Preparation method of N-alkyl-3-alkylpyridine-2-amine compound

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of an N-alkyl-3-alkylpyridine-2-amine compound. The preparation method comprises the following steps: reacting a compound II with R2NH2 in an organic solvent in the presence of organic alkali and sulfonyl chloride compounds to obtain a compound I; the organic base is not primary amine or secondary amine. According to the preparation method, the product N-alkyl-3-alkylpyridine-2-amine compound obtained by introducing amido to the alpha position on one side with relatively large steric hindrance can be selectively obtained, and the yield is up to 60% or above and is improved by 30% or above compared with the prior art. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly relates to a method for preparing N-alkyl-3-alkylpyridin-2-amine compounds. Background Art

[0002] N-alkyl-3-alkylpyridin-2-amine compounds are important pharmaceutical intermediates. For example, N-tert-butyl-3-methylpyridin-2-amine can not only be used to prepare AM2 receptor inhibitors for the treatment of proliferative diseases, etc. (WO2020099882A1); but also can be used to prepare CGRP receptor antagonists for the treatment of diseases such as migraine (WO2011005731A2).

[0003] In the prior art, 3-alkylpyridine oxides are commonly used as raw materials to prepare N-alkyl-3-alkylpyridin-2-amine compounds.

[0004] Method 1: Phosphonium Salt-Promoted C2-H Functionalization of Heterocyclic N-Oxides (Org. Lett. 2023, 25, 9181-9185) discloses that pyridine-N-oxide can introduce an amino group at the α-position of pyridine under the action of DIEA, AgBF4 and (2-MeOPh)3PI2. However, when there is a non-hydrogen substituent at one of the β-positions of pyridine, the amino group introduced by this method tends to enter the side with less steric hindrance. For example, when using 3-methylpyridine-N-oxide as the starting material, under the above reaction conditions, N-tert-butyl-5-methylpyridin-2-amine is obtained in a yield of 53%, while the yield of the product N-tert-butyl-3-methylpyridin-2-amine substituted on the side with larger steric hindrance is only 20%.

[0005]

[0006] Method 2: General and Mild Preparation of 2-Aminopyridines (Org. Lett., Vol. 12, No. 22, 2010, 5254-5257) discloses that pyridine-N-oxide can also introduce an amino group at the α-position of pyridine under the action of PyBroP and iPr2EtN. However, when there is a non-hydrogen substituent at one of the β-positions of pyridine, this method shows almost no selectivity. For example, when 3-methylpyridine-N-oxide is selected as the starting material, under the above reaction conditions, an equimolar mixture of N-cyclohexyl-5-methylpyridin-2-amine and N-cyclohexyl-3-methylpyridin-2-amine is obtained in a yield of 64%, without showing any selectivity.

[0007]

[0008] As can be seen from the above, in the prior art, there is a lack of a method for introducing an amino group at the more sterically hindered side of the α-position of pyridine with high selectivity and high yield, and improving its yield remains a technical problem that needs to be urgently solved by scientific researchers. Summary of the Invention

[0009] The present invention is made to solve the above problems, and its purpose is to provide a method for preparing N-alkyl-3-alkylpyridine-2-amine compounds. Using 3-alkylpyridine oxide as a raw material, under the reaction conditions of the present invention, an amino group can be introduced at the α-position on the more sterically hindered side with a yield of more than 60%, that is, N-alkyl-3-alkylpyridine-2-amine compounds can be prepared with a yield of more than 60%.

[0010] The present invention provides a method for preparing N-alkyl-3-alkylpyridine-2-amine compounds, which includes the following steps: in an organic solvent, in the presence of an organic base and a sulfonyl chloride compound, compound II and R 2 NH2 react to obtain compound I;

[0011]

[0012] wherein, R 1 is C 1-6 alkyl;

[0013] R 2 is C 1-6 alkyl, C 4-10 cycloalkyl or C 6-10 aryl;

[0014] The organic base is not a primary amine or a secondary amine.

[0015] In a certain embodiment, in R 1 the C 1-6 alkyl is preferably C 1-3 alkyl, such as methyl, ethyl, propyl or isopropyl.

[0016] In a certain embodiment, in R 2 the C 1-6 alkyl is preferably C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0017] In a certain embodiment, in R 2 the C 4-10 cycloalkyl is preferably cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.

[0018] In a certain embodiment, in R 2 the C6-10 The aryl group is preferably a phenyl group or a naphthyl group.

[0019] In one embodiment, the organic solvent is a mixed solvent of toluene and dichloromethane.

[0020] In one embodiment, in the organic solvent, the volume ratio of dichloromethane to toluene can be 1:(1 - 4), preferably 1:(2 - 3), such as 2:5.

[0021] In one embodiment, the organic base can be a tertiary amine organic base, preferably N,N - diisopropylethylamine, triethylamine or N - methylmorpholine.

[0022] In one embodiment, the sulfonyl chloride compound is preferably p - toluenesulfonyl chloride or benzenesulfonyl chloride.

[0023] In one embodiment, the 2 The molar ratio of R

[0024] In one embodiment, the molar ratio of the sulfonyl chloride compound to Compound II can be (2 - 5):1, preferably (3 - 4):1.

[0025] In one embodiment, the molar ratio of the organic base to Compound II can be (2 - 5):1, preferably (3 - 4):1.

[0026] In one embodiment, the volume - mass ratio of the organic solvent to Compound II can be (10 - 100) mL:1 g, preferably (20 - 50) mL:1 g.

[0027] In one embodiment, the reaction temperature of the reaction can be 0 - 30°C.

[0028] In one embodiment, the reaction time of the reaction can be 12 - 24 h.

[0029] In one embodiment, Compound II is Compound I is R 2 R

[0030] In one embodiment, the method for preparing the N - alkyl - 3 - alkylpyridin - 2 - amine compound includes the following steps: in an organic solvent, in the presence of an organic base and a sulfonyl chloride compound, 3 - methylpyridine N - oxide reacts with tert - butylamine to obtain N - tert - butyl - 3 - methylpyridin - 2 - amine; the organic base is not a primary amine or a secondary amine.

[0031]

[0032] In one embodiment, the method for preparing the N-alkyl-3-alkylpyridin-2-amine compound comprises the following steps: in an organic solvent, in the presence of N,N-diisopropylethylamine and p-toluenesulfonyl chloride, 3-picoline N-oxide reacts with tert-butylamine to obtain N-tert-butyl-3-methylpyridin-2-amine; the organic solvent is a mixed solvent of toluene and dichloromethane.

[0033] In one embodiment, the method for preparing the N-alkyl-3-alkylpyridin-2-amine compound comprises the following steps: in a mixed solvent of toluene and dichloromethane, in the presence of N,N-diisopropylethylamine and p-toluenesulfonyl chloride, 3-picoline N-oxide reacts with tert-butylamine at 0-30 °C for 12-24 h, after the reaction is completed, the solvent is removed, and N-tert-butyl-3-methylpyridin-2-amine is obtained by column chromatography.

[0034] In one embodiment, the method for preparing the N-alkyl-3-alkylpyridin-2-amine compound comprises the following steps: dissolving 3-picoline N-oxide, tert-butylamine and N,N-diisopropylethylamine in a mixed solvent composed of toluene and dichloromethane, adding a toluene / dichloromethane solution of p-toluenesulfonyl chloride at 0-10 °C, reacting at 0-30 °C for 12-24 h, after the reaction is completed, the solvent is removed, and column chromatography is carried out to obtain N-tert-butyl-3-methylpyridin-2-amine.

[0035] Functions and effects of the invention

[0036] The disclosed method for preparing an N-alkyl-3-alkylpyridin-2-amine compound uses 3-alkylpyridine N-oxide as a raw material. Under the reaction conditions of the present invention, the product N-alkyl-3-alkylpyridin-2-amine compound with an amino group introduced at the α-position on the side with larger steric hindrance can be selectively obtained, and the yield is as high as over 60%, which is increased by over 30% compared with the prior art. Detailed implementation manners

[0037] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be specifically described below in conjunction with embodiments.

[0038] In the following embodiments, unless otherwise specified, each raw material is a commercially available product.

[0039] Example 1

[0040]

[0041] Dissolve 9.3 g of 3-methylpyridine (100 mmol, 1.0 eq) in 93 mL of isopropyl acetate. Add 28.33 g of m-chloroperoxybenzoic acid (164 mmol, 1.64 eq) portionwise at 10 °C. Stir at 10 °C for 0.5 h, then raise the temperature to room temperature and stir for 1 h. Remove the solvent by distillation under reduced pressure. 8.7 g of 3-methylpyridine N-oxide with a purity of 99.1% and a yield of 79.8% is obtained by column chromatography.

[0042] Example 2

[0043]

[0044] Dissolve 3.0 g of 3-methylpyridine N-oxide (27.5 mmol, 1.0 eq), 8.5 g of tert-butylamine (116 mmol, 4.2 eq) and 10.7 g of N,N-diisopropylethylamine (82.5 mmol, 3.0 eq) in a mixed solvent of 45 mL of toluene and dichloromethane (V / V = 5:2). Dissolve 17.3 g of p-toluenesulfonyl chloride (90.8 mmol, 3.3 eq) in a mixed solvent of 30 mL of toluene and dichloromethane (V / V = 5:2). Slowly add it dropwise to the above system at 0 °C. After the addition is complete, raise the temperature to room temperature and stir for 16 h. Take a small amount of the reaction solution for LCMS test. The content ratio of N-(tert-butyl)-3-methylpyridin-2-amine to N-(tert-butyl)-5-methylpyridin-2-amine is 3.5:1. After the reaction is completed, remove the solvent by distillation. 3.2 g of N-(tert-butyl)-3-methylpyridin-2-amine with a purity of 99.5% and a yield of 70.9% is obtained by column chromatography.

[0045] Example 3

[0046]

[0047] Dissolve 1.0 g of 3-methylpyridine N-oxide (9.2 mmol, 1.0 eq), 4.8 g of tert-butylamine (66.2 mmol, 7.2 eq) and 3.6 g of N,N-diisopropylethylamine (27.6 mmol, 3.0 eq) in a mixed solvent of 15 mL of toluene and dichloromethane (V / V = 5:2). Dissolve 5.8 g of p-toluenesulfonyl chloride (30.4 mmol, 3.3 eq) in a mixed solvent of 10 mL of toluene and dichloromethane (V / V = 5:2). Slowly add it dropwise to the above system at 0 °C. After the addition is complete, raise the temperature to room temperature and stir for 16 h. After the reaction is completed, remove the solvent by distillation. 1.03 g of N-(tert-butyl)-3-methylpyridin-2-amine with a purity of 99.2% and a yield of 68.1% is obtained by column chromatography.

[0048] Example 4

[0049]

[0050] Dissolve 1.0 g of 3 - methylpyridine N - oxide (9.2 mmol, 1.0 eq), 2.8 g of tert - butylamine (38.3 mmol, 4.2 eq) and 3.6 g of N,N - diisopropylethylamine (27.9 mmol, 3.0 eq) in 15 mL of dichloromethane. Dissolve 5.8 g of p - toluenesulfonyl chloride (30.4 mmol, 3.3 eq) in 10 mL of dichloromethane and slowly add it dropwise to the above - mentioned system at 0 °C. After the addition is complete, raise the temperature to room temperature and stir for 16 hours. Take a small amount of the reaction solution for LCMS test. The content ratio of N - (tert - butyl) - 3 - methylpyridin - 2 - amine to N - (tert - butyl) - 5 - methylpyridin - 2 - amine is 2.1:1. After the reaction is completed, distill off the solvent and obtain 0.92 g of N - (tert - butyl) - 3 - methylpyridin - 2 - amine by column chromatography, with a purity of 99.0% and a yield of 60.9%.

[0051] Comparative Example 1

[0052]

[0053] Dissolve 1.0 g of 3 - methylpyridine N - oxide (9.2 mmol, 1.0 eq), 841 mg of tert - butylamine (11.5 mmol, 1.25 eq), 4.5 g of N,N - diisopropylethylamine (34.5 mmol, 3.75 eq) and 16.1 g of tripyrrolidinophosphonium bromide hexafluorophosphate (34.5 mmol, 3.75 eq) in 20 mL of dichloromethane. Slowly add it dropwise to the above - mentioned system at 0 °C. After the addition is complete, raise the temperature to room temperature and stir for 16 hours. After the reaction is completed, distill off the solvent and obtain 90.9 mg of N - (tert - butyl) - 3 - methylpyridin - 2 - amine by column chromatography, with a purity of 98.5% and a yield of 6.0%.

[0054] The preparation method of an N - hydrocarbyl - 3 - alkylpyridin - 2 - amine compound involved in the above - mentioned examples uses 3 - alkylpyridine N - oxide as a raw material, and can selectively obtain a product with an amino group introduced at the α - position on the side with larger steric hindrance, the N - hydrocarbyl - 3 - alkylpyridin - 2 - amine compound, and the yield is as high as over 60%, which is more than 30% higher than that of the prior art.

[0055] Furthermore, since a mixed solvent composed of toluene and dichloromethane is selected in Examples 2 - 3, it can improve the reaction selectivity to a certain extent to obtain more target products and improve the production efficiency. Specifically, when toluene and dichloromethane are used as the reaction solvent, the ratio of the target product (i.e., N - (tert - butyl) - 3 - methylpyridin - 2 - amine) to the by - product (i.e., N - (tert - butyl) - 5 - methylpyridin - 2 - amine) can reach 3.5:1, while in Example 4, dichloromethane is used alone, and the ratio of the target product to the by - product is 2.1:1.

[0056] The above embodiments are preferred examples of the present invention and are not used to limit the protection scope of the present invention.

Claims

1. A method for preparing N-alkyl-3-alkylpyridin-2-amine compounds, characterized in that, It includes the following steps: in an organic solvent, in the presence of an organic base and a sulfonyl chloride compound, compound II reacts with R 2 NH2 to obtain compound I; Among them, R 1 is C 1-6 alkyl; R 2 is C 1-6 alkyl, C 4-10 cycloalkyl or C 6-10 aryl; The organic base is not a primary amine or a secondary amine.

2. The preparation method according to claim 1, characterized in that, The organic solvent is a mixed solvent of dichloromethane and toluene.

3. The preparation method according to claim 2, characterized in that, In the organic solvent, the volume ratio of dichloromethane to toluene is 1:(1 - 4).

4. The preparation method according to claim 1, characterized in that, The organic base is a tertiary amine organic base.

5. The preparation method according to claim 4, characterized in that, The tertiary amine organic base is N,N - diisopropylethylamine, triethylamine or N - methylmorpholine.

6. The preparation method according to claim 1, characterized in that, The sulfonyl chloride compound is p - toluenesulfonyl chloride or benzenesulfonyl chloride.

7. The preparation method according to claim 1, characterized in that The R 2 The molar ratio of NH2 to the compound II is (1-10):

1.

8. The preparation method according to claim 1, characterized in that, The molar ratio of the sulfonyl chloride compound to Compound II is (2 - 5):

1.

9. The preparation method according to claim 1, wherein The molar ratio of the organic base to Compound II is (2 - 5):

1.

10. The preparation method according to claim 1, characterized in that, The preparation method of the N - hydrocarbyl - 3 - alkylpyridin - 2 - amine compound comprises the following steps: in an organic solvent, in the presence of an organic base and a sulfonyl chloride compound, 3 - methylpyridine N - oxide reacts with tert - butylamine to obtain N - tert - butyl - 3 - methylpyridin - 2 - amine; The organic base is not a primary amine or a secondary amine.

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