Patent GB-702269-A (GB)
Title: Tertiary allylamines of therapeutic value and the production thereof
Inventor: ADAMSON DONALD WALLACE
IPC: C07D333/20
Filed: 1950-01-06
Abstract: The invention comprises as new compounds having strong analgesic properties, 3-methylethylamino-1 : 1-di-(2-thienyl)-but-1-ene or a salt thereof and 3-diethylamino-1 : 1-di-(2-thienyl)-but-1-ene or a salt thereof.  The compounds may be prepared by treating the corresponding aminoalkanols with a dehydrating agent to remove the elements of water.  The aminoalkanols may be prepared by reacting together an alkyl ester of the formula: <FORM:0702269/IV(b)/1> in which NR2R3 is a diethylamino or methylethyl-amino group and R4 is an alkyl radical, or a salt thereof, and 2-thienyllithium or the organo - magnesium compound derived from 2-bromothiophen and then hydrolysing the organo-metallic compound so formed.  Alternatively the aminoalkanols may be prepared by reacting a 2-thienyl b -aminoalkyl ketone of the formula:-  <FORM:0702269/IV(b)/2> in which <FORM:0702269/IV(b)/3> is as defined above with 2-thienyllithium or the organo-magnesium compound derived from 2-bromothiophen and then hydrolysing the organo-metallic compound so formed.  In examples: (1) thiophen in anhydrous ether is added to an ethereal solution of n-butyllithium prepared from n-butyl chloride, lithium and anhydrous ether, and the mixture boiled under reflux in a stream of nitrogen. Methyl b -methylethylaminobutyrate is then added gradually with stirring and cooling to -20 DEG C.  Stirring is then continued at room temperature and ice added followed by glacial acetic acid until the solution is acidic to litmus.  The precipitated white solid is filtered, washed with ether, suspended in chloroform and treated with excess ammonia and 3-methyl-ethylamino-1-1-di-(2-thienyl)-butan-1-ol isolated from the chloroform extract.  The aminoalkanol is then warmed with concentrated hydrochloric acid and glacial acetic acid, the solution poured into water, extracted with ether to yield the product 3-methylethylamino-1:1-di-(2-thienyl)-but-1-ene the hydrochloride of which is also described; (2) ethyl b -diethylaminobutyrate is reacted with a solution of 2-thienyllithium in ether under conditions similar to those of (1) to give 3-diethylamino-1:1-di-(2-thienyl)-butan-1-ol the acid oxalate of which is also described.  The aminoalkanol is then heated with 6N hydrochloric acid, the solution cooled, excess ammonia added and the mixture extracted with chloroform to yield 3-diethylamino-1:1-di-(2-thienyl)-but-1-ene, the hydrochloride of which is also described.  Specification 657,301 is referred to. Methyl-b -methylethylaminobutyrate is prepared by reacting methylethylamine and methyl crotonate in methanol at room temperature.  The first Provisional Specification describes the production of the diethylamino compounds and of 3-N-pyrrolidino-(and 3-N-piperidino-)-1:1-di (21-thienyl) but-1-ene and 3-diamethylamino-1:1-di (21-thienyl) hex-1-ene and the corresponding aminoalkanols by similar methods and states that the aminoalkanols may be converted to water-soluble salts by treatment with acids such as hydrochloric, hydrobromic, phosphoric, maleic, mucic and succinic acids.  It also states that the dehydration of the amino alkanols may be effected by reacting them or their salts with mineral acids, carboxylic acid chlorides and carboxylic acid anhydrides and the acid oxalates of the aminobutanol derivatives as well as the hydrochlorides of the tertiary allylamines are described.  The preparation of methyl b -N-pyrrolidinobutyrate by reacting methyl crotonate with pyrrolidine and of methyl b -dimethyl aminocaproate by reacting methyl-b -norpropylacrylate with dimethylamine are also described.