A method for introducing an amino group having an acyl protective group at the alpha position of pyridine

Abstract

This invention relates to the field of organic synthesis, specifically to a method for introducing an acyl-protected amino group at the α-position of pyridine, the reaction formula being as follows: where R1, R2, and R3 are independently selected from H, halogens, alkyl groups, alkoxy groups, or haloalkyl groups; R4 and R5 are independently selected from aryl groups, substituted aryl groups, C1-C6 alkyl groups, or cyclic groups; the method includes the following steps: mixing compound 1, compound 2, a Lewis acid, a base reagent, and a solvent, reacting to obtain compound 3; the Lewis acid is a sulfonic anhydride compound and / or a sulfonyl halide compound, and the molar amount of the Lewis acid minus the molar amount of compound 2 is greater than or equal to 0. In this application, when Lewis acids, represented by sulfonyl halides or sulfonic anhydrides, are used as catalysts, imide compounds exhibit unusual reactivity in the reaction, enabling the introduction of an acyl-protected amino group at the α-position of pyridine with high selectivity and high yield in a relatively short reaction time.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically to a method for introducing an amino group with acyl protection at the α-position of pyridine. Background Technology

[0002] Pyridine derivatives with an acyl-protected amino group at the α-position have significant potential applications in organic synthesis. On one hand, these compounds can be deprotected using a simple, efficient, and mild method to yield 2-aminopyridine compounds, which are important synthetic intermediates for many drugs, such as Lumacaftor for treating cystic fibrosis and Danicopan for treating immune complex membrane proliferative glomerulonephritis, both of which contain 2-aminopyridine fragments. On the other hand, the acyl protecting group can be retained, allowing for further derivatization of the pyridine ring without affecting the amino group, thereby obtaining more complex pyridine derivatives.

[0003] In existing technologies, the Chichibabin amination reaction is a relatively common reaction to introduce an amino group at the α-position of pyridine. However, this reaction requires the use of a sensitive reagent such as sodium amide, and the reaction temperature is high, the reaction time is long, and sometimes the reaction needs to be carried out under high pressure, which is not conducive to industrial production.

[0004] Chinese patent application CN110627713 A discloses a method for preparing 2-amino-5-methyl-6-bromopyridine. This method uses pyridine oxides and ethanolamine as reactants and anhydride compounds as catalysts to introduce an amino group at the α-position of pyridine. However, this reaction lacks selectivity and also introduces an amino group at the 4-position of pyridine, thereby reducing the reaction yield. Furthermore, the reaction requires a long reaction time, up to 12-16 hours, to complete the reaction.

[0005] In addition, both of the above methods directly introduce the amino group. If further derivatization of the pyridine ring is required in the future, the amino group often needs to be protected, which adds an extra step.

[0006] Chinese patent application CN 112839945 A also discloses a method for preparing 6-bromo-3-methylpyridine-2-amine. This method uses pyridine nitrogen oxides and alkyl amines as reactants and trifluoromethanesulfonic anhydride as a catalyst to introduce an amino group at the α-position of pyridine. However, the yield of this reaction is low, only 17%.

[0007] Furthermore, the above method introduces alkylamino groups, which require stringent deprotection conditions. In particular, this method is not applicable when the pyridine ring has other acid-sensitive groups. Summary of the Invention

[0008] This invention was made to solve the above-mentioned problems, and its purpose is to provide a method for introducing an acyl-protected amino group at the α-position of pyridine with simple process conditions and relatively good yield.

[0009] The first aspect of this invention provides a method for introducing an acyl-protected amino group at the α-position of pyridine, the reaction formula of which is as follows:

[0010]

[0011] In the formula, R1, R2, and R3 are independently selected from H, halogen, alkyl, alkoxy, or haloalkyl;

[0012] R4 and R5 are independently selected from aryl, substituted aryl, C1-C6 alkyl groups or cyclic groups;

[0013] The method includes the following steps:

[0014] Compound 1, Compound 2, Lewis acid, base reagent and solvent are mixed and reacted to obtain Compound 3;

[0015] The Lewis acid is a sulfonic anhydride compound and / or a sulfonyl halide compound.

[0016] The molar amount of the Lewis acid minus the molar amount of compound 2 is greater than or equal to 0.

[0017] A second aspect of the present invention provides a method for preparing 2-aminopyridine compounds, comprising the following steps:

[0018] Step 1: Using the method described in the first aspect of the present invention to introduce an amino group with acyl protection at the α-position of pyridine, compound 3 is obtained;

[0019] Step 2: Compound 3 reacts with a deacylation reagent to obtain compound 4.

[0020] Compound 4 is

[0021] A third aspect of the present invention provides a pyridine derivative, wherein the structural formula of the pyridine derivative is:

[0022]

[0023] In the above formula, X represents a halogen.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] According to the method for introducing an acyl-protected amino group at the α-position of pyridine involved in this application, imide compounds exhibit unusual reactivity in the reaction when Lewis acids, represented by sulfonyl halides or sulfonic anhydrides, are used as catalysts, enabling the introduction of an acyl-protected amino group at the α-position of pyridine with high selectivity and high yield in a short reaction time. Attached Figure Description

[0026] Figure 1 This is the HPLC spectrum of compound 1a in Example 1 of the present invention.

[0027] Figure 2 This is the proton spectrum of compound 2a in Example 1 of the present invention.

[0028] Figure 3 This is the HPLC spectrum of compound 2a in Example 1 of the present invention. Detailed Implementation

[0029] The following details the methods for introducing an acyl-protected amino group at the α-position of pyridine, the preparation methods of 2-aminopyridine compounds, and the embodiments of pyridine derivatives.

[0030] Terminology Definition

[0031] Unless otherwise stated, the following words, phrases and symbols used in this specification generally have the meanings described below.

[0032] Generally, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including those for cell culture, organic chemistry, analytical chemistry, and pharmacology) are those well-known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. Additionally, in the claims and / or description, the term “a” or “an” used in conjunction with the term “comprising” or a noun may mean “one,” but also is consistent with the meanings of “one or more,” “at least one,” and “one or more.” Similarly, the term “another” or “other” may mean at least a second or more.

[0033] It should be understood that whenever this document uses the terms “comprising” or “including” to describe a particular aspect, other similar aspects described by “consisting of” and / or “substantially consisting of” are also provided.

[0034] In this article, the term "halogen" used alone or in combination refers to fluorine, chlorine, bromine, or iodine.

[0035] In this document, the term "alkyl" used alone or in combination may be straight-chain or branched, and the number of carbon atoms may be, for example, C1–C10, C1–C8, C1–C6, C1–C5, C1–C4, C1–C3, or C1–C2. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.

[0036] In this document, the term "alkoxy" as used alone or in combination refers to -O (alkyl). Optionally, the alkyl portion of an alkoxy group may include C1-C10, C1-C8, C1-C6, or C1-C4, etc. Alkoxy groups may include, for example, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, etc.

[0037] In this document, the term "halogenated alkyl" as used alone or in combination refers to an alkyl group in which one or more hydrogen atoms are substituted with a halogen. Herein, "halogen" refers to fluorine, chlorine, bromine, or iodine. By way of example, "halogenated alkyl" includes, but is not limited to, -CCl3, -CHCl2, -CH2Cl, -CH2-CCl3, -CH2-CHCl2, -CH2-CH2Cl, -CH2-CH2-CCl3, -CH2-CH2-CHCl2, -CH2-CH2-CH2Cl, -CH2-CH2-CH2-CCl3, -CH2-CH2-CH2-CHCl2, -CH2-CH2-CH2-CH2Cl, and -CH2-CH2

[0038] -CH2-CH2-CCl3, -CH2-CH2-CH2-CH2-CHCl2, -CH2-CH2-CH2-CH2-CH2Cl, -CF3, -CHF2, -CH2F, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CH2-CF3, -CH2-CH2-CHF2, -CH2-CH2-CH2F, -CH2-CH2-CH2-CF3, -CH2-CH2-CH2-CHF2, -CH2-CH2-CH2-CH2-CH2F, -CH2-CH2-CH2-CH2-CF3, -CH2-CH2-CH2-CH2-CHF2, -CH2-CH2-CH2-CH2-CH2F, etc. Here, the alkyl group is as defined above.

[0039] In this document, the term "aryl" as used alone or in combination refers to a monovalent carbocyclic aromatic group comprising one or more fused rings, such as C6-C10 aryl groups. Aryl groups can be monocyclic or polycyclic arylenes. In some embodiments, monocyclic aryl groups include, but are not limited to, phenyl, biphenyl, etc. Polycyclic aryl groups include, but are not limited to, naphthyl, etc.

[0040] In this disclosure, the term "substituted aryl" used alone or in combination refers to a substituted aryl group. A substituted aryl group is an aryl group that is substituted one or more times (e.g., 1-4 times, 1-3 times, or 1-2 times) by a substituent, such as a mono-, di-, or tri-substituted aryl group, wherein the substituent is optionally selected, for example, from deuterium, hydroxyl, amino, mercapto, halogen, cyano, nitro, carbonyl, ester, imide, oxo, phosphine oxide, trifluoromethyl, trifluoromethoxy, C1-C3 alkyl, C1-C3 alkoxy, and any combination thereof.

[0041] In this disclosure, the term "ring formation," used alone or in combination, refers to the formation of an aliphatic hydrocarbon ring, an aromatic hydrocarbon ring, an aliphatic heterocycle, an aromatic heterocycle, or a fused ring thereof. For example, R4 and R5 bonds are formed.

[0042] Method for introducing an acyl-protected amino group at the α-position of pyridine

[0043] This invention provides a method for introducing an acyl-protected amino group at the α-position of pyridine, the reaction formula of which is as follows:

[0044]

[0045] In the formula, R1, R2, and R3 are independently selected from H, halogen, alkyl, alkoxy, or haloalkyl; R4 and R5 are independently selected from aryl, substituted aryl, C1-C6 alkyl, or cyclic.

[0046] The method includes the following steps:

[0047] Compound 1, Compound 2, Lewis acid, base reagent, and solvent are mixed and reacted to obtain Compound 3.

[0048] The Lewis acid is a sulfonic anhydride compound and / or a sulfonyl halide compound, and the molar amount of the Lewis acid minus the molar amount of compound 2 is greater than or equal to 0.

[0049] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the molar ratio of compound 1 to compound 2 is 1:(1-1.5). In some embodiments, the molar ratio of compound 1 to compound 2 may also be 1:(1-1.2) or 1:(1.2-1.5), etc.

[0050] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the molar ratio of compound 1 to the Lewis acid is 1:(1.2-2.0). In some embodiments, the molar ratio of compound 1 to the Lewis acid may also be 1:(1.2-1.8), 1:(1.2-1.5), 1:(1.5-1.8), or 1:(1.8-2.0), etc.

[0051] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by this invention, the sulfonic anhydride compound is selected from p-toluenesulfonic anhydride and / or trifluoromethanesulfonic anhydride. The sulfonyl halide compound is p-toluenesulfonyl chloride.

[0052] Preferably, the Lewis acid is p-toluenesulfonyl chloride.

[0053] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the base reagent is an organic base, preferably N,N-diisopropylethylamine and / or triethylamine. More preferably, the base reagent is N,N-diisopropylethylamine.

[0054] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the molar ratio of compound 1 to the base reagent is 1:(1-3). In some embodiments, the molar ratio of compound 1 to the base reagent may be, for example, 1:(1-2) or 1:(2-3), etc.

[0055] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the reaction temperature is -10℃ to 35℃. In some embodiments, the reaction temperature may be, for example, -10℃ to 0℃, 0℃ to 10℃, 10℃ to 20℃, 20℃ to 30℃, or 30℃ to 35℃.

[0056] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the solvent is selected from one or more of dichloromethane, toluene, methyl tert-butyl ether, or ethyl acetate. Preferably, the solvent is selected from dichloromethane.

[0057] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, the mass-to-volume ratio of compound 1 to solvent is 1 g:(15-25) mL. In some embodiments, the mass-to-volume ratio of compound 1 to solvent may be, for example, 1 g:(15-20) mL, 1 g:(20-25) mL, 1 g:(15-18) mL, 1 g:(18-20) mL, 1 g:(20-22) mL, or 1 g:(22-25) mL, etc.

[0058] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by this invention, the molar amount of the Lewis acid minus the molar amount of compound 2 is greater than or equal to 0. When an excess of compound 2 (e.g., phthalimide) is used in the reaction, especially when the amount of compound 2 (e.g., phthalimide) is greater than 1 eq or more of the amount of Lewis acid, the reaction cannot proceed.

[0059] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, R1 is a halogen, such as fluorine, chlorine, bromine or iodine.

[0060] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, R2 and R3 are independently selected from alkyl or H. When R2 and R3 are independently selected from alkyl, for example, they can be selected from C1-C10 alkyl or C1-C6 alkyl. Optionally, R2 and R3 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0061] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by this invention, R4 and R5 are independently selected from C6-C20 aryl groups. Optionally, R4 and R5 are independently selected from phenyl or naphthyl groups, etc.

[0062] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, R4 and R5 are independently selected from substituted aryl groups of C6-C20. Optionally, R4 and R5 are independently selected from substituted phenyl or substituted naphthyl groups, etc.

[0063] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by the present invention, R4 and R5 are independently selected from C1-C4 alkyl groups. Optionally, R4 and R5 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0064] In the method for introducing an acyl-protected amino group at the α-position of pyridine provided by this invention, the R4 and R5 bonds form a ring. Optionally, the R4 and R5 bonds form... The structural formula of the corresponding compound 2 is

[0065] Preparation method of 2-aminopyridine compounds

[0066] This invention also provides a method for preparing 2-aminopyridine compounds, comprising the following steps:

[0067] Step 1: Using the method described in the first aspect of the present invention to introduce an amino group with acyl protection at the α-position of pyridine, compound 3 is obtained;

[0068] Step 2: Compound 3 reacts with a deacylation reagent to give compound 4.

[0069] Compound 4 is

[0070] In the preparation method of 2-aminopyridine compounds provided by the present invention, the deacylation reagent is selected from any one or more of hydrazine hydrate, NH3, and borohydrides.

[0071] In the preparation method of the 2-aminopyridine compound provided by the present invention, the molar ratio of compound 3 to the deacylation reagent is 1:(1-3). In specific embodiments, the molar ratio of compound 3 to the deacylation reagent can also be 1:(1-2) or 1:(2-3), etc.

[0072] In the preparation method of 2-aminopyridine compounds provided by the present invention, R1, R2, and R3 are independently selected from H, halogen, alkyl, alkoxy, or haloalkyl.

[0073] In the preparation method of 2-aminopyridine compounds provided by the present invention, R1 is a halogen, such as fluorine, chlorine, bromine or iodine.

[0074] In the method for preparing 2-aminopyridine compounds provided by this invention, R2 and R3 are independently selected from alkyl or H. When R2 and R3 are independently selected from alkyl, for example, they can be selected from C1-C10 alkyl or C1-C6 alkyl. Optionally, R2 and R3 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0075] Pyridine derivatives

[0076] Another aspect of the present invention provides a pyridine derivative, the structural formula of which is:

[0077]

[0078] In the above formula, X is a halogen. Optionally, X can be fluorine, chlorine, bromine, or iodine.

[0079] In some embodiments of the present invention, It can be prepared by introducing an amino group with acyl protection at the α-position of pyridine as described in the first aspect of this invention.

[0080] The technical solution of this application will be clearly and completely described below with reference to embodiments of the present invention. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention still fall within the scope of protection of the present invention.

[0081] Unless otherwise specified, all reagents, materials and instruments used in the following embodiments are commercially available.

[0082] In an embodiment of the present invention, The yield calculation method is as follows: Yield = (mass of actual product / mass of theoretical product) (Quantity) * 100% .

[0083] In an embodiment of the present invention, Liquid phase yield refers to the percentage of the product peak area in the HPLC spectrum (excluding solvent peaks). The percentage of the area outside the Lewis acid peak.

[0084] <Example 1>

[0085] Preparation of compound 1a

[0086] This embodiment provides a method for preparing compound 1a, and the reaction formula is as follows:

[0087]

[0088] Includes the following steps:

[0089] 140 g of compound 1 (0.8 mol, 1.0 eq), 248.5 g of m-chloroperoxybenzoic acid (1.44 mol, 1.8 eq), and 1400 mL of dichloromethane were added to a reaction vessel and reacted at 20-30 °C for 6 h. 1000 mL of water was added, and the mixture was kept at 15-20 °C and stirred for 30 min. Dichloromethane was removed under reduced pressure, and 1000 mL of MTBE was added. The mixture was heated to 40-45 °C and stirred for 1-1.5 h. After standing and separation, the aqueous phase was collected, and 1000 mL of dichloromethane was added for extraction. The organic phase was collected, and the organic solvent was removed under reduced pressure to obtain 113 g of compound 1a, a white solid, with a yield of 75.1% and a purity of 99.7%. The yield is calculated based on compound 1. In this example, the theoretical amount of product is 0.8 mol. The yield of compound 1a = [113 / (188*0.8)]*100% = 75.1%. The yield calculation method for other embodiments is the same as in Embodiment 1.

[0090] The HPLC chromatogram of compound 1a obtained in this embodiment is as follows: Figure 1 As shown.

[0091] <Example 2>

[0092] Preparation of compound 2a

[0093] This embodiment provides a method for preparing compound 2a, and the reaction formula is as follows:

[0094]

[0095] Includes the following steps:

[0096] 2 g of compound 1a (10.6 mmol, 1.0 eq), 1.9 g of phthalimide (12.7 mmol, 1.2 eq), 3 g of p-toluenesulfonyl chloride (15.9 mmol, 1.5 eq), 4.1 g of N,N-diisopropylethylamine (31.8 mmol, 3.0 eq), and 40 mL of dichloromethane were added to a reaction vessel and reacted at 30-35 °C for 4 h. A sample was sent for HPLC analysis. The liquid phase yield of compound 2a was 78.6%, and no compound with 4-amino substitution at the pyridine ring was detected. The reaction solution was de-dichloromethane under reduced pressure, filtered to dryness under reduced pressure, and the resulting solid was slurried with 3 mL of dichloromethane for 4 h. The dichloromethane was removed under reduced pressure, filtered to dryness, and dried under vacuum at 25 °C for 2 h to give 2.07 g of compound 2a, an off-white solid with a yield of 61.5% and a purity of 98.2%.

[0097] The proton NMR spectrum of compound 2a obtained in this embodiment is as follows: Figure 2 As shown, the HPLC spectrum is as follows: Figure 3 As shown.

[0098] <Example 3>

[0099] Screening of reaction temperature

[0100] This embodiment used the following experimental steps to screen the reaction temperature, and the reaction formula is as follows:

[0101]

[0102] Includes the following steps:

[0103] 2 g of compound 1a (10.6 mmol, 1.0 eq), 1.9 g of phthalimide (12.7 mmol, 1.2 eq), 3 g of p-toluenesulfonyl chloride (15.9 mmol, 1.5 eq), 4.1 g of N,N-diisopropylethylamine (31.8 mmol, 3.0 eq) and 40 mL of dichloromethane were added to a reaction vessel and reacted at a certain temperature for 4 h. Samples were then taken and sent for HPLC analysis.

[0104] The screening results are shown in Table 1.

[0105] Table 1 Screening of reaction temperatures

[0106] Serial Number Temperature (°C) Liquid phase yield (%) 1 -10～-5 71.1 2 0-5 74.0 3 10-15 76.7 4 30-35 78.6

[0107] As shown in the table above, within the reaction temperature range of -10℃ to 35℃, the liquid phase yield increases with increasing temperature, but the increase is not significant, and the liquid phase yield is between 71.1% and 78.6%.

[0108] <Example 4>

[0109] Screening of reaction solvents

[0110] In this embodiment, the reaction solvent was screened using the following method, and the reaction formula is as follows:

[0111]

[0112] Includes the following steps:

[0113] 2 g of compound 1a (10.6 mmol, 1.0 eq), 1.9 g of phthalimide (12.7 mmol, 1.2 eq), 4 g of p-toluenesulfonyl chloride (21.2 mmol, 2 eq), 4.1 g of N,N-diisopropylethylamine (31.8 mmol, 3.0 eq) and 50 mL of solvent were added to a reaction vessel and reacted at 30℃-35℃ for 16 h. Samples were then sent for HPLC analysis.

[0114] The screening results are shown in Table 2.

[0115] Table 2 Solvent Screening

[0116] Serial Number solvent Liquid phase yield (%) 1 Toluene 33.3 2 Methyl tert-butyl ether 36.3 3 Ethyl acetate 34.4

[0117] As shown in the table above, when toluene, methyl tert-butyl ether or ethyl acetate are used as solvents, even if the amount of p-toluenesulfonyl chloride is increased to 2 eq and the reaction time is extended to 16 h, the liquid phase yield of compound 2a is only about 30%-40%.

[0118] <Example 5>

[0119] Screening of Lewis acids

[0120] This embodiment used the following method to screen Lewis acids, with the reaction formula as follows:

[0121]

[0122] Includes the following steps:

[0123] 2 g of compound 1a (10.6 mmol, 1.0 eq), phthalimide, Lewis acid, 4.1 g of N,N-diisopropylethylamine (31.8 mmol, 3.0 eq) and 50 mL of dichloromethane were added to a reaction vessel and reacted at 0-5 °C for 4 h. Samples were then sent for HPLC analysis.

[0124] The screening results are shown in Table 3.

[0125] Table 3 Screening of Lewis Acids

[0126]

[0127] As shown in the table above, the applicant unexpectedly discovered that the reaction could not proceed when an excess of phthalimide was used in the reaction, especially when the amount of phthalimide was greater than 1 eq or more of Lewis acid.

[0128] The reaction proceeds smoothly when the amount of Lewis acid is greater than that of phthalimide, especially when p-toluenesulfonyl chloride is chosen as the Lewis acid.

[0129] <Example 6>

[0130] Screening of organic bases

[0131] In this embodiment, the following method was used to screen organic bases, and the reaction formula is as follows:

[0132]

[0133] Includes the following steps:

[0134] 2 g of compound 1a (10.6 mmol, 1.0 eq), 1.9 g of phthalimide (12.7 mmol, 1.2 eq), 4 g of p-toluenesulfonyl chloride (21.2 mmol, 2 eq), triethylamine, and 50 mL of dichloromethane were added to a reaction vessel and reacted at 10 °C–20 °C for 16 h. Samples were then sent for HPLC analysis.

[0135] The screening results are shown in Table 4.

[0136] Table 4 Screening of organic bases

[0137] Serial Number Dosage of organic base (eq) Liquid phase yield (%) 1 2 42.6 2 3 41.2

[0138] As shown in the table above, the reaction can proceed smoothly when triethylamine is used as a base reagent, but the yield is low.

[0139] <Example 7>

[0140] Preparation of compound 3a

[0141] This embodiment provides a method for preparing compound 3a, and the reaction formula is as follows:

[0142]

[0143] Includes the following steps:

[0144] 50 g of compound 2a (0.16 mol, 1.0 eq), 16 g of hydrazine hydrate (0.32 mol, 2 eq), 50 mL of ethanol and 250 mL of water were added to a reaction vessel and reacted at 80 °C for 4 h. After dilution with 100 mL of dichloromethane, the mixture was extracted, and the organic phase was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 24.5 g of compound 3a, with a yield of 83.1%.

[0145] <Comparative Example>

[0146] A method for preparing 2-aminopyridine compounds

[0147] This comparative example provides a method for preparing 2-aminopyridine compounds, and the reaction formula is as follows:

[0148]

[0149] Includes the following steps:

[0150] 14 g of compound 4a (74.5 mmol, 1.0 eq), 38.1 g of tert-butylamine (521.5 mmol, 7.0 eq), 147.1 g of trifluoromethanesulfonic anhydride (521.5 mmol, 7.0 eq) and 140 mL of dichloromethane were added to a reaction vessel and reacted at -25 °C for 4 h. The results were analyzed by HPLC, and the liquid phase yield of compound 5a was 28.6%.

[0151] The role and effect of the embodiments

[0152] The method for introducing an acyl-protected amino group at the α-position of pyridine according to the above embodiments is effective because imide compounds exhibit unusual reactivity in the reaction when Lewis acids, represented by sulfonyl halides or sulfonic anhydrides, are used as catalysts. This allows for the introduction of an acyl-protected amino group at the α-position of pyridine with high selectivity and high yield in a short reaction time.

[0153] Furthermore, this application selects dichloromethane as the solvent, which can achieve a higher liquid phase yield compared to other solvents;

[0154] Furthermore, this application selected p-toluenesulfonyl chloride as a Lewis acid, which resulted in a better reaction yield than when p-toluenesulfonic anhydride was used;

[0155] Furthermore, this application selects N,N-diisopropylethylamine as the organic base, which can achieve a better yield.

[0156] The applicant declares that the present invention illustrates the method for introducing an acyl-protected amino group at the α-position of pyridine through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0157] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0158] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for introducing an acyl-protected amino group at the α-position of a pyridine, characterized in that, The reaction formula is as follows: In the formula, R1 is a halogen, and R2 and R3 are independently selected from alkyl or H. The compound 2 is The method includes the following steps: Compound 1, Compound 2, a Lewis acid, a base reagent, and a solvent are mixed and reacted to obtain Compound 3; the Lewis acid is a sulfonyl halide compound. The sulfonyl halide compound is p-toluenesulfonyl chloride. The alkaline reagent is N,N-diisopropylethylamine. The solvent is dichloromethane. The molar amount of the Lewis acid minus the molar amount of compound 2 is greater than or equal to 0.

2. The method for introducing an acyl-protected amino group at the α-position of pyridine according to claim 1, characterized in that: in, The molar ratio of compound 1 to compound 2 is 1:(1-1.5).

3. The method for introducing an acyl-protected amino group at the α-position of pyridine according to claim 1, characterized in that: in, The molar ratio of compound 1 to the Lewis acid is 1:(1.2-2.0).

4. The method for introducing an acyl-protected amino group at the α-position of pyridine according to claim 1, characterized in that: in, The molar ratio of compound 1 to the base reagent is 1:(1-3).

5. The method for introducing an acyl-protected amino group at the α-position of pyridine according to claim 1, characterized in that: in, The reaction temperature is -10℃ to 35℃.

6. The method for introducing an acyl-protected amino group at the α-position of pyridine according to claim 1, characterized in that: in, The mass-to-volume ratio of compound 1 to the solvent is 1 g:(15-25) mL.

7. A method for preparing a 2-aminopyridine compound, characterized in that, Includes the following steps: Step 1: Using the method described in any one of claims 1-6, an amino group with acyl protection is introduced at the α-position of pyridine to obtain compound 3; Step 2: Compound 3 reacts with a deacylation reagent to obtain compound 4. Compound 4 is 8. The method for preparing 2-aminopyridine compounds according to claim 7, characterized in that: in, The deacylation reagent is selected from any one or more of hydrazine hydrate, NH3, and borohydrides; And / or, the molar ratio of compound 3 to the deacylated reagent is 1:(1-3).

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