Unlock instant, AI-driven research and patent intelligence for your innovation.

A kind of environment-friendly preparation method of istradefylline

A technology of istradefylline and cyclization reaction, applied in the field of medicinal chemistry, can solve the problems of unenvironmental protection in production process, unstable use, large amount of waste water, etc., and achieve the effects of low cost, few raw materials and few side reactions

Active Publication Date: 2020-08-11
XINFA PHARMA
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above two synthetic routes are cumbersome, and both use unstable and easily deteriorated 1,3-diethyl-5,6-diaminouracil, which leads to heavy color of istradefylline products; methylation is easy to produce 9- Methyl isomers, more by-products
Both routes require sodium nitrite aqueous solution and acetic acid aqueous solution to carry out nitrosation reaction, the amount of waste water is large, and the production process is not environmentally friendly

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of environment-friendly preparation method of istradefylline
  • A kind of environment-friendly preparation method of istradefylline
  • A kind of environment-friendly preparation method of istradefylline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1: The preparation of istradefylline (I) is prepared according to route 1

[0072] Step (a): Methyl 2-(N-methyl-N-(E)-3,4-dimethoxyphenylacryloyl)aminocyanoacetate (IV 1 ) preparation

[0073] In a 500 ml four-necked flask, add 250 g of dichloromethane, 25.5 g (0.2 moles) of methyl 2-methylaminocyanoacetate (II 1 ), 30 grams of triethylamine, cooling, cooling to 5-10 ° C, dropwise adding 45.5 grams (0.2 moles) of (E)-3,4-dimethoxyphenylacryloyl chloride (Ⅲ) and 100 grams of dichloromethane The mixed solution was dropped, reacted at 30-35°C for 5 hours, cooled to room temperature, filtered, the filter cake was washed once with 30 g of dichloromethane, the dichloromethane phase was combined, the solvent was recovered by distillation, and dried to obtain 60.7 g of light yellow solid 2 -Methyl (N-methyl-N-(E)-3,4-dimethoxyphenylacryloyl)aminocyanoacetate, liquid phase purity 99.9%, yield 95.5%.

[0074] Preparation of istradefylline (Ⅰ)

[0075] In a 500 ml f...

Embodiment 2

[0078] Embodiment 2: The preparation of istradefylline (I) is prepared according to route 1

[0079] Step (a): ethyl 2-(N-methyl-N-(E)-3,4-dimethoxyphenylacryloyl)aminocyanoacetate (IV 2 ) preparation

[0080] In a 500 ml four-neck flask, add 250 g of 1,2-dichloroethane, 28.5 g (0.2 moles) of ethyl 2-methylaminocyanoacetate (II 2 ), 30 grams of triethylamine, cooled, cooled to 15-20 ° C, dropwise added 45.5 grams (0.2 moles) of (E)-3,4-dimethoxyphenylacryloyl chloride (Ⅲ) and 100 grams of 1,2- The mixed solution of dichloroethane, dropwise, react at 50-55°C for 3 hours, cool down to room temperature, filter, wash the filter cake once with 30 grams of 1,2-dichloroethane, combine the organic phases, recover the solvent by distillation, and dry , to obtain 62.2 grams of light yellow solid 2-(N-methyl-N-(E)-3,4-dimethoxyphenylacryloyl) ethyl aminocyanoacetate, liquid phase purity 99.9%, yield 93.2% .

[0081] Preparation of istradefylline (Ⅰ)

[0082] In a 500 ml four-necked ...

Embodiment 3

[0083] Embodiment 3: The preparation of istradefylline (I) is prepared according to route 2

[0084] Step (a): Preparation of 1,3-diethyl-5-methylamino-6-aminouracil (Ⅵ)

[0085] In a 500 ml four-neck flask equipped with a distillation system, add 200 g of 1,4-dioxane, 12.8 g (0.1 mole) of methyl 2-methylaminocyanoacetate (Ⅱ 1 ), 14.0 grams (0.12 moles) of 1,3-diethylurea, reacted at 100-105 ° C for 4 hours, and distilled off the methanol produced at the same time. React at 95°C for 3 hours, recover 1,4-dioxane by distillation under reduced pressure, add 50 g of isopropanol to the residue, heat to reflux for 1 hour, filter while hot, cool the filtrate to room temperature, crystallize, filter, and dry. 20.3 g of off-white solid 1,3-diethyl-5-methylamino-6-aminouracil was obtained, the liquid phase purity was 99.97%, and the yield was 95.8%.

[0086] Step (b): 1,3-diethyl-5-(N-methyl-N-(E)-3,4-dimethoxyphenylacryloyl)amino-6-aminouracil (V) preparation

[0087] Into a 500 ml...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides an environment-friendly preparation method of istradefylline. 2-methyl aminocyanoacetate is taken as an initial raw material and is firstly subjected to an amidation reaction and then cyclized or firstly cyclized and then subjected to the amidation reaction, 1,3-diethyl-5-(N-methyl-N-(E)-3,4-dimethoxy phenylpropylene acryl)amino-6-aminouracil is prepared and then cyclized inthe presence of alkali, and istradefylline is prepared. According to the method, raw materials are cheap and easy to obtain, the step is simple and safe, and the method is green, environmentally friendly and low in cost; the prepared product has a shallow color and luster and is high in purity and yield.

Description

technical field [0001] The invention relates to an environment-friendly preparation method of istradefylline, which belongs to the technical field of medicinal chemistry. Background technique [0002] Parkinson's disease is a progressive disease caused by the degeneration of dopamine receptors in the basal ganglia. The clinical symptoms are slowness of movement, rigidity, resting tremor, and postural instability. Itradefylline (English name is Istradefylline), a selective adenosine A2A receptor antagonist developed by Kyowa Hakko Co., Ltd., as an innovative drug, was launched in May 2013. Combination of Parkinson's drugs can improve Parkinson's symptoms and treat other central nervous system diseases. [0003] The CAS number of istradefylline (I) is [155270-99-8], and the Chinese name is (E)-8-[2-(3,4-dimethoxyphenyl)vinyl]-1,3 -Diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione, the chemical structure is as follows: [0004] [0005] Currently, the production of istrade...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/06
CPCC07D473/06
Inventor 戚聿新鞠立柱张明峰吕强三
Owner XINFA PHARMA