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CN-122010913-A - Rhodamine-marked isoquinoline derivative and preparation method and application thereof

CN122010913ACN 122010913 ACN122010913 ACN 122010913ACN-122010913-A

Abstract

The invention belongs to the field of organic matter preparation, and particularly relates to a rhodamine-marked isoquinoline derivative, and a preparation method and application thereof. The Sigma-2 receptor targeting ligand 6, 7-dimethoxy tetrahydroisoquinoline is covalently linked with rhodamine fluorophores through a specific connecting bridge to prepare the compound containing rhodamine derivatives and 6, 7-dimethoxy tetrahydroisoquinoline. The rhodamine labeled isoquinoline derivative can complete the diagnosis and treatment effects through one-time administration, and has good biological activity, higher selectivity and lower toxicity.

Inventors

  • WANG ZHONGCHANG
  • JIANG XIANZHI
  • Tao Huaiyu
  • ZHOU JIANCHENG

Assignees

  • 淮阴师范学院

Dates

Publication Date
20260512
Application Date
20251226

Claims (10)

  1. 1. A rhodamine labeled isoquinoline derivative is characterized in that the structural formula is shown as X: Wherein R 1 is H, CH 3 or halogen element, and R 2 is 。
  2. 2. The rhodamine-labeled isoquinoline derivative according to claim 1, characterized in that the structure is represented by any one of the following structural formulas: 、 、 、 、 、 、 、 Or (b) 。
  3. 3. A process for the preparation of rhodamine-labeled isoquinoline derivatives according to claim 1 or 2, characterized by comprising the steps of using (2-bromoethyl) carbamic acid tert-butyl ester and compound 1: Nucleophilic substitution reaction is carried out to prepare the compound 2: ; Hydrolysis of compound 2 gives compound 3: ; Amidation of 4- (6, 7-dimethoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -4-oxobut-1-ammonium chloride with Compound 3 to obtain Compound 7 ; Removing tertiary butyl ester group at outer end of compound 7 to obtain compound 8 ; And carrying out amidation reaction on the compound 8 and rhodamine derivative to obtain rhodamine-labeled isoquinoline derivative.
  4. 4.A method for preparing a rhodamine-labeled isoquinoline derivative according to claim 3 characterized in that the rhodamine derivative comprises one or more of 5-carboxytetramethyl rhodamine, 5-carboxytetramethyl rhodamine succinimidyl ester, 6-carboxytetramethyl rhodamine or 6-carboxytetramethyl rhodamine succinimidyl ester.
  5. 5. A process for the preparation of rhodamine-labeled isoquinoline derivatives according to claim 3, characterized by the following steps: a. Adding water into the reaction liquid, extracting the reaction liquid by using ethyl acetate, then combining an organic layer, washing the organic layer by water, a saturated alkali solution and saturated saline water in sequence, drying the organic layer, removing a solvent, and obtaining a compound 2 by column chromatography; b. Stirring and reacting the compound 2 with an organic solution of alkali at 10-30 ℃ until the reaction is complete, removing the solvent, then adding water, extracting a water layer with ethyl acetate, adjusting the pH value of the water layer with an acid solution to be 2-3, then extracting with an organic solvent, drying the organic layer, and removing the solvent to obtain a compound 3; c. Dissolving a compound 3 and a condensing agent in an organic solvent, activating at-10 ℃, then adding 4- (6, 7-dimethoxy-3, 4-dihydro-isoquinoline-2 (1H) -yl) -4-oxo-1-ammonium chloride, reacting at room temperature, adding the organic solvent into a reaction solution after full reaction, washing an organic layer sequentially with acid, alkali solution and water, merging the organic phases, drying the organic layer, and purifying to obtain a compound 7; d. Reacting the compound 7 with an acid solution in an organic solvent at-10 ℃ for 1h, slowly heating to room temperature, continuously reacting for 4-6 h, and removing the solvent to obtain a compound 8; e. Dissolving rhodamine derivative in organic solvent to obtain rhodamine derivative solution, activating compound 8 and alkali in the organic solvent at room temperature, adding rhodamine derivative solution, mixing and reacting under protective atmosphere, removing solvent after full reaction, and purifying to obtain rhodamine-marked isoquinoline derivative.
  6. 6. The method for producing rhodamine-labeled isoquinoline derivatives according to claim 5, characterized in that the ratio of the amounts of the compounds 1 and t-butyl (2-bromoethyl) carbamate in step a is 1.1 to 1.5:1, the ratio of the base in step a to the amount of the compounds 1 is 1.3 to 3:1, the ratio of the compounds 2 to the base in step b is 1:2 to 10, the ratio of the condensing agent in step c to the amount of the compounds 3 is 1:1 to 3, the ratio of the compounds 7 to the acid in step d is 1:10 to 50, the ratio of the compounds 8 to the rhodamine derivatives in step e is 1.5 to 2:1, and the ratio of the compounds 8 to the base in step e is 1:20 to 50.
  7. 7. The method for preparing rhodamine labeled isoquinoline derivatives according to claim 5, wherein the organic solvent comprises dichloromethane or N, N-dimethylformamide, the base in step a is a basic carbonate, the acid in step d is an organic acid, and the base in step e is an organic base.
  8. 8. The method for preparing rhodamine-labeled isoquinoline derivatives according to claim 3, characterized in that the preparation of 4- (6, 7-dimethoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -4-oxobutan-1-ammonium chloride comprises the steps of condensing 4- [ N- (tert-butoxycarbonyl) amino ] butanoic acid with 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride under the action of a condensing agent to obtain (4- (6, 7-dimethoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -4-oxobutyl) carbamic acid tert-butyl ester; Then reacting for 1-3 hours at-10 ℃ under the action of hydrochloric acid to prepare 4- (6, 7-dimethoxy-3, 4-dihydro-isoquinoline-2 (1H) -yl) -4-oxo-butyl-1-ammonium chloride.
  9. 9. The method for producing rhodamine labeled isoquinoline derivatives according to claim 8, characterized in that the condensing agent comprises 1-ethyl- (3-dimethylaminopropyl) carbodiimide, the ratio of the amount of the condensing agent to the amount of the substance of 4- [ N- (tert-butoxycarbonyl) amino ] butanoic acid is 1.1 to 1:5, and the ratio of the amount of the substance of 4- [ N- (tert-butoxycarbonyl) amino ] butanoic acid to the amount of the substance of 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline hydrochloride is 1:0.8 to 1.2.
  10. 10. Use of a rhodamine-labeled isoquinoline derivative according to claim 1 or 2 in the preparation of an antitumor drug.

Description

Rhodamine-marked isoquinoline derivative and preparation method and application thereof Technical Field The invention belongs to the field of organic matter preparation, and particularly relates to a rhodamine-marked isoquinoline derivative, and a preparation method and application thereof. Background Cancer is a serious disease that severely jeopardizes human health, and early accurate diagnosis, efficient targeted therapy and real-time monitoring of the course of therapy remain significant challenges in current clinics. Targeted therapy has become an important development of accurate medicine by enhancing specific accumulation of drugs at focal sites and alleviating damage to normal tissues. Diagnosis and treatment functions are integrated into a single system by the diagnosis and treatment integrated technology, and an innovative strategy is provided for realizing the real-time positioning and synchronous intervention of tumors. Compared with the traditional diagnosis and treatment system relying on nano-carriers, the small molecule diagnosis and treatment reagent has the obvious advantages of clear chemical structure, easiness in synthesis and structural modification, relatively clear in-vivo metabolic path, good tissue permeability and the like, so that the small molecule diagnosis and treatment reagent has more potential in the aspect of conversion application. Disclosure of Invention In order to solve the problems that a nano system has technical bottlenecks and is difficult to promote the development of accurate diagnosis and treatment of tumors in the prior art, the invention mainly provides a small molecule diagnosis and treatment candidate compound which has the advantages of clear structure, simple synthesis, strong targeting and environmental responsiveness imaging function, and a preparation method and application thereof. The technical scheme is as follows: rhodamine labeled isoquinoline derivative has a structural formula shown as X: Wherein R 1 is H, CH 3 or halogen element, and R 2 is 。 Further, the structure is shown in any one of the following structural formulas: 、 、 、 、 、 、 、 Or (b) 。 A preparation method of the rhodamine-labeled isoquinoline derivative comprises the following steps of using (2-bromoethyl) carbamic acid tert-butyl ester and a compound 1: Nucleophilic substitution reaction is carried out to prepare the compound 2: ; Hydrolysis of compound 2 gives compound 3: ; Amidation of 4- (6, 7-dimethoxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -4-oxobut-1-ammonium chloride with Compound 3 to obtain Compound 7 ; Removing tertiary butyl ester group at outer end of compound 7 to obtain compound 8; And carrying out amidation reaction on the compound 8 and rhodamine derivative to obtain rhodamine-labeled isoquinoline derivative. Further, the reaction process is as follows: 。 Further, the reaction conditions are: 。 further, the rhodamine derivative comprises one or more of 5-carboxyl tetramethyl rhodamine, 5-carboxyl tetramethyl rhodamine succinimide ester, 6-carboxyl tetramethyl rhodamine or 6-carboxyl tetramethyl rhodamine succinimide ester. Further, the method comprises the following steps: a. Adding water into the reaction liquid, extracting the reaction liquid by using ethyl acetate, then combining an organic layer, washing the organic layer by water, a saturated alkali solution and saturated saline water in sequence, drying the organic layer, removing a solvent, and obtaining a compound 2 by column chromatography; b. Stirring and reacting the compound 2 with an organic solution of alkali at 10-30 ℃ until the reaction is complete, removing the solvent, then adding water, extracting a water layer with ethyl acetate, adjusting the pH value of the water layer with an acid solution to be 2-3, then extracting with an organic solvent, drying the organic layer, and removing the solvent to obtain a compound 3; c. Dissolving a compound 3 and a condensing agent in an organic solvent, activating at-10 ℃, then adding 4- (6, 7-dimethoxy-3, 4-dihydro-isoquinoline-2 (1H) -yl) -4-oxo-1-ammonium chloride, reacting at room temperature, adding the organic solvent into a reaction solution after full reaction, washing an organic layer sequentially with acid, alkali solution and water, merging the organic phases, drying the organic layer, and purifying to obtain a compound 7; d. Reacting the compound 7 with an acid solution in an organic solvent at-10 ℃ for 1h, slowly heating to room temperature, continuously reacting for 4-6 h, and removing the solvent to obtain a compound 8; e. Dissolving rhodamine derivative in organic solvent to obtain rhodamine derivative solution, activating compound 8 and alkali in the organic solvent at room temperature, adding rhodamine derivative solution, mixing and reacting under protective atmosphere, removing solvent after full reaction, and purifying to obtain rhodamine-marked isoquinoline derivative. Further, the ratio of the amount of the compound 1 to the amount of the tert