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Improved synthesis technology of istradefylline

A technology of istradefylline and a process method, which is applied in the research field of the synthesis process route of istraphylline, can solve the problems of increasing the difficulty of purifying intermediates and products, high price, etc. mild effects

Inactive Publication Date: 2018-04-17
FUKANGREN BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the catalyst brominated dimethylsulfur bromide (BDMS) used in the condensation ring-closing reaction in the process is expensive, and DMSO, HBr, Me 2 By-products such as S will inevitably increase the difficulty of purification of intermediates and products

Method used

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  • Improved synthesis technology of istradefylline

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Add 650g (3.06mol) of the starting material SM-III into a 20L reaction flask, add 10L of 30% aqueous potassium carbonate solution to it, stir at 30-50°C, add 2964g (15.3mol) of 90% hydrosulfite to the reaction solution , stirred at room temperature for 1.0 hour, the solution was clear, TLC (DCM:MeOH=50:1) showed that the starting material disappeared, and the aqueous solution of intermediate YN-II was obtained, which was directly used in the next reaction without treatment.

[0015] Synthesis of YN-III

[0016] We replace the more corrosive thionyl chloride with oxalyl chloride, which can improve the yield of intermediate YN-III; if the reaction solvent is replaced by tetrahydrofuran or dioxane from dichloromethane, the reaction yield is significantly reduced, Therefore choose to adopt dichloromethane as condensation reaction solvent. The feed of the starting material (E)-3,4-dimethoxyphenylacrylic acid (SM-I) was reduced to 0.95 equivalents. The result has no differe...

Embodiment 2

[0018] Add 605.2g (2.91mol) of the starting material SM-I into a 10L reaction flask, add 3.5L of dichloromethane and 6.5mL of DMF, stir at 25°C, and drop 369.4g (2.91mol) of oxalyl chloride within 20 minutes. After stirring at 25°C for 1.5 hours, the solution became clear. The reaction solution was slowly added dropwise to the aqueous solution of YN-II obtained in step 1, and the temperature of the reaction solution was controlled at 0-5°C. After the drop was completed, stir at room temperature for 1 hour, and monitor by TLC (DCM:MeOH=50:1, UV 254nm) that the reaction of YN-II was complete. A light yellow solid was precipitated, filtered, recrystallized from 50% ethanol, and the obtained light yellow solid was dried overnight at 60°C to obtain 1016g of intermediate YN-III with a yield of 90%.

[0019] Synthesis of YN-IV

[0020] In this step of synthesis, the intermediate YN-III was treated with 10M sodium hydroxide, and the reaction was complete in 1h, and many impurities w...

Embodiment 3

[0022] Take YN-III 895.1g (2.30mol) into a 20L reaction flask, add 5.75L each of dioxane and 5M NaOH aqueous solution, stir at 60°C for 2 hours, monitor by TLC (DCM:MeOH=30:1, UV 254nm) basically no raw material remains. After cooling down to room temperature, 2657 ml of concentrated hydrochloric acid was added thereto to adjust the pH to 2, and solids were precipitated. Stop heating, naturally cool down to room temperature, stir for 3 hours, and filter. 3.16 L of water was washed twice to obtain a white solid, which was dried at 45°C for 17 hours to obtain 683.6 g of intermediate YN-IV with a yield of 80.1%.

[0023] Intermediate YN-IV quality control method:

[0024] Synthesis of Crude Itradefylline (YN-I)

[0025] We investigated the reaction solvent, the feed ratio of methyl iodide and potassium carbonate, etc., and used TLC or HPLC to monitor the reaction as required. After experimenting, it was determined that the intermediate YN-IV was used as the raw material, pota...

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Abstract

The invention provides an improved synthesis technology of istradefylline. According to the technology, istradefylline is prepared from 1,3-diethyl-6-amino-5-nitrosouracil (SM-III) as a starting material through four steps.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to the research on the synthesis process route of istradefylline. Background technique [0002] Parkinson's disease (PD) is a common neurodegenerative disease, more common in the elderly, with an average age of onset of about 60 years old. The prevalence of PD in people over 65 years old in my country is about 1.7%. Most patients with Parkinson's disease are sporadic cases, and less than 10% of patients have a family history. [0003] The main pathological change of Parkinson's disease is the degeneration and death of dopamine (DA) neurons in the substantia nigra of the midbrain, which leads to a significant decrease in the content of DA in the striatum and causes the disease. [0004] Itraphylline is a selective adenosine A developed by Japan Kyowa Hakko Kogyo Co., Ltd. 2a Receptor antagonist is a new type of anti-Parkinson's disease drug, which is used in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 张洪志
Owner FUKANGREN BIO PHARMA
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