阅读说明：本技术 一种fso2n3在制备重氮试剂中的应用 (FSO (free space optical output)2N3Application in preparing diazo reagent ) 是由 梁玉飞 董佳家 于 2019-12-04 设计创作，主要内容包括：本发明公开了一种FSO-2N-3在制备重氮试剂中的应用。本发明的应用包括如下步骤：在碱的存在下,将FSO-2N-3与如式2所示的丙酮基磷酸二甲酯进行如下所示的反应,得到Bestmann-Ohira和/或Seyferth-Gilbert试剂即可。本发明的应用,半小时内可以高产率地得到Seyferth-Gilbert试剂和/或者Bestmann-Ohira试剂,而且反应生成的两种混合试剂无需分离,一锅法直接应用于末端炔类化合物的合成。和/或(The invention discloses an FSO 2 N 3 Application in preparing diazo reagent. The application of the invention comprises the following steps: in the presence of a base, adding FSO 2 N 3 And acetone-based dimethyl phosphate shown as a formula 2 to obtain Bestmann-Ohira and/or Seyforth-Gilbert reagent. The Seyferth-Gilbert reagent and/or the Bestmann-Ohira reagent can be obtained with high yield within half an hour by applying the method, and two mixed reagents generated by the reaction are not required to be separated, and the method is directly applied to synthesis of terminal alkyne compounds by a one-pot method. And/or)

1. FSO (free space optical output)₂N₃Use in the preparation of Bestmann-Ohira and/or Seyferth-Gilbert reagents, characterized in that said use may comprise the following steps: in a solvent, in the presence of a base, FSO₂N₃Reacting with acetonyl dimethyl phosphate shown in a formula 2 to obtain Bestmann-Ohira and/or Seyferth-Gilbert reagent;

2. the use according to claim 1,

the solvent is one or more of an ether solvent, an alcohol solvent, a nitrile solvent, an aromatic solvent, an amide solvent, a sulfone solvent and a pyrrolidone solvent;

and/or the volume mol ratio of the solvent to the acetonyl dimethyl phosphate shown in the formula 2 is 2.0L/mol to 8.0L/mol;

and/or, the alkali is organic alkali or inorganic alkali;

and/or the molar ratio of the alkali to the acetonyl dimethyl phosphate shown in the formula 2 is 1.5-4.5;

and/or, said FSO₂N₃Is FSO₂N₃In the form of solution with organic solvent, wherein the organic solvent is ether solvent;

and/or, said FSO₂N₃The molar ratio of the acetone to the dimethyl acetonyl phosphate shown in the formula 2 is 1.0-2.0;

and/or the temperature of the reaction is room temperature.

3. The use according to claim 2,

the solvent is an ether solvent;

and/or, when the solvent is an ether solvent, the ether solvent is MTBE and/or THF;

and/or, when the solvent is an alcohol solvent, the alcohol solvent is one or more of methanol, ethanol and isopropanol;

and/or, when the solvent is a nitrile solvent, the nitrile solvent is acetonitrile;

and/or, when the solvent is an aromatic hydrocarbon solvent, the aromatic hydrocarbon solvent is toluene;

and/or, when the solvent is an amide solvent, the amide solvent is DMF;

and/or when the solvent is a sulfone solvent, the sulfone solvent is DMSO;

and/or, when the solvent is a pyrrolidone solvent, the pyrrolidone solvent is NMP;

and/or the organic base is a tertiary amine base, such as DBU, DIPEA and Et₃One or more of N, preferably DBU;

and/or the inorganic base is one or more of alkali metal carbonate, alkali metal bicarbonate, alkaline earth metal carbonate and alkaline earth metal oxide; the carbonate of alkali metal is preferably NaCO₃、K₂CO₃And CsCO₃One or more of; the alkali metal bicarbonate is preferably NaHCO₃And/or KHCO₃(ii) a The carbonate of the alkaline earth metal is preferably MgCO₃(ii) a The oxide of the alkaline earth metal is preferably MgO; the inorganic base is preferably K₂CO₃And/or MgO;

and/or the molar ratio of the alkali to the acetonyl dimethyl phosphate shown in the formula 2 is 2.0-3.75;

and/or, when the organic solvent is an ether solvent, the ether solvent is MTBE and/or THF;

and/or, said FSO₂N₃In solution with an organic solvent, said FSO₂N₃The molar concentration of the compound is 350 mM-500 mM;

and/or, the application comprises the following steps: adding FSO to a mixed solution of acetonyl dimethyl phosphate, said solvent and said base₂N₃And (c) carrying out the reaction.

4. The use according to claim 3,

when the alkali is DBU, a Bestmann-Ohira reagent is obtained;

or, when the alkali is MgO, KHCO₃、Na₂CO₃、NaHCO₃DIPEA and MgCO₃When one or more of the above-mentioned compounds are contained, a Seyforth-Gilbert reagent is obtained; preferably, the alkali is MgO;

or, when the base is Et₃N and/or K₂CO₃Then, a mixture of the Bestmann-Ohira reagent and the Seyforth-Gilbert reagent is obtained; preferably, the base is K₂CO₃。

5. A preparation method of a terminal alkyne compound shown as a formula B is characterized by comprising the following steps: (1) in a solvent, in the presence of a base, FSO₂N₃Reacting with acetonyl dimethyl phosphate to obtain Bestmann-Ohira reagent and/or Seyferth-Gilbert reagent; (2) in methanol, at K₂CO₃And/or in the presence of DBU, carrying out recarburization reaction shown in the following on the Bestmann-Ohira reagent and/or the Seyferroth-Gilbert reagent obtained in the step (1) and an aldehyde compound containing the structural fragment shown in the formula A to obtain a terminal alkyne compound containing the structural fragment shown in the formula B;

6. the method according to claim 5,

the method and conditions of step (1) are as defined in any one of claims 1 to 4;

and/or, the Bestmann-Ohira reagent and/or the Seyforth-Gilbert reagent prepared in the step (1) are directly used in the step (2) without treatment;

and/or in the step (2), the volume mol ratio of the methanol to the aldehyde compound containing the structural segment shown in the formula A is 1.0L/mol to 10.0L/mol;

and/or, in step (2), said K₂CO₃And/or the molar ratio of DBU to the aldehyde compound containing the structural fragment shown in the formula A is 1.2-3.0;

and/or in the step (2), the molar ratio of the aldehyde compound containing the structural fragment shown in the formula A to the compound shown in the formula 2 is 0.5-1.0;

and/or, in the step (2), the temperature of the recarburization reaction is room temperature;

and/or, step (2) further comprises post-treatment, and the post-treatment can comprise the following steps: after the recarburization reaction is finished, adjusting the pH value of the reaction system to 6-7 by using acid;

and/or the aldehyde compound containing the structural segment shown in the formula A is an aromatic aldehyde compound or an aliphatic aldehyde compound.

7. The method according to claim 6,

the aldehyde compound containing the structural fragment shown in the formula A is shown in the formula A-1, and the terminal alkyne compound containing the structural fragment shown in the formula B is correspondingly obtained and is shown in the formula B-1:

wherein R is C₆-C₃₀Aryl radicals, substituted by one or more R¹Substituted C₆-C₃₀Aryl, 5-14 membered heteroaryl, substituted with one or more R²Substituted 5-14 membered heteroaryl, C₁～C₂₀Alkyl, or substituted by one or more R³Substituted C₁～C₂₀An alkyl group; said 5-to 14-membered heteroaryl, or substituted with one or more R²The heteroatom in the 5-14 membered heteroaryl in the substituted 5-14 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1-3; when a plurality of substituents are present, the substituents may be the same or different;

said R¹、R²And R³Independently selected from the following substituents: halogen, halogen substituted C₁～C₄Alkyl radical, C₁～C₄Alkoxy, halogen substituted C₁～C₄Alkoxy, phenyl and C₁～C₄Alkyl substituted C₁～C₄An alkenyl group.

8. The method according to claim 7,

said C₆-C₃₀Aryl and substituted by one or more R¹Substituted C₆-C₃₀C in aryl₆-C₃₀Aryl is C₆-C₁₀Aryl, preferably phenyl;

and/or said 5-14 membered heteroaryl, or substituted with one or more R²The 5-14 membered heteroaryl in the substituted 5-14 membered heteroaryl is 5-6 membered heteroaryl, wherein the heteroatoms are selected from one or more of N, O and S, and the number of the heteroatoms is 1-2; preferably thiazolyl or furyl;

and/or, said C₁～C₂₀Alkyl and substituted by one or more R³Substituted C₁～C₂₀C in alkyl₁～C₂₀Alkyl is independently C₁～C₄Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl;

and/or, said C₁～C₄Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl;

and/or, said C₁～C₄Alkyl substituted C₁～C₄C in alkenyl₁～C₄Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl; said C₁～C₄Alkyl substituted C₁～C₄The alkenyl radical is preferably

And/or, said C₁～C₄Alkyl substituted C₁～C₄C in alkenyl₁～C₄Alkenyl is ethenyl, propenyl, n-butenyl, sec-butenyl or isobutenyl;

and/or said halogen, halogen substituted C₁～C₄Alkyl and halogen substituted C₁～C₄Halogen in alkoxy is preferably fluorine, chlorine, bromine or iodine; such as fluorine, chlorine or bromine;

and/or, said halogen substituted C₁～C₄Alkyl and halogen radicalsSubstituted C₁～C₄The number of halogen substitutions in an alkoxy group may be 1,2 or 3, for example 3; said halogen substituted C₁～C₄The alkyl group is preferably trifluoromethyl; said halogen substituted C₁～C₄The alkoxy group is preferably trifluoromethoxy.

9. The method according to claim 8, wherein the aldehyde compound containing the structural fragment represented by formula a and the corresponding terminal alkyne compound containing the structural fragment represented by formula B are of any one of the following structures:

10. a preparation method of a compound containing a structural fragment shown as a formula I is characterized by comprising the following steps: (i) in a solvent, in the presence of a base, FSO₂N₃Reacting with acetonyl dimethyl phosphate to obtain Bestmann-Ohira reagent and/or Seyferth-Gilbert reagent; (ii) in methanol, at K₂CO₃And/or in the presence of DBU, carrying out recarburization reaction shown in the following on the Bestmann-Ohira reagent and/or the Seyferroth-Gilbert reagent obtained in the step (i) and an aldehyde compound containing the structural fragment shown in the formula A to obtain a terminal alkyne compound containing the structural fragment shown in the formula B; (iii) in a solvent, in the presence of a monovalent copper catalyst, carrying out azide-alkynyl Husigen cycloaddition reaction shown in the specification on a reaction liquid containing a terminal alkyne compound with a structural fragment shown in a formula B and an azide compound shown in a formula C to obtain a compound containing a structural fragment shown in a formula I;

11. the method according to claim 10,

the method and conditions of step (1) are as defined in any one of claims 1 to 4;

and/or, the method and condition of step (2) are as defined in any one of claims 5 to 9;

and/or, in step (iii), the solvent is an alcohol solvent; the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol;

and/or in the step (iii), the volume mol ratio of the solvent to the azide compound shown in the formula C is 1.0L/mol to 10.0L/mol;

and/or in the step (iii), the molar ratio of the azide compound containing the structural fragment shown in the formula C to the aldehyde compound containing the structural fragment shown in the formula A is 1.0-1.5;

and/or in step (iii), the monovalent copper catalyst is obtained by reducing halogenated sulfoxide or divalent copper salt by a reducing agent; the halogenated cuprous can be one or more of cuprous iodide, cuprous bromide and cuprous chloride; the cupric salt is preferably copper sulfate; the reducing agent can be sodium ascorbate; the sodium ascorbate is preferably added in the form of an aqueous solution of sodium ascorbate; the molar concentration of the sodium ascorbate water solution is 0.1-1.0 mol/L;

and/or in the step (iii), the mole ratio of the monovalent copper catalyst to the aldehyde compound containing the structural fragment shown in the formula A is 0.1-1.0; when the cuprous catalyst is obtained by reducing a cupric salt by a reducing agent, the molar ratio of the cupric salt to an aldehyde compound containing a structural fragment shown in the formula A is preferably 0.1-1.0; the mol ratio of the reducing agent to the cupric salt is preferably 1.0-10.0;

and/or, in the step (iii), the azide compound shown as the formula C is

And/or, in step (iii), the temperature of the reaction is 30 ℃ to 80 ℃.

12. The method according to claim 11,

when the aldehyde compound containing the structural fragment shown in the formula A is shown in the formula A-1, the terminal alkyne compound containing the structural fragment shown in the formula B is correspondingly obtained and is shown in the formula B-1, and the compound containing the structural fragment shown in the formula I is shown in the formula I-1:

the definition of R is as defined in any one of claims 7 to 9.

Technical Field

The invention relates to an FSO₂N₃Application in preparing diazo reagent.

Background

Bestmann-Ohira reagent, dimethyl (1-diazo-2-oxopropyl) phosphonate^[1]Is a practical and storage-resistant commercial reagent. The reagent can promote the homologation of aldehydes and corresponding terminal alkynes under mild alkaline conditions, and can also perform 1, 3-dipolar cycloaddition reaction with dipole substances to generate phosphono nitrogen-containing heterocyclic compounds.

The development of this reagent began in the early 70's of the 20 th century, in 1969, Regitz and Ansch ü tz^[2]A process for producing diethyl P- (diazomethyl) phosphate by reacting diethyl (formylmethyl) phosphate as a starting material with potassium ethoxide to give an enol form and then with P-toluenesulfonylazide has been reported, however, this process is not practical. 1970, SeyAccording to the method, N-hydroxymethyl phthalimide is used as a raw material for ferth and Marmor, and the dimethyl P- (diazomethyl) phosphate is obtained through four steps of bromination, Michaelis-Arbuzov phosphonic acid esterification, dephthalylation and diazotization, wherein the yield is 46%. In 1977, Colvin et al reported that P- (diazomethyl) dimethyl phosphate could convert aromatic carbonyl compounds into the corresponding homologous acetylenic compounds. Later, Gilbert and weeasoriya were inspired by Colvin et al to study in detail the reaction mechanism and reactivity of dimethyl P- (diazomethyl) phosphate to convert carbonyl compounds into corresponding homologous acetylenic compounds and to extend the substrate applicability to the conversion of aromatic, aliphatic carbonyl compounds. Because of the universality of the method in synthesizing the terminal alkyne compounds, the method is uniformly named as Seyferth-Gilbert homogenization recarburization. Hereafter, dimethyl P- (diazomethyl) phosphate is referred to as Seyferth-Gilbert reagent. However, the main disadvantages of this reagent are: 1) the preparation is not easy, and the synthesis needs four-step reaction; 2) the stability is poor; 3) the reaction requires a strong base and thus also limits its application.

In 1984, Vandewale and colleagues reported a method for preparing (1-diazo-2-oxopropyl) phosphonic acid dimethyl ester with high efficiency and simplicity. The dimethyl (1-diazo-2-oxopropyl) phosphonate is prepared by taking acetonyl phosphate as a raw material, taking sodium hydrogen as an alkali, taking p-toluenesulfonyl azide as a diazo transfer reagent in a THF/benzene solution, and reacting in a yield of 80%. In 1989, Ohira found that the anion of the Seyferth-Gilbert reagent could be generated in situ from dimethyl (1-diazo-2-oxopropyl) phosphonate under mildly basic conditions. Several years later, Bestmann and colleagues have studied dimethyl (1-diazo-2-oxopropyl) phosphonate as a replacement for the Seyferth-Gilbert reagent on the homogenization recarburization. And a further improvement scheme is provided, the reagent is generated in situ on the acetonyl dimethyl phosphate, and the one-pot method is directly used for synthesizing the acetylene compounds and is also applied to a considerable extent. Because of the availability and stock stability of dimethyl (1-diazo-2-oxopropyl) phosphonate, it is known as the Bestmann-Ohira reagent and is also widely marketed. In 2006, Pietrusszka and Witt reported 4-acetamidobenzenesulfonyl azide as diazo transfer reagent for preparationBestmann-Ohira reagent, 77% yield (40-50 g scale). In 2014, Jepsen and Kristensen also reported an imidazole-1-sulfonyl azide hydrochloride salt (ImSO)₂N₃HCl) as diazo transfer reagent, Bestmann-Ohira reagent was prepared in situ, and the one-pot method was applied directly to the preparation of terminal acetylenic compounds.

Thus, most of the current protocols for the synthesis of Bestmann-Ohira reagents are based on acetonyl dimethyl phosphate starting with an analogous p-toluenesulfonyl azide (TsN)₃) 4-Acetaminophenylsulfonylazide (p-ABSA), imidazole-1-sulfonylazide hydrochloride (ImSO)₂N₃HCl), etc. as diazo transfer reagents. These diazo transfer reagents have poor stability and are liable to cause risks such as explosion during preparation, storage, transportation and the like. And the sulfonyl azide compounds are all organic molecules, the reaction alkali condition is mostly strong, the reaction time is long, the yield is not high, and the post-treatment is complex.

Disclosure of Invention

The invention aims to solve the technical problems that diazo transfer reagents used in the prior art for synthesizing the Seyferth-Gilbert reagent and the Bestmann-Ohira reagent have the defects of poor stability, strong reaction alkaline conditions, long reaction time, low yield, complex post-treatment and the like, and provides the FSO₂N₃Application in preparing diazo reagent. By this application, different bases are used in the reaction, Seyferth-Gilbert reagent or Bestmann-Ohira reagent can be obtained in high yield within half an hour, and the work-up is simple, requiring only filtration and extraction steps to obtain pure product. Two mixed reagents generated by the reaction do not need to be separated, and the one-pot method is directly applied to the synthesis of the terminal alkyne compound.

The invention provides an FSO₂N₃Use in the preparation of Bestmann-Ohira and/or Seyferth-Gilbert reagent comprising the steps of: in a solvent, in the presence of a base, FSO₂N₃Reacting with acetonyl dimethyl phosphate shown in formula 2 to obtain Bestmann-Ohira (shown in formula 3) and/or Seyferth-Gilbert reagent (shown in formula 4);

the solvent may be a conventional solvent in the art for performing such a reaction, for example, one or more of an ether-based solvent (e.g., MTBE (methyl tert-butyl ether) and/or THF (tetrahydrofuran)), an alcohol-based solvent (e.g., one or more of methanol, ethanol, and isopropanol), a nitrile-based solvent (e.g., acetonitrile), an aromatic-based solvent (e.g., toluene), an amide-based solvent (e.g., DMF (N, N-dimethylformamide)), a sulfone-based solvent (e.g., DMSO (dimethyl sulfoxide)), and a pyrrolidone-based solvent (e.g., NMP (N-methyl-2-pyrrolidone)), preferably an ether-based solvent.

The solvent may be used in an amount conventionally used in the art for such a reaction, and preferably, it is used in a volume molar ratio of 2.0L/mol to 8.0L/mol, for example, 5.0L/mol, with respect to acetonyl dimethyl phosphate represented by formula 2.

The base may be conventional in the art for carrying out such reactions and may be an organic or inorganic base.

The organic base is preferably a tertiary amine base, for example DBU (1, 8-diazabicycloundec-7-ene, DIPEA (N, N-diisopropylethylamine) and Et₃One or more of N; more preferably DBU.

The inorganic base is preferably one or more of an alkali metal carbonate, an alkali metal bicarbonate, an alkaline earth metal carbonate and an alkaline earth metal oxide. The carbonate of alkali metal is preferably NaCO₃、K₂CO₃And CsCO₃One or more of (a). The alkali metal bicarbonate is preferably NaHCO₃And/or KHCO₃. The carbonate of the alkaline earth metal is preferably MgCO₃. The oxide of the alkaline earth metal is preferably MgO. The inorganic base is more preferably K₂CO₃And/or MgO.

The amount of the base can be the conventional amount used in the art for carrying out such a reaction, and preferably the molar ratio of the base to the acetonyl dimethyl phosphate shown in formula 2 is 1.5 to 4.5, for example, 2.0 to 3.75.

The FSO₂N₃May be in a form conventional in the art, e.g. FSO₂N₃In the form of solution with organic solvent, wherein the organic solvent is ether solvent; the ether solvent is preferably MTBE and/or THF. In said solution, said FSO₂N₃The molarity of (b) is preferably 350mM to 500mM, for example 435mM, 480mM, 479mM, 484mM, 470mM or 400 mM.

The FSO₂N₃The amount of (b) may be an amount conventionally used in the art for carrying out such a reaction, and preferably the molar ratio of (b) to the acetonyl dimethyl phosphate represented by formula 2 is 1.0 to 2.0, for example, 1.2 or 1.25.

In one aspect of the application, the method preferably comprises the following steps: adding FSO to a mixed solution of acetonyl dimethyl phosphate, said solvent and said base₂N₃And (c) carrying out the reaction.

The temperature of the reaction is a temperature conventional for such reactions, preferably room temperature.

The progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is generally terminated when the acetonyl dimethyl phosphate, as shown in formula 2, disappears or its content no longer changes. The reaction time is preferably 0.5 to 2.0 hours, for example, 0.5 hour.

In a preferred embodiment of the invention, when the base is DBU, the Bestmann-Ohira reagent is obtained. Preferably, the solvent is the ether solvent.

In a preferred embodiment of the invention, when the base is MgO, KHCO₃、Na₂CO₃、NaHCO₃DIPEA and MgCO₃To give a Seyforth-Gilbert reagent. Preferably, the base is MgO. Preferably, the solvent is the ether solvent.

In a preferred embodiment of the invention, when the base is Et₃N and/or K₂CO₃Then Bestmann-Ohir is obtaineda mixture of reagent and Seyforth-Gilbert reagent. Preferably, the base is K₂CO₃. Preferably, the mixture has a mole ratio of Bestmann-Ohira reagent to Seyferth-Gilbert reagent of 1: 3. Preferably, the solvent is the ether solvent.

The reaction may also include post-treatment. The post-treatment preferably comprises the steps of: concentrating, diluting the reaction solution with organic solvent (such as halogenated hydrocarbon solvent (such as dichloromethane) and water, separating, extracting water phase, combining organic phases, drying, and concentrating. When the reaction solution contains a precipitate, the operation of filtration is preferably included before the liquid separation.

The invention also provides a preparation method of the terminal alkyne compound shown in the formula B, which comprises the following steps: (1) in a solvent, in the presence of a base, FSO₂N₃Reacting with acetonyl dimethyl phosphate to obtain Bestmann-Ohira reagent and/or Seyferth-Gilbert reagent; (2) in methanol, at K₂CO₃And/or in the presence of DBU, carrying out recarburization reaction shown in the following on the Bestmann-Ohira reagent and/or the Seyferroth-Gilbert reagent obtained in the step (1) and an aldehyde compound containing the structural fragment shown in the formula A to obtain a terminal alkyne compound containing the structural fragment shown in the formula B;

the method and conditions of step (1) are as described above.

The Bestmann-Ohira reagent and/or the Seyferrot-Gilbert reagent prepared in the step (1) can be directly used in the step (2) without being processed.

In the step (2), the amount of the methanol may be an amount conventionally used in the art, and is preferably in a volume molar ratio of 1.0L/mol to 10.0L/mol, for example, 5.0L/mol, with respect to the aldehyde compound containing the structural segment shown in formula a.

In the step (2), K is₂CO₃And/or DBU can be used in amountsThe molar ratio of the aldehyde compound to the aldehyde compound containing the structural segment shown in the formula A is preferably 1.2-3.0, for example, 2.0.

In the step (2), the amount of the aldehyde compound containing the structural fragment shown in the formula a may be an amount conventionally used in the art, and preferably the molar ratio of the aldehyde compound to the compound shown in the formula 2 is 0.5 to 1.0, for example, 0.83.

In the step (2), the temperature of the recarburization reaction is the conventional temperature of such reaction, and is preferably room temperature.

In step (2), the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), and is generally determined as the end point of the reaction when the aldehyde compound, such as the compound represented by formula a, disappears. The reaction time is preferably 3 to 15 hours, for example, 15 hours.

The step (2) can also comprise post-treatment, and the post-treatment can comprise the following steps: and after the recarburization reaction is finished, adjusting the pH value of the reaction system to 6-7 by using acid. The acid may be an acid conventional in this type of work-up in the art, for example, phosphoric acid, preferably 4M phosphoric acid.

The aldehyde compound containing the structural segment shown in the formula A can be a conventional aldehyde compound in the reaction in the field, such as an aromatic aldehyde compound or an aliphatic aldehyde compound.

In a certain scheme, the aldehyde compound containing the structural fragment shown in the formula A is shown in the formula A-1, and the terminal alkyne compound containing the structural fragment shown in the formula B is correspondingly obtained and is shown in the formula B-1:

wherein R is C₆-C₃₀Aryl radicals, substituted by one or more R¹Substituted C₆-C₃₀Aryl, 5-14 membered heteroaryl, substituted with one or more R²Substituted 5-14 membered heteroaryl, C₁～C₂₀Alkyl, or substituted by one or more R³Substituted C₁～C₂₀An alkyl group; said 5-to 14-membered heteroaryl, or substituted with one or more R²The heteroatom in the 5-14 membered heteroaryl in the substituted 5-14 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1-3; when a plurality of substituents are present, the substituents may be the same or different;

said R¹、R²And R³Independently selected from the following substituents: halogen, halogen substituted C₁～C₄Alkyl radical, C₁～C₄Alkoxy, halogen substituted C₁～C₄Alkoxy, phenyl and C₁～C₄Alkyl substituted C₁～C₄An alkenyl group.

Said C₆-C₃₀Aryl and substituted by one or more R¹Substituted C₆-C₃₀C in aryl₆-C₃₀Aryl is preferably C₆-C₁₀Aryl, more preferably phenyl.

Said 5-to 14-membered heteroaryl, or substituted with one or more R²The 5-14 membered heteroaryl group in the substituted 5-14 membered heteroaryl group is preferably a 5-6 membered heteroaryl group in which the number of heteroatoms is 1-2 and one or more of N, O and S are selected; more preferably a thiazolyl group (e.g.,) Or a furyl group (for example,)。

said C₁～C₂₀Alkyl and substituted by one or more R³Substituted C₁～C₂₀C in alkyl₁～C₂₀Alkyl is independently preferably C₁～C₄Alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

Said C₁～C₄Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

Said C₁～C₄Alkyl substituted C₁～C₄C in alkenyl₁～C₄Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

Said C₁～C₄Alkyl substituted C₁～C₄C in alkenyl₁～C₄Alkenyl is preferably ethenyl, propenyl, n-butenyl, sec-butenyl or isobutenyl.

Said C₁～C₄Alkyl substituted C₁～C₄The alkenyl radical is preferably

The halogen, halogen-substituted C₁～C₄Alkyl and halogen substituted C₁～C₄Halogen in alkoxy is preferably fluorine, chlorine, bromine or iodine; such as fluorine, chlorine or bromine.

Said halogen substituted C₁～C₄Alkyl and halogen substituted C₁～C₄The number of halogen substitutions in the alkoxy group may be 1,2 or 3, for example 3.

Said halogen substituted C₁～C₄The alkyl group is preferably trifluoromethyl.

Said halogen substituted C₁～C₄The alkoxy group is preferably trifluoromethoxy.

In some preferred technical schemes, the aldehyde compound containing the structural fragment shown in the formula A and the corresponding terminal alkyne compound containing the structural fragment shown in the formula B are in any one of the following structures:

the invention also provides a preparation method of the compound containing the structural fragment shown in the formula I, which comprises the following steps: (i) in a solvent in the presence of a baseWill FSO₂N₃Reacting with acetonyl dimethyl phosphate to obtain Bestmann-Ohira reagent and/or Seyferth-Gilbert reagent; (ii) in methanol, at K₂CO₃And/or in the presence of DBU, carrying out recarburization reaction shown in the following on the Bestmann-Ohira reagent and/or the Seyferroth-Gilbert reagent obtained in the step (i) and an aldehyde compound containing the structural fragment shown in the formula A to obtain a terminal alkyne compound containing the structural fragment shown in the formula B; (iii) in a solvent, in the presence of a cuprous catalyst, carrying out Azide-alkynyl Husigen Cycloaddition reaction (coater-Catalyzed Azide-Alkyne Cycloaddition) shown as follows on a reaction liquid containing a terminal Alkyne compound with a structural fragment shown as a formula B and an Azide compound shown as a formula C to obtain a compound containing a structural fragment shown as a formula I;

the method and conditions of step (i) and step (ii) are as described above.

In step (iii), the solvent may be a conventional solvent in the art for performing such a reaction, and is preferably an alcohol solvent. The alcohol solvent is preferably one or more of methanol, ethanol and isopropanol.

In step (iii), the solvent may be used in an amount conventional in the art for carrying out such a reaction, and preferably, the volume molar ratio of the solvent to the azide compound containing compound represented by formula C is 1.0L/mol to 10.0L/mol, for example, 5.0L/mol.

In the step (iii), the molar ratio of the azide compound shown in the formula C to the aldehyde compound containing the structural fragment shown in the formula a may be a conventional molar ratio in the art for performing such a reaction, and is preferably 1.0 to 1.5, for example, 1.0.

In step (iii), the monovalent copper catalyst may be a monovalent copper catalyst conventionally used in the art for such reactions, and is preferably a halogenated sulfine or a divalent copper salt reduced by a reducing agent. The halogenated cuprous chloride can be one or more of cuprous iodide, cuprous bromide and cuprous chloride. The cupric salt is preferably copper sulfate. The reducing agent can be sodium ascorbate. The sodium ascorbate is preferably added in the form of an aqueous solution of sodium ascorbate. The molar concentration of the sodium ascorbate water solution is 0.1-1.0 mol/L, for example, 0.5 mol/L.

In step (iii), the monovalent copper catalyst may be used in an amount conventionally used in the art for such reactions, and preferably, the molar ratio of the monovalent copper catalyst to the aldehyde compound containing the structural segment shown in formula a is 0.1 to 1.0, for example, 0.2.

When the cuprous catalyst is obtained by reducing a cupric salt by a reducing agent, the molar ratio of the cupric salt to the aldehyde compound containing the structural fragment shown in the formula A is preferably 0.1-1.0, for example, 0.2. The molar ratio of the reducing agent to the cupric salt is preferably 1.0-10.0, for example, 5.0.

In step (iii), the temperature of the reaction is preferably from 30 ℃ to 80 ℃, for example, 50 ℃.

In step (iii), the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is generally at the end of the reaction when the terminal alkyne compound containing the structural fragment of formula B is eliminated. The reaction time is preferably 3.0 to 11.0 hours, for example, 3.0 hours, 5.0 hours, 8.0 hours, or 11.0 hours.

In step (iii), the post-treatment of the reaction preferably comprises the steps of: diluting with water, extracting water phase with organic solution, mixing organic phases, drying, and concentrating to obtain crude product. And (4) performing column chromatography purification to obtain the compound shown in the formula I.

In a certain scheme, the aldehyde compound containing the structural fragment shown in the formula A is shown in the formula A-1, the terminal alkyne compound containing the structural fragment shown in the formula B correspondingly obtained is shown in the formula B-1, and the compound containing the structural fragment shown in the formula I is shown in the formula I-1:

wherein R is C₆-C₃₀Aryl radicals, substituted by one or more R¹Substituted C₆-C₃₀Aryl, 5-14 membered heteroaryl, substituted with one or more R²Substituted 5-14 membered heteroaryl, C₁～C₂₀Alkyl, or substituted by one or more R³Substituted C₁～C₂₀An alkyl group; said 5-to 14-membered heteroaryl, or substituted with one or more R²The heteroatom in the 5-14 membered heteroaryl in the substituted 5-14 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1-3; when a plurality of substituents are present, the substituents may be the same or different;

said R¹、R²And R³Independently selected from the following substituents: halogen, halogen substituted C₁～C₄Alkyl radical, C₁～C₄Alkoxy, halogen substituted C₁～C₄Alkoxy, phenyl and C₁～C₄Alkyl substituted C₁～C₄An alkenyl group.

Said C₆-C₃₀Aryl and substituted by one or more R¹Substituted C₆-C₃₀C in aryl₆-C₃₀Aryl is preferably C₆-C₁₀Aryl, more preferably phenyl.

Said 5-to 14-membered heteroaryl, or substituted with one or more R²The 5-14 membered heteroaryl group in the substituted 5-14 membered heteroaryl group is preferably a 5-6 membered heteroaryl group in which the number of heteroatoms is 1-2 and one or more of N, O and S are selected; more preferably a thiazolyl group (e.g.,) Or a furyl group (for example,)。

said C₁～C₂₀Alkyl and substituted by one or more R³Substituted C₁～C₂₀C in alkyl₁～C₂₀Alkyl is independently preferably C₁～C₄Alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

Said C₁～C₄Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

Said C₁～C₄Alkyl substituted C₁～C₄C in alkenyl₁～C₄Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or isobutyl.

Said C₁～C₄Alkyl substituted C₁～C₄C in alkenyl₁～C₄Alkenyl is preferably ethenyl, propenyl, n-butenyl, sec-butenyl or isobutenyl.

Said C₁～C₄Alkyl substituted C₁～C₄The alkenyl radical is preferably

The halogen, halogen-substituted C₁～C₄Alkyl and halogen substituted C₁～C₄Halogen in alkoxy is preferably fluorine, chlorine, bromine or iodine; such as fluorine, chlorine or bromine.

Said halogen substituted C₁～C₄Alkyl and halogen substituted C₁～C₄The number of halogen substitutions in the alkoxy group may be 1,2 or 3, for example 3.

Said halogen substituted C₁～C₄The alkyl group is preferably trifluoromethyl.

Said halogen substituted C₁～C₄The alkoxy group is preferably trifluoromethoxy.

In step (iii), the azide compound having the formula C may be

In some preferred technical schemes, when the azide compound containing the formula C isWhen the aldehyde compound containing the structural fragment shown in the formula A, the corresponding terminal alkyne compound containing the structural fragment shown in the formula B and the compound containing the structural fragment shown in the formula I are any one of the following structures:

on the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

In the present invention, compound 5 is used for the preparation of which reference is made to: nature 574, 86-89 (2019) doi:10.1038/s41586-019-1589-1, and other reagents and raw materials used are commercially available.

In the invention, the room temperature is 10-35 ℃.

The positive progress effects of the invention are as follows:

by fluorosulfonyl azide (FSO)₂N₃) Seyferth-Gilbert reagent or Bestmann-Ohira reagent can be obtained in high yield within half an hour by using different bases in the reaction, and the post-treatment is simple, and pure products can be obtained only by filtration and extraction steps. Two mixed reagents generated by the reaction do not need to be separated, and the one-pot method is directly applied to the synthesis of the terminal alkyne compound.

Drawings

FIG. 1 is a graph showing the results of measurement after the completion of the diazo transfer reaction in example 4³¹And (4) a spectrum P.

FIG. 2 is a graph showing a result measured after the completion of the diazo transfer reaction of example 4-1³¹And (4) a spectrum P.

FIG. 3 is a graph showing a result measured after the completion of the diazo transfer reaction of example 4-2³¹And (4) a spectrum P.

FIG. 4 is a graph showing the results obtained after the completion of the diazo transfer reaction in example 4-3³¹And (4) a spectrum P.

FIG. 5 is a graph showing the results obtained after the completion of the diazo transfer reaction in examples 4 to 4³¹And (4) a spectrum P.

FIG. 6 is a graph showing results obtained after completion of the diazo transfer reaction in examples 4 to 5³¹And (4) a spectrum P.

FIG. 7 is a graph showing results obtained after completion of the diazo transfer reaction in examples 4 to 6³¹And (4) a spectrum P.

FIG. 8 is a graph showing results obtained after completion of the diazo transfer reaction in examples 4 to 7³¹And (4) a spectrum P.

FIG. 9 is a graph showing results obtained after completion of the diazo transfer reaction in examples 4 to 8³¹And (4) a spectrum P.

In the context of figures 1 to 9,³¹the peak of P displacement between 22.44 and 22.52 is ³¹The peak of P displacement between 14.28 and 14.58 is ³¹The peak of P displacement between 23.32 and 23.38 is

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1 fluorosulfonyl azide solvent (FSO)₂N₃Preparation of/MTBE)

Add NaN to 250mL cylindrical Plastic bottle₃[ Compound 7](1.96g,30mmol), distilled water (70mL), and methyl tert-butyl ether (60 mL). 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 6 ]](11.10g, 36mmol) was completely dissolved in acetonitrile (4mL) and the resulting viscous solution was rapidly added to vigorously stirred NaN under ice-water bath conditions₃/H₂O/MTBE mixture. The reaction mixture was stirred vigorously under ice-water bath conditions for 10 minutes, and then the mixture was poured into a glass separatory funnel. The mixture was allowed to stand well in the funnel at room temperature, and then phase separation was performed. Leaving free FSO₂N₃The organic phase of (a) was placed in a sealed plastic bottle in a cool reagent cabinet for at least 12 hours. Removing the orange-red residual aqueous phase, i.e. the colorless organic phase, FSO, generated during the standing period by using a plastic pipette₂N₃MTBE solution (varying over time due to slight differences in concentration between preparations, concentration ranging from 350mM to 500mM) was prepared by¹⁹F NMR measurement of FSO₂N₃The concentration and yield of the/MTBE solution can then be used as such.

EXAMPLE 2 preparation of Bestmann-Ohira reagent

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](335.6mg,2.0mmol), tetrahydrofuran (10mL) and DBU (603.4mg,4.0mmol), and FSO was added last₂N₃MTBE solution (5.5mL,435mM,2.4mmol), stirred at room temperature for 30 min and TLC monitored for completion. Stopping reaction, rotary evaporating and concentrating, adding dichloromethane (20mL) and water (30mL) for dilution, separating an organic phase, extracting an aqueous phase with dichloromethane (20mL multiplied by 3), combining the organic phases, drying with anhydrous sodium sulfate, and rotary evaporating and concentrating to obtain a yellow transparent liquid (A)1-diazo-2-oxopropyl) phosphonic acid dimethyl ester [ Compound 3 ]](375.3mg, 98% yield).

A yellow clear liquid;¹H NMR(400MHz,CDCl₃)δ3.84(d,J＝11.9Hz,6H),2.26(s,3H)；¹³C NMR(100MHz,CDCl₃)δ189.84,189.71,53.56,53.51,27.06；³¹P NMR(162MHz,CDCl₃)δ14.25；LC-MS(t_R):0.699min,ESI-MS(m/z):151。

example 3 preparation of Seyferth-Gilbert reagent

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](335.6mg,2.0mmol), tetrahydrofuran (10mL) and MgO (164.3mg,4.0mmol), and FSO was added last₂N₃MTBE solution (5.5mL,435mM,2.4mmol), stirred at room temperature for 30 min and TLC monitored for completion. Stopping reaction, filtering precipitate, rotary steaming for concentration, adding dichloromethane (20mL) and water (30mL) for dilution, separating organic phase, extracting water phase with dichloromethane (20mL × 5), mixing organic phases, drying with anhydrous sodium sulfate, and rotary steaming for concentration to obtain yellow transparent liquid P- (diazomethyl) dimethyl phosphate [ compound 4](290.8mg, yield 97%).

A yellow clear liquid;¹H NMR(400MHz,CDCl₃)δ3.76(d,J＝11.9Hz,7H)；¹³C NMR(100MHz,CDCl₃)δ53.00,52.95,29.22,23.88；³¹P NMR(162MHz,CDCl₃)δ22.58；LC-MS(t_R):0.902min,ESI-MS(m/z):193。

EXAMPLE 4 preparation of Bestmann-Ohira and Seyferth-Gilbert mixing reagents

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](166.1mg,1.0mmol), tetrahydrofuran (5mL) and K₂CO₃(276.4mg, 2.0mmol), most preferablyPost-addition of FSO₂N₃MTBE solution (2.5mL, 480mM,1.2mmol), stirred at room temperature for 30 min and TLC monitored for completion.³¹P NMR was confirmed to obtain [ Compound 3 ]]And [ Compound 4 ]]The molar ratio of the two reagents was 1:3 by nuclear magnetic integration.³¹P NMR (162MHz, THF) δ 22.44,14.28 external standard: phosphoric acid.

Using the reaction conditions of example 4, K therein₂CO₃Respectively replaced by bases shown in Table 1 below

KHCO₃、Na₂CO₃、NaHCO₃、Et₃N, DIPEA, DBU, MgO, or MgCO₃Other conditions and parameters being unchanged, using³¹P NMR is qualitative, and the results are shown in the figure. Wherein the test conditions are as follows:³¹p NMR (32MHz, THF), external standard: phosphoric acid

TABLE 1

Example 5 screening of reaction conditions:

to a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](332. mu.L, 2.4mmol), solvent (10.0mL) and Base A (5.0mmol) and finally FSO was added₂N₃Solution of MTBE (6.0mL,485mM,2.88 mmol). Stir for 60 minutes at room temperature and monitor by TLC that the reaction is complete. m-Cyanobenzaldehyde (264.6mg,2.0mmol) was dissolved in methanol (10mL), the solution was added to the reaction, and Base B (4.0 mmol) was addedmmol) at room temperature for 15 hours. The reaction was monitored by LC-MS for completion. Stopping the reaction, filtering the reaction system, washing a filter cake by using dichloromethane, and concentrating an organic phase to obtain a crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: petroleum ether ═ 1:4, product R_f0.35) to yield m-cyanophenylacetylene as a pale yellow solid. The yields vary depending on the solvent used, Base A and Base B, and are specified in Table 2. As can be seen from Table 2, when the solvent is THF, both Base A and Base B are K₂CO₃The highest yield was 88%.

Pale yellow solid, m.p.43.6-45.6 deg.C, 223.7mg, 88% yield;¹H NMR(400MHz,CDCl₃)δ7.82-7.56(m,3H),7.45(t,J＝7.8Hz,1H),3.19(s,1H)；¹³C NMR(100MHz,CDCl₃)δ136.16,135.38,132.02,129.31,123.70,117.85,112.86,81.16,79.92.

TABLE 2

In Table 2, "ND" indicates that no product was detected.

Example preparation of 63-Ethyl-5-methyl 2- ((2- (4- (4-bromophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.5mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.50mL,479mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking p-bromobenzaldehyde [ compound 8 ]](93.0mg,0.5mmol) was dissolved in methanol (2.5mL), and the solution was added to the reaction and reacted at room temperature for 15 hours. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Taking [ compound 5 ]](217.2mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.3mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to goose-yellow, and the mixture was added to the reaction system with mixing. The reaction was heated to 50 ℃ for 8 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol 50:1, product R_f0.50) to yield 3-ethyl-5-methyl 2- ((2- (4- (4-bromophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester [ compound 9 ] as a yellow solid](269.1mg,87％)。

Yellow solid, m.p.160.0-163.6 ℃,269.1mg, yield 87%;¹H NMR(400MHz,CDCl₃)δ7.85(s,1H),7.74-7.68(m,2H),7.59-7.53(m,2H),7.32(dd,J＝7.9,1.7Hz,1H),7.21(dt,J＝7.9,1.1Hz,1H),7.10(td,J＝7.4,1.4Hz,1H),7.05-6.97(m,2H),5.37(s,1H),4.84-4.72(m,2H),4.66(q,J＝3.9,3.3Hz,2H),4.09-3.96(m,4H),3.59(d,J＝0.8Hz,3H),2.27(s,3H),1.17(td,J＝7.1,0.8Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.96,167.21,147.05,145.62,144.47,144.23,132.40,132.14,131.53,129.33,129.32,127.48,127.27,126.93,122.32,120.51,103.90,102.03,69.16,68.14,59.96,50.85,50.17,37.33,19.34, 14.30; HRMS (ESI, m/z) calculated value C₂₈H₂₉BrClN₄O₅:615.1004[M+H]⁺The actual value is 615.1004.

EXAMPLE 73 preparation of ethyl-5-methyl-4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (3- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(310.5mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.50mL,479mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking m-trifluoro-methoxybenzaldehyde [ compound 10](95.3mg,0.5mmol) was dissolved in methanol (2.5mL), and the solution was added to the reaction and reacted at room temperature for 15 hours. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.5mg,0.5mmol) was added to the reaction system, sodium ascorbate (98.4mg,0.5mmol) was dissolved in distilled water (2.5mL), and a copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then added to the reaction system with mixing. The reaction was heated to 50 ℃ for 3 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol 50:1, product R_f0.42) to yield an off-white solid, 3-ethyl-5-methyl 4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (3- (trifluoromethoxy) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 11: [ compound](263.8mg,85％)。

Off-white solid, m.p.132.0-135.8 ℃,263.8mg, yield 85%;¹H NMR(400MHz,CDCl₃)δ7.89(s,1H),7.77(d,J＝7.8Hz,1H),7.70(s,1H),7.46(t,J＝8.0Hz,1H),7.32(dd,J＝7.8,1.7Hz,1H),7.24-7.16(m,2H),7.10(td,J＝7.5,1.4Hz,1H),7.06-6.95(m,2H),5.37(s,1H),4.85–4.73(m,2H),4.67(d,J＝5.3Hz,2H),4.03(qd,J＝7.1,5.3,2.6Hz,4H),3.59(s,3H),2.28(s,3H),1.17(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.98,167.23,149.84,146.72,145.63,144.46,144.24,132.44,132.40,131.53,130.48,129.32,127.49,126.93,124.39,124.04,121.83,120.93,120.67,119.27,118.28,116.71,103.92,102.05,69.16,68.15,59.97,50.85,50.22,37.33,19.31, 14.29; HRMS (ESI, m/z) calculated value C₂₉H₂₉ClF₃N₄O₆:621.1722[M+H]⁺The actual value is 621.1723.

Example preparation of 83-Ethyl-5-methyl 2- ((2- (4-benzyl-1H-1, 2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.3mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.49mL,484mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking benzyl formaldehyde [ compound 12 ]](61.0mg,0.5mmol) was dissolved in methanol (2.5mL), and the solution was added to the reaction and reacted at room temperature for 15 hours. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.4mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.2mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 8 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol 50:1, product R_f0.48) to yield a brown yellow viscous liquid, 3-ethyl-5-methyl 2- ((2- (4-benzyl-1H-1, 2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 13 ]](230.2mg,84％)。

A brown yellow viscous liquid, 230.2mg, 84% yield;¹H NMR(400MHz,CDCl₃)δ7.36-7.27(m,4H),7.25-7.20(m,3H),7.15-7.07(m,2H),7.03(tt,J＝7.6,1.7Hz,1H),5.38(s,1H),4.80-4.68(m,2H),4.54(t,J＝5.0Hz,2H),4.11(s,2H),4.03(dtdt,J＝10.9,6.4,3.7,2.3Hz,2H),3.94(dq,J＝10.2,5.3Hz,2H),3.61(d,J＝1.5Hz,3H),2.30(d,J＝1.5Hz,3H),1.17(td,J＝7.1,1.5Hz,3H)；13C NMR(100MHz,CDCl₃) δ 167.94,167.13,145.67,144.63,144.40,138.81,132.26,131.43,129.19,128.66,127.36,126.86,126.59,122.24,103.71,101.75,69.08,68.05,59.83,50.75,49.86,37.16,32.21,19.28, 14.23; HRMS (ESI, m/z) calculated value C₂₉H₃₂ClN₄O₅:551.2056[M+H]⁺The actual value is 551.2053.

EXAMPLE 93 preparation of Ethyl-5-methyl-4- (2-chlorophenyl) -2- ((2- (4- (2, 5-difluorophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.5mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.49mL,484mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking 2, 5-difluorobenzaldehyde [ compound 14 ]](71.0mg,0.5mmol) was dissolved in methanol (2.5mL), and the solution was added to the reaction and reacted at room temperature for 15 hours. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.7mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.1mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 3 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol ═ 100:1, product R_f0.37) to give 3-ethyl-5-methyl-4- (2-chlorophenyl) -2- ((2- (4- (2, 5-difluorophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 15 ] as an off-white solid](274.0mg,96％)。

Off-white solid, m.p.165.7-166.4 ℃,274.0mg, 96% yield;¹H NMR(400MHz,CDCl₃)δ8.08-7.97(m,2H),7.32(ddd,J＝7.7,1.8,0.9Hz,1H),7.21(dt,J＝7.9,1.2Hz,1H),7.15-7.07(m,2H),7.05-6.95(m,3H),5.37(s,1H),4.84-4.72(m,2H),4.70(dt,J＝6.4,2.6Hz,2H),4.10–3.96(m,4H),3.59(d,J＝0.9Hz,3H),2.27(s,3H),1.17(td,J＝7.1,0.9Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.95,167.16,160.31,160.29,157.90,157.88,156.40,153.98,153.95,145.66,144.44,144.20,140.61,132.33,131.48,129.25,127.43,126.92,123.83,123.70,119.92,119.83,119.76,119.67,117.09,117.01,116.84,116.76,116.08,115.99,115.83,115.74,114.09,114.05,113.83,113.79,103.90,101.93,69.15,68.13,59.92,50.82,50.16,37.20,19.21, 14.28; HRMS (ESI, m/z) calculated value C₂₈H₂₈ClF₂N₄O₅:573.1711[M+H]⁺The actual value is 573.1706.

Example preparation of 103-Ethyl-5-methyl 2- ((2- (4- (2-bromophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.0mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.50mL,480mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. O-bromobenzaldehyde [ compound 16 ]](93.2mg,0.5mmol) was dissolved in methanol (2.5mL), and the solution was added to the reaction and reacted at room temperature for 15 hours. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Taking compound 5(217.3mg,0.5mmol) and adding to the reaction system, taking sodium ascorbate (99.6mg,0.5mmol) and dissolving in distilled water (2.5mL), adding copper sulfate solution (500 uL, 100mM, 10% mmol), changing the solution from colorless to tan to yolk color, and mixing uniformly and adding to the reaction system. Heating to 50 deg.C, reacting for 11.0 hr, and introducingThe reaction was monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol ═ 100:1, product R_f0.28) to yield 3-ethyl-5-methyl 2- ((2- (4- (2-bromophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 17 ] as a yellow solid](283.9mg,92％)。

Yellow solid, m.p.55.4-60.0 deg.C, 283.9mg, yield 92%;¹H NMR(400MHz,CDCl₃)δ8.35(s,1H),8.15(dd,J＝7.8,1.7Hz,1H),7.66(dt,J＝8.0,1.0Hz,1H),7.45-7.40(m,1H),7.33(dd,J＝7.7,1.7Hz,1H),7.25-7.19(m,2H),7.11(td,J＝7.5,1.4Hz,1H),7.05-6.99(m,2H),5.37(s,1H),4.85-4.74(m,2H),4.70(dd,J＝6.0,3.9Hz,2H),4.10-3.99(m,4H),3.59(d,J＝0.8Hz,3H),2.28(s,3H),1.17(td,J＝7.1,0.8Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.95,167.17,145.69,144.53,144.31,133.63,132.30,131.47,130.98,130.56,129.58,129.23,127.86,127.41,126.94,121.13,103.88,101.91,69.19,68.15,59.90,50.80,50.12,37.18,19.35, 14.28; HRMS (ESI, m/z) calculated value C₂₈H₂₉BrClN₄O₅:615.1004[M+H]⁺The actual value is 615.1005.

EXAMPLE 113 preparation of ethyl-5-methyl 2- ((2- (4- (2-bromophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.7mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.50mL,480mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking 3, 7-dimethyl octyl-6-olefine aldehyde [ compound 18 ]](77.2mg,0.5mmol) was dissolved in methanol (2.5mL) and the solution was added to the reactionAnd reacting at room temperature for 15 hours. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.8mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.8mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 5 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol ═ 100:1, product R_f0.30) to give 4-ethyl-5-methyl 4- (2-chlorophenyl) -2- ((2- (4- (2, 6-dimethylhept-5-en-1-yl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 19 ] as an off-white solid](189.4mg,65％)。

Off-white solid, m.p.84.8-86.3 ℃,189.4mg, yield 65%;¹H NMR(400MHz,CDCl₃)δ7.33(dd,J＝8.0,2.1Hz,2H),7.21(dd,J＝7.9,1.4Hz,1H),7.11(td,J＝7.4,1.4Hz,2H),7.03(td,J＝7.6,1.7Hz,1H),5.38(s,1H),5.11-5.04(m,1H),4.83-4.70(m,2H),4.58(dd,J＝6.2,3.9Hz,2H),4.02(qdd,J＝15.5,8.4,4.4Hz,4H),3.60(s,3H),2.75(dd,J＝14.4,5.7Hz,1H),2.55(dd,J＝14.4,8.0Hz,1H),2.34(s,3H),2.00(ddt,J＝22.1,14.6,7.3Hz,3H),1.90-1.77(m,2H),1.40(ddd,J＝19.3,10.8,5.9Hz,1H),1.17(t,J＝7.1Hz,3H),0.91(d,J＝6.6Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.99,167.23,145.75,144.73,144.43,132.37,131.53,131.44,129.27,127.42,126.92,124.56,122.04,103.87,101.80,69.27,68.20,59.90,50.82,49.85,37.24,36.76,33.07,25.77,25.59,19.41,17.73, 14.31; HRMS (ESI, m/z) calculated value C₃₁H₄₂ClN₄O₅:585.2838[M+H]⁺The actual value is 585.2837.

Example preparation of 123-Ethyl-5-methyl 2- ((2- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.5mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.535mL,470mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking 3, 5-bis (trifluoromethyl) benzaldehyde [ compound 20 ]](121.2mg,0.5mmol) was dissolved in methanol (2.5mL), the solution was added to the reaction and reacted at room temperature for 13 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.4mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.5mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 3 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: petroleum ether: acetone ═ 4:6:0.4, product R_f0.23) gave 3-ethyl-5-methyl 2- ((2- (4- (3, 5-bis (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 21 ] as an off-white solid](266.1mg,79％)。

Off-white solid, m.p.159.7-161.3 ℃,266.1mg, yield 79%;¹H NMR(400MHz,CDCl₃)δ8.33-8.27(m,2H),8.03(s,1H),7.85(d,J＝1.8Hz,1H),7.33(dd,J＝7.7,1.7Hz,1H),7.22(dd,J＝7.9,1.4Hz,1H),7.10(td,J＝7.5,1.4Hz,1H),7.03(td,J＝7.6,1.7Hz,1H),6.97(s,1H),5.38(s,1H),4.86-4.74(m,2H),4.74-4.67(m,2H),4.13-3.97(m,4H),3.60(s,3H),2.30(s,3H),1.17(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ167.97,167.20,145.51,145.36,144.31,144.08,132.89,132.63,132.55,132.43,132.22,131.89,131.54,129.34,127.51,127.31,126.88,125.65,124.60,12188,121.80,121.76,121.72,121.57,119.17,103.92,102.07,69.07,68.17,59.98,50.85,50.38,37.39,19.34, 14.25; HRMS (ESI, m/z) calculated value C₃₀H₂₈ClF₆N₄O₅:673.1647[M+H]⁺The actual value is 673.1647.

Example preparation of 133-Ethyl-5-methyl-4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.2mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.54mL,470mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking p-trifluoromethyl benzaldehyde [ compound 22](88.0mg,0.5mmol) was dissolved in methanol (2.5mL), the solution was added to the reaction and reacted at room temperature for 13 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.7mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.9mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 3 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol ═ 100:1, product R_f0.33) to yield an off-white solid 3-ethyl-5-methyl 4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (4- (trifluoromethyl) phenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 23 ]](258.0mg,85％)。

Off-white solid, m.p.178.7-179.3 deg.C, 258.0mg, yield 85%；¹H NMR(400MHz,CDCl₃)δ7.99-7.91(m,3H),7.69(d,J＝8.1Hz,2H),7.32(dd,J＝7.7,1.8Hz,1H),7.22(dd,J＝7.8,1.5Hz,1H),7.10(td,J＝7.5,1.4Hz,1H),7.03(td,J＝7.5,1.7Hz,1H),6.99(s,1H),5.37(s,1H),4.85-4.73(m,2H),4.69(td,J＝4.6,2.0Hz,2H),4.10-3.96(m,4H),3.59(d,J＝0.6Hz,3H),2.28(s,3H),1.21-1.13(m,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.96,167.18,146.65,145.59,144.43,144.21,133.84,132.39,131.51,130.31,129.99,129.31,127.48,126.90,126.01,125.97,125.93,125.87,125.46,122.76,121.24,103.87,102.03,69.11,68.14,59.95,50.83,50.21,37.33,19.31, 14.26; HRMS (ESI, m/z) calculated value C₂₉H₂₉ClF₃N₄O₅:605.1773[M+H]⁺The actual value is 605.1773.

EXAMPLE 143 preparation of ethyl-5-methyl-4- (2-chlorophenyl) -2- ((2- (4- (3-chlorophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.5mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.80mL,400mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking m-chlorobenzaldehyde [ compound 24 ]](70.9mg,0.5mmol) was dissolved in methanol (2.5mL), the solution was added to the reaction and reacted at room temperature for 13 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.9mg,0.5mmol) was added to the reaction system, sodium ascorbate (100.1mg,0.5mmol) was dissolved in distilled water (2.5mL), and a copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 6 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction system was diluted with water (20mL), extracted with methylene chloride (20 mL. times.3),and combining organic phases, drying the organic phases by using anhydrous sodium sulfate, and concentrating the organic phases to obtain a crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol 200:1, product R_f0.52) to yield an off-white solid, 3-ethyl-5-methyl 4- (2-chlorophenyl) -2- ((2- (4- (3-chlorophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 25](253.0mg,89％)。

Off-white solid, m.p.132.8-135.0 ℃,253.0mg, yield 89%;¹H NMR(400MHz,CDCl₃)δ7.86(s,1H),7.83(t,J＝1.8Hz,1H),7.73(dt,J＝7.6,1.5Hz,1H),7.40-7.30(m,3H),7.21(dd,J＝7.9,1.4Hz,1H),7.10(td,J＝7.5,1.5Hz,1H),7.06-6.97(m,2H),5.37(s,1H),4.84-4.73(m,2H),4.67(td,J＝4.4,1.8Hz,2H),4.10-3.97(m,4H),3.59(s,3H),2.28(s,3H),1.17(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.95,167.17,146.74,145.62,144.45,144.24,134.89,132.35,132.14,131.50,130.29,129.27,128.35,127.45,126.92,125.74,123.79,120.85,103.86,102.00,69.13,68.11,59.93,50.81,50.16,37.29,19.31, 14.28; HRMS (ESI, m/z) calculated value C₂₈H₂₉Cl₂N₄O₅:571.1510[M+H]⁺The actual value is 571.1510.

EXAMPLE preparation of 153-Ethyl-5-methyl-4- (2-chlorophenyl) -2- ((2- (4- (2-chlorophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.3mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.80mL,400mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking m-chlorobenzaldehyde [ compound 26 ]](71.0mg,0.5mmol) was dissolved in methanol (2.5mL), the solution was added to the reaction and reacted at room temperature for 13 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Taking and transformingCompound 5(217.6mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.6mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 11.0 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol 200:1, product R_f0.46) to yield an off-white solid, 3-ethyl-5-methyl 4- (2-chlorophenyl) -2- ((2- (4- (2-chlorophenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 27](246.2mg,86％)。

Off-white solid, m.p.128.9-130.1 ℃,246.2mg, yield 86%;¹H NMR(400MHz,CDCl₃)δ8.33–8.25(m,2H),7.46(dd,J＝8.0,1.3Hz,1H),7.39(td,J＝7.6,1.4Hz,1H),7.35–7.27(m,2H),7.21(dd,J＝7.9,1.4Hz,1H),7.10(td,J＝7.5,1.5Hz,1H),7.02(td,J＝7.6,1.8Hz,2H),5.37(s,1H),4.85–4.74(m,2H),4.70(dd,J＝6.2,3.8Hz,2H),4.10–3.97(m,4H),3.59(s,3H),2.27(s,3H),1.17(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.93,167.15,145.69,144.52,144.29,144.19,132.30,131.46,131.12,130.28,129.76,129.25,129.22,128.97,127.40,127.32,126.92,124.01,103.87,101.91,69.18,68.13,59.88,50.78,50.08,37.18,19.27, 14.27; HRMS (ESI, m/z) calculated value C₂₈H₂₉Cl₂N₄O₅:571.1510[M+H]⁺The actual value is 571.1510.

Example preparation of 163-Ethyl-5-methyl-4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (thiazol-2-yl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.3mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.80mL,400mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking thiazole-2-formaldehyde [ compound 28](57.1mg,0.5mmol) was dissolved in methanol (2.5mL), the solution was added to the reaction and reacted at room temperature for 14 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Taking compound 5(217.3mg,0.5mmol) and adding to the reaction system, taking sodium ascorbate (99.3mg,0.5mmol) and dissolving in distilled water (2.5mL), adding copper sulfate solution (500 uL, 100mM, 10% mmol), changing the solution from colorless to tan to yolk color, and mixing uniformly and adding to the reaction system. The reaction was heated to 50 ℃ for 3 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol ═ 100:1, product R_f0.20) to yield 3-ethyl 5-methyl 4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (thiazol-2-yl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 29 ] as a yellow solid](202.0mg,74％)。

Yellow solid, m.p.104.6-106.4 deg.C, 202.0mg, yield 74%;¹H NMR(400MHz,CDCl₃)δ8.26(s,1H),7.90(s,1H),7.42(s,1H),7.31(dd,J＝7.7,1.7Hz,1H),7.21(dd,J＝7.9,1.4Hz,1H),7.11(td,J＝7.5,1.4Hz,1H),7.02(td,J＝7.6,1.7Hz,1H),6.93(s,1H),5.36(s,1H),4.84-4.72(m,2H),4.72-4.67(m,2H),4.09-3.96(m,4H),3.59(d,J＝1.7Hz,3H),2.27(s,3H),1.17(t,J＝7.1Hz,3H)；¹³c NMR (100MHz, CDCl3) δ 167.90,167.12,145.62,144.26,144.22,132.24,131.42,129.19,127.40,126.93,121.74,103.83,102.08,68.99,68.02,59.90,50.79,50.33,37.12,19.25, 14.24; HRMS (ESI, m/z) calculated value C₂₅H₂₇ClN₅O₅S:544.1416[M+H]⁺The actual value is 544.1416.

EXAMPLE 173 preparation of ethyl-5-methyl-2- (2- (4- (5-bromofuran-2-yl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -4- (2-chlorophenyl) yl) -6-methyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](83. mu.L, 0.6mmol), tetrahydrofuran (2.5mL) and K₂CO₃(311.2mg,2.25mmol) and FSO was added last₂N₃Solution of MTBE (1.80mL,400mM,0.75 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking 5-bromofuran-2-formaldehyde [ compound 30 ]](87.5mg,0.5mmol) was dissolved in methanol (2.5mL), the solution was added to the reaction and reacted at room temperature for 14 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(217.4mg,0.5mmol) was added to the reaction system, sodium ascorbate (99.4mg,0.5mmol) was dissolved in distilled water (2.5mL), and copper sulfate solution (500. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 5 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (20mL), extracted with dichloromethane (20 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Column chromatography purification (silica gel 300-400 mesh, dichloromethane: methanol ═ 100:1, product R_f0.42) to yield 3-ethyl 5-methyl 4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (thiazol-2-yl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 31 ] as a yellow solid](202.0mg,73％)。

Yellow solid, m.p.91.4-93.6 deg.C, 220.1mg, 73% yield;¹H NMR(400MHz,CDCl₃)δ7.84(s,1H),7.32(dd,J＝7.8,1.7Hz,1H),7.21(dd,J＝8.0,1.4Hz,1H),7.12(td,J＝7.5,1.4Hz,1H),7.03(td,J＝7.4,1.7Hz,1H),6.91(s,1H),6.85(d,J＝3.4Hz,1H),6.42(dd,J＝3.4,0.7Hz,1H),5.37(s,1H),4.84-4.71(m,2H),4.66(dt,J＝6.2,2.5Hz,2H),4.03(dddt,J＝14.4,10.7,6.7,4.0Hz,4H),3.60(s,3H),2.29(s,3H),1.17(t,J＝7.1Hz,3H)；¹³C NMR(100MHz,CDCl₃)δ167.95,167.17,147.89,145.62,14436,144.22,139.84,132.31,131.47,129.25,127.45,126.94,121.80,120.19,113.36,109.29,103.88,102.03,69.08,68.07,59.94,50.84,50.17,37.19,19.30, 14.28; HRMS (ESI, m/z) calculated value C₂₆H₂₇BrClN₄O₆:605.0797[M+H]⁺The actual value is 605.0799.

Example preparation of 183-Ethyl-5-methyl-4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (3,4, 5-trimethoxyphenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](166. mu.L, 1.2mmol), tetrahydrofuran (5.0mL) and K₂CO₃(622.1mg,4.5mmol) and FSO was added last₂N₃Solution of MTBE (3.2mL,450mM,1.44 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking 3,4, 5-trimethoxybenzaldehyde [ compound 32 ]](196.5mg,1.0mmol) was dissolved in methanol (5.0mL), the solution was added to the reaction and reacted at room temperature for 15 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(434.9mg,1.0mmol) was added to the reaction system, sodium ascorbate (198.0mg,1.0mmol) was dissolved in distilled water (5.0mL), and a copper sulfate solution (1000. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 5 hours and monitored by LC-MS for completion. The reaction was stopped, the reaction was diluted with water (50mL), extracted with dichloromethane (40 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Purifying by column chromatography (silica gel 300-400 mesh, acetone: petroleum ether: 3:7, product R)_f0.33) to yield 3-ethyl 5-methyl 4- (2-chlorophenyl) -6-methyl-2- ((2- (4- (3,4, 5-trimethoxyphenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 33 ] as a yellow solid](348.4mg,56％)。

Yellow solid, m.p.63.4-680 ℃,348.4mg, 56% yield;¹H NMR(400MHz,CDCl₃)δ7.84(s,1H),7.34-7.30(m,1H),7.21(dt,J＝7.9,1.1Hz,1H),7.11(dt,J＝7.4,1.2Hz,1H),7.07(d,J＝0.9Hz,2H),7.02(tdd,J＝7.3,1.8,0.9Hz,1H),6.98(s,1H),5.37(s,1H),4.84-4.73(m,2H),4.67(dd,J＝6.2,3.8Hz,2H),4.06-3.98(m,4H),3.92(d,J＝0.9Hz,6H),3.88(d,J＝0.9Hz,3H),3.59(d,J＝0.9Hz,3H),2.29(s,3H),1.17(td,J＝7.1,0.9Hz,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.89,167.12,153.66,147.85,145.54,144.47,144.21,138.21,132.26,131.43,129.20,127.40,126.85,125.92,120.24,103.75,102.92,101.86,69.13,68.01,60.92,59.86,56.21,50.75,50.04,37.19,19.25, 14.21; HRMS (ESI, m/z) calculated value C₃₁H₃₆ClN₄O₈:627.2216[M+H]⁺The actual value is 627.2217.

Example 193 preparation of Ethyl 5-methyl 4- (2-chlorophenyl) -2- ((2- (4- (4-methoxyphenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester

To a 50mL single-neck egg-shaped bottle was added acetonyl dimethyl phosphate [ Compound 2 ] in sequence](166. mu.L, 1.2mmol), tetrahydrofuran (5.0mL) and K₂CO₃(622.2mg,4.5mmol) and FSO was added last₂N₃Solution of MTBE (3.2mL,450mM,1.44 mmol). Stir for 30 minutes at room temperature and monitor by TLC that the reaction is complete. Taking 4-methoxybenzaldehyde [ compound 34 ]](136.8mg,1.0mmol) was dissolved in methanol (5.0mL), the solution was added to the reaction and reacted at room temperature for 15 hours, and the completion of the reaction was monitored by LC-MS. The reaction was stopped and the pH of the reaction system was adjusted to 6-7 using phosphoric acid (4M). Compound 5(403.2mg,1.0mmol) was added to the reaction system, sodium ascorbate (198.4mg,1.0mmol) was dissolved in distilled water (5.0mL), and a copper sulfate solution (1000. mu.L, 100mM, 10% mmol) was added to change the solution from colorless to tan to yolk, which was then mixed well and added to the reaction system. The reaction was heated to 50 ℃ for 5 hours and monitored by LC-MS for completion. The reaction was stopped, and water (50mL) was added to dilute the reaction system,extraction was performed with dichloromethane (40 mL. times.3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product. Purifying by column chromatography (silica gel 300-400 mesh, acetone: petroleum ether: 3:7, product R)_f0.40) to yield 3-ethyl 5-methyl 4- (2-chlorophenyl) -2- ((2- (4- (4-methoxyphenyl) -1H-1,2, 3-triazol-1-yl) ethoxy) methyl) -6-1, 4-dihydropyridine-3, 5-dicarboxylic acid diester [ compound 35 ] as a yellow solid](191.6mg,34％)。

Yellow solid, m.p.154.0-156.9 ℃,191.6mg, yield 34%;¹H NMR(400MHz,CDCl₃)δ7.82-7.72(m,3H),7.32(dd,J＝7.6,1.8Hz,1H),7.21(dd,J＝7.9,1.5Hz,1H),7.10(td,J＝7.3,1.5Hz,1H),7.02(td,J＝7.6,1.8Hz,2H),6.96(d,J＝8.6Hz,2H),5.37(s,1H),4.84-4.72(m,2H),4.65(q,J＝3.8Hz,2H),4.08-3.96(m,4H),3.87-3.81(m,3H),3.62-3.53(m,3H),2.27(s,3H),1.21-1.12(m,3H)；¹³C NMR(100MHz,CDCl₃) δ 167.96,167.18,159.77,147.89,145.69,144.59,144.38,132.29,131.48,129.23,127.42,127.03,126.93,122.97,119.62,114.36,103.81,101.91,69.21,68.07,59.90,55.34,50.80,50.02,37.20,19.29, 14.27; HRMS (ESI, m/z) calculated value C₂₉H₃₂ClN₄O₆:567.2005[M+H]⁺The actual value is 567.2005.