3,3-Diethoxypropyne → tert-Butyl 2-(diethoxymethyl)-1h-pyrrolo[3,2-c]pyridine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Scheme 3 discloses a synthesis of 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester 5b-1. In Scheme 3, step h, a mixture of (3-iodo-pyridin-4-yl)carbamic acid 1,1-dimethylethyl ester (7b-1), 3,3-diethoxy-1-propyne, a base such as for example triethylamine or Hunig's base (N,N-diisopropylethylamine), dichlorobis(triphenylphosphine)palladium(II) and copper iodide is heated in a suitable solvent such as for example dry DMF under an inert atmosphere at about 90° C. for about three hours. The reaction mixture is cooled to about 70° C. and treated with a suitable base such as for example 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), followed by stirring for about three hours at about 70° C. and then stirring at room temperature for about twelve hours. The reaction mixture is poured into ethyl acetate, washed with water and brine and the organic phase dried, filtered and concentrated to provide 2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (8b-1) which is purified by chromatography or other methods as are well known to one skilled in the art. As shown in Scheme 3, step i, hydrolysis of compound 8b-1 is effected under acidic conditions to afford 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde. Treatment of 8b-1 with a mineral acid such as for example hydrochloric acid for a suitable period of time such as about 20 hours at room temperature affords a mixture of 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (9b-1) and 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester after isolation and chromatographic separation of the product mixture by methods well known to one skilled in the art. Acidic hydrolysis of 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester by refluxing with a suitable acid such as for example trifluoroacetic acid and a suitable solvent such as for example dichloromethane affords 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde, 9b-1. As shown in Scheme 3, step j, treatment of 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde (9b-1) in a suitable solvent such as methanol with sodium cyanide and manganese dioxide with cooling at about 0° C. and stirring for about five hours provides 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester 5b-1 after filtering, washing with water and isolation by methods as are well known to one skilled in the art.

Provenance & Evidence