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Istradefylline synthesis process

A technology for istradefylline and a synthesis process, applied in the field of istradefylline synthesis technology, can solve the problems of complex process, obstacles to large-scale production of istradefylline, and high product cost, and achieves simple synthesis route, easy purification, The effect of the best stability

Inactive Publication Date: 2015-10-14
NANJING CORE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, the process of istradefylline is relatively complicated, and neurotoxic methylating reagents, such as methyl iodide, etc., will be produced during the preparation process, which hinders the large-scale production of istradefylline, making The cost of the product is relatively high, which brings a greater burden to patients

Method used

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  • Istradefylline synthesis process
  • Istradefylline synthesis process
  • Istradefylline synthesis process

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Preparation of istradefylline:

[0039] 1) Put 180g of 1,3-diethylformamide and 125g of cyanoacetic acid in 185ml of acetic anhydride for ring formation reaction. The reaction condition is to heat and reflux at 50°C for 2.5h. After the reaction is completed, add sodium hydroxide, adjust the pH to 7, and pump filtered, washed twice with water, and the resulting white solid was compound Ⅰ;

[0040] 2) Add 260 g of compound I to 1 L of acetic acid, stir for 30 minutes, and then add sodium nitrite for nitration reaction. The reaction time is 3 hours. After the reaction is completed, the solid obtained by suction filtration and drying is compound II;

[0041] 3) Pass hydrogen through 260 g of compound II and 2.2 L of methanol for reduction reaction. The reaction time is 20 h. After the reaction is completed, the yellow solid obtained by HPLC detection and spin-drying is compound III;

[0042] 4) Under dark and oxygen-free conditions, 150g of compound III, 200g of 3-(3,4-dim...

Embodiment 2

[0046] Preparation of istradefylline:

[0047] 1) Put 180g of 1,3-diethylformamide and 120g of cyanoacetic acid in 180ml of acetic anhydride for a ring-forming reaction. The reaction condition is to heat and reflux at 60°C for 3 hours. After the reaction is completed, add sodium hydroxide, adjust the pH to 7, and pump filtered, washed twice with water, and the resulting white solid was compound Ⅰ;

[0048] 2) Add 260 g of compound I to 1 L of acetic acid, stir for 30 minutes, and then add sodium nitrite for nitration reaction. The reaction time is 3 hours. After the reaction is completed, the solid obtained by suction filtration and drying is compound II;

[0049] 3) Pass hydrogen through 260 g of compound II and 2.5 L of methanol for reduction reaction. The reaction time is 24 hours. After the reaction is completed, the yellow solid obtained by HPLC detection and spin-drying is compound III;

[0050] 4) Under dark and oxygen-free conditions, 150g of compound III, 200g of 3-(...

Embodiment 3

[0054] Preparation of istradefylline:

[0055] 1) Put 180g of 1,3-diethylformamide and 122g of cyanoacetic acid in 182ml of acetic anhydride for ring formation reaction, the reaction condition is to heat and reflux at 70°C for 3.5h, add sodium hydroxide after the reaction is completed, and adjust the pH to 7 Suction filtration, washing twice with water, the obtained white solid is compound Ⅰ;

[0056] 2) Add 260 g of compound I to 1 L of acetic acid, stir for 30 minutes, and then add sodium nitrite for nitration reaction. The reaction time is 3 hours. After the reaction is completed, the solid obtained by suction filtration and drying is compound II;

[0057] 3) Pass hydrogen through 260 g of compound II and 2.6 L of methanol for reduction reaction. The reaction time is 26 hours. After the reaction is completed, the yellow solid obtained by HPLC detection and spin-drying is compound III;

[0058] 4) Under dark and anaerobic conditions, 150g of compound III, 200g of 3-(3,4-dim...

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Abstract

The invention discloses an istradefylline synthesis process comprising the following steps: a compound I is prepared from 1,3-diethylformamide and cyanoacetic acid in acetic anhydride; the compound I is added into acetic acid, and the mixture is stirred for 30min; sodium nitrite is added, and thus a compound II is prepared; hydrogen gas is introduced into the compound II and methanol, such that a compound III is obtained; the compound III, 3-(3,4-dimethoxyl-phenol)-acryloyl chloride, sodium hydroxide and dichloromethane are prepared into a compound IV; the compound IV and sodium hydroxide are added into 1,4-dioxane, such that a compound V is prepared; the compound V, dimethyl carbonate, DMF, and sodium hydroxide are subjected to a methylation reaction; and cooling, suction filtration and washing are carried out, such that istradefylline is obtained. With the process, the final product can be obtained with high efficiency; the synthesis route is simple; purification is easy; the application of a highly toxic or neurotoxic methylation reagent, such as iodomethane, is avoided. The process is suitable for industrialized productions, and assists in reducing the production cost.

Description

technical field [0001] The invention relates to chemical synthesis, in particular to a synthesis process of istradefylline. Background technique [0002] PD is a progressive disease, mainly caused by the degeneration of dopamine receptors in the basal ganglia. It involves many clinical symptoms, among which the four main clinical symptoms are bradykinesia, rigidity, resting tremor and postural instability. Among them, the presence of 2 symptoms was used as the diagnostic feature. [0003] As an innovative drug for the treatment of Parkinson's disease, istradefylline is used as an adjuvant drug in combination with levodopa and other anti-Parkinson drugs to improve the motor symptoms of patients with Parkinson's disease. In the prior art, the process of istradefylline is relatively complicated, and neurotoxic methylating reagents, such as methyl iodide, etc., will be produced during the preparation process, which hinders the large-scale production of istradefylline, making T...

Claims

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Application Information

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IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 王雪根何凌云史全全金皓洁汪洋夏珏妤
Owner NANJING CORE TECH CO LTD
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