阅读说明：本技术 一种4-氯-6-环丙基嘧啶-5-胺的合成方法 (Synthesis method of 4-chloro-6-cyclopropyl pyrimidine-5-amine ) 是由 郭立涛 崔宁宁 马绍辉 陈锦春 于 2020-12-08 设计创作，主要内容包括：本发明涉及一种4-氯-6-环丙基嘧啶-5-胺的合成方法,其特征在于,所述的合成方法为：(1)在氮气氛围下,将和无水乙酸钾加入到溶剂中,在搅拌条件下氮气鼓泡除氧；(2)加入催化剂,继续氮气鼓泡除氧；(3)转氮气流保护,加热,搅拌反应,TLC显示反应完毕；(4)将反应体系降至室温,负压过滤反应液,浓缩除去溶剂,加入水,并用乙酸乙酯多次萃取,合并有机相,无水硫酸钠干燥,浓缩得粗品,粗品过硅胶柱,得4-氯-6-环丙基嘧啶-5-胺的纯品。所述合成方法操作简单,不需要严格无水无氧,大大降低了操作难度,而且环丙基硼酸可直接购买,相对廉价,稳定性好,可以长期储存。(The invention relates to a synthetic method of 4-chloro-6-cyclopropyl pyrimidine-5-amine, which is characterized by comprising the following steps: (1) under the nitrogen atmosphere, the mixture is)

1. A synthetic method of 4-chloro-6-cyclopropyl pyrimidine-5-amine is characterized by comprising the following steps:

(1) under the nitrogen atmosphere, the mixture isAnd anhydrous potassium acetate are added into the solvent, and nitrogen bubbling is carried out to remove oxygen under the stirring condition;

(2) adding a catalyst, and continuously carrying out nitrogen bubbling for deoxygenation;

(3) rotating nitrogen flow for protection, heating, stirring for reaction, and displaying the completion of the reaction by TLC;

(4) cooling the reaction system to room temperature, filtering the reaction solution under negative pressure, concentrating to remove the solvent, adding water, extracting with ethyl acetate for multiple times, combining organic phases, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and passing the crude product through a silica gel column to obtain a pure product of 4-chloro-6-cyclopropyl pyrimidine-5-amine.

2. The method for synthesizing 4-chloro-6-cyclopropylpyrimidin-5-amine according to claim 1, wherein in step (1), the solvent is a mixed solvent of dioxane and water, and the volume ratio of dioxane to water is 3: 2.

3. the method for synthesizing 4-chloro-6-cyclopropylpyrimidin-5-amine according to claim 1, wherein in step (1),the molar ratio of (A) to (B) is 1-2: 1, anhydrous potassium acetate withThe molar ratio of (a) to (b) is 8-9: 1.

4. the method for synthesizing 4-chloro-6-cyclopropylpyrimidin-5-amine according to claim 1, wherein in step (2), the catalyst is tetrakistriphenylphosphine palladium, and the tetrakistriphenylphosphine palladium is reacted with the tetrakistriphenylphosphine palladiumThe mass ratio of (1): 20.

5. the synthesis method of 4-chloro-6-cyclopropylpyrimidine-5-amine according to claim 1, wherein the heating reaction in step (3) is carried out at 50-70 ℃ and the stirring reaction is carried out for 18-20 hours.

Technical Field

The invention relates to a method for synthesizing 4-chloro-6-cyclopropyl pyrimidine-5-amine, belonging to the technical field of organic synthesis.

Background

4-chloro-6-cyclopropyl pyrimidine-5-amine and related derivatives have wide application in pharmaceutical chemistry and organic synthesis, and the synthesis method of 4-chloro-6-cyclopropyl pyrimidine-5-amine is rarely reported at present. Only WO2019/213516 reports that this compound is prepared using cyclopropyl zinc bromide:

the 4-chloro-6-cyclopropyl pyrimidine-5-amine is prepared by using cyclopropyl zinc bromide, the yield is lower than 38%, and the method has the advantages of expensive zinc reagent, difficult storage and difficult preparation, and is not suitable for industrial operation and production.

Therefore, the method for preparing the 4-chloro-6-cyclopropyl pyrimidine-5-amine by developing a synthetic method which has the advantages of easily available and cheap raw materials, proper yield and suitability for industrial production has important value.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a synthesis method of 4-chloro-6-cyclopropyl pyrimidine-5-amine, which replaces a zinc reagent which is difficult to obtain and unstable with cheap and stable cyclopropyl boric acid, and synthesizes the 4-chloro-6-cyclopropyl pyrimidine-5-amine through suzuki reaction.

The technical scheme for solving the technical problems is as follows: a synthetic method of 4-chloro-6-cyclopropyl pyrimidine-5-amine comprises the following steps:

(1) under the nitrogen atmosphere, the mixture isAnd anhydrous potassium acetate are added into the solvent, and nitrogen bubbling is carried out to remove oxygen under the stirring condition;

(2) adding a catalyst, and continuously carrying out nitrogen bubbling for deoxygenation;

(3) rotating nitrogen flow for protection, heating, stirring for reaction, and displaying the completion of the reaction by TLC;

(4) cooling the reaction system to room temperature, filtering the reaction solution under negative pressure, concentrating to remove the solvent, adding water, extracting with ethyl acetate for multiple times, combining organic phases, drying with anhydrous sodium sulfate, concentrating to obtain a crude product, and passing the crude product through a silica gel column to obtain a pure product of 4-chloro-6-cyclopropyl pyrimidine-5-amine.

Preferably, in the step (1), the solvent is a mixed solvent of dioxane and water, and the volume ratio of dioxane to water is 3: 2.

preferably, in the step (1),the molar ratio of (A) to (B) is 1-2: 1, anhydrous potassium acetate withThe molar ratio of (a) to (b) is 8-9: 1.

preferably, in the step (2), the catalyst is tetratriphenylphosphine palladium, and the tetratriphenylphosphine palladium and the palladium quaternary catalyst are mixedThe mass ratio of (1): 20.

preferably, the heating reaction temperature in the step (3) is 50-70 ℃, and the stirring reaction time is 18-20 hours.

The invention has the beneficial effects that: 1) the cost and the operation difficulty are reduced, strict water and oxygen free are not needed, and industrial amplification can be carried out; 2) the raw materials are stable and easily obtained and are relatively cheap; 3) the raw materials have low toxicity and are more environment-friendly; 4) the catalyst can be recovered and regenerated, and is green and environment-friendly.

Detailed Description

The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

Example 1

Bench scale experiment for the synthesis of 4-chloro-6-cyclopropylpyrimidin-5-amine:

dioxane (600ml), deionized water (400ml), a compound 2(20.00g, 122mmol), a compound 1(15.7g, 183mmol) and anhydrous potassium acetate (99.5g,976mmol) are put into a 2000ml glass three-neck flask in sequence, nitrogen is bubbled for deoxygenation for 15min under magnetic stirring, then tetratriphenylphosphine palladium 1g is added, and bubbling for deoxygenation is continued for 15 min. The reaction was stirred at 60 ℃ for 20h under protection of nitrogen flow and TLC indicated completion of the reaction. Then cooling to room temperature, filtering the reaction solution under negative pressure, concentrating to remove the solvent, adding 500ml of water, 500ml of 3 ethyl acetate for extraction, combining organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product. Passing the crude product through a silica gel column to obtain 17.2g of a pure 4-chloro-6-cyclopropylpyrimidine-5-amine product, wherein the yield is as follows: 83.5 percent.

The nuclear magnetic data for the 4-chloro-6-cyclopropylpyrimidin-5-amine product is as follows:

¹H NMR(400MHz,CDCl₃)δ＝8.26(1H,s)4.17(2H,br s)1.83-1.90(1H,m)1.15-1.21(2H,m)1.08-1.15(2H,m).

example 2

Kilogram scale amplification experiment for synthesis of 4-chloro-6-cyclopropylpyrimidin-5-amine:

putting dioxane (30L), deionized water (20L), a compound 2(1000g), a compound 1(785g) and anhydrous potassium acetate (5kg) into a 100L double-layer glass reaction kettle in sequence, carrying out nitrogen bubbling to remove oxygen for 2h under stirring, then adding 50g of tetratriphenylphosphine palladium, and continuing to carry out bubbling to remove oxygen for 1 h. The reaction was stirred at 60 ℃ for 20h under protection of nitrogen flow and TLC indicated completion of the reaction. Then cooling to room temperature, filtering the reaction solution under negative pressure, concentrating to remove the solvent, adding 20L of water, extracting with 10L of 3-ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product. Passing the crude product through a silica gel column to obtain 892g of a pure product, wherein the yield is as follows: 86.3 percent.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.