Method for preparing oxetan-2-yl methylamine or salt thereof

Abstract

The present disclosure relates to a process for the preparation of oxetan-2-yl methylamine or a salt thereof. Specifically, the method disclosed by the invention comprises the step of reacting a compound of a formula E under a trimethyl sulfoxide halide / alkali condition or a trimethyl sulfonium halide / alkali condition to form a compound of a formula F. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing oxetane-2-ylmethylamine or a salt thereof. Background Art

[0002] 2-Aminomethyloxetane is a pharmaceutical intermediate and a fragment of many new drugs under development, such as the active molecule PF06882961 for the treatment of obesity reported in WO2018109607.

[0003] CN114728923 discloses a method for synthesizing 2-aminomethyloxetane. The method uses epichlorohydrin as a raw material, opens the ring through dibenzylamine, closes oxirane, expands the ring to oxetane, and removes benzyl through palladium catalytic hydrogenation. Although the method has a short route, the ring expansion yield is low, the intermediate is an oily substance, column chromatography purification is required, and catalytic hydrogenation has high safety risks and a large amount of precious metals, which is not suitable for industrial production.

[0004] In addition, Jamieson, Megan L et al. also reported a technical scheme of "using epoxypropane as a raw material, first protecting the hydroxyl group with benzyl group and then performing ring expansion reaction, and obtaining C3 in almost quantitative yield" (Organic Letters, 2016, 18.3: 468-471.). However, when preparing C4 by hydrogenation and debenzylation, only precious metals (such as palladium) can be used, and the reaction yield is not high.

[0005] Summary of the invention

[0006] The present disclosure provides a novel method for preparing a compound of formula G or a salt thereof

[0007] The method comprises the steps of reacting a compound of formula E under sulfur halide / alkaline conditions to form a compound of formula F,

[0008]

[0009] in,

[0010] R 1 , R 2 Each independently selected from 6-membered aryl or 5-6-membered heteroaryl, the aryl or heteroaryl is optionally substituted by halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted, for example phenyl or pyridyl;

[0011] R 3 is an optional amino protecting group.

[0012] In some embodiments, the sulfur halide compound is selected from trimethylsulfonium halide or trimethylsulfonium halide. In some embodiments, the trimethylsulfonium halide is selected from trimethylsulfonium fluoride, trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide. In some embodiments, the trimethylsulfonium halide is selected from trimethylsulfonium fluoride, trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide.

[0013] In some embodiments, the sulfur halide compound is selected from trimethylsulfonium iodide or trimethylsulfonium iodide.

[0014] In some embodiments, the sulfur halide compound is trimethylsulfoxide iodide.

[0015] In some embodiments, the base is selected from potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium tert-amylate, potassium hydride, sodium hydride, n-butyllithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide.

[0016] In some embodiments, the base is selected from potassium tert-butoxide.

[0017] In some embodiments, the solvent used in the reaction of the compound of formula E is selected from tert-butyl alcohol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or tert-amyl alcohol.

[0018] In some embodiments, the solvent used in the reaction of the compound of formula E is selected from tert-butyl alcohol.

[0019] In other embodiments, the molar ratio of the compound of formula E to trimethylsulfoxide halide or trimethylsulfonium halide is 1:1 to 1:3, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3 or any value between two numbers. In other embodiments, the molar ratio of the compound of formula E to trimethylsulfoxide halide or trimethylsulfonium halide is 1:1.5 to 1:2.5.

[0020] In other embodiments, the molar ratio of the compound of formula E to trimethylsulfoxide iodide or trimethylsulfonium iodide is 1:1.5 to 1:2.5.

[0021] In other embodiments, the molar ratio of the compound of formula E to the base is 1:1 to 1:3, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3 or any value between two numbers. In other embodiments, the molar ratio of the compound of formula E to the base is 1:1.5 to 1:2.5.

[0022] In other embodiments, the molar ratio of the compound of formula E to potassium tert-butoxide is 1:1.5 to 1:2.5.

[0023] Some embodiments provide a method for preparing a compound of formula G or a salt thereof, comprising the step of reacting a compound of formula E under trimethylsulfonium iodide / potassium tert-butoxide conditions or under trimethylsulfonium iodide / potassium tert-butoxide conditions to form a compound of formula F,

[0024] In some embodiments, R 1 is phenyl, said phenyl being optionally substituted with halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0025] In some embodiments, R 2 is phenyl, said phenyl being optionally substituted with halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0026] In some embodiments, R 3 is selected from benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, p-toluenesulfonylmethoxycarbonyl, ethoxycarbonyl, phthaloyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, wherein R 3 Optionally halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0027] In some embodiments, R 3 is benzyl, wherein the benzyl is optionally substituted by halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0028] In some embodiments, the compound of formula E in the method is a compound of formula E-1 The method comprises the steps of reacting a compound of formula E-1 under trimethylsulfonium halide / base conditions or under trimethylsulfonium halide / base conditions to form a compound of formula F-1,

[0029]

[0030] In some embodiments, the method for preparing the compound of formula G comprises the step of reacting the compound of formula E-1a under trimethylsulfoxide iodide / potassium tert-butoxide conditions or under trimethylsulfonium iodide / potassium tert-butoxide conditions to form the compound of formula F-1a,

[0031]

[0032] Furthermore, the method for preparing the compound of formula G or its salt disclosed herein further comprises reacting the compound of formula D with R 3 -X to form a compound of formula E,

[0033]

[0034] Where: X is a halogen; R 1 , R 2 , R 3 As defined above.

[0035] In some embodiments, X is selected from fluorine, chlorine, bromine, and iodine. In certain specific embodiments, X is selected from chlorine and bromine.

[0036] In some embodiments, the compound of formula D and R 3 -X reacts under basic conditions to form a compound of formula E.

[0037] In some embodiments, the base is selected from but not limited to: sodium carbonate, potassium carbonate, DBU, DIPEA, NaH, Et3N, n-BuLi. In certain specific embodiments, the base is potassium carbonate.

[0038] In some embodiments, the solvent used for the reaction of the compound of formula D is selected from but not limited to: DMF, DCM, acetonitrile. In certain specific embodiments, the solvent is acetonitrile.

[0039] In some embodiments, the method for preparing a compound of formula G or a salt thereof further comprises: reacting a compound of formula D-1 with a benzyl halide under basic conditions to form a compound of formula E-1,

[0040]

[0041] Wherein, X is as defined above.

[0042] In some embodiments, the method for preparing a compound of formula G or a salt thereof further comprises the step of reacting a compound of formula D-1a with benzyl bromide under potassium carbonate / acetonitrile conditions to form a compound of formula E-1a,

[0043]

[0044] Furthermore, the method for preparing the compound of formula G or its salt disclosed herein further comprises the steps of: reacting the compound of formula A with the compound of formula B to form a compound of formula C, and converting the compound of formula C into a compound of formula D under alkaline conditions.

[0045]

[0046] Wherein: Y is selected from cyano, hydroxyl, halogen; R 1 , R 2 As defined above.

[0047] In some embodiments, Y is selected from halogen, such as fluorine, chlorine, bromine, iodine. In some embodiments, Y is chlorine.

[0048] In some embodiments, the compound of formula A is reacted with the compound of formula B in an alcoholic solution to form the compound of formula C.

[0049] In some embodiments, the alcohol solution is selected from, but not limited to, methanol, ethanol, propanol, isopropanol, butanol, pentanol, and hexanol. In some embodiments, the alcohol solution is selected from isopropanol.

[0050] In some embodiments, the molar ratio of the compound of formula A to the compound of formula B is 1:1 to 3:1, including but not limited to 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1 or any value between two numbers. In other embodiments, the molar ratio of the compound of formula A to the compound of formula B is 1.5:1 to 2.5:1.

[0051] In some embodiments, the compound of formula C is converted to the compound of formula D under alkaline conditions. In some embodiments, the base is selected from but not limited to: potassium carbonate, sodium hydroxide, potassium hydroxide. In certain specific embodiments, the base is potassium carbonate.

[0052] In some embodiments, the solvent used in the reaction of the compound of formula C is selected from but not limited to: acetonitrile, ethanol, acetone. In some embodiments, the solvent is acetonitrile.

[0053] In some embodiments, the method for preparing a compound of formula G or a salt thereof further comprises: reacting a compound of formula A-1 with a compound of formula B-1 in an alcohol solution to form a compound of formula C-1, and converting the compound of formula C-1 into a compound of formula D-1 under alkaline conditions.

[0054]

[0055] Some embodiments provide a method for preparing a compound of formula G or a salt thereof, comprising: reacting a compound of formula A-1a with a compound of formula B-1a in an isopropanol solvent to form a compound of formula C-1a, and converting the compound of formula C-1a into a compound of formula D-1a under potassium carbonate / acetonitrile conditions,

[0056]

[0057] Furthermore, the method for preparing the compound of formula G or its salt disclosed herein further comprises the step of converting the compound of formula F into the compound of formula G:

[0058]

[0059] Where: R 1 , R 2 , R 3 As defined above.

[0060] In some embodiments, the compound of formula F is converted to the compound of formula G by reacting with hydrogen under catalytic conditions.

[0061] In some embodiments, the catalyst is a palladium catalyst. In some embodiments, the catalyst is selected from Pd / C, PdCl2, Pd(AcO)2, Pd(OH)2 / C. In some embodiments, the catalyst is Pd / C.

[0062] In some embodiments, the compound of formula F-1 is converted into a compound of formula G by reacting with hydrogen under palladium catalyst conditions:

[0063]

[0064] In some other embodiments, the compound of formula G in the method is (S)-oxetane-2-ylmethylamine (compound of formula G-1) or (R)-oxetane-2-ylmethylamine (compound of formula G-2),

[0065]

[0066] In some other embodiments, the compound of formula G or its salt is a compound of formula G-1 or its salt, and the method for preparing the compound of formula G-1 or its salt further comprises the step of converting the compound of formula F-1a into the compound of formula G-1 by reacting with hydrogen under Pd / C conditions:

[0067]

[0068] Some embodiments provide a method for preparing a compound of formula G or a salt thereof comprising:

[0069] Step 1) reacting a compound of formula A with a compound of formula B to form a compound of formula C,

[0070] Step 2) The compound of formula C is converted into the compound of formula D under alkaline conditions,

[0071] Step 3) Compound D and R 3 -X reacts under basic conditions to form a compound of formula E,

[0072] Step 4) The compound of formula E is reacted under trimethylsulfoxide halide / base conditions or under trimethylsulfonium halide / base conditions to form a compound of formula F,

[0073] Step 5) the compound of formula F is reacted with hydrogen under catalyst conditions to be converted into a compound of formula G,

[0074]

[0075] In some embodiments, the method for preparing the compound of formula G or a salt thereof comprises the following steps:

[0076] Step 1) reacting a compound of formula A with a compound of formula B in an alcohol solution to form a compound of formula C,

[0077] Step 2) The compound of formula C is converted into the compound of formula D under potassium carbonate / acetonitrile conditions,

[0078] Step 3) Compound D and R 3 -X is reacted under potassium carbonate / acetonitrile conditions to form a compound of formula E,

[0079] Step 4) The compound of formula E is reacted under trimethylsulfoxide iodide / potassium tert-butoxide conditions or under trimethylsulfonium iodide / potassium tert-butoxide conditions to form a compound of formula F,

[0080] Step 5) The compound of formula F is converted into the compound of formula G by reacting with hydrogen under Pd / C conditions.

[0081] Some embodiments provide a method for preparing a compound of formula G or a salt thereof comprising:

[0082] Step 1) The compound of formula A-1 reacts with the compound of formula B-1 in an alcohol solution to form a compound of formula C-1,

[0083] Step 2) The compound of formula C-1 is converted into the compound of formula D-1 under alkaline conditions,

[0084] Step 3) reacting a compound of formula D-1 with a benzyl halide under alkaline conditions to form a compound of formula E-1,

[0085] Step 4) The compound of formula E-1 is reacted under trimethylsulfonium halide / base conditions or under trimethylsulfonium halide / base conditions to form a compound of formula F-1,

[0086] Step 5) The compound of formula F-1 is reacted with hydrogen under catalytic conditions to be converted into the compound of formula G.

[0087]

[0088] Some embodiments provide a method for preparing a compound of formula G or a salt thereof comprising:

[0089] Step 1) The compound of formula A-1a reacts with the compound of formula B-1a in an alcohol solvent to form a compound of formula C-1a

[0090] Step 2) The compound of formula C-1a is converted into the compound of formula D-1a under alkaline conditions,

[0091] Step 3) reacting the compound of formula D-1a with a benzyl halide under basic conditions to form a compound of formula E-1a,

[0092] Step 4) The compound of formula E-1a is reacted under trimethylsulfoxide halide / base conditions or under trimethylsulfonium halide / base conditions to form a compound of formula F-1a,

[0093] Step 5) The compound of formula F-1a is converted into the compound of formula G by reacting with hydrogen under catalytic conditions.

[0094]

[0095] In some embodiments, the method for preparing the compound of formula G or a salt thereof comprises the following steps:

[0096] Step 1) The compound of formula A-1a reacts with the compound of formula B-1a in isopropanol solvent to form a compound of formula C-1a,

[0097] Step 2) The compound of formula C-1a is converted into the compound of formula D-1a under potassium carbonate / acetonitrile conditions,

[0098] Step 3) The compound of formula D-1a is reacted with benzyl bromide under potassium carbonate / acetonitrile conditions to form a compound of formula E-1a,

[0099] Step 4) The compound of formula E-1a is reacted under trimethylsulfoxide iodide / potassium tert-butoxide conditions or under trimethylsulfonium iodide / potassium tert-butoxide conditions to form a compound of formula F-1a,

[0100] Step 5) The compound of formula F-1a is reacted with hydrogen under Pd / C conditions to form the compound of formula G-1.

[0101] In another aspect, the present disclosure also provides a compound of formula E or a salt thereof, Where R 1 , R 2 , R 3 As defined above.

[0102] In some embodiments, the compound of formula E is a compound of formula E-1

[0103] In some embodiments, the compound of formula E is a compound of formula E-1a or a compound of formula E-1b

[0104] In another aspect, the present disclosure also provides a compound of formula F or a salt thereof, Where R 1 , R 2 , R 3 As defined above.

[0105] In some embodiments, the compound of formula F is a compound of formula F-1

[0106] In some embodiments, the compound of formula F is a compound of formula F-1a or a compound of formula F-1b

[0107] In another aspect, the present disclosure also provides a method for preparing a compound of formula K or a salt thereof,

[0108] The method comprises the aforementioned method for preparing the compound of formula G, and the step of reacting the compound of formula H with the compound of formula G to form the compound of formula J,

[0109] Where R 4 Selected from C 1-6 In some embodiments, the R 4 Selected from methyl or ethyl.

[0110] In some embodiments, the compound of formula K is a compound of formula K-1

[0111] The method comprises the steps of reacting a compound of formula H-1 with a compound of formula G to form a compound of formula J-1,

[0112]

[0113] In some embodiments, the compound of formula K is a compound of formula K-1a,

[0114] The method comprises the steps of reacting a compound of formula H-1 with a compound of formula G-1 to form a compound of formula J-1a,

[0115]

[0116] Furthermore, the method for preparing the compound of formula K or a salt thereof further comprises the step of reacting the compound of formula J in the presence of a reducing agent to form the compound of formula K. In some embodiments, the reducing agent is selected from iron powder.

[0117] Some embodiments provide a method for preparing a compound of formula K or a salt thereof, comprising the steps of reacting a compound of formula H with a compound of formula G to form a compound of formula J, and reacting the compound of formula J in the presence of a reducing agent to form a compound of formula K,

[0118]

[0119] Some embodiments provide a method for preparing a compound of formula K-1 or a salt thereof, comprising the steps of reacting a compound of formula H-1 with a compound of formula G to form a compound of formula J-1, and reacting the compound of formula J-1 in the presence of a reducing agent to form a compound of formula K-1,

[0120]

[0121] Some embodiments provide a method for preparing a compound of formula K-1a or a salt thereof, comprising the steps of reacting a compound of formula H-1 with a compound of formula G-1 to form a compound of formula J-1a, and reacting the compound of formula J-1a in the presence of a reducing agent to form a compound of formula K-1a,

[0122]

[0123] In another aspect, the present disclosure also provides a method for preparing a compound of formula L or a salt thereof,

[0124] The method comprises the steps of reacting a compound of formula K with 2-halogeno-1,1,1-trimethoxyethane to form a compound of formula L,

[0125] Where R 4 Selected from C 1-6 alkyl, Z is halogen, such as Cl. In some embodiments, R 4 Selected from methyl or ethyl.

[0126] In some embodiments, the compound of formula L is a compound of formula L-1,

[0127] The method comprises the steps of reacting a compound of formula K-1 with 2-chloro-1,1,1-trimethoxyethane to form a compound of formula L-1,

[0128]

[0129] In some embodiments, the compound of formula L is a compound of formula L-1a,

[0130] The method comprises the steps of reacting a compound of formula K-1a with 2-chloro-1,1,1-trimethoxyethane to form a compound of formula L-1a,

[0131] The reaction operation can refer to the operation in WO2018 / 109607, and the relevant content is introduced into this article for illustration.

[0132] The present invention also discloses the use of the aforementioned method for preparing the compound of formula G, the method for preparing the compound of formula L, the aforementioned compound of formula E, and the aforementioned compound of formula F in preparing a GLP-1 receptor agonist.

[0133] In some embodiments, the GLP-1 receptor agonist is selected from but not limited to:

[0134]

[0135] The present disclosure also provides a method for preparing a compound of formula AA or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of formula G or the aforementioned method for preparing a compound of formula L,

[0136]

[0137] Furthermore, the method for preparing the compound of formula AA or a salt thereof further comprises the step of reacting the compound of formula AA-1 with the compound of formula L-1a to form the compound of formula AA-2.

[0138] The reaction conditions and operations refer to those in WO2018 / 109607, and the relevant contents are introduced herein for illustration.

[0139] The present disclosure also provides a method for preparing a compound of formula AA or a salt thereof, the method comprising the steps of the aforementioned method for preparing a compound of formula G or the aforementioned method for preparing a compound of formula K,

[0140]

[0141] Furthermore, the method for preparing the compound of formula BB or its salt further comprises the step of reacting the compound of formula BB-1 with the compound of formula K-1a to form the compound of formula BB-2.

[0142] The reaction conditions and operations refer to those in WO2022007979, and the relevant contents are introduced herein for illustration.

[0143] The preparation method disclosed in the present invention further comprises one or more steps of filtering, washing, drying, concentrating or recondensing.

[0144] The salts of the disclosed compounds / intermediates include but are not limited to addition salts of the free state of the compounds / intermediates with acids or bases, and the acid used to form the salts includes but is not limited to hydrochloric acid or methanesulfonic acid. In some embodiments, the salts of the compounds / intermediates include but are not limited to hydrochloride, p-toluenesulfonate, methanesulfonate or oxalate.

[0145] The terms "to form" and "to convert into" do not specifically mean that the conversion reaction between two substrates is a single step, and can be a single step or multi-step reaction between two substrates. If the intermediate contains a protecting group, the intermediate is subjected to a step of removing the protecting agent, and then reacting with the corresponding substrate to obtain the corresponding target product.

[0146] The numerical values ​​in this disclosure are instrumental measurements, which have a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used needs to be considered. For example, the particle size of the active ingredient, the numerical value is the error change after measurement does not exceed plus or minus 10%, which can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

[0147] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations. Key Indicates the existence of chiral isomers in the structure, and also contains Two configurations.

[0148] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including alkyl groups having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl.

[0149] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy.

[0150] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0151] The term "aryl" refers to a 6-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, such as phenyl. Aryl groups may be substituted or unsubstituted.

[0152] The term "heteroaryl" refers to a heteroaromatic system containing 5 to 6 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group may be substituted or unsubstituted.

[0153] The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Examples of amino protecting groups include, but are not limited to, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, p-toluenesulfonylmethoxycarbonyl, ethoxycarbonyl, phthaloyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl.

[0154] The term "DMF" refers to dimethylformamide.

[0155] The term "DBU" refers to 1,8-diazabicycloundec-7-ene.

[0156] The term "DCM" refers to dichloromethane.

[0157] The term "DIPEA" refers to N,N-diisopropylethylamine.

[0158] The term "n-BuLi" refers to n-butyllithium.

[0159] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

[0160] The term "substituent" includes but is not limited to 6-membered aryl, 5-6-membered heteroaryl, amino protecting group, halogen, C 1-6 Alkyl, C 1-6 Alkoxy. DETAILED DESCRIPTION

[0161] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0162] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0163] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm).

[0164] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent was deuterated chloroform (CDCl3).

[0165] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0166] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.2mm±0.03mm, and the specification of thin layer chromatography separation and purification product was 0.4mm-0.5mm.

[0167] Embodiment 1:

[0168]

[0169] Step 1: Synthesis of compound 1e

[0170] Under nitrogen protection, 100.0 g of compound 1b and 100 g of compound 1a were added to a 2L reaction bottle in sequence, and isopropanol was used as solvent to stir and react overnight. TLC was used to detect that the raw materials had reacted completely. 226 g of potassium carbonate was added to the reaction solution, and 1 L of acetonitrile was added to continue stirring and reacting overnight. The reaction was complete as detected by TLC.

[0171] 112 g of benzyl bromide was added to the reaction solution, refluxed overnight to stop the reaction, cooled and filtered, the filtrate was dried, 800 ml of dichloromethane and 800 ml of water were added to the dried product, separated and concentrated under reduced pressure to obtain 144 g of white solid (yield 80%, purity 96.7%).

[0172] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.48-7.38 (m, 6H), 7.35-7.28 (m, 6H), 7.24 (dd, J = 7.1, 2.4Hz, 3H), 5.02 (s, 1H), 3.85 (d, J = 14.2Hz ,1H),3.64(d,J=14.2Hz,1H),3.11-3.00(m,1H),2.70(dd,J=14.1,4.3Hz,1H),2.62-2.51(m,2H),2.22(dd,J=5.0,2.7Hz,1H).

[0173] Step 2: Synthesis of Compound 1f

[0174] Under nitrogen protection, 30g of compound 1e, 44.1g of trimethylsulfoxide iodide, 22.5g of potassium tert-butoxide and 1L of tert-butanol were added to a 2L reaction bottle in sequence, and the reaction was stirred at 60-80°C overnight. The reaction was stopped when compound 1e disappeared by TLC detection. After cooling, the filtrate was filtered and concentrated, and 300ml of cyclohexane and 30ml of water were added, and the liquids were separated and concentrated to obtain a crude oil. 60ml of isopropanol was added, stirred and crystallized, and suction filtered to obtain 23.5g of a white solid (yield 75%, purity 95%).

[0175] 1H NMR (400MHz, CDCl3): δ (ppm) 7.40 (t, J = 7.1Hz, 6H), 7.36-7.28 (m, 6H), 7.28-7 .19(m,3H),5.08-4.95(m,2H),4.57(td,J=8.0,5.9Hz,1H),4.37(dt,J=9.1,5 .8Hz,1H),3.74(d,J=14.3Hz,1H),3.64(d,J=14.3Hz,1H),2.91(dd,J=13.9,6 .6Hz,1H),2.70(dd,J=13.9,4.8Hz,1H),2.54-2.43(m,1H),2.29-2.15(m,1H).

[0176] Step 3: Synthesis of compound 1

[0177] In a hydrogenation reaction bottle, add 3.0g of compound 1f, 0.15g of Pd / C (wet), 90mL of methanol, and 1.5g of p-toluenesulfonic acid in sequence. After hydrogen replacement three times, maintain the hydrogen pressure at 50-60psi and react overnight. TLC detection shows that the reaction is complete and the reaction is stopped. Filter and recover Pd / C, concentrate, add 30mL of ethyl acetate to the concentrate, solid precipitates, and filter to obtain 1.88g of white solid (yield 83%, purity 98%).

[0178] 1 H NMR (400 MHz, DMSO): δ (ppm) 7.55-7.44 (m, 2H), 7.12 (d, J = 7.8 Hz, 2H), 4.87 (ddd, J = 14.5, 6.7, 4.0 Hz, 1H), 4.56 (ddd, J = 13.1, 7.2, 5.9 Hz,1H),4.46(dt,J=9.1,6.0 Hz,1H),3.09(dt,J=19.6,9.8 Hz,1H),3.02(dd,J=13.4,4.0 Hz,1H),2.76-2.59(m,1H),2.49-2.38(m,1H),2.29(s,3H).

Claims

1. Method for preparing a compound of formula G or a salt thereof The method comprises the steps of reacting a compound of formula E under trimethylsulfonium halide / base conditions or under trimethylsulfonium halide / base conditions to form a compound of formula F, in, R 1 , R 2 Each is independently selected from 6-membered aryl or 5-6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted, for example phenyl or pyridyl; R 3 It is an amino protecting group.

2. The method according to claim 1, wherein the trimethyl sulfoxide halide is selected from trimethyl sulfoxide fluoride, trimethyl sulfoxide chloride, trimethyl sulfoxide bromide, trimethyl sulfoxide iodide, preferably trimethyl sulfoxide iodide.

3. The method according to claim 1, wherein the trimethylsulfonium halide is selected from trimethylsulfonium fluoride, trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium iodide, preferably trimethylsulfonium iodide.

4. according to the method described in any one of claims 1 to 3, wherein the alkali is selected from potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-amyl alcoholate, sodium tert-amyl alcoholate, lithium tert-amyl alcoholate, potassium hydride, sodium hydride, n-butyl lithium, bis(trimethylsilyl) lithium amide, bis(trimethylsilyl) sodium amide or bis(trimethylsilyl) potassium amide, preferably potassium tert-butoxide.

5. The method according to any one of claims 1 to 4, wherein the solvent used in the reaction of the compound of formula E is selected from tert-butyl alcohol, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or tert-amyl alcohol, preferably tert-butyl alcohol.

6. The method according to any one of claims 1 to 5, further comprising the compound of formula D and R 3 -X is reacted under basic conditions to form a compound of formula E, in: X is halogen; R 1 , R 2 , R 3 As defined in claim 1.

7. The method according to claim 6, wherein the base is selected from sodium carbonate, potassium carbonate, DBU, DIPEA, NaH, Et3N, n-BuLi, preferably potassium carbonate.

8. The method according to any one of claims 1 to 7, further comprising the step of converting the compound of formula F into the compound of formula G by reacting with hydrogen under catalyst conditions, Where R 1 , R 2 , R 3 As defined in claim 1.

9. The method according to claim 8, wherein the catalyst is a palladium catalyst, preferably Pd / C, PdCl2, Pd(AcO)2, Pd(OH)2 / C, most preferably Pd / C.

10. The method according to any one of claims 1 to 9, wherein R 3 Selected from benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, p-toluenesulfonylmethoxycarbonyl, ethoxycarbonyl, phthaloyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, preferably benzyl.

11. The method according to any one of claims 1 to 10, wherein the compound of formula G is a compound of formula G-1, 12. The method according to any one of claims 1 to 11, comprising: Step 1) reacting a compound of formula A-1 with a compound of formula B-1 to form a compound of formula C-1, Step 2) The compound of formula C-1 is converted into the compound of formula D-1 under alkaline conditions, Step 3) reacting a compound of formula D-1 with a benzyl halide under alkaline conditions to form a compound of formula E-1, Step 4) The compound of formula E-1 is reacted under trimethylsulfonium halide / base conditions or under trimethylsulfonium halide / base conditions to form a compound of formula F-1, Step 5) The compound of formula F-1 is reacted with hydrogen under catalyst conditions to be converted into a compound of formula G, Wherein: X is as defined in claim 6.

13. A compound of formula E or a salt thereof, Where R 1 , R 2 Each is independently selected from 6-membered aryl or 5-6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted, such as phenyl or pyridyl; R 3 is an optional amino protecting group; further, the compound of formula E is preferably a compound of formula E-1 14. A compound of formula F or a salt thereof, Where R 1 , R 2 Each is independently selected from 6-membered aryl or 5-6-membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by halogen, C 1-6 Alkyl or C 1-6 Alkoxy substituted, such as phenyl or pyridyl; R 3 is an optional amino protecting group; further, the compound of formula F is preferably a compound of formula F-1 15. A process for preparing a compound of formula K or a salt thereof, The method comprises the method according to any one of claims 1 to 12, and the step of reacting a compound of formula H with a compound of formula G to form a compound of formula J, Where R 4 Selected from C 1-6 The alkyl group is preferably a methyl group or an ethyl group.

16. The method according to claim 15, further comprising the step of reacting the compound of formula J in the presence of a reducing agent to form the compound of formula K, wherein the reducing agent is preferably iron powder.

17. Use of the method according to any one of claims 1 to 12, the method according to claim 15 or 16, the compound of formula E according to claim 13, or the compound of formula F according to claim 14 in the preparation of a GLP-1 receptor agonist.

18. A method for preparing a compound of formula AA or a salt thereof, the method comprising the method according to any one of claims 1 to 12 or the method according to claim 15 or 16, 19. A method for preparing a compound of formula BB or a salt thereof, the method comprising the method according to any one of claims 1 to 12 or the method according to claim 15 or 16,

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