阅读说明：本技术 一种（3-环丙基吡啶-2-基）甲胺的合成方法 (Synthesis method of (3-cyclopropylpyridine-2-yl) methylamine ) 是由 史建云 许义波 戴红升 于 2020-05-19 设计创作，主要内容包括：本发明属于医药中间体技术领域,具体涉及一种(3-环丙基吡啶-2-基)甲胺的合成方法。本发明首次提供了一种(3-环丙基吡啶-2-基)甲胺的合成方法,为(3-环丙基吡啶-2-基)甲胺的合成方法提供了合成路线,且(3-环丙基吡啶-2-基)甲胺的合成方法路线简短,设计合理,且操作简单,易于控制,同时本发明所得到的产物收率较高。(The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of (3-cyclopropylpyridin-2-yl) methylamine. The invention provides a synthetic method of (3-cyclopropylpyridine-2-yl) methylamine for the first time, provides a synthetic route for the synthetic method of (3-cyclopropylpyridine-2-yl) methylamine, and the synthetic method of (3-cyclopropylpyridine-2-yl) methylamine is short in route, reasonable in design, simple to operate and easy to control, and meanwhile, the yield of the obtained product is high.)

1. A method for synthesizing (3-cyclopropyl pyridine-2-yl) methylamine is characterized by comprising the following steps: the synthesis method comprises the following steps:

(1) dissolving 3-bromopyridine in an organic solvent, adding an oxidant at the temperature of minus 10-0 ℃, and carrying out oxidation reaction to obtain a compound A

；

(2) Dissolving the compound A in acetonitrile, carrying out cyanation reaction with trimethylsilyl cyanide and triethylamine under the protection of nitrogen at 70-80 ℃ to obtain a compound B

；

(3) Dissolving the compound B in toluene, sequentially adding cyclopropylboronic acid, potassium phosphate, tricyclohexylphosphine, water and palladium acetate under the protection of nitrogen, and performing coupling reaction at 100-105 ℃ to obtain a compound C

；

(4) Dissolving the compound C in methanol, adding Raney nickel and ammonia water in hydrogen atmosphere, and carrying out reduction reaction to obtain (3-cyclopropyl pyridine-2-yl) methylamine

。

2. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine as claimed in claim 1, wherein in step (1), the organic solvent is dichloromethane, the oxidant is m-chloroperoxybenzoic acid, and the mass ratio of the strong oxidant to 3-bromopyridine is 2-4: 1.

3. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine as claimed in claim 1, wherein the mass ratio of compound a, trimethylsilyl cyanide and triethylamine in step (2) is 1: 1.5-2: 1-1.4.

4. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine as claimed in claim 1, wherein the mass ratio of the compound B, cyclopropylboronic acid, tricyclohexylphosphine, potassium phosphate and palladium acetate in step (3) is 9-12: 5.5-7: 1.8-3: 38-50: 0.5-1.2, and the volume ratio of water to methanol is 1-5: 100.

5. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine as claimed in claim 1, wherein the mass ratio of raney nickel to compound C in step (4) is 1:2 to 5, and the volume ratio of ammonia water to methanol is 1:5 to 8.

Technical Field

The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of (3-cyclopropylpyridin-2-yl) methylamine.

Background

The compound (3-cyclopropyl pyridine-2-yl) methylamine and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of (3-cyclopropyl pyridine-2-yl) methylamine is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.

Disclosure of Invention

The technical problems to be solved by the invention are as follows: in view of the above problems, a method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine is provided.

In order to solve the technical problems, the invention adopts the following technical scheme:

a synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine comprises the following steps:

(1) dissolving 3-bromopyridine in an organic solvent, adding an oxidant at the temperature of minus 10-0 ℃, and carrying out oxidation reaction to obtain a compound A

；

(2) Dissolving the compound A in acetonitrile, carrying out cyanation reaction with trimethylsilyl cyanide and triethylamine under the protection of nitrogen at 70-80 ℃ to obtain a compound B

；

(3) Dissolving the compound B in toluene, sequentially adding cyclopropylboronic acid, potassium phosphate, tricyclohexylphosphine, water and palladium acetate under the protection of nitrogen, and performing coupling reaction at 100-105 ℃ to obtain a compound C

；

(4) Dissolving the compound C in methanol, adding Raney nickel and ammonia water in hydrogen atmosphere, and carrying out reduction reaction to obtain (3-cyclopropyl pyridine-2-yl) methylamine

。

Meanwhile, the chemical equation of the synthesis method is as follows:

preferably, in the step (1), the organic solvent is dichloromethane, the oxidant is m-chloroperoxybenzoic acid, and the mass ratio of the strong oxidant to the 3-bromopyridine is 2-4: 1.

Preferably, the mass ratio of the compound A, the trimethylsilyl cyanide and the triethylamine in the step (2) is 1: 1.5-2: 1-1.4.

Preferably, in the step (3), the mass ratio of the compound B, the cyclopropylboronic acid, the tricyclohexylphosphine, the potassium phosphate and the palladium acetate is 9-12: 5.5-7: 1.8-3: 38-50: 0.5-1.2, and the volume ratio of water to methanol is 1-5: 100.

Preferably, the mass ratio of the raney nickel to the compound C in the step (4) is 1: 2-5, and the volume ratio of the ammonia water to the methanol is 1: 5-8.

Compared with other methods, the method has the beneficial technical effects that:

(1) the invention provides a synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine for the first time, and provides a synthetic route for the synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine;

(2) the synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine provided by the invention is short in route, reasonable in design, simple to operate and easy to control;

(3) the product obtained by the method has high yield.

Detailed Description

The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.

A synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine comprises the following steps:

(1) dissolving 3-bromopyridine in an organic solvent, adding an oxidant at the temperature of-10-0 ℃, and carrying out an oxidation reaction to obtain a compound A;

(2) dissolving the compound A in acetonitrile, carrying out cyanation reaction with trimethylsilyl cyanide and triethylamine at 70-80 ℃ under the protection of nitrogen to obtain a compound B;

(3) dissolving the compound B in toluene, sequentially adding cyclopropylboronic acid, potassium phosphate, tricyclohexylphosphine, water and palladium acetate under the protection of nitrogen, and performing coupling reaction at 100-105 ℃ to obtain a compound C;

(4) and dissolving the compound C in methanol, adding Raney nickel and ammonia water in a hydrogen atmosphere, and carrying out reduction reaction to obtain (3-cyclopropyl pyridine-2-yl) methylamine.

In the step (1), the organic solvent is dichloromethane, the oxidant is m-chloroperoxybenzoic acid, and the mass ratio of the strong oxidant to the 3-bromopyridine is 2-4: 1.

In the step (2), the mass ratio of the compound A to the trimethylsilyl cyanide to the triethylamine is 1: 1.5-2: 1-1.4.

In the step (3), the mass ratio of the compound B, the cyclopropylboronic acid, the tricyclohexylphosphine, the potassium phosphate and the palladium acetate is 9-12: 5.5-7: 1.8-3: 38-50: 0.5-1.2, and the volume ratio of water to methanol is 1-5: 100.

In the step (4), the mass ratio of the Raney nickel to the compound C is 1: 2-5, and the volume ratio of the ammonia water to the methanol is 1: 5-8.