阅读说明：本技术 一种制备tnni3k抑制剂的方法 (Method for preparing TNNI3K inhibitor ) 是由 孟冲 艾瑶 李峰 于 2018-08-23 设计创作，主要内容包括：本发明公开了一种制备TNNI3K抑制剂的方法,其步骤为：将间溴苯磺酰胺在铱络合物催化剂和碱的参与下,加热数小时后,冷却到室温,旋干溶剂,然后通过柱分离,得到N-甲基-3-溴苯磺酰胺；将N-甲基-3-溴苯磺酰胺和氨水在CuCl催化条件下,加热数小时后,冷却到室温,加入乙酸乙酯萃取,旋干有机相溶剂,得到N-甲基-3-氨基苯磺酰胺；将6-氯嘌呤和N-甲基-3-氨基苯磺酰胺在三氟甲磺酸银存在下,微波反应,反应结束后冷却到室温,旋干溶剂,然后通过柱分离,得到目标产物。本发明采用水溶性双功能铱络合物催化剂作为反应体系的催化剂,反应在水中进行,反应条件温和,无环境污染；反应的原子经济性高。符合绿色化学的要求,具有广阔的发展前景。(The invention discloses a method for preparing a TNNI3K inhibitor, which comprises the following steps: heating m-bromobenzenesulfonamide for several hours in the presence of an iridium complex catalyst and alkali, cooling to room temperature, spin-drying the solvent, and then separating by a column to obtain N-methyl-3-bromobenzenesulfonamide; heating N-methyl-3-bromobenzenesulfonamide and ammonia water for several hours under the catalysis of CuCl, cooling to room temperature, adding ethyl acetate for extraction, and spin-drying an organic phase solvent to obtain N-methyl-3-aminobenzenesulfonamide; carrying out microwave reaction on 6-chloropurine and N-methyl-3-aminobenzenesulfonamide in the presence of silver trifluoromethanesulfonate, cooling to room temperature after the reaction is finished, spin-drying the solvent, and then separating through a column to obtain a target product. The invention adopts the water-soluble bifunctional iridium complex catalyst as the catalyst of the reaction system, the reaction is carried out in water, the reaction condition is mild, and no environmental pollution is caused; the atom economy of the reaction is high. Meets the requirement of green chemistry and has wide development prospect.)

1. A method of preparing a TNNI3K inhibitor comprising the steps of:

(1) heating m-bromobenzenesulfonamide II for several hours in the presence of an iridium complex catalyst and alkali, cooling to room temperature, spin-drying the solvent, and then separating by a column to obtain N-methyl-3-bromobenzenesulfonamide III;

(2) heating N-methyl-3-bromobenzenesulfonamide III and ammonia water for several hours under the catalysis of CuCl, cooling to room temperature, adding ethyl acetate for extraction, and spin-drying an organic phase solvent to obtain N-methyl-3-aminobenzenesulfonamide IV;

(3) carrying out microwave reaction on 6-chloropurine V and N-methyl-3-aminobenzenesulfonamide IV in the presence of silver trifluoromethanesulfonate, cooling to room temperature after the reaction is finished, spin-drying the solvent, and then separating through a column to obtain a target product I;

2. the method of claim 1, wherein in step (1), the iridium complex catalyst is a water-soluble bifunctional catalyst having the following structure:

3. the method of claim 1, wherein in step (1), the base is potassium hydroxide.

4. The method according to claim 1, wherein in the step (1), the iridium complex catalyst is used in a molar ratio of 1.0 mol% relative to the m-bromobenzenesulfonamide; the molar ratio of base to m-bromobenzenesulfonamide was 1equiv.

5. The method of claim 1, wherein in step (1), the reaction temperature is 130 ± 10 ℃; the reaction time is not less than 12 hours.

6. The method according to claim 1, wherein in the step (1), the reaction system uses a mixed solvent of methanol and water in a volume ratio of 1: 3.

7. The method of claim 1, wherein in step (2), the amount of CuCl is used in a 0.1equiv molar ratio with respect to the N-methyl-3-bromobenzenesulfonamide.

8. The method of claim 1, wherein in step (2), the reaction temperature is 130 ℃; the reaction time is not less than 12 hours.

9. The method according to claim 1, wherein in the step (3), the N-methyl-3-aminobenzenesulfonamide is used in a molar ratio of 1.3equiv to 6-chloropurine; the molar ratio of silver trifluoromethanesulfonate to 6-chloropurine was 1equiv.

10. The method of claim 1, wherein in step (3), the microwave reaction temperature is 150 ℃; the microwave reaction time is not less than 1.5 hours.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing a TNNI3K inhibitor.

Background

Cardiac troponin kinase (TNNI3K) is a functionally active protein kinase. (a) Zhao, y.; meng, x.m.; wei, y.j.; zhao, x.w.; liu, d.q.; cao, h.q.; liew, c.c.; ding, j.f.j.mol.med.2003,81,297-304.b) Lal, h.; ahmad, f.; parikh, s.; force, T.Circuit.J.2014, 78, 1514-1519.). Not only can autophosphorylation occur, but also can phosphorylate the basic protein myelin, a general substrate of kinase. Can promote cell differentiation to cardiac muscle cells, enhance cardiac muscle function and protect cardiac muscle from injury. (Li, P.; Petrov, V.J.mol.cell.Cardiol.1999,31, 949-; zhang, W; han, Y.biochem.Biophys.Res.Commun.2005,330, 1127-1131.). However, overexpression of TNNI3K triggered myocardial hypertrophy of neonatal rat ventricular myocytes in vitro. In setting up a number of in vivo models, including an dilated cardiomyopathy model, a pressure overload-induced heart failure model, and an ischemia and reperfusion injury model, the results show that overexpression of TNNI3K exacerbates disease progression. In complementation studies, TNNI3K in TNNI3K knock-out mice was shown to reduce ischemic injury. (a) Vagnozzi, r.j.; gatto, g.j.; kalander, l.s.; hoffman, n.e.; mallilankaraman, k.; ballard, v.l.t.; lawhorn, b.g.; stoy, P.; philip, j.; graves, a.p.; naito, y.; lepore, j.j.; gao, e.; madesh, M.; force, T.Sci.Transl.Med.2013,5, 207-. These studies indicate that TNNI3K inhibitors may serve as a treatment to reduce acute ischemic injury and cardiac cell damage. Although the synthesis of TNNI3K inhibitors has been developed, in the original report, the synthesis method uses toxic chemicals, multiple organic reactions, low atom economy and environmental pollution. (a) Miyamura, s.; araki, m.; eta, y.; itoh, y.; yasuda, s.; masuda, t.; taniguchi, y.; sowa, t.; yamaguchi, j.org.biomol.chem.,2016,14,8576-8585.b) Lawrence, r.h.; kazi, a.; luo, t.y.; kendig, r.; ge, y.y.; jain, j.s.; daniel, k.; santiago, d.; guida, c.w.; sebti, S.M.Bioorganic Medicinal Chemistry 2010,18,5576-

Recently, the group of our subjects used metal catalysts as catalysts to achieve the use of methanol as the methylating agent N-methylated sulfonamide as the key step in the preparation of TNNI3K inhibitors. (org.lett.2017_,19_,5790-5793), however, the reaction is carried out in a large amount of methanol as a reaction reagent and a solvent, which easily causes the waste of methanol and environmental pollution.

Disclosure of Invention

The invention aims to provide a method for synthesizing a TNNI3K inhibitor.

The invention is realized by the following technical scheme:

a method of synthesizing a TNNI3K inhibitor comprising the steps of:

(1) heating m-bromobenzenesulfonamide II for several hours in the presence of an iridium complex catalyst and alkali, cooling to room temperature, spin-drying the solvent, and then separating by a column to obtain N-methyl-3-bromobenzenesulfonamide III;

(2) heating N-methyl-3-bromobenzenesulfonamide III and ammonia water for several hours under the catalysis of CuCl, cooling to room temperature, adding ethyl acetate for extraction, and spin-drying an organic phase solvent to obtain N-methyl-3-aminobenzenesulfonamide IV;

(3) carrying out microwave reaction on 6-chloropurine V and N-methyl-3-aminobenzenesulfonamide IV in the presence of silver trifluoromethanesulfonate, cooling to room temperature after the reaction is finished, spin-drying the solvent, and then separating through a column to obtain a target product I;

preferably, in the step (1), the iridium complex catalyst is a water-soluble bifunctional catalyst having the following structure:

preferably, in the step (1), the alkali is potassium hydroxide; the molar ratio of the iridium complex catalyst to the m-bromobenzenesulfonamide is 1.0 mol%; the reaction system adopts a mixed solvent of methanol and water with the volume ratio of 1:3, and the molar ratio of the alkali to the m-bromobenzenesulfonamide is 1 equiv; the reaction temperature is 130 +/-10 ℃; the reaction time is not less than 12 hours.

Preferably, in the step (2), the molar ratio of the CuCl used relative to the N-methyl-3-bromobenzenesulfonamide is 0.1 equiv; the reaction temperature is 130 ℃; the reaction time is not less than 12 hours.

Preferably, in the step (3), the molar ratio of the N-methyl-3-aminobenzenesulfonamide to the 6-chloropurine is 1.3 equiv; the molar ratio of the silver trifluoromethanesulfonate to 6-chloropurine was 1 equiv; the reaction temperature is 150 ℃; the microwave reaction time is not less than 1.5 hours.

Compared with the prior art, the invention has the advantages that: the invention adopts the water-soluble bifunctional iridium complex catalyst as the catalyst of the reaction system, the reaction is carried out in water, the reaction condition is mild, and no environmental pollution is caused; the atom economy of the reaction is high. Meets the requirement of green chemistry and has wide development prospect.

Detailed Description

The following examples are shown to illustrate certain embodiments of the present invention and should not be construed as limiting the scope of the invention. Many modifications, variations and changes in materials, methods and reaction conditions may be made simultaneously with respect to the disclosure herein. All such modifications, variations and changes are intended to fall within the spirit and scope of the present invention.

New route to the synthesis of TNNI3K inhibitors (formula VI)