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Medical intermediate compound and synthesis method thereof

A synthesis method and compound technology, applied in the fields of drug combination, organic chemistry, bulk chemical production, etc., can solve the problems of catechol group without method, not method, improvement, etc.

Inactive Publication Date: 2019-07-23
HAINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its disadvantage is that this patent is committed to proposing a systematic and universal method for preparing ketal-protected L-DOPA derivatives, but it may not be the optimal method for synthesizing a specific target compound
World patent application WO2013 / 168021A1 has no methodological improvement in acetonylation of catechol groups

Method used

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  • Medical intermediate compound and synthesis method thereof
  • Medical intermediate compound and synthesis method thereof
  • Medical intermediate compound and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Embodiment 1: the impact of strong acid TsOH catalysis on the reaction of acetone

[0067] (1) Add sodium tetraborate decahydrate (19.1g, 50mmol) and water (250ml) into a 500ml three-neck flask, stir with a magnetic stirrer, and pass through argon to deoxygenate for 30 minutes. Then add L-DOPA (19.7g, 100mmol) and Na to the mixed solution 2 CO 3 (10.6g, 100mmol), get Fmoc-OSu (33.8g, 100mmol), be dissolved in 200ml THF, adopt dropping funnel to add reaction body dropwise, mixture is stirred at room temperature 4 hours, adopt thin-layer chromatography (TLC) to monitor Response progress. Use 1N HCl solution to acidify the pH value of the reaction system to pH = 1, rotary evaporate THF in the mixed solution, use EtOAc to extract the mixed solution, take the organic layer, and wash with MgSO 4 After drying to remove water, the product was dried in a vacuum oven after rotary evaporation to obtain Fmoc-DOPA-OH as a foamy white solid (37 g, 88%).

[0068] (2) Add Fmoc-DOPA...

Embodiment 2

[0069] Embodiment 2: a kind of synthetic method of Fmoc-DOPA (Acetonide)-OH, specifically comprises the following steps:

[0070] (1) Add sodium tetraborate decahydrate (19.1g, 50mmol) and water (250ml) into a 500ml three-neck flask, stir with a magnetic stirrer, and pass through argon to deoxygenate for 30 minutes. Then add L-DOPA (19.7g, 100mmol) and Na to the mixed solution 2 CO 3 (10.6g, 100mmol), get Fmoc-OSu (40.48g, 120mmol), be dissolved in 200ml THF, adopt dropping funnel to add reaction body dropwise, mixture is stirred at room temperature 4 hours, adopt thin-layer chromatography (TLC) to monitor Response progress. Use 1N HCl solution to acidify the pH value of the reaction system to pH = 1, rotary evaporate THF in the mixed solution, use EtOAc to extract the mixed solution, take the organic layer, and wash with MgSO 4 After drying to remove water, the product was dried in a vacuum oven after rotary evaporation to obtain Fmoc-DOPA-OH as a foamy white solid (39.9 g...

Embodiment 3

[0072] Embodiment 3 A kind of synthetic method of Fmoc-DOPA (Acetonide)-OH, specifically comprises the following steps:

[0073] (1) Add sodium tetraborate decahydrate (19.1g) and water (250ml) into a 500ml three-necked flask, stir with a magnetic stirrer, feed argon to remove oxygen for 30 minutes, then add L- DOPA (19.7g) and Na 2 CO 3 (5.6g), get Fmoc-OSu (40.48g), be dissolved in 50ml THF, adopt drop funnel to add reaction body dropwise, mixture is stirred at room temperature 4 hours, adopt thin-layer chromatography (TLC) to monitor reaction progress situation. Use 1N HCl solution to acidify the pH value of the reaction system to pH = 1, rotary evaporate THF in the mixed solution, use EtOAc to extract the mixed solution, take the organic layer, and wash with MgSO 4 After drying to remove water, the product was dried in a vacuum oven after rotary evaporation to obtain Fmoc-DOPA-OH as a foamy white solid (37.5 g, 89%).

[0074] (2) Take the dried Fmoc-DOPA-OH (2.1g) inter...

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Abstract

The invention provides a medical intermediate compound and a synthesis method thereof and belongs to the field of medicine synthesis. The compound has the structural formula shown in the description,wherein the substance shown in the description is obtained with a two-step method. Firstly, a product shown in the description is prepared and then dissolved in an organic solvent, reflux is performedin a non-polar solvent, carboxylic acid contained in an intermediate is an acetonide treatment catalyst, the production cost is saved, an acetonide reaction is complete, and the reaction yield is increased to about 90% and the purity reaches 99% or above by means of the route; a reactant Fmoc-DOPA-OH is almost completely cleared by means of the synthesis route, pollution to main products is avoided, the problem of difficulty in separation and purification of the main products is solved, and the whole reaction process is simple and convenient to operate; the utilization rate of raw materials is greatly increased, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine synthesis, and in particular relates to a medicine intermediate compound and a synthesis method thereof. Background technique [0002] Levodopa (L-DOPA) is currently the most effective drug for the treatment of Parkinson's disease, known as the gold standard. The development of many new anti-Parkinson's disease drugs is based on the modification of L-DOPA. At the same time, L-DOPA is a rare natural amino acid, and oligopeptides, polypeptides or polymer materials containing L-DOPA have broad medical application prospects. [0003] Since the catechol group of L-DOPA is easily oxidized by oxygen in the air or other oxidants, it is necessary to protect the catechol with a suitable protecting group (PG) in the chemical derivation of L-DOPA. A large number of literatures show that acetonide is a very suitable protecting group for dopa. The Fmoc-based solid-phase peptide synthesis method has become a routine c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/60
CPCC07D317/60A61P25/16Y02P20/55C07K5/06078Y02E60/10A61K47/542
Inventor 刘中强何延淼胡碧煌陈思康钟仕博万影姚蕊李梦迪
Owner HAINAN UNIVERSITY
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