阅读说明：本技术 一种2-噁唑甲胺杂环化合物的制备方法 (Preparation method of 2-oxazole methylamine heterocyclic compound ) 是由 海龙 姜苏 刘玉强 凌青 徐久振 于 2019-10-25 设计创作，主要内容包括：本发明涉及一种2-噁唑甲胺杂环化合物的制备方法,包括以下步骤：将1H-1,2,3-三氮唑与氯乙酰氯在DIPEA作用下进行反应,并加热转化为2-氯甲基噁唑；生成物分批加入到亚氨二甲酸二叔丁酯与氢化钠的反应体系中,形成2-[(二叔丁氧羰基氨基)甲基]噁唑；产物溶解于氯化氢甲醇溶液中,反应完全,浓缩后加入甲基叔丁醚,过滤干燥,即得。本发明提供了一条有效制备2-噁唑甲胺杂环化合物的工艺路线方法。(The invention relates to a preparation method of a 2-oxazole methylamine heterocyclic compound, which comprises the following steps: reacting 1H-1,2, 3-triazole with chloroacetyl chloride under the action of DIPEA, and heating to convert into 2-chloromethyl oxazole; adding the resultant into a reaction system of di-tert-butyl imidodicarboxylate and sodium hydride in batches to form 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole; dissolving the product in a hydrogen chloride methanol solution, reacting completely, concentrating, adding methyl tertiary butyl ether, filtering and drying to obtain the product. The invention provides a process route method for effectively preparing 2-oxazole methylamine heterocyclic compounds.)

1. The preparation method of the 2-oxazole methylamine heterocyclic compound is characterized by comprising the following steps:

step 1: dissolving 1H-1,2, 3-triazole and DIPEA in a dry chloroform solvent, cooling to below 10 ℃, dropwise adding chloroacetyl chloride, and naturally heating to room temperature after the reaction is finished, and stirring for reaction for 8-24 hours; adding ice water to quench the reaction, separating and extracting, drying an organic layer and concentrating; dissolving the concentrate in sulfolane, stirring the system at 80 ℃ for reaction for 9-10 h, heating to 100 ℃ for reaction for 4-5 h, heating the system to 120 ℃, stirring for reaction for 1-2 h, naturally cooling, and distilling the obtained mixture under reduced pressure to obtain 2-chloromethyl oxazole;

step 2: dissolving sodium hydride in anhydrous tetrahydrofuran, cooling to 0-5 ℃, slowly dropwise adding a tetrahydrofuran solution of di-tert-butyl imidodicarboxylate, and stirring and reacting at room temperature for 1-3 h; then adding the 2-chloromethyl oxazole prepared in the step 1, stirring the mixture to react for 3-5 h, quenching the mixture with ice water to react, extracting with ethyl acetate, mixing organic layers, drying and concentrating to obtain 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole;

and step 3: and (3) dissolving the 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole prepared in the step (2) in 3-4M hydrogen chloride methanol solution, stirring at room temperature for 24-36 h for reaction, concentrating the system to one third of volume under reduced pressure after the reaction is completed, adding methyl tert-butyl ether, continuously stirring for 0.5-2 h under ice bath, filtering and drying to obtain 2-oxazole methylamine hydrochloride, namely the 2-oxazole methylamine heterocyclic compound.

2. The preparation method of the 2-oxazole methylamine heterocyclic compound according to claim 1, wherein in the step 1, the mass ratio of trichloromethane to 1H-1,2, 3-triazole is (15-20): 1.

3. the method for preparing 2-oxazole methylamine heterocyclic compound according to claim 1, wherein in the step 1, the molar ratio of 1H-1,2, 3-triazole, chloroacetyl chloride and DIPEA is 1: 1: (1-1.2).

4. The preparation method of the 2-oxazole methylamine heterocyclic compound according to claim 1, wherein in the step 1, the mass ratio of sulfolane to 1H-1,2, 3-triazole is (8-10): 1.

5. the method for preparing a 2-oxazolylmethylamine heterocyclic compound according to claim 1, wherein in the step 1, the degree of vacuum of reduced pressure distillation is 25 to 40 mmHg.

6. The method for preparing a 2-oxazolylmethylamine heterocyclic compound according to claim 1, wherein in step 2, the mass ratio of tetrahydrofuran to sodium hydride is (15 to 20): 1.

7. the process for preparing 2-oxazolylmethylamine heterocyclic compound according to claim 1, wherein in step 2, the molar ratio of di-tert-butyl imidodicarboxylate, 2-chloromethyloxazole and sodium hydride is 1: 1: 1.

8. the method for preparing a 2-oxazolylmethylamine heterocyclic compound according to claim 1, wherein in step 3, the mass ratio of the methanolic hydrogen chloride solution to 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole is (3 to 5): 1.

9. the method for preparing a 2-oxazolylmethylamine heterocyclic compound according to claim 1, wherein in step 3, the mass ratio of methyl-tert-butyl ether to 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole is (5 to 8): 1.

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a process method of a nitrogen-oxygen heterocyclic compound.

Background

The nitrogen-oxygen heterocyclic compound has a cyclic structure, and atoms on the ring contain a nitrogen atom and an oxygen atom in addition to a carbon atom. The nitrogen-oxygen heterocyclic compound is an important organic heterocyclic compound, and the special heterocyclic structure of the compound is matched with the spatial structure of different biological macromolecules in a living body, so that the compound can possibly generate unique biological activity and even pharmacological effect. The nitrogen oxygen heterocyclic unit, especially the 2-oxazole methylamine heterocycle is also an important unit structure for constructing complex active molecules, and has very important application value in the fields of biology, medicine, pesticide, materials and the like.

The J.Med.chem.2010,53, 5620-5628 of the American chemical society pharmaceutical chemistry discloses an imidazo [1,2-a ] pyrimidine bioactive molecule (1) containing a 2-oxazole methylamine heterocyclic unit, which has strong inhibitory activity and obvious selectivity on dipeptidyl peptidase-4 and has wide prospects in the aspect of developing drugs for treating type 2 diabetes. European patent EP2202228A1 discloses a pyrimidine derivative micromolecule compound (2) containing 2-oxazole methylamine heterocyclic unit, the compound shows good inhibition activity on renin target, and is expected to be developed into a high-efficiency renin inhibitor for development of treatment medicines for hypertension diseases, organ injury caused by hypertension and the like.

In addition, the journal of the chemical society of chemistry of the U.S. J.Med.chem.2014,57, 1276-1288 reports that the pyrrolidine derivative active small molecule (3) containing the 2-oxazole methylamine heterocyclic unit shows strong direct inhibition effect on mycobacterium tuberculosis and can be used for research and development of drugs for treating tuberculosis. Recently, world patent WO2018/212774A discloses Ras protein and a target point regulator related to upstream and downstream signal transduction pathways thereof, the quinazoline small molecule (4) regulator also contains a 2-oxazole methylamine heterocyclic unit, can effectively regulate Ras signal transduction, and provides hope and possibility for development and research of new-generation antitumor drugs.

At present, 2-oxazole methylamine heterocyclic structural compounds show more and more important functions and effects in the field of biomedicine. The intensive research and development of an effective process for preparing 2-oxazole methylamine heterocyclic compounds are urgent.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of the prior art by research and provide a preparation method of a 2-oxazole methylamine heterocyclic compound.

In order to solve the technical problem, the invention provides a preparation method of a 2-oxazole methylamine heterocyclic compound, which is characterized by comprising the following steps:

step 1: dissolving 1H-1,2, 3-triazole and DIPEA in a dry chloroform solvent, cooling to below 10 ℃, dropwise adding chloroacetyl chloride, and naturally heating to room temperature after the reaction is finished, and stirring for reaction for 8-24 hours; adding ice water to quench the reaction, separating and extracting, drying an organic layer and concentrating; dissolving the concentrate in sulfolane, stirring the system at 80 ℃ for reaction for 9-10 h, heating to 100 ℃ for reaction for 4-5 h, heating the system to 120 ℃, stirring for reaction for 1-2 h, naturally cooling, and distilling the obtained mixture under reduced pressure to obtain 2-chloromethyl oxazole;

step 2: dissolving sodium hydride in anhydrous tetrahydrofuran, cooling to 0-5 ℃, slowly dropwise adding a tetrahydrofuran solution of di-tert-butyl imidodicarboxylate, and stirring and reacting at room temperature for 1-3 h; then adding the 2-chloromethyl oxazole prepared in the step 1, stirring the mixture to react for 3-5 h, quenching the mixture with ice water to react, extracting with ethyl acetate, mixing organic layers, drying and concentrating to obtain 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole;

and step 3: and (3) dissolving the 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole prepared in the step (2) in 3-4M hydrogen chloride methanol solution, stirring at room temperature for 24-36 h for reaction, concentrating the system to one third of volume under reduced pressure after the reaction is completed, adding methyl tert-butyl ether, continuously stirring for 0.5-2 h under ice bath, filtering and drying to obtain 2-oxazole methylamine hydrochloride, namely the 2-oxazole methylamine heterocyclic compound.

Preferably, in the step 1, the mass ratio of the trichloromethane to the 1H-1,2, 3-triazole is (15-20): 1.

preferably, in the step 1, the molar ratio of 1H-1,2, 3-triazole to chloracetyl chloride to DIPEA is 1: 1: (1-1.2).

Preferably, in the step 1, the mass ratio of the sulfolane to the 1H-1,2, 3-triazole is (8-10): 1.

preferably, in the step 1, the vacuum degree of the reduced pressure distillation is 25-40 mmHg.

Preferably, in the step 2, the mass ratio of tetrahydrofuran to sodium hydride is (15-20): 1.

preferably, in the step 2, the molar ratio of the di-tert-butyl imidodicarboxylate, the 2-chloromethyl oxazole and the sodium hydride is 1: 1: 1.

preferably, in the step 3, the mass ratio of the hydrogen chloride methanol solution to the 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole is (3-5): 1.

preferably, in the step 3, the mass ratio of methyl tertiary butyl ether to 2- [ (di-tert-butoxycarbonylamino) methyl ] oxazole is (5-8): 1.

compared with the prior art, the invention has the beneficial effects that:

(1) the invention provides a process route method for effectively preparing 2-oxazole methylamine heterocyclic compounds, which utilizes 1H-1,2, 3-triazole and chloracetyl chloride as starting raw materials to complete the construction of target molecules through heterocyclic rearrangement reaction conversion.

(2) The process route method of the oxazole methylamine heterocycle provided by the invention can be used for preparing the 2-oxazole methylamine heterocycle and the derivatives thereof, has the technical characteristics of high yield, strong applicability and the like, and can be applied to different fields of chemical synthesis, pharmaceutical research and the like.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.