Patent GB-750925-A (GB)
Title: Improvements in and relating to pyridine derivatives and the manufacture thereof
Inventor: COPP FREDERICK CHARLES
IPC: C07D213/74
Filed: 1953-10-26
Abstract: The invention comprises substituted pyridines of the general formula <FORM:0750925/IV(a)/1> wherein R1 represents a straight-chain alkyl or hydroxyalkyl group having from 1 to 3 carbon atoms and R2 represents a group of the formula -(CH2)nNR3R4 or <FORM:0750925/IV(a)/2> n being 2, 3 or 4, and R3 and R4 represent the same or different alkyl groups which contain from 1 to 3 carbon atoms, or R3 and R4 together with the nitrogen atom form the 1-pyrrolidinyl or piperidino group, and acid addition salts thereof, and the preparation thereof by heating a 2-halogeno-5-nitropyridine with an amine of the formula NHR1R2, wherein R1 and R2 have the above significance, e.g. in a solvent such as ethanol.  The reaction may be carried out in the presence of an acid binding agent, e.g. sodium acetate.  An alternative method claimed for the preparation of compounds of the above general formula in which R2 represents the <FORM:0750925/IV(a)/3> group is by reacting 2-halogeno-5-nitropyridine with a substituted phenol of the formula <FORM:0750925/IV(a)/4> and reacting the resulting product of the formula <FORM:0750925/IV(a)/5> with formaldehyde and an amine of the formula NHR3R4 wherein R3 and R4 have the above significance. Suitable salts mentioned are the hydrochloride, acid oxalate and embonate salts.  In Example 1, 2-[N-(b -hydroxyethyl)-N-(b  - piperidinoethyl) amino] - 5 - nitropyridine is prepared by heating b -piperidinoethylamine and ethylene oxide in a closed vessel to form b - (b  - piperidinoethylamino) - ethanol which is then reacted with 2-chloro-5-nitropyridine, and is converted to the hydrochloride salt. By a similar procedure the following compounds are prepared:-b  - (b - diethylaminoethylamino) - ethanol which forms 2-[N-(b -diethylaminoethyl)-N - (b  - hydroxyethyl) - amino] - 5 - nitropyridine and the acid oxalate thereof; b -(g -methylisopropylaminopropylamino) - ethanol which forms 2 - [N - (b - hydroxyethyl) - N - (g  - methylisopropylaminopropyl) - amino] - 5 - nitropyridine and the acid oxalate thereof; b  - (g  - 1 - pyrrolidinylpropylamino) - ethanol which forms 2-[N-(b -hydroxyethyl)-N-(g -1-pyrrolidinylpropyl) - amino] - 5 - nitropyridine and the acid oxalate thereof; b -(g -piperidinopropylamino)-ethanol which forms 2-[N-(b -hydroxyethyl) - N - (g  - piperidinopropyl) - amino] - 5 - nitropyridine and the acid oxalate thereof; b  - (g  - dipropylaminopropylamino) - ethanol which forms 2 - [N - (g  - dipropylaminopropyl)-N - (b  - hydroxyethyl) - amino] - 5 - nitropyridine and the acid oxalate thereof; b -(d -piperidinobutylamino)-ethanol which forms 2-[N-(b -hydroxyethyl) - N - (d  - piperidinobutyl) - amino] - 5 - nitropyridine and the acid oxalate thereof.  In Example 2, 2-[N-(g -hydroxypropyl) - N - (g  - 1 - pyrrolidinylpropyl)-amino]-5-nitropyridine is prepared by heatin g -1-pyrrolidinylpropylamine and g -chloropropanol to form g -(g -1-pyrrolidinylpropylamino) propanol which is then reacted with 2-chloro-5-nitropyridine, and may be converted into the acid oxalate salt.  In Example 3, 2-[N-ethyl-N-(g  - 1 - pyrrolidinylpropyl) - amino] - 5 - nitropyridine is prepared by reacting g -1-pyrrolidinylpropanol with hydrobromic acid and the resulting substituted propyl bromide is reacted with ethylamine by heating in an autoclave to form N - (g  - 1 - pyrrolidinylpropyl) ethylamine which is then reacted with 2-chloro-5-nitropyridine, and may be converted into the hydrochloride salt.  By a similar procedure the following compounds are prepared:-N-(g -piperidinopropyl) methylamine which forms 2 - [N - methyl - N - (g piperidinopropyl)-amino]-5-nitropyridine and the acid oxalate thereof; N - (g  - piperidinopropyl) ethylamine which forms 2 - [N - ethyl - N - (g  - piperidinopropyl) amino] - 5 - nitropyridine and the acid oxalate, and embonate salts thereof; N-(g -isopropylpropylaminopropyl) ethylamine which forms 2 - [N - ethyl - N - (g  - isopropylpropylaminopropyl) amino]-5-nitropyridine and the acid oxalate salt thereof.  In Example 4, 2-[(4-hydroxy - 3 - piperidinomethyl) - N - methylanilino] - 5 - nitropyridine is prepared by heating 4 - hydroxy - N - methylacetanilide, formalin and piperidine to form 4-hydroxy-3-piperidinomethyl - N - methylacetanilide which is converted to the hydrochloride salt, treated with concentrated hydrochloric acid to form 4 - methylamino - 2 - piperidinomethylphenol dihydrochloride which is reacted with 2-chloro-5-nitropyridine in the presence of sodium acetate and potassium carbonate, and is converted to the hydrochloride salt. By a similar procedure the following compounds are prepared: 3-diethylaminomethyl - 4 - hydroxy - N - methylacetanilide hydrochloride, 2 - diethylaminomethyl - 4 - methylaminophenol dihydrochloride and 2-[(3 - diethylaminomethyl - 4 - hydroxy) - N - methylanilino] - 5 - nitropyridine and the hydrochloride salt thereof.  In Example 5, 2-[(3 - diethylaminomethyl - 4 - hydroxy) - N - methylanilino] - 5 - nitropyridine is prepared by reacting 2 - chloro - 5 - nitropyridine and 4-methylaminophenol in the presence of sodium acetate to form 2-(41-hydroxy-N-methylanilino)-5-nitropyridine which is then heated with paraformaldehyde, diethylamine, and is converted to the hydrochloride salt.  By a similar procedure 2 - [(4 - hydroxy - 3 - 11 - pyrrolidinylmethyl) - N - methylanilino] - 5 - nitropyridine is prepared from 2-(41-hydroxy-N-methylanilino)-5-nitropyridine, paraformaldehyde and pyrrolidine and is converted to the hydrochloride salt; 2 - [(4 - hydroxy - 3 - piperidinomethyl) - N - ethylanilino] - 5 - nitropyridine is prepared from 2 - (41 - hydroxy - N - ethylanilino) - 5 - nitropyridine (obtained by reacting 4-ethylaminophenol and 2-chloro-5-nitropyridine), piperidine and paraformaldehyde, and is converted to the hydrochloride and embonate salts; 2 - [(4 - hydroxy - 3 - piperidinomethyl) - N - propylanilino] - 5 - nitropyridine is prepared from 2 - (41 - hydroxy - N - propylanilino) - 5 - nitropyridine (obtained by reacting 4-propylaminophenol and 2 - chloro - 5 - nitropyridine), piperidine and paraformaldehyde, and is converted to the acid oxalate salt.