CN114805340A - Process for producing imidazopyridine compound and intermediate thereof - Google Patents

Process for producing imidazopyridine compound and intermediate thereof Download PDF

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Publication number
CN114805340A
CN114805340A CN202210072873.8A CN202210072873A CN114805340A CN 114805340 A CN114805340 A CN 114805340A CN 202210072873 A CN202210072873 A CN 202210072873A CN 114805340 A CN114805340 A CN 114805340A
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formula
reaction
optionally
intermediate shown
compound
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张学军
李群
臧杨
叶大炳
常少华
李学强
李莉娥
杨俊�
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Humanwell Healthcare Group Co ltd
Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings

Abstract

The invention provides a preparation method of an imidazopyridine compound shown in a formula IV and an intermediate shown in a formula I, a formula II or a formula III. The imidazopyridine compound shown in the formula IV can antagonize a P2X3 receptor, and has the effects of suppressing cough and relieving pain.

Description

Process for producing imidazopyridine compound and intermediate thereof
PRIORITY INFORMATION
The present application claims priority and benefit of a patent application having patent application number 202110090342.7, filed 2021, month 01, 22 with the intellectual property office of china, and is incorporated herein by reference in its entirety.
Technical Field
The invention relates to a preparation method of imidazopyridine compounds and intermediates thereof.
Background
The P2X receptor is a nonselective ATP-gated ion channel receptor, a purinergic receptor, that binds extracellular ATP, which originates primarily from damaged or inflamed tissue. The receptor is widely expressed in nervous, immune, cardiovascular, skeletal, gastrointestinal, respiratory, endocrine systems, and the like, and is involved in a variety of physiological processes such as regulation of heart rhythm and contractility, regulation of vascular tone, regulation of nociception, particularly chronic pain, vasoconstriction of vas deferens during ejaculation, contraction of bladder during urination, platelet aggregation, activation of macrophages, apoptosis, and neuron-glial interactions. The P2X receptors mentioned above include seven homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, and P2X7, three heterologous receptors: P2X2/3, P2X4/6 and P2X 1/5.
P2X3 is a subtype of the P2X receptor family, and is selectively expressed in dorsal root ganglia, spinal cord and brain neurons of the nerve endings, i.e., primary sensory neurons of medium and small diameter.
Numerous studies have shown that activation of P2X3 and P2X2/3 expressed in primary sensory neurons plays an important role in acute injury, hyperalgesia, and hypersensitivity in rodents. Many studies have shown that upregulation of P2X3 receptor expression can lead to hyperalgesia and is involved in pain signaling. P2X3 knockout mice show reduced pain responses and P2X3 receptor antagonists show reduced nociceptive effects in models of pain and inflammatory pain.
P2X3 is distributed in primary afferents around the airways and is capable of modulating cough. Studies have shown that ATP released from damaged or inflamed tissues of the airways acts on P2X3 receptors of primary neurons, triggering depolarization and action potentials that propagate to cause cough impulses that trigger coughing. Preclinical and clinical data strongly demonstrate that the P2X3 receptor plays an important role in cough-reflex hypersensitivity, leading to chronic cough. By antagonizing the binding to P2X3 receptor, the hypersensitivity reaction of cough reflex can be inhibited, thereby inhibiting excessive cough of chronic cough patients.
P2X3 was reported to be involved in afferent pathways controlling bladder volume reflexes, with a significant decrease in micturition frequency and a significant increase in bladder volume in P2X3 knockout mice. Therefore, inhibition of the binding of P2X3 receptor antagonists to P2X3 receptors has the effect of treating disorders of storage and micturition disorders, such as overactive bladder. Therefore, the P2X3 antagonist can be a potential drug for treating diseases related to overactive bladder and the like.
In addition, studies have shown that P2X3 antagonists can be used to treat chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension or asthma, and therefore P2X3 antagonists are expected to be new drugs for treating the above diseases.
P2X3 antagonists show great promise in a number of disease areas, and therefore, the development of P2X3 antagonists is of clinical importance.
Disclosure of Invention
The invention provides a preparation method of an imidazopyridine compound and an intermediate thereof. The preparation method has the advantages of mild conditions, stable process and simple operation, and is suitable for amplification and industrial production.
The invention provides an intermediate shown as a formula I, a formula II or a formula III:
Figure BDA0003482913530000021
wherein the content of the first and second substances,
the R is 1 Is selected from PG 1 Or
Figure BDA0003482913530000022
The R is 2 Selected from halogen, carboxyl or
Figure BDA0003482913530000023
The R is 2a Is selected from C 1 -C 6 Alkyl or benzyl;
the R is 3 Selected from methyl or chlorine;
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
and X is selected from H or Br.
In a preferred embodiment of the invention, when R is 2 When halogen is used, the halogen is Br or I, preferably Br.
In a preferred embodiment of the present invention, R is 2a Is C 1 -C 6 An alkyl group; preferably, R is 2a Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In a preferred embodiment of the present invention, the intermediate of formula II as described hereinbefore is selected from any one of the following intermediates:
Figure BDA0003482913530000031
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Selected from halogen, carboxyl or
Figure BDA0003482913530000032
The R is 2a Having the definitions as described hereinbefore.
The invention also provides a preparation method of the intermediate shown in the formula II-1, which comprises the following steps:
step 1: under the action of an amino metal compound or an alkyl metal compound, an intermediate shown as a formula II-1 is prepared by reacting an intermediate shown as a formula I-3 with a compound shown as a formula 1;
Figure BDA0003482913530000033
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Selected from halogen, carboxyl or
Figure BDA0003482913530000034
The R is 2a Having the definitions as described hereinbefore.
In the step 1, the amino metal compound is lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium bistrimethylsilyl amide, sodium bistrimethylsilyl amide, preferably lithium diisopropylamide or bistrimethylsilyl amide.
In the step 1, the alkyl metal compound is methyl grignard reagent, ethyl grignard reagent, isopropyl grignard reagent or alkyl lithium compound, preferably methyl lithium or n-butyl lithium.
In the step 1, when the R is 2 In the case of halogens, the reaction is carried out under the action of an amino metal compound.
In the step 1, when the R is 2 Is carboxyl or
Figure BDA0003482913530000035
When the reaction is carried out under the action of an amino metal compound or an alkyl metal compound.
In step 1, the reaction may be carried out in an organic solvent conventional in the art, including but not limited to diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably tetrahydrofuran.
In the step 1, the reaction temperature of the reaction is-80 to 0 ℃, preferably-10 to 0 ℃ or-80 to-60 ℃.
In the step 1, the molar ratio of the compound shown in the formula I to the compound shown in the formula 1 is 1: 1-1: 1.6, preferably 1: 1-1.2 or 1: 1.5-1: 1.6, and more preferably 1:1.2 or 1: 1.5.
In the step 1, the reaction time of the reaction is 2 to 4 hours, preferably 2.5 hours.
In the step 1, when the reaction is performed under the action of an alkyl lithium compound, the reaction in the step 1 further comprises a stabilizer, and the stabilizer is N, N' -tetramethylethylenediamine.
The invention also provides a preparation method of the intermediate shown in the formula I, which comprises the following steps;
step 2: under the action of organic alkali and a condensing agent, reacting an intermediate shown as a formula I-2 with a compound shown as a formula 2 to prepare the intermediate shown as the formula I;
Figure BDA0003482913530000041
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
In the step 2, the reaction temperature of the reaction is 20-25 ℃.
In the step 2, the organic base is selected from N, N-diisopropylethylamine.
In the step 2, the condensing agent is 1-propyl phosphoric anhydride.
In the step 2, the molar ratio of the intermediate shown in the formula I-2 to the compound shown in the formula 2 is 1: 1-1: 2, preferably 1: 1.2.
In the step 2, the molar ratio of the intermediate shown in the formula I-2 to the organic base compound is 1: 2-1: 4, preferably 1: 2.8-1: 3.2, and more preferably 1:3.
In the step 2, the molar ratio of the intermediate shown in the formula I-2 to the condensing agent is 1: 1-1: 2, preferably 1: 1.5.
In the step 2, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
In the step 2, the reaction is carried out in dichloromethane.
According to an embodiment of the invention, the preparation method of the intermediate shown in the formula I also comprises a preparation method of the intermediate shown in the formula I-2, and the preparation method of the intermediate shown in the formula I-2 comprises the following steps:
and step 3: preparing an intermediate shown as a formula I-1 by carrying out reduction reaction on a compound shown as a formula 3;
Figure BDA0003482913530000051
and 4, step 4: under the action of inorganic base, hydrolyzing the intermediate shown in the formula I-1 to prepare an intermediate shown in the formula I-2;
Figure BDA0003482913530000052
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
In the step 3, the reaction further comprises hydrogen.
In the step 3, the reaction further comprises palladium on carbon.
In the step 3, the reaction temperature of the reaction is 20-25 ℃.
In the step 3, the pressure of hydrogen in the reaction is 0.8 to 1.2 atm, preferably 1 atm.
In the step 3, the mass ratio of the palladium carbon to the compound 3 is 1:18 to 1:22, preferably 1: 20.
In the step 3, the reaction time is 22 to 26 hours, preferably 24 hours.
In step 4, the inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide.
In the step 4, the reaction temperature of the reaction is 20-25 ℃.
In the step 4, the molar ratio of the intermediate shown in the formula I-1 to the inorganic base is 1: 1-1: 4, preferably 1:2.
In the step 4, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
In the step 4, the reaction is carried out in methanol.
The invention also provides a preparation method of the intermediate shown in the formula II-1A, wherein the intermediate shown in the formula II-1A is prepared from the intermediate shown in the formula II-1, and the preparation method of the intermediate shown in the formula II-1A comprises the following steps;
and 5: under the action of a catalyst and organic base, reacting the intermediate shown as the formula II-1 with carbon monoxide and a compound shown as the formula 4 to obtain an intermediate shown as the formula II-1A;
Figure BDA0003482913530000053
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is halogen;
the R is 2a Having the definitions as described hereinbefore.
In the step 5, the catalyst transition metal catalyst includes palladium metal catalyst, ruthenium metal catalyst, iron metal catalyst, cobalt metal catalyst, nickel metal catalyst, rhodium metal catalyst, preferably palladium metal catalyst;
preferably, the palladium catalyst comprises tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, 1-bis (diphenylphosphino) ferrocene palladium chloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, 1, 4-bis (diphenylphosphinobutane) palladium dichloride, and more preferably the palladium metal catalyst is 1, 1-bis (diphenylphosphino) ferrocene palladium chloride.
In step 5, the organic base includes, but is not limited to, triethylamine or N, N-diisopropylethylamine, preferably triethylamine.
In the step 5, the reaction is carried out in pressurized carbon monoxide, and the pressure of the carbon monoxide is 40-50 psi, preferably 45 psi.
In the step 5, the reaction temperature of the reaction is 55-65 ℃.
In the step 5, the reaction time is 22 to 26 hours, preferably 24 hours.
The invention also provides a preparation method of the intermediate shown in the formula II-1A, wherein the intermediate shown in the formula II-1A is prepared from the intermediate shown in the formula II-1, and the preparation method of the intermediate shown in the formula II-1A comprises the following steps;
step 6: under the action of alkali, an intermediate shown as a formula II-1A is obtained by reacting the intermediate shown as a formula II-1 with a compound shown as a formula 5;
Figure BDA0003482913530000061
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is a carboxyl group;
the R is 2a Having the definitions as described hereinbefore.
In the step 6, the molar ratio of the intermediate shown in the formula II-1 to the compound shown in the formula 5 is 1: 1-1: 2, preferably 1: 1.5.
In the step 6, the reaction temperature of the reaction is 20-25 ℃.
In the step 6, the alkali is sodium bicarbonate.
In the step 6, the reaction is carried out in N, N-dimethylformamide.
In the step 6, the reaction time is 22 to 26 hours, preferably 24 hours.
The invention also provides a preparation method of the intermediate shown in the formula II-2, and the preparation method of the intermediate shown in the formula II-2 comprises the following steps:
and 7: removing the intermediate protecting group PG shown as the formula II-1A 1 To obtain a product of removing a protecting group; reacting the product of removing the protecting group with a compound shown as a formula 6 under the action of alkali to obtain an intermediate shown as a formula II-2;
Figure BDA0003482913530000071
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2a Having the definitions as described hereinbefore.
In the step 7, the molar ratio of the intermediate shown in the formula II-1A to the compound shown in the formula 6 is 1: 1-1: 2, preferably 1: 1.5.
In the step 7, the intermediate protecting group PG shown as the formula II-1A is removed 1 Under the action of hydrochloric acid.
In the step 7, the intermediate protecting group PG shown as the formula II-1A is removed 1 Under reaction with hydrogen.
In the step 7, the reaction temperature of the reaction is 20-25 ℃.
In step 7, the base includes, but is not limited to, triethylamine or N, N-diisopropylethylamine, preferably triethylamine.
In the step 7, the reaction of the deprotected group is carried out in 1, 4-dioxane.
In the step 7, the reaction time of the deprotection group is 2 to 4 hours, preferably 3 hours.
In the step 7, the reaction of the product of the deprotection group and the compound shown in the formula 6 is carried out in dichloromethane under the action of alkali.
In the step 7, the reaction time of the product of the deprotection group and the compound shown in the formula 6 under the action of the alkali is 10-14 hours, preferably 12 hours.
The invention also provides a preparation method of the intermediate shown in the formula II-3, the intermediate shown in the formula II-3 is prepared from the intermediate shown in the formula II-2, and the preparation method of the intermediate shown in the formula II-3 comprises the following steps:
and 8: reacting the intermediate shown as the formula II-2 with a brominating reagent to obtain an intermediate shown as a formula II-3;
Figure BDA0003482913530000081
wherein R is 2a Having the definitions as described hereinbefore.
In step 8, the brominating agent includes N-bromosuccinimide, dibromohydantoin, pyridine tribromide, liquid copper bromide or liquid bromine, preferably liquid bromine.
In the step 8, the molar ratio of the intermediate shown in the formula II-2 to the brominating reagent is 1: 1-1: 3, preferably 1: 1.2.
In the step 8, the reaction is carried out in dichloromethane.
In the step 8, the reaction temperature of the reaction is 20-25 ℃.
In the step 8, the reaction time of the reaction is 0.5 to 2 hours, preferably 1 hour.
The invention also provides a preparation method of the intermediate shown in the formula III, the intermediate shown in the formula III is prepared from the intermediate shown in the formula II-3, and the preparation method of the intermediate shown in the formula III comprises the following steps:
and step 9: reacting the intermediate shown as the formula II-3 with the compound shown as the formula 7 to obtain an intermediate shown as the formula III;
Figure BDA0003482913530000082
wherein the content of the first and second substances,
the R is 2a Having the definitions as hereinbefore described;
the R is 3 Selected from methyl or chlorine.
In the step 9, the molar ratio of the intermediate shown in the formula II-3 to the compound shown in the formula 7 in the reaction is 1: 1-1: 3, preferably 1:2.
In step 9, the reaction may be carried out in an organic solvent conventional in the art, including but not limited to acetonitrile, dimethylsulfoxide, ethanol, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, 1, 4-dioxane, N-propanol or N-butanol, preferably acetonitrile.
In the step 9, the reaction temperature of the reaction is 110 to 130 ℃, preferably 120 ℃.
In the step 9, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
The invention also provides a preparation method of the imidazopyridine compound shown in the formula IV, which comprises the following steps:
step 10: reacting the intermediate shown in the formula III with methylamine to obtain a compound shown in the formula IV;
Figure BDA0003482913530000091
wherein the content of the first and second substances,
the R is 2a Having the definitions as hereinbefore described;
the R is 3 Selected from methyl or chlorine.
In the step 10, the molar ratio of the intermediate shown in the formula III to methylamine is 1: 4-1: 6, preferably 1: 5.
In the step 10, the reaction temperature of the reaction is 20-25 ℃.
In the step 10, the reaction is carried out in methanol.
In the step 10, the reaction time is 4 to 6 hours, preferably 5 hours.
The invention also provides a preparation method of the intermediate shown in the formula 3, wherein the preparation method of the intermediate shown in the formula 3 comprises the following steps;
step 11: reacting the intermediate shown as the formula 3-1 with a dess-martin oxidant to obtain an intermediate shown as the formula 3-2; reacting the intermediate shown as the formula 3-2 with a compound shown as the formula 8 to obtain an intermediate shown as the formula 3;
Figure BDA0003482913530000092
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
In the step 11, the molar ratio of the intermediate shown as the formula 3-1 to the dess-martin oxidant is 1: 1.2.
In the step 11, the reaction temperature of the intermediate shown as the formula 3-1 and the dess-Martin oxidant is 20-25 ℃.
In the step 11, the reaction time of the intermediate shown in the formula 3-1 and the dess-martin oxidant is 1-3 hours, preferably 2 hours.
In the step 11, the reaction of the intermediate shown as the formula 3-1 and a dess-martin oxidant is carried out in dichloromethane.
In the step 11, the molar ratio of the intermediate shown in the formula 3-2 to the compound 8 is 1: 1-1: 2, preferably 1: 1.1.
In the step 11, the reaction temperature of the intermediate shown in the formula 3-1 and the compound 8 is 20-25 ℃.
In the step 11, the reaction time of the intermediate shown in the formula 3-1 and the compound 8 is 14 to 18 hours, preferably 16 hours.
In the step 11, the reaction of the intermediate shown as the formula 3-1 and a dess-martin oxidant is carried out in dichloromethane.
Terms and definitions
Unless otherwise indicated, the terms and definitions used in the present application, including in the specification and claims of the present application, are as follows.
It will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,
Figure BDA0003482913530000101
for delineating chemical bonds, which are the points at which moieties or substituents are attached to a core structure or a backbone structure.
The term "C 1 -C 6 Alkyl "is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group, or the like, or isomers thereof. In particular, the radicals have 1,2 or 3 carbon atoms ("C) 1 -C 3 Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "metal alkyl compound" refers to an organic compound formed by a metal atom directly bonded to an alkyl carbon atom. The alkyl group includes, but is not limited to, alkyl or cycloalkyl, such as C 1 -C 6 An alkyl group. Including but not limited to potassium, sodium, lithium, magnesium, or aluminum. The alkyl metal compound includes but is not limited to grignard reagent, alkyl lithium compound.
The term "amino metal compound" refers to a compound formed by a metal atom covalently or coordinately bound to an amino group, the "amino group being primary (i.e., -NH) 2 ) Secondary (i.e., -NRH) and tertiary (i.e., -NRR) amines, said R including but not limited to C 1 -C 6 Including but not limited to potassium, sodium, lithium or magnesium, and amino metal compounds including but not limited to lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium bistrimethylsilyl amide, sodium amide, potassium amide, lithium amide.
The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine.
The term "catalyst" refers to any substance or agent that can affect, induce, increase or promote the reactivity or reaction of a compound.
The term "transition metal catalyst" refers to any metal having an electron in its d orbital, for example a metal selected from groups 3-12 of the periodic table or the lanthanide series of elements. Catalysts useful in the process of the present invention include atoms, ions, salts or complexes of transition metals from groups 8 to 11 of the periodic Table. "groups 3 to 12 of the periodic Table of the elements" means the groups of the periodic Table numbered according to the IUPAC method. Thus, group 8-11 transition metals include iron, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, and gold. Such catalysts include, but are not limited to, CuI, CuCl, CuBr 2 、Cu 2 Cl 2 、Cu 2 O、Cu、Pd 2 (dba) 2 、Pd/C、PdCl 2 、Pd(OAc) 2 、(CH 3 CN) 2 PdCl 2 、Pd[P(C 6 H 5 ) 3 ] 4 、NiCl 2 [P(C 6 H 5 )] 2 And Ni (COD) 2 。
The term "R 2a -I "means containing R 2a The iodine reagent of (1).
In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
Detailed Description
The scheme of the invention will be explained with reference to the following examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to techniques or conditions described in literature in the art or according to the product specification. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
Unless otherwise specified, the compounds of the present invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). NMR shift in units of 10 -6 (ppm). Solvents for NMR measurement were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and an internal standard was Tetramethylsilane (TMS).
Abbreviations of the present invention are defined as follows:
m: molar concentration, e.g. 1M hydrochloric acid for 1mol/L hydrochloric acid solution
DIPEA: also can be written as DIEA, diisopropylethylamine, i.e., N-diisopropylethylamine
DMF: n, N-dimethylformamide
DCM: methylene dichloride
Et 3 N: triethylamine
Dess-Martin: dess-martin oxidizer
T 3 P: 1-Propylphosphoric acid anhydride
LDA: lithium diisopropylamide
n-BuLi: n-butyl lithium
TMEDA: n, N, N ', N' -tetramethylethylenediamine
NaHCO 3 : sodium bicarbonate
THF: tetrahydrofuran (THF)
Pd(dppf)Cl 2 :1, 1-bis (diphenylphosphino) ferrocene palladium chloride
LC-MS: liquid chromatography-mass spectrometry
TLC: thin layer chromatography
Preparation 1: preparation of intermediate (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A)
Figure BDA0003482913530000121
The synthetic route of the target intermediate a is shown below:
Figure BDA0003482913530000122
the first step is as follows: synthesis of tert-butyl (R) -2-formylmorpholine-4-carboxylate (A-2)
Figure BDA0003482913530000123
In a 2L three-necked flask were added (R) -tert-butyl 2-hydroxymethylmorpholine-4-carboxylate (A-1) (100g,460mmol) and dichloromethane (1L). The reaction temperature was adjusted to 0-5 deg.C and dess-martin oxidant (234g,552mmol) was added slowly in portions while maintaining the reaction temperature at 0-5 deg.C and the reaction was continued stirring at 0-5 deg.C for 0.5 h. The reaction temperature was adjusted to 20-25 ℃ and stirring was continued for 2h, TLC showed the starting material reaction was complete. The reaction was slowly poured into saturated solution sodium bicarbonate (1L) and stirred for 0.5h, filtered, separated and the organic phase collected. The organic phase was washed with a saturated sodium bicarbonate solution (1L. times.2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R) -tert-butyl 2-formylmorpholine-4-carboxylate (A-2) as a colorless oil (99g, 100% yield).
The second step is that: synthesis of (S) -2- (3-methoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylic acid tert-butyl ester (A-3)
Figure BDA0003482913530000131
To a 2L three-necked flask were added (R) -2-formylmorpholine-4-carboxylic acid tert-butyl ester (A-2) (99g,460mmol) and dichloromethane (1L). The reaction temperature was adjusted to 20-25 ℃ and the starting material was added slowly in portions to the carbomethoxymethylene triphenylphosphine (154g,460mmol) while maintaining the reaction temperature at 20-25 ℃ and the reaction was continued to stir at 20-25 ℃ for 16h, TLC showing complete reaction. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl (S) -2- (3-methoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylate (A-3) as a colorless oil (75g, yield 60.1%).
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).
The third step: synthesis of (S) -tert-butyl 2- (3-methoxy-3-oxopropyl) morpholine-4-carboxylate (A-4)
Figure BDA0003482913530000132
(S) -2- (3-methoxy-3-oxoprop-1-en-1-yl) morpholine-4-carboxylic acid tert-butyl ester (A-3) (75g,276mmol), methanol (750mL) were added to a 2L single-neck flask, the reaction system was purged with nitrogen 3 times, Pd/C (3.75g) was added, the reaction system was purged with hydrogen 3 times, the reaction temperature was adjusted to 20-25 ℃ and stirred under 1atm hydrogen atmosphere for 24h, TLC showed complete reaction of the starting materials. The reaction system was purged with nitrogen 3 times, and filtered to obtain a methanol solution of tert-butyl (S) -2- (3-methoxy-3-oxopropyl) morpholine-4-carboxylate (A-4) (76g, yield 100%) which was used directly in the next step.
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)。
The fourth step: synthesis of (S) -3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionic acid (A-5)
Figure BDA0003482913530000141
A2L three-necked flask was charged with a solution of (S) -tert-butyl 2- (3-methoxy-3-oxopropyl) morpholine-4-carboxylate (A-4) (76g, 278mmol) in methanol (750mL), 75mL of water were added, the reaction temperature was adjusted to 20-25 deg.C, lithium hydroxide monohydrate (23.3g,556mmol) was slowly added while maintaining the reaction temperature at 20-25 deg.C, and the reaction was stirred for a further 16h at 20-25 deg.C. The dried methanol was concentrated under reduced pressure, 400mL of water was added, the aqueous phase was washed with ethyl acetate (200 mL. times.2), the aqueous phase was collected, the temperature of the aqueous phase was adjusted to 0-5 ℃, the pH was adjusted to 4-5 with 4M aqueous hydrochloric acid solution under stirring, the aqueous phase was extracted with dichloromethane (400 mL. times.3), the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionic acid (A-5) as a colorless oil (72g, 99.8% yield).
1 H 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),2.97-2.81(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).
The fifth step: synthesis of (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A)
Figure BDA0003482913530000142
In a 2L three-necked flask were charged (S) -3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionic acid (A-5) (72g,278mmol), N, O-dimethylhydroxylamine hydrochloride (32.5g,333mmol) and dichloromethane (720mL), and the reaction temperature was adjusted to 0-5 ℃. DIEA (108g,833mmol) and 1-propylphosphoric anhydride (50% DMF solution, 265g, 417 mmol) were slowly added dropwise to the reaction mixture). The reaction internal temperature was adjusted to 20-25 ℃ and stirred for 16 h. 500mL of saturated NaHCO 3 The solution was slowly added dropwise to the reaction solution, and the organic phase was separated and collected. The organic phase is washed with 500mL of saturated sodium bicarbonate solution and concentrated to dryness under reduced pressure. To the residue was added 360mL of ethyl acetate, washed with saturated ammonium chloride (300 mL. times.3), and the organic phase was concentrated under reduced pressure to dryness to give (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (a) as a colorless oil (71g, 85% yield).
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)。
Preparation 2: preparation of intermediate (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Figure BDA0003482913530000151
The synthetic route of the target intermediate B is shown below:
Figure BDA0003482913530000152
the first step is as follows: synthesis of (S) -tert-butyl 2- (3- (4-bromo-2, 3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-1)
Figure BDA0003482913530000153
Adding 2,3, 5-trifluorobromobenzene (74.3g,352mmol) and anhydrous tetrahydrofuran (710mL) into a 2L three-necked flask under nitrogen atmosphere, adjusting the reaction temperature to-10-0 ℃, slowly dropwise adding lithium diisopropylamide (176mL,352mmol,2mol/L tetrahydrofuran solution) while maintaining the reaction temperature at-10-0 ℃, after the reaction liquid is continuously stirred for 1h, slowly dropwise adding a tetrahydrofuran (140mL) solution of tert-butyl (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A) (71g,235mmol), continuously stirring for 2h at-10-0 ℃, and TLC shows that the reaction is complete. Saturated ammonium chloride solution (500mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, 500mL of ethyl acetate was added to dilute, the aqueous phase was separated and extracted with 500mL of ethyl acetate, the combined organic phases were washed with saturated ammonium chloride (1L), the collected organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give (S) -tert-butyl 2- (3- (4-bromo-2, 3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-1) (91g, yield 86%) as a white solid.
1 H NMR(400MHz,Chloroform-d)δ7.22–7.15(m,1H),3.85–3.78(m,3H),3.44(td,J＝11.7,2.8Hz,1H),3.36(ddt,J＝12.8,10.2,3.1Hz,1H),3.07–2.80(m,3H),2.68–2.54(s,1H),1.92(dtd,J＝14.5,7.3,3.7Hz,1H),1.81(tq,J＝14.0,8.0,6.8Hz,1H),1.45(s,9H).
LC-MS,M/Z:352.1[M+H] +
The second step is that: synthesis of (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Figure BDA0003482913530000154
Tert-butyl (S) -2- (3- (4-bromo-2, 3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-1) (91.0g, 201mmol) was dissolved in methanol (1L), triethylamine (60g, 603mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (5.90g, 8.05mmol) were added, vacuum was applied, nitrogen was applied three times, carbon monoxide was applied three times, and the reaction was carried out at 55-65 ℃ for 24h under carbon monoxide (45 psi). TLC showed the reaction was complete, the reaction was concentrated to dryness, then water (1L) was added, neutralized with citric acid, then extracted with ethyl acetate (800mL × 2), combined with organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (82g, 93.5% yield) as a brown oil.
1 H NMR(400MHz,Chloroform-d)δ7.52–7.27(m,1H),3.98(s,3H),3.85–3.82(m,3H)，3.46–3.38(m,2H)，3.05–2.90(m,2H)，2.90–2.77(m,1H)，2.75–2.51(m,1H)，1.96–1.82(m,2H)，1.47(s,9H).
LC-MS,M/Z:332.2[M+H] + 。
Preparation 3: preparation of intermediate (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Figure BDA0003482913530000161
The synthetic route of the target intermediate B is shown below:
Figure BDA0003482913530000162
the first step is as follows: synthesis of (S) -tert-butyl 2- (3- (4-bromo-2, 3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-2)
Figure BDA0003482913530000163
Under nitrogen atmosphere, 2,3, 5-trifluorobromobenzene (10.5g,50mmol) and anhydrous tetrahydrofuran (100mL) are added into a 500mL three-necked flask, the reaction temperature is adjusted to-80 to-60 ℃, lithium diisopropylamide (25mL,50mmol,2mol/L tetrahydrofuran solution) is slowly dripped while maintaining the reaction temperature at-80 to-60 ℃, after the reaction liquid is continuously stirred for 1h, a tetrahydrofuran (20mL) solution of tert-butyl (A) (10g,33mmol) of (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate is slowly dripped into the solution, and the reaction is continuously stirred for 2h at-80 to-60 ℃, and TLC shows that the reaction is complete. Saturated ammonium chloride solution (100mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, 100mL of ethyl acetate was added to dilute, the aqueous phase was separated and extracted with 100mL of ethyl acetate, the combined organic phases were washed with saturated ammonium chloride (200mL), the collected organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give (S) -tert-butyl 2- (3- (4-bromo-2, 3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-2) (9.3g, yield 62%) as a white solid.
LC-MS,M/Z:352.1[M+H] +
The second step is that: synthesis of (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Figure BDA0003482913530000171
Tert-butyl (S) -2- (3- (4-bromo-2, 3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-2) (9.3g, 20.5mmol) was dissolved in methanol (93mL), triethylamine (6.12g, 61.5mmol) and 1, 1-bis (diphenylphosphino) ferrocene palladium chloride (0.6g, 0.82mmol) were added, the mixture was evacuated, replaced with nitrogen three times, replaced with carbon monoxide three times, and then reacted under carbon monoxide (45psi) at 55-65 ℃ for 24 h. TLC showed completion of the reaction, concentrated to dryness, then added water (100mL), neutralized with citric acid, then extracted with ethyl acetate (100mL × 2), combined with organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (8g, 91% yield) as a brown oil.
LC-MS,M/Z:332.2[M+H] + 。
Preparation 4: preparation of intermediate (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Figure BDA0003482913530000172
The synthetic route of the target intermediate B is shown below:
Figure BDA0003482913530000181
the first step is as follows: synthesis of (S) -4- (3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionyl) -2,3, 5-trifluorobenzoic acid (B-3)
Figure BDA0003482913530000182
Under a nitrogen atmosphere, 2,3, 5-trifluorobenzoic acid (7.0g,40mmol), TMEDA (10.2g,88mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the reaction temperature is adjusted to-10 to 0 ℃, n-butyllithium (35.2mL,88mmol,2.5mol/L n-hexane solution) is slowly added dropwise while maintaining the reaction temperature at-10 to 0 ℃, after the reaction solution is continuously stirred for 0.5h, a tetrahydrofuran (20mL) solution of (S) -tert-butyl 2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate (A) (10g,33mmol) is slowly added dropwise into the solution, and the mixture is continuously stirred for 2h at-10 to 0 ℃, and TLC shows that the reaction is complete. Water (100mL) was slowly added dropwise to the reaction solution, the reaction solution was allowed to warm to room temperature, the pH of the aqueous phase was adjusted to 4-5 with 1M aqueous hydrochloric acid, 100mL of ethyl acetate was added for dilution, the aqueous phase was separated and extracted with 100mL of ethyl acetate, the organic phases were combined, and the collected organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -4- (3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionyl) -2,3, 5-trifluorobenzoic acid (B-3) as a white solid (7.6g, 55% yield).
LC-MS,M/Z:318.1[M+H] +
The second step is that: synthesis of (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B)
Figure BDA0003482913530000183
(S) -4- (3- (4- (tert-butoxycarbonyl) morpholin-2-yl) propionyl) -2,3, 5-trifluorobenzoic acid (B-3) (7.6g, 18.2mmol) was dissolved in N, N-dimethylformamide (76mL), and sodium hydrogencarbonate (3.06g, 36.4mmol) and iodomethane (3.87g, 27.3mmol) were added to react at 20-25 ℃ for 24 hours. TLC showed completion of the reaction, added water (100mL) to the reaction solution, then extracted with ethyl acetate (100mL × 2), combined the organic phases, washed with saturated sodium bicarbonate solution (300mL × 2) and saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -tert-butyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (7.2g, 91% yield) as a brown oil.
LC-MS,M/Z:332.2[M+H] + 。
Preparation 5: preparation of intermediate (S) -tert-butyl 2- (3- (4- (tert-butoxycarbonyl) -2,3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu)
Figure BDA0003482913530000191
The synthetic route of the target intermediate B-Bu is shown as follows:
Figure BDA0003482913530000192
the first step is as follows: synthesis of tert-butyl (S) -2- (3- (4- (tert-butoxycarbonyl) -2,3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu)
Figure BDA0003482913530000193
Under nitrogen atmosphere, adding tert-butyl 2,3, 5-trifluorobenzoate (11.5g,49.5mmol) and anhydrous tetrahydrofuran (100mL) into a 250mL three-necked flask, adjusting the reaction temperature to-10-0 ℃, slowly dropwise adding lithium diisopropylamide (24.8mL,49.5mmol,2mol/L n-hexane solution) while maintaining the reaction temperature at-10-0 ℃, after continuously stirring the reaction solution for 1h, slowly dropwise adding a tetrahydrofuran (20mL) solution of tert-butyl (A) (10g,33mmol) of (S) -2- (3- (methoxy (methyl) amino) -3-oxopropyl) morpholine-4-carboxylate into the solution, and continuously stirring at-10-0 ℃ for 3h, wherein TLC shows that the reaction is complete. Saturated ammonium chloride solution (100mL) was slowly added dropwise to the reaction solution, the reaction solution was warmed to room temperature, 100mL of ethyl acetate was added to dilute, the aqueous phase was separated and extracted with 100mL of ethyl acetate, the combined organic phases were washed with saturated ammonium chloride (200mL), 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 ═ 1:5) to give (S) -tert-butyl 2- (3- (4- (tert-butoxycarbonyl) -2,3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu) as a white solid (9.2g, 59% yield).
LC-MS,M/Z:374.1[M+H] + 。
Preparation 6: preparation of intermediate methyl (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
Figure BDA0003482913530000201
The synthetic route of the target intermediate C is shown below:
Figure BDA0003482913530000202
the first step is as follows: synthesis of (S) -methyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1)
Figure BDA0003482913530000203
To a 2L three-necked flask were added tert-butyl (S) -2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (B) (82g,190mmol) and 1, 4-dioxane (200mL) under a nitrogen atmosphere, and the reaction temperature was adjusted to 20 to 25 ℃. A solution of 1, 4-dioxane (143mL,4mol/L) in hydrochloric acid was slowly added to the solution, the reaction temperature was maintained at 20-25 deg.C, the reaction was stirred for 3h, and LC-MS showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (820mL) was added to the residue, the temperature of the reaction mixture was adjusted to 0-5 ℃, triethylamine (48.1g,475mmol) was slowly added dropwise, and then methyl chloroformate (26.9g,285mmol) was added. The reaction temperature is adjusted to 20-25 ℃, the reaction solution is stirred for 12h at 20-25 ℃, and TLC shows that the reaction is complete. To the reaction solution, 400mL of a saturated sodium chloride solution was added, and the organic phase was separated and collected, washed with 1L of saturated ammonium chloride, and concentrated to dryness to give methyl (S) -2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) as a brown oil (71g, 96% yield).
LC-MS,M/Z:390.1[M+H] +
The second step is that: synthesis of methyl (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
Figure BDA0003482913530000204
To a 2L three-necked flask were added (S) -methyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) (71g,182mmol), dichloromethane (710mL) and 33% acetic acid hydrogen bromide solution (2.24g,9.12 mmol). The reaction temperature was adjusted to 20-25 deg.C, liquid bromine (35g,219mmol) was slowly added dropwise to the reaction solution, the reaction was stirred at 20-25 deg.C for 1h, TLC showed complete reaction. To the reaction system were added 300mL of a saturated sodium bisulfite solution, and 800mL of a saturated sodium bicarbonate solution. The organic phase was separated and collected, washed with 800mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:3) to give (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylic acid methyl ester (C) (76g, yield 89%) as a brown oil.
1 H NMR(400MHz,Chloroform-d)δ7.51(ddd,J＝9.3,4.7,2.2Hz,1H),5.16–5.11(m,1H),3.97–3.83(d,J＝0.7Hz,6H),3.71(s,3H),3.69–3.36(m,2H),2.98–2.95(m,1H),2.76–2.68(m,1H),2.59–2.29(m,1H),2.24–2.07(m,1H).
LC-MS,M/Z:468.0[M+H] + 。
Preparation 7: preparation of intermediate methyl (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
Figure BDA0003482913530000211
The synthetic route of the target intermediate C is shown below:
Figure BDA0003482913530000212
the first step is as follows: synthesis of (S) -2,3, 5-trifluoro-4- (3- (4- (methoxycarbonyl) morpholin-2-yl) propionyl) benzoic acid (C-2)
Figure BDA0003482913530000213
To a 250mL three-necked flask, tert-butyl (S) -2- (3- (4- (tert-butoxycarbonyl) -2,3, 6-trifluorophenyl) -3-oxopropyl) morpholine-4-carboxylate (B-Bu) (9.2g,19.4mmol) and 1, 4-dioxane (20mL) were added under a nitrogen atmosphere, and the reaction temperature was adjusted to 20-25 ℃. A solution of hydrochloric acid in 1, 4-dioxane (20.0mL,4mol/L) was slowly added to the solution, the reaction temperature was maintained at 20-25 deg.C, and the reaction was continued with stirring for 15 h. The reaction mixture was concentrated to dryness under reduced pressure, methylene chloride (72mL) was added to the residue, the temperature of the reaction mixture was adjusted to 0-5 deg.C, triethylamine (6.87g,67.9mmol) was slowly added dropwise, followed by methyl chloroformate (2.36g,29.1 mmol). The reaction temperature is adjusted to 20-25 ℃, and the reaction liquid is stirred for 12h at 20-25 ℃. To the reaction solution was added 100mL of water, the pH of the aqueous phase was adjusted to 4-5 with 5M hydrochloric acid solution, the organic phase was separated and collected, the aqueous phase was extracted with dichloromethane (100mL × 2), and the combined organic phases were concentrated to dryness to give (S) -2,3, 5-trifluoro-4- (3- (4- (methoxycarbonyl) morpholin-2-yl) propionyl) benzoic acid (C-2) (6.0g, 83% yield) as a white solid.
LC-MS,M/Z:376.1[M+H] +
The second step is that: synthesis of (S) -methyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1)
Figure BDA0003482913530000221
(S) -2,3, 5-trifluoro-4- (3- (4- (methoxycarbonyl) morpholin-2-yl) propanoyl) benzoic acid (C-2) (6.0g, 16.0mmol) was dissolved in N, N-dimethylformamide (60mL), and sodium bicarbonate (2.69g, 32.0mmol) and iodomethane (3.40g, 24mmol) were reacted at 20-25 ℃ for 24 hours. TLC showed completion of the reaction, added water (100mL) to the reaction mixture, then extracted with ethyl acetate (100mL × 2), combined with organic phase, washed with saturated sodium bicarbonate solution (300mL × 2) and saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound (S) -methyl 2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) (4.67g, 75% yield) as a white oil.
LC-MS,M/Z:390.1[M+H] +
The third step: synthesis of methyl (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C)
Figure BDA0003482913530000222
A100 mL three-necked flask was charged with methyl (S) -2- (3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C-1) (4.67g,12.0mmol), dichloromethane (50mL) and a 33% acetic acid solution of hydrogen bromide (0.15g,0.61 mmol). The reaction temperature was adjusted to 20-25 deg.C, liquid bromine (2.3g,14.4mmol) was slowly added dropwise to the reaction solution, the reaction was stirred at 20-25 deg.C for 1h, TLC indicated complete reaction. To the reaction system were added 30mL of a saturated sodium bisulfite solution and 50mL of a saturated sodium bicarbonate solution. The organic phase was separated and collected, washed with 50mL of a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:3) to give (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylic acid methyl ester (C) (5.3g, yield 95%) as a brown oil.
LC-MS,M/Z:468.0[M+H] + 。
Preparation 8: preparation of intermediate methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (D)
Figure BDA0003482913530000231
The synthetic route of the target intermediate D is shown below:
Figure BDA0003482913530000232
the first step is as follows: synthesis of methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (D)
Figure BDA0003482913530000233
To a 350mL reaction flask were added methyl (2S) -2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C) (15g,31.4mmol), 2-amino-4-methylpyridine (6.93g, 62.8mmol) and acetonitrile (150mL), the reaction flask was closed, the reaction temperature was adjusted to 120 ℃ and stirred for 24h, cooled to room temperature and filtered, the filtrate was concentrated to dryness under reduced pressure, and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give (S) -2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [ 1) as a yellow solid, 2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester (D) (8g, 52% yield)
LC-MS,M/Z:478.2[M+H] + 。
Preparation 9: preparation of intermediate methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (E)
Figure BDA0003482913530000241
The synthetic route of the target intermediate E is shown below:
Figure BDA0003482913530000242
the first step is as follows: synthesis of methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (E)
Figure BDA0003482913530000243
To a 1L reaction flask was added (2S) -methyl 2- (2-bromo-3-oxo-3- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) propyl) morpholine-4-carboxylate (C) (60g,128mmol), 2-amino-4-chloropyridine (32.9g, 256mmol) and acetonitrile (600 mL). The reaction flask was stirred at 120 ℃ for 24h, cooled to room temperature and filtered, the filtrate was concentrated to dryness under reduced pressure and finally purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (E) (30g, 47% yield) as a yellow solid.
LC-MS,M/Z:498.1[M+H] + 。
Example 1: preparation of methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (1)
Figure BDA0003482913530000251
The synthetic route for the target compound 1 is shown below:
Figure BDA0003482913530000252
the first step is as follows: synthesis of methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate preparation (1)
Figure BDA0003482913530000253
To a 100mL reaction flask was added (S) -methyl 2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (D) (8g,16.7mmol), methanol (16 mL). To the reaction solution was added a 33% solution of methylamine in methanol (7.8g, 83mmol), the reaction temperature was adjusted to 20-25 ℃ and stirred for 5 h. TLC indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to give methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (1) as a yellow solid (7.7g, yield 97%).
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).
LC-MS,M/Z:477.2[M+H] + 。
Example 2: preparation of methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (2)
Figure BDA0003482913530000261
The synthetic route for the target compound 2 is shown below:
Figure BDA0003482913530000262
the first step is as follows: synthesis of methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (2)
Figure BDA0003482913530000263
To a 100mL reaction flask was added (S) -methyl 2- ((2- (2,3, 6-trifluoro-4- (methoxycarbonyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (E) (30g,60.3mmol), methanol (60 mL). To the reaction solution was added 33% methylamine methanol solution (28.4g, 301mmol), the reaction temperature was adjusted to 20-25 ℃ and stirred for 5 h. TLC indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to dryness and purified by silica gel column chromatography to give methyl (S) -2- ((2- (2,3, 6-trifluoro-4- (methylcarbamoyl) phenyl) -7-chloroimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (2) as a yellow solid (27g, yield 90%).
1H NMR(400MHz,Chloroform-d)δ8.27(d,J＝7.4Hz,1H),7.69(ddd,J＝9.6,5.6,2.1Hz,1H),7.60(dd,J＝2.1,0.8Hz,1H),6.81(m,4.1Hz,2H),4.04–3.73(m,3H),3.67(s,3H),3.60–3.50(m,1H),3.35(t,J＝11.7Hz,1H),3.06(dd,J＝4.9,1.0Hz,3H),3.02–2.81(m,3H),2.60(t,J＝11.8Hz,1H).
LC-MS,M/Z:497.2[M+H] + 。

Claims (22)

1. An intermediate of formula I, formula II or formula III:
Figure FDA0003482913520000011
wherein the content of the first and second substances,
the R is 1 Is selected from PG 1 Or
Figure FDA0003482913520000012
The R is 2 Selected from halogen, carboxyl or
Figure FDA0003482913520000013
The R is 2a Is selected from C 1 -C 6 Alkyl or benzyl;
the R is 3 Selected from methyl or chlorine;
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
and X is selected from H or Br.
2. The intermediate of formula II according to claim 1,
when R is 2 When halogen is used, the halogen is Br or I, preferably Br;
and/or, said R 2a Is C 1 -C 6 An alkyl group; preferably, R is 2a Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
3. The intermediate of claim 1 or claim 2, wherein the intermediate of formula II is selected from any one of the following intermediates:
Figure FDA0003482913520000014
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Selected from halogen, carboxyl or
Figure FDA0003482913520000021
The R is 2a Having the definition as claimed in claim 1 or claim 2.
4. A process for the preparation of an intermediate of formula II-1, as defined in claim 3, comprising the steps of:
step 1: under the action of an amino metal compound or an alkyl metal compound, an intermediate shown as a formula I and a compound shown as a formula 1 are reacted to prepare an intermediate shown as a formula II-1;
Figure FDA0003482913520000022
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Selected from halogen,Carboxyl or
Figure FDA0003482913520000023
The R is 2a Having the definition as claimed in claim 1 or claim 2.
5. A process for the preparation of an intermediate of formula I as defined in claim 1, comprising the steps of:
and 2, step: under the action of organic alkali and a condensing agent, reacting an intermediate shown as a formula I-2 with a compound shown as a formula 2 to prepare the intermediate shown as the formula I;
Figure FDA0003482913520000024
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
6. The method for preparing the intermediate shown in the formula I according to claim 5, wherein the method for preparing the intermediate shown in the formula I further comprises a method for preparing the intermediate shown in the formula I-2, and the method for preparing the intermediate shown in the formula I-2 comprises the following steps:
and step 3: preparing an intermediate shown as a formula I-1 by carrying out reduction reaction on a compound shown as a formula 3;
Figure FDA0003482913520000025
and 4, step 4: under the action of inorganic base, hydrolyzing the intermediate shown in the formula I-1 to prepare an intermediate shown in the formula I-2;
Figure FDA0003482913520000031
wherein the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.
7. A method for preparing an intermediate shown as a formula II-1A in an intermediate shown as a formula II-1A according to claim 3, wherein the intermediate shown as the formula II-1A is prepared from an intermediate shown as a formula II-1, and the method for preparing the intermediate shown as the formula II-1A comprises the following steps:
and 5: under the action of a catalyst and organic base, reacting the intermediate shown as the formula II-1 with carbon monoxide and a compound shown as the formula 4 to obtain an intermediate shown as the formula II-1A;
Figure FDA0003482913520000032
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2 Is halogen;
the R is 2a Having the definition as claimed in claim 1 or claim 2.
8. A method for preparing an intermediate shown as a formula II-1A in an intermediate shown as a formula II-1A according to claim 3, wherein the intermediate shown as the formula II-1A is prepared from an intermediate shown as a formula II-1, and the method for preparing the intermediate shown as the formula II-1A comprises the following steps:
step 6: under the action of alkali, reacting the intermediate shown as the formula II-1 with the compound shown as the formula 5 to obtain an intermediate shown as the formula II-1A;
Figure FDA0003482913520000033
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzylAn oxycarbonyl group or a benzyl group;
the R is 2 Is a carboxyl group;
the R is 2a Having the definition as claimed in claim 1 or claim 2.
9. A method for preparing an intermediate shown as a formula II-2 in an intermediate shown as a formula II-2 according to claim 3, wherein the intermediate shown as the formula II-2 is prepared from an intermediate shown as a formula II-1A, and the method for preparing the intermediate shown as the formula II-2 comprises the following steps:
and 7: removing the intermediate protecting group PG shown as the formula II-1A 1 To obtain a product of removing a protecting group; reacting the product of removing the protecting group with a compound shown as a formula 6 under the action of alkali to obtain an intermediate shown as a formula II-2;
Figure FDA0003482913520000041
wherein the content of the first and second substances,
the PG 1 Selected from tert-butoxycarbonyl, benzyloxycarbonyl or benzyl;
the R is 2a Having the definition as claimed in claim 1 or claim 2.
10. A method for preparing an intermediate shown as a formula II-3 in an intermediate shown as a formula II-3 according to claim 3, wherein the intermediate shown as the formula II-3 is prepared from an intermediate shown as a formula II-2, and the method for preparing the intermediate shown as the formula II-3 comprises the following steps:
and 8: reacting the intermediate shown as the formula II-2 with a bromination reagent to obtain an intermediate shown as the formula II-3;
Figure FDA0003482913520000042
wherein R is 2a Having the meaning as claimed in claim 1 or claimThe definition as set forth in claim 2.
11. A method for preparing an intermediate shown as a formula III in claim 1, wherein the intermediate shown as the formula III is prepared from an intermediate shown as a formula II-3, and the method for preparing the intermediate shown as the formula III comprises the following steps:
and step 9: reacting the intermediate shown as the formula II-3 with the compound shown as the formula 7 to obtain an intermediate shown as the formula III;
Figure FDA0003482913520000043
wherein the content of the first and second substances,
the R is 2a Having the definition of claim 1 or claim 2;
the R is 3 Selected from methyl or chlorine.
12. A preparation method of an imidazopyridine compound shown in formula IV comprises the following steps:
step 10: reacting the intermediate shown in the formula III with methylamine to obtain a compound shown in the formula IV;
Figure FDA0003482913520000051
wherein the content of the first and second substances,
the R is 2a Having the definition of claim 1 or claim 2;
said R is 3 Selected from methyl or chlorine.
13. The method for preparing the intermediate represented by the formula II-1 according to claim 4, wherein in the step 1,
the amino metal compound is lithium diisopropylamide, lithium bistrimethylsilyl amide, potassium bistrimethylsilyl amide, sodium bistrimethylsilyl amide, preferably lithium diisopropylamide or lithium bistrimethylsilyl amide;
optionally, the alkyl metal compound is methyl grignard reagent, ethyl grignard reagent, isopropyl grignard reagent, alkyl lithium compound, preferably methyl lithium or n-butyl lithium;
optionally, when said R is 2 In the case of halogen, the reaction is carried out under the action of an amino metal compound;
optionally, when said R is 2 Is carboxyl or
Figure FDA0003482913520000052
When the reaction is carried out under the action of an amino metal compound or an alkyl metal compound;
optionally, the reaction temperature of the reaction is-80 to 0 ℃, preferably-10 to 0 ℃ or-80 to-60 ℃;
optionally, the molar ratio of the intermediate shown in the formula I to the compound shown in the formula 1 in the reaction is 1: 1-1: 1.6, preferably 1: 1-1.2 or 1: 1.5-1: 1.6, more preferably 1:1.2 or 1: 1.5;
optionally, the reaction is carried out in an organic solvent comprising diethyl ether, dichloromethane, toluene, 2-methyltetrahydrofuran or tetrahydrofuran, preferably tetrahydrofuran;
optionally, the reaction time of the reaction is 2-4 hours, preferably 2.5 hours;
optionally, when the organometallic compound is an alkyllithium compound, the reaction further comprises a stabilizer which is N, N' -tetramethylethylenediamine.
14. The method for preparing the intermediate shown in the formula I according to claim 5, wherein in the step 2,
the molar ratio of the intermediate shown in the formula I-2 to the compound shown in the formula 2 is 1: 1-1: 2, preferably 1: 1.2;
optionally, the molar ratio of the intermediate shown in the formula I-2 to the compound of the organic base is 1:2 to 1:4, preferably 1:2.8 to 1:3.2, and more preferably 1: 3;
optionally, the molar ratio of the intermediate shown as the formula I-2 to the condensing agent is 1: 1-1: 2, preferably 1: 1.5;
optionally, the organic base is N, N-diisopropylethylamine;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the condensing agent is 1-propyl phosphoric anhydride;
optionally, the reaction is carried out in dichloromethane;
optionally, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
15. The method for preparing the intermediate shown in the formula I according to claim 6, wherein in the step 3,
the reaction further comprises hydrogen;
optionally, the reaction further comprises palladium on carbon;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the pressure of hydrogen in the reaction is 0.8 to 1.2 atmospheres, preferably 1 atmosphere;
optionally, the mass ratio of the palladium carbon to the compound 3 is 1: 18-1: 22, preferably 1: 20;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
16. The method for preparing the intermediate shown in the formula I according to claim 6, characterized in that in the step 4,
the inorganic base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the molar ratio of the intermediate shown in the formula I-1 to the inorganic base is 1: 1-1: 4, preferably 1: 2;
optionally, the reaction is carried out in methanol;
optionally, the reaction time of the reaction is 14 to 18 hours, preferably 16 hours.
17. The method for preparing the intermediate as shown in the formula II-1A according to claim 7, characterized in that in the step 5,
the catalyst is a transition metal catalyst, and the transition metal catalyst comprises a palladium metal catalyst, a ruthenium metal catalyst, an iron metal catalyst, a cobalt metal catalyst, a nickel metal catalyst and a rhodium metal catalyst; preferably a palladium metal catalyst;
preferably, the palladium metal catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, 1-bis (diphenylphosphino) ferrocene palladium chloride, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, 1, 4-bis (diphenylphosphinobutane) palladium dichloride; more preferably, the palladium metal catalyst is 1, 1-bis (diphenylphosphino) ferrocene palladium chloride;
optionally, the organic base is triethylamine or N, N-diisopropylethylamine, preferably triethylamine;
optionally, the reaction is carried out in pressurized carbon monoxide at a pressure of 40 to 50psi, preferably 45 psi;
optionally, the reaction temperature of the reaction is 55-65 ℃;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
18. The method for preparing the intermediate represented by the formula II-1A according to claim 8, wherein in the step 6,
the molar ratio of the intermediate shown in the formula II-1A to the compound shown in the formula 5 is 1: 1-1: 2, preferably 1: 1.5;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the base is sodium bicarbonate;
optionally, the reaction is carried out in N, N-dimethylformamide;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
19. The method for preparing the intermediate represented by the formula II-2 according to claim 9, wherein in the step 7,
the molar ratio of the intermediate shown in the formula II-1A to the compound shown in the formula 6 is 1: 1-1: 2, preferably 1: 1.5;
optionally, removing the intermediate protecting group PG shown as the formula II-1A 1 Under the action of hydrochloric acid;
optionally, removing the intermediate protecting group PG shown as the formula II-1A 1 Under reaction with hydrogen;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the base is triethylamine or N, N-diisopropylethylamine, preferably triethylamine;
optionally, the reaction of the deprotected group is carried out in 1, 4-dioxane;
optionally, the reaction time for removing the protecting group is 2-4 hours, preferably 3 hours;
optionally, the reaction of the product of deprotection and the compound shown as the formula 6 is carried out in dichloromethane under the action of alkali;
optionally, the reaction time of the product of the deprotection group and the compound shown in the formula 6 under the action of alkali is 10-14 hours, preferably 12 hours.
20. The method for preparing the intermediate represented by the formula II-3 according to claim 10, wherein in the step 8,
the brominating reagent is N-bromosuccinimide, dibromohydantoin, pyridine tribromide, copper bromide or liquid bromine, preferably liquid bromine;
optionally, the molar ratio of the intermediate shown in the formula II-2 to the brominating reagent is 1: 1-1: 3, preferably 1: 1.2;
optionally, the reaction is carried out in dichloromethane;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the reaction time of the reaction is 0.5 to 2 hours, preferably 1 hour.
21. The method for preparing the intermediate shown in the formula III according to claim 11, wherein in the step 9,
in the reaction, the molar ratio of the intermediate shown in the formula II-3 to the compound shown in the formula 7 is 1: 1-1: 3, preferably 1: 2;
optionally, the reaction is carried out in an organic solvent comprising acetonitrile, dimethyl sulfoxide, ethanol, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, 1, 4-dioxane, N-propanol or N-butanol, preferably acetonitrile;
optionally, the reaction temperature of the reaction is 110-130 ℃, preferably 120 ℃;
optionally, the reaction time of the reaction is 22 to 26 hours, preferably 24 hours.
22. The method of claim 12, wherein in step 10,
the molar ratio of the intermediate shown in the formula III to methylamine is 1: 4-1: 6, preferably 1: 5;
optionally, the reaction temperature of the reaction is 20-25 ℃;
optionally, the reaction is carried out in methanol;
optionally, the reaction time of the reaction is 4 to 6 hours, preferably 5 hours.
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