CN113336752A

CN113336752A - Preparation method of secondary amine and tertiary amine derivative containing imidazo [1,2-a ] pyridine

Info

Publication number: CN113336752A
Application number: CN202110610772.7A
Authority: CN
Inventors: 曹华; 刘想; 汪裕涵
Original assignee: Guangdong Pharmaceutical University
Current assignee: Guangdong Pharmaceutical University
Priority date: 2021-06-01
Filing date: 2021-06-01
Publication date: 2021-09-03
Anticipated expiration: 2041-06-01
Also published as: CN113336752B

Abstract

The invention provides a method for preparing secondary amine and tertiary amine derivatives containing imidazo [1,2-a ] pyridine from triazine compounds and imidazo [1,2-a ] pyridine, and relates to the field of pharmaceutical chemistry. According to the invention, through the reaction of the triazine compound and the imidazo [1,2-a ] pyridine compound, the reaction conditions such as temperature, time and the like of the reaction are controlled through Lewis acid catalysis, the controllable cracking and site-specific selectivity of the triazine compound are utilized to synthesize different imidazo [1,2-a ] pyridine secondary amine and tertiary amine containing derivatives, the synthesis method is simple, multi-step reaction is not needed, the product purity is high, the yield is high, the selectable substrate range is wide, and the method can be well applied to the pharmaceutical field.

Description

Preparation method of secondary amine and tertiary amine derivative containing imidazo [1,2-a ] pyridine

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of a derivative containing imidazo [1,2-a ] pyridine secondary amine and tertiary amine, in particular to a novel method for preparing a derivative containing imidazo [1,2-a ] pyridine secondary amine and tertiary amine from a triazine compound and an imidazo [1,2-a ] pyridine compound.

Background

Amines are widely found in natural products and synthetic drugs, and some of them are important for maintaining life activities and exhibiting vital physiological functions, and play a vital role in many fields such as biology, pharmacy, agrochemicals, and materials. Therefore, the synthesis of amine compounds has been the focus of research in the field of medicine. Furthermore, imidazo [1,2-a ] pyridines are known to be one of the most preferred structural motifs, possessing a variety of biological and pharmaceutical properties, such as anti-cancer, anti-viral, antibacterial and anti-inflammatory biological activities. C3-substituted imidazo [1,2-a ] pyridines are the core backbones of several commercially available drugs, such as alitame, zolpidem, nepidine and surrepide. Therefore, it would be very attractive to develop efficient and regioselective synthesis strategies for a variety of imidazo [1,2-a ] pyridine-containing amines.

For example, U.S. patent application No. 5,5446153 discloses imidazo [4,5-c ] pyridin-4-amines that induce interferon (α) biosynthesis in human cells, pharmaceutical compositions containing these compounds and methods of inducing interferon (α) biosynthesis involving the use of these compounds.

For example, chinese patent application CN100387597C discloses that imidazopyridine compounds containing an amide function at the 1-position can be used as immune response modifiers. The compounds and compositions of the present invention can induce the biosynthesis of various cytokines and are therefore useful in the treatment of a variety of diseases including viral diseases and neoplastic diseases.

Furthermore, an efficient regioselective synthesis of 2, 3-dihaloimidazo [1,2-a ] pyridines is disclosed in the literature Regiontronated functionalization of 2, 3-dihalogenoimidazole [1,2-a ] pyridines by Suzuki-Miyaura and Sonogashira cross-linking reactions (C.Enguehard-Gueiffeira. Gueiffer, Mini-Rev.Med.Chem.2007,7, 888-899). By using cross-coupling reactions to selectively introduce aryl, heteroaryl, alkyl and alkynyl substituents at the 2-and 3-positions, derivatives variously substituted at the 2-and 3-positions can be prepared simply from a common, stable and readily available starting material.

The preparation of amine derivatives from imidazopyridine amine compounds in the prior art has the following problems:

1. the preparation is complex and the cost is high. A multi-step reaction is needed, the requirement on reaction conditions is high, and the inhibition is caused to the drug development and the marketing;

2. the variety of derivatives that can be prepared is limited and needs to be further expanded. No research is specially carried out on synthesizing amine derivatives aiming at the excellent structural motif of imidazo [1,2-a ] pyridine, and the market has a large vacancy.

Disclosure of Invention

The invention provides a preparation method of secondary and tertiary imidazo [1,2-a ] pyridine derivatives, aiming at the problems in the prior art, the invention ensures that 1,3, 5-triazine substitutes various imidazo [1,2-a ] pyridine compounds to synthesize different secondary and tertiary imidazo [1,2-a ] pyridine derivatives by controllably cracking triazine, has simple synthesis method, high product purity and high yield, can select imidazo [1,2-a ] pyridine with wider range, and can be well applied to the pharmaceutical field.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a preparation method of imidazo [1,2-a ] pyridine secondary amine derivatives comprises the following steps of reacting triazine compounds with imidazo [1,2-a ] pyridine compounds to prepare imidazo [1,2-a ] pyridine secondary amine derivatives:

wherein R is selected from alkyl of-H, C1-C6, halogenated hydrocarbon of C1-C6, halogen atom, aryl of C6-C10 or halogenated aryl of C6-C10; r₁Selected from the group consisting of-H, C1-C6 alkyl, C1-C6 halohydrocarbon, C6-C10 aryl or C6-C10 haloaryl; r₂Is selected from aryl of C6-C10, halogenated aryl of C6-C10 or pyridine.

Furthermore, in the preparation method, the ratio of the amounts of the triazine compounds and the imidazo [1,2-a ] pyridine compounds is 1: 1.5-2.

Further, the preparation method comprises the following specific steps: mixing triazine compounds with formula amount and imidazo [1,2-a ] pyridine compounds, adding a catalyst, dissolving with a solvent, stirring, and carrying out chromatographic separation to obtain a target product; wherein the stirring temperature is 90-150 ℃, and the stirring time is 8-16 h.

Further, in the preparation method, the catalyst is selected from one or more of boron trifluoride diethyl etherate, trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, hydrochloric acid and pivalic acid; wherein the mass ratio of the catalyst to the substance of imidazo [1,2-a ] pyridine is 0.1-1.5: 1.

Furthermore, in the preparation method, the solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, acetone, glycol and 1, 4-dioxane; wherein the solvent is mixed with imidazo [1,2-a]The volume mol ratio of the pyridine compounds is 1 (0.5-3) multiplied by 10^-4ml/mol。

A preparation method of imidazo [1,2-a ] pyridine tertiary amine derivatives is prepared by reacting triazine compounds with imidazo [1,2-a ] pyridine compounds, and the reaction formula is as follows:

wherein R is selected from alkyl of-H, C1-C6, halogenated hydrocarbon of C1-C6, aryl of C6-C10 or halogenated aryl of C6-C10; r₁Selected from the group consisting of-H, C1-C6 alkyl, C1-C6 halohydrocarbon, C6-C10 aryl or C6-C10 haloaryl; r₂Is C1-C6 alkyl.

Further, the preparation method comprises the following specific steps: mixing triazine compounds with formula amount and imidazo [1,2-a ] pyridine compounds, adding a catalyst, dissolving with a solvent, stirring, and carrying out chromatographic separation to obtain a target product; wherein the stirring temperature is 100-130 ℃, and the stirring time is 9-18 h.

Further, in the preparation method, the catalyst is selected from one or more of boron trifluoride diethyl etherate, trifluoroacetic acid, acetic acid and trifluoromethanesulfonic acid; wherein the mass ratio of the catalyst to the imidazo [1,2-a ] pyridine compound is 0.1-1.5: 1.

Furthermore, in the preparation method, the solvent is selected from one or more of ethylene glycol, acetonitrile, tetrahydrofuran, toluene and 1, 4-dioxane; wherein the solvent is mixed with imidazo [1,2-a]The volume mol ratio of the pyridine compounds is 1 (0.5-3) multiplied by 10^-4ml/mol。

Compared with the prior art, the invention has the following beneficial effects:

1. the reaction substrate has wide application range, and various imidazo [1,2-a ] pyridine compounds are selected as the substrate, so that various imidazo [1,2-a ] pyridine secondary amine and tertiary amine derivatives can be prepared;

2. the regioselectivity is good, and the triazine can directly reach a site to synthesize a required product by utilizing controllable cracking and site-specific selectivity of triazine;

3. simple reaction, no need of multi-step reaction, high product yield, good purity, environmental protection and wide application prospect in the aspects of bioscience, pharmaceutical industry and material science.

Drawings

FIG. 1 is a hydrogen spectrum and FIG. 2 is a carbon spectrum of a compound obtained in example 1;

FIG. 3 is a hydrogen spectrum and FIG. 4 is a carbon spectrum of the compound obtained in example 2;

FIG. 5 is a hydrogen spectrum and FIG. 6 is a carbon spectrum of a compound obtained in example 3;

FIG. 7 is a hydrogen spectrum and FIG. 8 is a carbon spectrum of the compound obtained in example 4;

FIG. 9 is a hydrogen spectrum and FIG. 10 is a carbon spectrum of the compound obtained in example 5;

FIG. 11 is a hydrogen spectrum and FIG. 12 is a carbon spectrum of a compound obtained in example 6;

FIG. 13 is a hydrogen spectrum and FIG. 14 is a carbon spectrum of a compound obtained in example 7;

FIG. 15 is a hydrogen spectrum and FIG. 16 is a carbon spectrum of a compound obtained in example 8;

FIG. 17 is a hydrogen spectrum and FIG. 18 is a carbon spectrum of a compound obtained in example 9;

FIG. 19 is a hydrogen spectrum and FIG. 20 is a carbon spectrum of a compound obtained in example 10;

FIG. 21 is a hydrogen spectrum and FIG. 22 is a carbon spectrum of a compound obtained in example 11;

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below. The following examples are, however, merely preferred and not exhaustive of the invention. In the interest of clarity, not all features of an actual implementation are described. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.

The sources of the raw materials used in the present invention are not limited, and the raw materials used in the present invention are all those commonly available in the art unless otherwise specified.

Example 1

35.4mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 142mg (0.45mmol) of hexahydrotrityanogen substrate were added to a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of the catalyst BF 3. OEt₂After dissolving MeCN (2ml) in water, the mixture was stirred at room temperature for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 91% yield.

The specific reaction formula is as follows:

the specific hydrogen spectrum, carbon spectrum and mass spectrum data are as follows:

¹H NMR(400MHz,CDCl₃)δ8.16(d,J＝6.8Hz,1H),7.68(d,J＝9.1Hz,1H),7.62(s,1H),7.26–7.19(m,3H),6.83(dt,J＝17.3,7.1Hz,2H),6.75(d,J＝8.0Hz,2H),4.60(s,2H),3.81(s,1H).

¹³C NMR(100MHz,CDCl₃)δ142.8,127.4,124.8,120.2,119.6,116.4,113.8,113.0,108.6,108.0,72.6,72.6,72.4,72.0,33.8.

HRMS MALDI m/z calcd forC₁₄H₁₄N₃[M+H]⁺:224.1188,found:224.1188.

specific hydrogen spectra and carbon spectra are shown in fig. 1 and 2, respectively.

Example 2

58.2mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 188mg (0.45mmol) of hexahydrotrityl cyanide substrate were added to a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of the catalyst BF 3. OEt₂After dissolving MeCN (2ml) in water, the mixture was stirred at room temperature for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 90% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,DMSO-d₆)δ8.37(d,J＝7.0Hz,1H),7.79(d,J＝7.6Hz,2H),7.66(d,J＝9.0Hz,1H),7.49(t,J＝7.5Hz,2H),7.38(dt,J＝15.7,7.8Hz,2H),7.10(d,J＝8.5Hz,2H),7.01(t,J＝6.8Hz,1H),6.66(d,J＝8.5Hz,2H),6.35(t,J＝4.7Hz,1H),4.62(d,J＝4.1Hz,2H).

¹³C NMR(101MHz,DMSO-d₆)δ147.4,144.2,143.4,134.4,128.8,128.6,128.2,127.8,125.2,125.2,119.8,117.2,116.8,113.8,112.4,37.0.

HRMS MALDI(m/z):calcd for C₂₀H₁₇ClN₃[M+H]⁺:334.1111,found:334.1114.

specific hydrogen spectra and carbon spectra are shown in fig. 3 and 4, respectively.

Example 3

68.4mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 142mg (0.45mmol) of hexahydrotrityanogen substrate were added to a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of the catalyst BF 3. OEt₂Then, after dissolving the compound in MeCN (2ml) solvent, the mixture was stirred at room temperature for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 88% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,DMSO-d₆)δ8.33(d,J＝6.9Hz,1H),7.80(d,J＝7.6Hz,2H),7.63(d,J＝9.0Hz,1H),7.48(t,J＝7.5Hz,2H),7.38(t,J＝7.3Hz,1H),7.33–7.28(m,1H),6.96(t,J＝6.8Hz,1H),6.89(d,J＝7.9Hz,2H),6.57(d,J＝8.0Hz,2H),5.92(t,J＝5.0Hz,1H),4.61(d,J＝4.5Hz,2H),2.15(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ146.2,144.0,143.2,134.4,129.4,128.6,128.0,127.6,125.2,124.8,124.8,117.6,116.8,112.6,112.2,37.2,20.2.

HRMS MALDI m/z calcd.for C₂₁H₂₀N₃[M+H]⁺:314.1657,found:314.1657.

specific hydrogen spectra and carbon spectra are shown in fig. 5 and 6, respectively.

Example 4

58.2mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 143mg (0.45mmol) of hexahydrotrityanogen substrate were added to a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of the catalyst BF₃·OEt₂After dissolving MeCN (2ml) in water, the mixture was stirred at room temperature for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography with a yield of 70%.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ8.21(d,J＝6.9Hz,1H),8.14(d,J＝5.2Hz,1H),7.78(d,J＝7.5Hz,2H),7.65(d,J＝9.0Hz,1H),7.44(q,J＝7.5Hz,3H),7.37(t,J＝7.3Hz,1H),7.25–7.20(m,1H),6.81(t,J＝6.8Hz,1H),6.66(t,J＝6.2Hz,1H),6.44(d,J＝8.4Hz,1H),5.02(d,J＝4.2Hz,2H).

¹³C NMR(100Hz,CDCl₃)δ157.87,147.21,145.21,144.67,138.10,134.03,128.86,128.62,128.18,125.18,124.58,117.53,116.99,113.64,112.70,108.65,35.65.

HRMS MALDI(m/z):calcd for C₂₀H₁₇N₃[M+H]⁺:305.1453,found:305.1457.

specific hydrogen spectra and carbon spectra are shown in fig. 7 and 8, respectively.

Example 5

52.2mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 142mg (0.45mmol) hexahydrotrityanogen substrate were added to a reaction tube with a stirrer followed by 8.5mg (0.06mmol) of the catalyst BF₃·OEt₂After dissolving MeCN (2ml) in water, the mixture was stirred at room temperature for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 77% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ7.98(d,J＝6.9Hz,1H),7.63(d,J＝9.0Hz,1H),7.31–7.22(m,2H),7.17(d,J＝7.1Hz,1H),6.81(t,J＝7.4Hz,1H),6.80–6.70(m,3H),4.66(s,2H),3.57(s,1H),1.49(s,9H).

¹³C NMR(100MHz,CDCl₃)δ153.64,147.80,143.69,129.54,124.18,123.56,118.36,117.22,115.07,113.09,112.20,38.61,33.48,31.21.

HRMS MALDI m/z calcdforC₁₈H₂₁N₃[M+H]⁺:280.1814,found:280.1813.

specific hydrogen spectra and carbon spectra are shown in fig. 9 and 10, respectively.

Example 6

78.6mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 142mg (0.45mmol) of hexahydrotrityl substrate are added to the flaskTo the stirred tube was then added 8.5mg (0.06mmol) of BF as catalyst₃·OEt₂After dissolving MeCN (2ml) in water, the mixture was stirred at room temperature for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 81% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ8.12(d,J＝6.9Hz,1H),7.74(dd,J＝8.5,5.6Hz,2H),7.67(d,J＝9.0Hz,1H),7.28(d,J＝7.6Hz,4H),7.11(t,J＝8.6Hz,2H),6.85(q,J＝7.8Hz,2H),6.77(d,J＝8.6Hz,2H),4.65(s,2H),4.03(m,1H).

¹³C NMR(100MHz,CDCl₃)δ163.0(d,J＝246Hz),147.6,144.8,143.0,130.2(d,J＝8.0Hz),129.6,129.4,125.8,124.4,118.6,117.2,116.6,116.0(d,J＝21.0Hz),113.2,113.2,38.2.

HRMS MALDI m/z calcd.for C₂₀H₁₇FN₃[M+H]⁺:318.1407,found:318.1406.

specific hydrogen spectra and carbon spectra are shown in fig. 11 and 12, respectively.

Example 7

58.2mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 58.0mg (0.45mmol) of 1,3, 5-trimethylhexyloxy-1, 3, 5-triazine substrate are introduced into a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of BF as catalyst₃·OEt₂After dissolving in ethylene glycol (2ml) solvent, the mixture was stirred at 110 ℃ for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 48% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ8.40(d,J＝5.7Hz,1H),7.80(d,J＝7.5Hz,2H),7.63(d,J＝8.0Hz,1H),7.48–7.43(m,2H),7.37(d,J＝7.9Hz,1H),7.25–7.16(m,1H),6.81(t,J＝6.8Hz,1H),3.89(s,2H),2.25(s,6H).

¹³C NMR(100MHz,CDCl₃)δ145.0,145.0,134.8,129.0,128.6,127.8,125.4,124.6,117.4,117.4,112.0,53.0,45.0.

HRMS MALDI(m/z):calcd for C₁₆H₁₈N₃[M+H]⁺:252.1501,found:252.109.

specific hydrogen spectra and carbon spectra are shown in fig. 13 and 14, respectively.

Example 8

62.4mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 58.0mg (0.45mmol) of 1,3, 5-trimethylhexyloxy-1, 3, 5-triazine substrate are introduced into a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of BF as catalyst₃·OEt₂After dissolving in ethylene glycol (2ml) solvent, the mixture was stirred at 110 ℃ for 10 hours, and after spin-drying, the desired product was isolated by silica gel chromatography in 47% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ8.15(s,1H),7.79(d,J＝7.8Hz,2H),7.56(d,J＝9.1Hz,1H),7.45(t,J＝7.5Hz,2H),7.39–7.33(m,1H),7.08(d,J＝8.9Hz,1H),3.91(s,2H),2.37(s,3H),2.27(s,6H).

¹³C NMR(100MHz,CDCl₃)δ144.80,144.17,134.76,128.97,128.53,127.97,127.71,122.99,121.74,116.63,52.81,45.08,18.66.

HRMS MALDI(m/z):C₁₇H₁₉N₃[M+H]⁺:266.1657,found:266.1656.

specific hydrogen spectra and carbon spectra are shown in fig. 15 and 16, respectively.

Example 9

68.4mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 58.0mg (0.45mmol) of 1,3, 5-trimethylhexyloxy-1, 3, 5-triazine substrate are introduced into a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of BF as catalyst₃·OEt₂After dissolving in ethylene glycol (2ml) solvent, the mixture was stirred at 110 ℃ for 10 hours, and after spin-drying, the desired product was isolated by silica gel chromatography in 46% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ8.50(s,1H),7.76(d,J＝7.6Hz,2H),7.57(d,J＝9.5Hz,1H),7.49–7.42(m,2H),7.39(d,J＝7.9Hz,1H),7.18(d,J＝9.5Hz,1H),3.89(s,2H),2.26(s,6H).

¹³C NMR(100MHz,CDCl₃)δ146.0,143.4,134.2,129.0,128.6,128.0,126.0,123.6,120.0,117.8,117.6,53.0,45.0.

HRMS MALDI(m/z):calcd for C₁₆H₁₇ClN₃[M+H]⁺:286.1111,found:286.1116.

specific hydrogen spectra and carbon spectra are shown in fig. 17 and 18, respectively.

Example 10

72.6mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 58.0mg (0.45mmol) of 1,3, 5-trimethylhexyloxy-1, 3, 5-triazine substrate are introduced into a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of BF as catalyst₃·OEt₂Then, ethylene glycol (2ml) was added thereto and dissolved, followed by stirring at 110 ℃ for 10 hours, spin-drying and silica gel chromatography to obtain the desired product in 40% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ8.39(d,J＝7.3Hz,1H),7.70–7.59(m,3H),7.28(s,2H),6.80(dd,J＝7.3,2.1Hz,1H),3.91(s,2H),2.41(s,3H),2.25(s,6H).

¹³C NMR(100MHz,CDCl₃)δ146.01,144.88,137.94,131.31,131.26,129.39,128.82,126.03,116.03,113.54,52.77,44.90,21.44.

HRMS MALDI(m/z):calcd for C₁₇H₁₈ClN₃[M+H]⁺:300.1268,found:300.1266.

specific hydrogen spectra and carbon spectra are shown in fig. 19 and 20, respectively.

Example 11

68.4mg (0.3mmol) of imidazo [1,2-a ] as shown below]Pyridine, 58.0mg (0.45mmol) of 1,3, 5-trimethylhexyloxy-1, 3, 5-triazine substrate are introduced into a reaction tube with stirrer, followed by 8.5mg (0.06mmol) of BF as catalyst₃·OEt₂After dissolving in ethylene glycol (2ml) solvent, the mixture was stirred at 110 ℃ for 10 hours, and after spin-drying, the target product was isolated by silica gel chromatography in 41% yield.

The specific reaction formula is as follows:

¹H NMR(400MHz,CDCl₃)δ7.79(d,J＝7.3Hz,2H),7.62(d,J＝7.0Hz,1H),7.43(dd,J＝14.0,6.7Hz,3H),7.33(t,J＝7.4Hz,1H),6.94–6.90(m,2H),6.63–6.60(m,2H),6.56(d,J＝5.4Hz,1H),4.35(s,2H),3.47(s,2H),2.68(q,J＝7.6Hz,2H),1.27(t,J＝7.5Hz,3H).

¹³C NMR(100MHz,CDCl₃)δ145.04,143.65,133.66,133.20,130.14,128.67,125.34,124.79,117.57,117.24,112.07,52.79,45.03.

HRMS MALDI(m/z):calcd for C₁₆H₁₇ClN₃[M+H]⁺:286.1111,found:286.1113.

specific hydrogen spectra and carbon spectra are shown in fig. 21 and 22, respectively.

Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A method for preparing an imidazo [1,2-a ] pyridine secondary amine derivative, which is characterized by comprising the following steps: imidazo [1,2-a ] pyridine secondary amine derivatives are prepared by reacting a triazine compound with an imidazo [1,2-a ] pyridine compound, according to the following reaction formula:

2. The method of claim 1, wherein: the mass ratio of the triazine compounds to the imidazo [1,2-a ] pyridine compounds is 1-2: 1.

3. The method of claim 2, wherein: the preparation method comprises the following specific steps: mixing triazine compounds with formula amount and imidazo [1,2-a ] pyridine compounds, adding a catalyst, dissolving with a solvent, stirring, and carrying out chromatographic separation to obtain a target product; wherein the stirring temperature is 90-150 ℃, and the stirring time is 8-16 h.

4. The production method according to claim 3, characterized in that: the catalyst is selected from one or more of boron trifluoride diethyl etherate, trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, hydrochloric acid and pivalic acid; wherein the mass ratio of the catalyst to the substance of imidazo [1,2-a ] pyridine is 0.1-1.5: 1.

5. The production method according to claim 3, characterized in that: the solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, acetone, glycol and 1, 4-dioxane; wherein the solvent is mixed with imidazo [1,2-a]The volume mol ratio of the pyridine compounds is 1 (0.5-3) multiplied by 10^-4ml/mol。

6. A method for preparing an imidazo [1,2-a ] pyridine tertiary amine derivative, which is characterized by comprising the following steps: prepared by reacting triazine compounds with imidazo [1,2-a ] pyridine compounds, and the reaction formula is as follows:

wherein R is selected from alkyl of-H, C1-C6, halogen, atoms, halogenated hydrocarbon of C1-C6, aryl of C6-C10 or halogenated aryl of C6-C10; r₁Selected from the group consisting of-H, C1-C6 alkyl, C1-C6 halohydrocarbon, C6-C10 aryl or C6-C10 haloaryl; r₂Is C1-C6 alkyl.

7. The method of claim 6, wherein: the mass ratio of the triazine compound to the imidazo [1,2-a ] pyridine compound is 1: 1.5-2.

8. The preparation method according to claim 7, comprising the following specific steps: mixing triazine compounds with formula amount and imidazo [1,2-a ] pyridine compounds, adding a catalyst, dissolving with a solvent, stirring, and carrying out chromatographic separation to obtain a target product; wherein the stirring temperature is 100-130 ℃, and the stirring time is 9-18 h.

9. The method of claim 8, wherein: the catalyst is selected from one or more of boron trifluoride ethyl ether, trifluoroacetic acid, acetic acid and trifluoromethanesulfonic acid; wherein the mass ratio of the catalyst to the imidazo [1,2-a ] pyridine compound is 0.1-1.5: 1.

10. The method of claim 8, wherein: the solvent is one or more selected from ethylene glycol, acetonitrile, tetrahydrofuran, toluene and 1, 4-dioxane; wherein the solvent is mixed with imidazo [1,2-a]The volume mol ratio of the pyridine compounds is 1 (0.5-3) multiplied by 10^-4ml/mol。