Preparation and application background and overview of 2,3-dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride
2,3-Dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride can be used as a pharmaceutical synthesis intermediate. It can be prepared through a four-step reaction from propargylamine and ethyl chloroformate as raw materials. . There are reports in the literature that it can be used to prepare an A2A receptor antagonist.
Preparation and application of 2,3-dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride
Preparation and application of 2,3-dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride a) N-propargyl ethyl carbamate
Take 115 grams (2.1 mol) of propargylamine dissolved in 1 liter of toluene, add 91 grams of sodium hydroxide dissolved in ml of water, and add 239 grams (2.2 mol) of chloroformic acid dropwise at 10°C Ethyl ester. The mixture was stirred at room temperature for three hours, the organic phase was separated, the aqueous phase was extracted with toluene, the organic solution was dried over magnesium sulfate, concentrated and distilled. Yield 221 g (83% of theory), boiling point 101°C / 20 mbar.
Preparation and application of 2,3-dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride b) 2-(N-ethoxycarbonyl-N-propargylamino) Methyl)pyrimidine
Dissolve 11.5 g (91 mmol) N-propargyl ethyl carbamate in 90 ml toluene, add 20.3 g KOH powder and 0.5 g triethylbenzyl ammonium chloride, and 13.5 g (104 mmol) 2-Chloromethylpyrimidine (DOS 2 932 643). The mixture was stirred at room temperature overnight, the salt was filtered off with suction, the filtrate was washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated and distilled. Yield 10.4 g (51% of theory), boiling point 130°C/0.35mbar.
Preparation and application of 2,3-dihydro-1H-pyrrolo[3,4-C]pyridine dihydrochloride c) 5,7-dihydro-6H-pyrrolo[3,4- b]Ethyl pyridine-6-carboxylate
Reflux 7.7g (35mmol) of 2-(N-ethoxycarbonyl-N-propargylaminomethyl)pyrimidine in 150ml xylene for 40 hours, concentrate it and remove the residue from petroleum ether Recrystallization. Yield 5.5 g (81.7% of theory), melting point 77-79°C.
Preparation and application of 2,3-dihydro-1H-pyrrole[3,4-C]pyridine dihydrochlorided) 2,3-dihydro-1H-pyrrole[3,4-C ]Pyridine dihydrochloride dihydrochloride
Heat 8.5g (44mmol) of ethyl 5,7-dihydro-1H-pyrrolo[3,4-b]pyridine-6-carboxylate in 90ml of concentrated hydrochloric acid overnight. The solution was concentrated, the residue was stirred with acetone, the salts were filtered off with suction and dried in air. Yield 7.5 g (88% of theory).
Preparation and application of 2,3-dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride
2,3-Dihydro-1H-pyrrole[3,4-C]pyridine dihydrochloride can be used to prepare triazolotriazine derivatives with the following structure. This compound is an A2A receptor antagonist. Adenosine is a naturally occurring purine nucleoside that regulates various physiological functions. Adenosine binds to purinergic receptors that are members of the G protein-coupled receptor (GPCR) family, including adenosine A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R). Among them, the adenosine A2A receptor (A2AR) can couple with adenylyl cyclase in a stimulatory manner, thereby inducing the classic second messenger signaling pathway, including the generation of cyclic adenosine monophosphate. A2AR can mediate adenosine to exert various physiological effects in the central nervous system and peripheral tissues. The functional interaction of A2AR with dopamine D2 receptors in the basal ganglia has prompted decades of research into A2AR antagonists as drugs for the treatment of Parkinson’s disease. Other medical applications of A2AR antagonists include cognitive enhancement, neuroprotection, and analgesia. Recent studies have shown that inhibition of A2AR may also be a potent approach to cancer treatment.
References
[1] From Eur. Pat. Appl. (1992), EP 520277 A2 19921 Synthetic mica 230.
[2] [Invented in China] CN201880048405.9 Triazolotriazine derivatives that can be used as A2A receptor antagonists
