane (400 mL × 3), the combined organic phases were dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain colorless oily (S)-3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (A-5) (61 g, yield 98%).

[0200] 1H NMR(400MHz,Chloroform-d)δ3.97–3.69(m,3H),3.46(td,J=11.7,2.8Hz,1H),3.41–3.32(m,1H),2.9 7-2.81(m,1H),2.67–2.38(m,J=21.0,16.7,9.5Hz,3H),1.76(qd,J=9.9,8.6,6.1Hz,2H),1.44(s,9H).

[0201] Step 5: Synthesis of (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A)

[0202]

[0203] In a 2L three-necked flask, add (S)-3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionic acid (A-5) (61 g, 235 mmol), N,O-dimethylhydroxylamine hydrochloride (27.5 g, 282 mmol), and dichloromethane (610 mL), and adjust the reaction temperature to 0–5 °C. Slowly add DIEA (91 g, 706 mmol) and 1-propylphosphoric anhydride (50% DMF solution, 225 g, 353 mmol) dropwise to the reaction mixture. Adjust the internal reaction temperature to 20–25 °C and stir for 16 h. Slowly add 500 mL of saturated sodium bicarbonate solution to the reaction mixture, separate the layers, and collect the organic phase. Wash the organic phase with 500 mL of saturated sodium bicarbonate solution and concentrate to dryness under reduced pressure. Add 360 mL of ethyl acetate to the residue, wash with saturated NH4Cl (300 mL × 3), and concentrate the organic phase under reduced pressure to obtain colorless oily (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A) (60 g, yield 84%).

[0204] 1 H NMR(400MHz,Chloroform-d)δ3.96–3.74(m,3H),3.67(s,3H),3.46(td,J=11.7,2.9Hz,1H),3.36(td,J=7.9,6 .8,4.2Hz,1H),3.16(s,3H),2.98–2.83(m,1H),2.55(dd,J=13.8,6.6Hz,3H),1.87–1.70(m,2H),1.44(s,9H).

[0205] Preparation 2: Preparation of intermediate (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B)

[0206]

[0207] The synthetic route for target intermediate B is shown below:

[0208]

[0209] Step 1: Synthesis of (S)-2-(3-(4-bromo-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-1)

[0210]

[0211] Under a nitrogen atmosphere, 3,5-difluorobromobenzene (57.9 g, 300 mmol) and anhydrous tetrahydrofuran (600 mL) were added to a 2 L three-necked flask. The reaction temperature was adjusted to -10 to 0 °C, and lithium diisopropylaminolithium (150 mL, 300 mmol, 2 mol / L tetrahydrofuran solution) was slowly added dropwise while maintaining the reaction temperature at -10 to 0 °C. After stirring the reaction solution for 1 h, a tetrahydrofuran (120 mL) solution of (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A) (60 g, 198 mmol) was slowly added dropwise to the solution. The mixture was stirred at -10 to 0 °C for 2 h. TLC showed that the reaction was complete. Slowly add 500 mL of saturated NH4Cl solution to the reaction solution. After the reaction solution is brought to room temperature, dilute with 500 mL of ethyl acetate. Separate the solution and extract the aqueous phase with 500 mL of ethyl acetate. Combine the organic phases and wash with 1 L of saturated NH4Cl. Dry the collected organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and finally purify by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain a white solid (S)-2-(3-(4-bromo-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-1) (65 g, yield 74.8%).

[0212] LC-MS, M / Z: 334.1 [M+H] +

[0213] Step 2: Synthesis of (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B)

[0214]

[0215] (S)-2-(3-(4-bromo-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-1) (65 g, 150 mmol) was dissolved in methanol (650 mL), and triethylamine (45.4 g, 449 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (5.48 g, 7.48 mmol) were added. The mixture was evacuated, purged three times with nitrogen, and purged three times with carbon monoxide. The mixture was then reacted at 55-65 °C for 24 hours under carbon monoxide (45 psi). TLC showed that the reaction was complete. The reaction solution was concentrated to dryness, and then water (650 mL) was added. The solution was adjusted to neutral with citric acid and then extracted with ethyl acetate (650 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to give a brown oily compound (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B) (56 g, yield 90%).

[0216] LC-MS, M / Z: 314.2 [M+H] + .

[0217] Preparation 3: Preparation of intermediate (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B)

[0218]

[0219] The synthetic route for target intermediate B is shown below:

[0220]

[0221] Step 1: Synthesis of (S)-2-(3-(4-bromo-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-2)

[0222]

[0223] Under a nitrogen atmosphere, 3,5-difluorobromobenzene (9.6 g, 50 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The reaction temperature was adjusted to -80 to -60 °C. Lithium diisopropylamino (25 mL, 50 mmol, 2 mol / L tetrahydrofuran solution) was slowly added dropwise while maintaining the reaction temperature at -80 to -60 °C. After stirring the reaction solution for 1 h, a tetrahydrofuran (20 mL) solution of (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A) (10 g, 33 mmol) was slowly added dropwise. The mixture was stirred at -80 to -60 °C for 2 h. TLC showed that the reaction was complete. Slowly add 100 mL of saturated NH4Cl solution to the reaction solution. After the reaction solution is brought to room temperature, dilute with 100 mL of ethyl acetate. Separate the solution and extract the aqueous phase with 100 mL of ethyl acetate. Combine the organic phases and wash with 200 mL of saturated NH4Cl. Dry the collected organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and finally purify by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain a white solid (S)-2-(3-(4-bromo-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-2) (7.46 g, yield 52%).

[0224] LC-MS, M / Z: 334.1 [M+H] +

[0225] Step 2: Synthesis of (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B)

[0226]

[0227] (S)-2-(3-(4-bromo-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-2) (7.46 g, 17.2 mmol) was dissolved in methanol (75 mL), and triethylamine (5.13 g, 51.6 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.63 g, 0.86 mmol) were added. The mixture was evacuated, purged three times with nitrogen, and purged three times with carbon monoxide. The mixture was then reacted at 55-65 °C for 24 hours under carbon monoxide (45 psi). TLC showed that the reaction was complete. The reaction solution was concentrated to dryness, and then water (100 mL) was added. The solution was adjusted to neutral with citric acid and then extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to give a brown oily compound (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B) (6.6 g, yield 93%).

[0228] LC-MS, M / Z: 314.2 [M+H] + .

[0229] Preparation 4: Preparation of intermediate (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B)

[0230]

[0231] The synthetic route for target intermediate B is shown below:

[0232]

[0233] Step 1: Synthesis of (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionyl)-3,5-difluorobenzoic acid (B-3)

[0234]

[0235] Under a nitrogen atmosphere, 3,5-difluorobenzoic acid (6.26 g, 39.2 mmol), TMEDA (10.0 g, 87 mmol), and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The reaction temperature was adjusted to -10 to 0 °C, and n-butyllithium (35 mL, 87 mmol, 2.5 mol / L n-hexane solution) was slowly added dropwise while maintaining the reaction temperature at -10 to 0 °C. After stirring the reaction solution for 0.5 h, a tetrahydrofuran (20 mL) solution of (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A) (10 g, 33 mmol) was slowly added dropwise. The reaction was stirred at -10 to 0 °C for 2 h. TLC showed that the reaction was complete. Water (100 mL) was slowly added dropwise to the reaction solution. The reaction solution was brought to room temperature. The pH of the aqueous phase was adjusted to 4-5 with 1 M hydrochloric acid aqueous solution. 100 mL of ethyl acetate was added. The mixture was separated and the aqueous phase was extracted with 100 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a white solid (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionyl)-3,5-difluorobenzoic acid (B-3) (6.72 g, yield 51%).

[0236] LC-MS, M / Z: 300.1 [M+H] +

[0237] Step 2: Synthesis of (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B)

[0238]

[0239] (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propionyl)-3,5-difluorobenzoic acid (B-3) (6.72 g, 16.8 mmol) was dissolved in N,N-dimethylformamide (70 mL), sodium bicarbonate (2.82 g, 33.6 mmol) and methyl iodoforme (3.57 g, 25.2 mmol) were added, and the reaction was carried out at 20-25 °C for 24 hours. TLC showed that the reaction was complete. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phases were combined and washed with saturated sodium bicarbonate solution (300 mL × 2) and saturated sodium chloride solution (300 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily compound (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B) (5.9 g, yield 85%).

[0240] LC-MS, M / Z: 314.2 [M+H] + .

[0241] Preparation 5: Preparation of intermediate (S)-2-(3-(4-(4-tert-butoxycarbonyl)-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-Bu)

[0242]

[0243] The synthetic route for the target intermediate B-Bu is shown below:

[0244]

[0245] Step 1: Synthesis of (S)-2-(3-(4-(4-tert-butoxycarbonyl)-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-Bu)

[0246]

[0247] Under a nitrogen atmosphere, tert-butyl 3,5-difluorobenzoate (10.6 g, 49.5 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The reaction temperature was adjusted to -10 to 0 °C, and lithium diisopropylamino (24.8 mL, 49.5 mmol, 2 mol / L n-hexane solution) was slowly added dropwise while maintaining the reaction temperature at -10 to 0 °C. After stirring the reaction solution for 1 h, a tetrahydrofuran (20 mL) solution of (S)-2-(3-(methoxy(methyl)amino)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (A) (10 g, 33 mmol) was slowly added dropwise. The reaction was stirred at -10 to 0 °C for 3 h. TLC showed that the reaction was complete. Slowly add 100 mL of saturated ammonium chloride solution to the reaction solution. After the reaction solution is brought to room temperature, add 100 mL of ethyl acetate to dilute it. Separate the solution and extract the aqueous phase with 100 mL of ethyl acetate. Combine the organic phases and wash them with 200 mL of saturated ammonium chloride solution. Dry the collected organic phase with anhydrous sodium sulfate, concentrate it under reduced pressure, and finally purify it by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain a white solid (S)-2-(3-(4-(4-tert-butyloxycarbonyl)-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-Bu) (7.06 g, yield 47%).

[0248] LC-MS, M / Z: 356.2 [M+H] + .

[0249] Preparation 6: Preparation of intermediate (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C)

[0250]

[0251] The synthetic route for target intermediate C is shown below:

[0252]

[0253] Step 1: Synthesis of (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C-1)

[0254]

[0255] Under a nitrogen atmosphere, (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid tert-butyl ester (B) (56 g, 135 mmol) and 1,4-dioxane (150 mL) were added to a 2 L three-necked flask, and the reaction temperature was adjusted to 20-25 °C. A 1,4-dioxane solution of HCl (135 mL, 4 mol / L) was slowly added to the solution, maintaining the reaction temperature at 20-25 °C. The reaction was stirred for 3 h, and LC-MS showed complete reaction. The reaction solution was concentrated to dryness under reduced pressure. Dichloromethane (600 mL) was added to the residue, and the reaction temperature was adjusted to 0-5 °C. Triethylamine (41.1 g, 406 mmol) was slowly added dropwise, followed by methyl chloroformate (19.2 g, 203 mmol). The reaction temperature was adjusted to 20-25℃, and the reaction solution was stirred at 20-25℃ for 12 h. TLC showed that the reaction was complete. 400 mL of saturated sodium chloride solution was added to the reaction solution, the liquid was separated and the organic phase was collected. The organic phase was washed with 1 L of saturated NH4Cl and concentrated to dryness to give brown oily (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C-1) (47 g, yield 93%).

[0256] LC-MS, M / Z: 372.1 [M+H] + .

[0257] Step 2: Synthesis of (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C)

[0258]

[0259] Add (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C-1) (47 g, 127 mmol), dichloromethane (470 mL), and 33% hydrogen bromide acetic acid solution (1.55 g, 6.33 mmol) to a 1 L three-necked flask. Adjust the reaction temperature to 20–25 °C, and slowly add liquid bromine (24.27 g, 152 mmol) dropwise to the reaction solution. Continue stirring at 20–25 °C for 1 h. TLC shows that the reaction is complete. Add 300 mL of saturated sodium bisulfite solution and 400 mL of saturated sodium bicarbonate solution to the reaction system. The organic phase was separated and collected. The organic phase was washed with 400 mL of saturated sodium bicarbonate solution. The collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain brown oily (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C) (50 g, yield 88%).

[0260] LC-MS, M / Z: 450.0 [M+H] + .

[0261] Preparation 7: Preparation of intermediate (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C)

[0262]

[0263] The synthetic route for target intermediate C is shown below:

[0264]

[0265] Step 1: Synthesis of (S)-3,5-difluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2)

[0266]

[0267] Under a nitrogen atmosphere, (S)-2-(3-(4-(tert-butyloxycarbonyl)-2,6-difluorophenyl)-3-oxopropyl)morpholine-4-carboxylic acid tert-butyl ester (B-4) (7.06 g, 15.5 mmol) and 1,4-dioxane (20 mL) were added to a 250 mL three-necked flask, and the reaction temperature was adjusted to 20-25 °C. A 1,4-dioxane solution of hydrochloric acid (16.0 mL, 4 mol / L) was slowly added to the solution, maintaining the reaction temperature at 20-25 °C, and the reaction was stirred for 15 h. The reaction solution was concentrated to dryness under reduced pressure, and dichloromethane (70 mL) was added to the residue. The reaction solution temperature was adjusted to 0-5 °C, and triethylamine (5.5 g, 54.3 mmol) was slowly added dropwise, followed by methyl chloroformate (1.9 g, 23.3 mmol). Adjust the reaction temperature to 20-25℃ and stir the reaction solution at 20-25℃ for 12 hours. Add 100 mL of water to the reaction solution and adjust the pH of the aqueous phase to 4-5 with 5M hydrochloric acid solution. Separate the liquid and collect the organic phase. Extract the aqueous phase with dichloromethane (100 mL × 2). Concentrate the combined organic phases to dryness to give a white solid (S)-3,5-difluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2) (4.3 g, yield 78%).

[0268] LC-MS, M / Z: 358.1 [M+H] +

[0269] Step 2: Synthesis of (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C-1)

[0270]

[0271] (S)-3,5-difluoro-4-(3-(4-(methoxycarbonyl)morpholin-2-yl)propionyl)benzoic acid (C-2) (4.3 g, 12.1 mmol) was dissolved in N,N-dimethylformamide (43 mL), sodium bicarbonate (2.0 g, 24.2 mmol), and iodomethane (2.57 g, 18.2 mmol). The reaction was carried out at 20–25 °C for 24 hours. TLC showed that the reaction was complete. Water (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL × 2). The organic phases were combined, washed with saturated sodium bicarbonate solution (300 mL × 2) and saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white oily compound (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C-1) (3.32 g, yield 73%).

[0272] LC-MS, M / Z: 372.1 [M+H]+

[0273] Step 3: Synthesis of (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C)

[0274]

[0275] Add (S)-2-(3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C-1) (3.32 g, 8.83 mmol), dichloromethane (40 mL), and 33% hydrogen bromide acetic acid solution (0.11 g, 0.45 mmol) to a 100 mL three-necked flask. Adjust the reaction temperature to 20–25 °C, and slowly add liquid bromine (1.7 g, 10.6 mmol) dropwise to the reaction solution. Continue stirring at 20–25 °C for 1 h. TLC showed that the reaction was complete. Add 30 mL of saturated sodium bisulfite solution and 40 mL of saturated sodium bicarbonate solution to the reaction system. The organic phase was separated and collected. The organic phase was washed with 40 mL of saturated sodium bicarbonate solution. The collected organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain brown oily (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C) (3.6 g, yield 91%).

[0276] LC-MS, M / Z: 450.0 [M+H] + .

[0277] Preparation 8: Preparation of intermediate (S)-2-((2-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D)

[0278]

[0279] The synthetic route for target intermediate D is shown below:

[0280]

[0281] Step 1: Synthesis of (S)-2-((2-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D)

[0282]

[0283] (2S)-2-(2-bromo-3-oxo-3-(2,6-difluoro-4-(methoxycarbonyl)phenyl)propyl)morpholine-4-carboxylic acid methyl ester (C) (50 g, 111 mmol), 2-amino-4-methylpyridine (24.0 g, 222 mmol) and acetonitrile (500 mL) were added to a 1 L reaction flask. The reaction flask was sealed, the reaction temperature was adjusted to 120 °C and stirred for 24 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Finally, the mixture was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain yellow solid (S)-2-((2-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (D) (25 g, yield 47%).

[0284] LC-MS, M / Z: 460.2 [M+H] + .

[0285] Example 1: Preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (1)

[0286]

[0287] The synthetic route for target compound 1 is shown below:

[0288]

[0289] Step 1: Preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (1) Synthesis

[0290]

[0291] (S)-2-((2-(2,6-difluoro-4-(methoxycarbonyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (D) (8 g, 16.7 mmol) and methanol (16 mL) were added to a 100 mL reaction flask. A 33% methanol solution of methylamine (7.8 g, 83 mmol) was added to the reaction solution, and the reaction temperature was adjusted to 20-25 °C and stirred for 5 h. TLC showed the reaction was complete. The reaction solution was concentrated to dryness under reduced pressure and purified by silica gel column chromatography to obtain a yellow solid (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (1) (7.7 g, 97% yield).

[0292] 1 H NMR(400MHz,Chloroform-d)δ8.13(d,J=7.1Hz,1H),7.62(ddd,J=9.6,5.6,2.1Hz,1H),7.32(dt,J=2.0,1.1Hz,1H),7.00(s,1H),6.64(dd,J=7.1,1.7Hz,1H),3.95–3.68(m,3H),3.62(s,3H),3.54–3.47(m,1H),3.37–3.27(m,1H),3.02(d,J=4.8,0.9Hz,3H),3.00–2.78(m,3H),2.55(dd,J=13.0,10.6Hz,1H),2.37(d,J=1.1Hz,3H).

[0293] LC-MS,M / Z:459.2[M+H] + 。

Claims

1. A method for preparing an imidazopyridine compound as shown in Formula IV, comprising the following steps: Step 10: React the intermediate shown in Formula III with methylamine to obtain the compound shown in Formula IV; in, said R 2a is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; The reaction is carried out in methanol.

2. The production method according to claim 1, characterized by, It also includes the following steps: Step 9: The intermediate shown in Formula II-3 is reacted with the compound shown in Formula 7 to obtain the intermediate shown in Formula III; in, The R 2a is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

3. The production method according to claim 2, characterized by, It also includes the following steps: Step 8: React the intermediate shown in Formula II-2 with a brominating agent to obtain the intermediate shown in Formula II-3; in, The R 2a is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

4. The production method according to claim 3, characterized by, It also includes the following steps: Step 7: removal of the protecting group PG of the intermediate as shown in Formula II-1A 1 to give the deprotected product; The deprotected product is reacted with a compound as shown in Formula 6 under the action of a base to give an intermediate as shown in Formula II-2. in, The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl; The R 2a is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

5. A method for preparing compound II-1A as described in claim 4, characterized in that, The intermediate shown in Formula II-1A is prepared from the intermediate shown in Formula II-1, and the method for preparing the intermediate shown in Formula II-1A includes the following steps: Step 5: Under the action of a catalyst and an organic base, the intermediate shown in Formula II-1 is reacted with carbon monoxide and the compound shown in Formula 4 to obtain the intermediate shown in Formula II-1A. in, The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl; The R 2 It is a halogen; said R 2a is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

6. A process for the preparation of a compound of claim 4, II-1A, characterized by, The intermediate shown in Formula II-1A is prepared from the intermediate shown in Formula II-1, and the method for preparing the intermediate shown in Formula II-1A includes the following steps: Step 6: Under the action of a base, the intermediate shown in Formula II-1 is reacted with the compound shown in Formula 5 to obtain the intermediate shown in Formula II-1A; in, The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl; The R 2 It is a carboxyl group; said R 2a is selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl.

7. The production method according to claim 5 or 6, characterized by, It also includes the following steps: Step 1: Under the action of an amino metal compound or an alkyl metal compound, an intermediate as shown in Formula I is prepared by reacting the intermediate shown in Formula I with a compound shown in Formula 1; in, The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl; said R 2 selected from halogen, carboxyl.

8. The method of claim 7, wherein, It also includes the following steps: Step 2: The intermediate shown in Formula I is prepared by reacting the intermediate shown in Formula I-2 with the compound shown in Formula 2 under the action of an organic base and a condensing agent. wherein the PG is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or benzyl. 1 wherein the PG is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or benzyl.

9. The production method according to claim 8, characterized by, It also includes the following steps: Step 3: Prepare the intermediate shown in Formula I-1 by reducing the compound shown in Formula 3; Step 4: Under the action of an inorganic base, the intermediate shown in Formula I-1 is hydrolyzed to prepare the intermediate shown in Formula I-2; wherein the PG is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or benzyl. 1 wherein the PG is selected from tert-butyloxycarbonyl, benzyloxycarbonyl or benzyl. 10.The method of claim 1, wherein the compound of Formula IV is prepared by, In step 10, The molar ratio of the intermediate shown in Formula III to methylamine is 1:4 to 1:6; Optionally, the reaction temperature is 20~25°C; Optionally, the reaction time is 4 to 6 hours.

11. The method for preparing the compound as shown in Formula IV according to claim 10, characterized in that, The molar ratio of the intermediate shown in Formula III to methylamine is 1:5; Optionally, the reaction time is 5 hours.

12. The process for the preparation of an intermediate as shown in Formula III according to claim 2, wherein, In step 9 In the reaction, the molar ratio of the intermediate shown in Formula II-3 to the compound shown in Formula 7 is 1:1 to 1:3; Optionally, the reaction is carried out in an organic solvent, including acetonitrile, dimethyl sulfoxide, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, n-propanol or n-butanol; Optionally, the reaction temperature is 110~130℃; Optionally, the reaction time is 22 to 26 hours.

13. The method for preparing the intermediate as shown in Formula III according to claim 12, characterized in that, In the reaction, the molar ratio of the intermediate shown in Formula II-3 to the compound shown in Formula 7 is 1:2; Optionally, the organic solvent is acetonitrile; Optionally, the reaction temperature is 120°C; Optionally, the reaction time is 24 hours.

14. The process for the preparation of an intermediate as shown in formula II-3 according to claim 3, wherein, In step 8 The brominating agent is N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide, or liquid bromine; Optionally, the molar ratio of the intermediate as shown in Formula II-2 to the brominizing agent is 1:1 to 1:3; Optionally, the reaction is carried out in dichloromethane; Optionally, the reaction temperature is 20~25°C; Optionally, the reaction time is 0.5 to 2 hours.

15. The method for preparing the intermediate as shown in Formula II-3 according to claim 14, characterized in that, The brominating reagent is liquid bromine; Optionally, the molar ratio of the intermediate as shown in Formula II-2 to the brominizing agent is 1:1.2; Optionally, the reaction time is 1 hour.

16. The process for the preparation of an intermediate as shown in formula II-2 according to claim 4, wherein, In step 7 The molar ratio of the intermediate shown in Formula II-1A to the compound shown in Formula 6 is 1:1 to 1:2; Optionally, the removal of the intermediate protecting group PG as shown in Formula II-1A 1 under the action of hydrochloric acid; Optionally, the removal of the intermediate protecting group PG as shown in Formula II-1A 1 under reaction with hydrogen gas; Optionally, the reaction temperature is 20~25°C; Optionally, the base is triethylamine or N,N-diisopropylethylamine; Optionally, the deprotection reaction is carried out in a 1,4-dioxane; Optionally, the deprotection reaction time is 2 to 4 hours; Optionally, the reaction of the deprotected product with a compound as shown in Formula 6 under the action of a base is carried out in dichloromethane; Optionally, the reaction time of the deprotected product with the compound shown in Formula 6 under the action of a base is 10 to 14 hours.

17. The method for preparing the intermediate as shown in Formula II-2 according to claim 16, characterized in that, The molar ratio of the intermediate shown in Formula II-1A to the compound shown in Formula 6 is 1:1.5; Optionally, the base is triethylamine; Optionally, the deprotection reaction time is 3 hours; Optionally, the reaction time of the deprotected product with the compound shown in Formula 6 under the action of a base is 12 hours.

18. The process for the preparation of an intermediate as shown in formula II-1A according to claim 5, wherein, In step 5 The catalyst is a transition metal catalyst, which is selected from palladium metal catalysts, ruthenium metal catalysts, iron metal catalysts, cobalt metal catalysts, nickel metal catalysts, and rhodium metal catalysts. Optionally, the organic base is triethylamine or N,N-diisopropylethylamine; Optionally, the reaction is carried out in pressurized carbon monoxide at a pressure of 40-50 psi; Optionally, the reaction temperature is 55~65°C; Optionally, the reaction time is 22 to 26 hours.

19. The method for preparing the intermediate as shown in Formula II-1A according to claim 18, characterized in that, The transition metal catalyst is a palladium metal catalyst; the palladium metal catalyst is tetra(triphenylphosphine)palladium, palladium acetate, bis(triphenylphosphine)palladium dichloride, 1,1-bis(diphenylphosphine)ferrocene palladium chloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, tris(dibenzylideneacetone)palladium, bis(dibenzylideneacetone)palladium, 1,4-bis(diphenylphosphinebutane)palladium dichloride; Optionally, the organic base is triethylamine; Optionally, the pressure of the carbon monoxide is 45 psi; Optionally, the reaction time is 24 hours.

20. The method of claim 19, wherein the intermediate of Formula II-1A is prepared by the process of claim 19. The palladium metal catalyst is 1,1-bis(diphenylphosphine)ferrocene palladium chloride.

21. The process for the preparation of an intermediate as shown in formula II-1A according to claim 6, wherein, In step 6 The molar ratio of the intermediate shown in Formula II-1 to the compound shown in Formula 5 is 1:1 to 1:2; Optionally, the reaction temperature is 20~25°C; Optionally, the base is sodium bicarbonate; Optionally, the reaction is carried out in N,N-dimethylformamide; Optionally, the reaction time is 22 to 26 hours.

22. The method for preparing the intermediate as shown in Formula II-1A according to claim 21, characterized in that, The molar ratio of the intermediate shown in Formula II-1 to the compound shown in Formula 5 is 1:1.5; Optionally, the reaction time is 24 hours.

23. The process for the preparation of an intermediate as shown in formula II-1 according to claim 7, wherein, In step 1, The amino metal compound is lithium diisopropylamino, lithium bistrimethylsilylamino, potassium bistrimethylsilylamino, or sodium bistrimethylsilylamino. Optionally, the alkyl metal compound is a methyl Grignard reagent, an ethyl Grignard reagent, an isopropyl Grignard reagent, or an alkyl lithium compound; Optionally, when said R 2 is halogen, the reaction is carried out in the presence of an ammine metal compound; Optionally, when said R 2 is carboxyl, said reaction is carried out in the presence of an ammonia metal compound or an alkyl metal compound. Optionally, the reaction temperature is -80 to 0°C; Optionally, the molar ratio of the intermediate shown in Formula I to the compound shown in Formula 1 in the reaction is 1:1 to 1:1.6; The reaction is carried out in an organic solvent, including diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran, or tetrahydrofuran; Optionally, the reaction time is 2 to 4 hours; Optionally, when the reaction is carried out in the presence of an alkyllithium compound, the reaction further includes a stabilizer, wherein the stabilizer is N,N,N',N'-tetramethylethylenediamine.

24. The method of claim 23, wherein, The amino metal compound is lithium diisopropylamino or lithium bistrimethylsilylamino; Optionally, the alkyl metal compound is methyllithium or n-butyllithium; Optionally, the reaction temperature is -10~0℃ or -80~-60℃; Optionally, the alkyl metal compound is methyllithium or n-butyllithium; Optionally, the molar ratio of the intermediate shown in Formula I to the compound shown in Formula 1 in the reaction is 1:1 to 1.2 or 1:1.5 to 1:1.6; Optionally, the organic solvent is tetrahydrofuran; Optionally, the reaction time is 3 hours.

25. The method of claim 24, wherein, In the reaction, the molar ratio of the intermediate shown in Formula I to the compound shown in Formula 1 is 1:1.2 or 1:1.

5.

26. The method for preparing the intermediate as shown in Formula I according to claim 8, characterized in that, In step 2, The molar ratio of the intermediate shown in Formula I-2 to the compound shown in Formula 2 is 1:1 to 1:2; Optionally, the molar ratio of the intermediate as shown in Formula I-2 to the organic base compound is 1:2 to 1:4; Optionally, the molar ratio of the intermediate as shown in Formula I-2 to the condensing agent is 1:1 to 1:2; Optionally, the organic base is N,N-diisopropylethylamine; Optionally, the reaction temperature is 20-25°C; the reaction is carried out in dichloromethane; Optionally, the condensing agent is 1-propylphosphonic anhydride; Optionally, the reaction is carried out in dichloromethane; Optionally, the reaction time of the reaction is 14-18 hours.

27. The method for preparing the intermediate as shown in Formula I according to claim 26, characterized in that, The molar ratio of the intermediate as shown in formula I-2 to the compound as shown in formula 2 is 1:1.2; Optionally, the molar ratio of the intermediate as shown in formula I-2 to the compound of the organic base is 1:2.8-1:3.2; Optionally, the molar ratio of the intermediate as shown in formula I-2 to the condensing agent is 1:1.5; Optionally, the reaction time of the reaction is 16 hours.

28. The method for preparing the intermediate as shown in Formula I according to claim 27, characterized in that, The molar ratio of the intermediate as shown in formula I-2 to the compound of the organic base is 1:

3.

29. The method for preparing the intermediate as shown in Formula I according to claim 9, characterized in that, In the step 3, The reaction further comprises hydrogen gas; Optionally, the reaction further comprises palladium on carbon; Optionally, the reaction temperature of the reaction is 20-25℃; Optionally, the pressure of the hydrogen gas in the reaction is 0.8-1.2 atmospheres; Optionally, the mass ratio of the palladium on carbon to compound 3 is 1:18-1:22; Optionally, the reaction time of the reaction is 22-26 hours.

30. The method for preparing the intermediate as shown in Formula I according to claim 29, characterized in that, The pressure of the hydrogen gas in the reaction is 1 atmosphere; Optionally, the mass ratio of the palladium on carbon to compound 3 is 1:20; Optionally, the reaction time of the reaction is 24 hours.

31. The method for preparing the intermediate as shown in Formula I according to claim 9, characterized in that, In the step 4, The inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; Optionally, the reaction temperature of the reaction is 20-25℃; Optionally, the molar ratio of the intermediate as shown in formula I-1 to the inorganic base is 1:1-1:4; the reaction is carried out in methanol; Optionally, the reaction time of the reaction is 14-18 hours.

32. The method for preparing the intermediate as shown in Formula I according to claim 31, characterized in that, The inorganic base is lithium hydroxide; Optionally, the molar ratio of the intermediate as shown in formula I-1 to the inorganic base is 1:2; Optionally, the reaction time of the reaction is 16 hours.

33. An intermediate as shown in formula II: wherein, The R 1 selected from PG 1 or ; said R 2 selected from halogen; The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl; The X is selected from H or Br.

34. The intermediate as shown in formula II according to claim 33, wherein, When R 2 is halogen, said halogen is Br or I.

35. The intermediate as shown in formula II according to claim 33, wherein, When R 2 is halogen, said halogen is Br.

36. The intermediate as shown in formula II according to claim 33, which is selected from any one of the following intermediates: wherein, The X is selected from H or Br. The PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl, or benzyl; said R 2 selected from halogen.

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