Process for preparing an a2a-adenosine receptor agonist and its polymorphs
A solid and solvent technology, applied in the field of preparation of A2A-adenosine receptor agonists and their polymorphs, can solve problems such as undesired large-scale synthesis
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[0091] Preparation of step 1-structural formula (2) compound
[0092] Compounds of formula (2) are prepared from compounds of formula (1) by reaction with hydrazine monohydrate in the absence of solvent. The reaction is carried out at a temperature of about 45-55°C. When the reaction is complete, the product of formula (2) is isolated by stirring with a protic solvent in which the compound of formula (2) has limited solubility, such as ethanol or isopropanol. The mixture was stirred for about 1-5h, then filtered. The solid was purified by stirring with water, filtered and rinsed with water followed by isopropanol and dried in vacuo and was used in the next step without purification.
[0093] The preparation of step 2-structural formula (3) compound
[0094] Compounds of formula (2) are then converted to compounds of formula (3) by reaction with about 1 to 1.2 molar equivalents of ethyl 2-formyl-3-oxopropionate. The reaction is carried out in a protic solvent, preferabl...
Embodiment 1
[0123] Preparation of ethyl 2-formyl-3-oxopropionate
[0124]
[0125]A three or four necked round bottom flask equipped with a magnetic stirring bar, thermocouple, digital thermometer, gas inlet and outlet, and dropping funnel was purged with argon. A tetrahydrofuran solution of ethyl 3,3-diethoxypropionate (64.5 g) was added to the dropping funnel. Sodium hydride (21.2 g of a 60% dispersion) was added to the reaction flask, followed by tetrahydrofuran. The contents of the flask were cooled to 0-5°C in an ice bath, and ethyl formate (257 g) was added. The mixture was cooled to 0-5°C, and the contents of the dropping funnel were added dropwise, maintaining the internal temperature below 5°C. The ice bath was removed, and the contents were allowed to warm to room temperature. The consumption of ethyl 3,3-diethoxypropionate was monitored by TLC analysis. The reaction was quenched (quenched) by the addition of ice water (10.6 vol) and extracted 3 times with methyl tert-b...
Embodiment 2
[0127] a. Preparation of 2-hydrazinoadenosine (2)
[0128]
[0129] The flask equipped with mechanical stirring, gas inlet, gas outlet and thermocouple was purged with argon. 2-Chloradenosine hemihydrate (53.1 g) was added followed by hydrazine monohydrate (134 g). The mixture was heated to 40-45 °C for 2 h while stirring. The progress of the reaction was followed by TLC analysis. When the reaction was complete, the heat was removed and ethanol (800 mL) was added. The mixture was stirred at room temperature for 2 h, then the precipitate was collected by filtration. The filter cake was washed with ethanol and dried under reduced pressure for 30 min. The solid was transferred to a clean flask equipped with mechanical stirring, and water (300 mL) was added. The suspension was stirred at room temperature for 18 h and the solid was isolated by filtration. The filter cake was rinsed with ice-cold water (300 mL) followed by ice-cold ethanol (300 mL). The solid was dried u...
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