Patent GB-657301-A (GB)
Title: Improvements in and relating to the preparation of substituted amino-alcohols and derivatives thereof
Inventor: ADAMSON DONALD WALLACE
IPC: C07D333/20
Filed: 1948-02-25
Abstract: 3 - Tertiaryamino - 1 : 1 - di - (2 - thienyl) - propan-1-ols of formula <FORM:0657301/IV (b)/1> (wherein R1 is H or CH3, R2 and R3 may be either identical or different and denote alkyl groups having together not more than 4 carbon atoms or NR2R3 may denote pyrrolidino or piperidino groups) are made by reacting an alkyl ester of the appropriately substituted tertiaryamino carboxylic acid of formula <FORM:0657301/IV (b)/2> (wherein R1, R2 and R3 are as above and R4 is alkyl) or a salt thereof with 2-thienyl-lithium or the organo-magnesium compound derived from 2-bromothiophene and subsequently hydrolysing the organo-metallic compound so formed. The products may be converted into the corresponding prop-1-enes of formula <FORM:0657301/IV (b)/3> by treatment with a dehydrating agent to remove the elements of water.  The organo-metallic reactant is dissolved in an anhydrous solvent and added to the ester or its salt reaction taking place at room temperature or on heating.  Hydrolysis is preferably effected with aqueous acid, particularly acetic acid, when usually a salt of the free base is obtained which is filtered off, suspended in a solvent such as chloroform and shaken with aqueous alkali, e.g. ammonia, so that the free base passes to the solvent layer from which it is recovered.  If the base forms soluble salts the above acid solution is basified and the free base recovered by solvent extraction.  The free bases are usually insoluble in water and may be converted to water-soluble salts, e.g. hydrochlorides, by treatment with the requisite acid.  Dehydration may be effected by treating the bases or their salts with agents usually employed for the dehydration of tertiary alcohols, e.g. mineral acids and carboxylic acid chlorides and anhydrides.  Thus the aminopropanol or a salt thereof may be warmed with aqueous HCl and the solution evaporated under reduced pressure and allowed to cool.  If the hydrochloride of the propene is deposited it is filtered off, otherwise evaporation is continued to dryness, the residue suspended in water and the free base recovered by solvent extraction after basifying with an alkali such as conc. ammonia. Dehydration may also be effected by passing excess dry HCl into the amino-propanol dissolved in an organic solvent such as chloroform or ethanol and warming.  The compounds are therapeutic agents having spasmolytic and analgesic properties.  In examples: (1) ethyl-b -N-piperidinopropionate is reacted in ether solution with the Grignard reagent made from magnesium and 2-bromo-thiophene, hydrolysed with acetic acid, the precipitated salt filtered off and the free base 3 - N - piperidino - 1 : 1 - di - (21 - thienyl) - propan-1-ol together with some b -piperidino-propiothienone recovered by vacuum distillation of the chloroform extract of an ammoniacal solution of the salt, the hydrochloride of the free base being also made; (2) the propan-1-ol of (1) is heated in 6N.HCl solution and the hydrochloride, from which the free base is obtained in conventional manner, of 3-N-piperidino - 1 : 1 - di - (21 - thienyl) - prop - 1 - ene is deposited in cooling as a hydrate; (3) 2-thienyllithium is made by reacting thiophene with phenyllithium in ether solution and then reacted with ethyl-b -N-pyrrolidinopropionate, also in ether solution, at 25 DEG  C., to yield 3-N-pyrrolidino - 1 : 1 - di - (21 - thienyl) - propan - 1 - ol, from which the hydrochloride is made, after hydrolysis with acetic acid; (4) 3-diethylamino - 1 : 1 - di - (21 - thienyl) - propan - 1 - ol is made from ethyl-b -diethylaminopropionate and the Grignard reagent of (1) by the method of (1); (5) 3-dimethylamino-1 : 1-di-(21-thienyl)-butan-1-ol is made from ethyl-b -dimethylamino-butyrate and 2-thienyl-lithium by the method of (3) and the hydrochloride made therefrom; and in (6) excess dry HCl is passed into the butanol of (5) in chloroform solution and the hydrochloride of 3-dimethylamino-1 : 1-di-(21-thienyl)-but-1-ene recovered and converted to the free base.  Ethyl-b -N-pyrrolidinopropionate used in (2) is made by refluxing equimolar quantities of pyrrolidine and ethyl acrylate for 6 hours and distilling the product.  In the Provisional Specification compounds of formula <FORM:0657301/IV (b)/4> (wherein R1 is alkyl, cycloalkyl, thienyl, aryl or aralkyl optionally substituted, e.g. with alkyl or alkoxy groups, R2 and R3 are H, alkyl or aryl, R4 and R5 may be identical or different and denote alkyl, alkenyl, cycloalkyl, aryl or aralkyl groups or NR4R5 may be morpholino, pyrrolidino or piperidino groups optionally substituted by one or more alkyl groups) are made by reacting the corresponding ketone of formula <FORM:0657301/IV (b)/5> or a salt thereof with the appropriate organo-magnesium halide or other reactive organo-metallic compound (e.g. an organo-lithium compound) and hydrolysing as above.  Alternatively some of the products may be made by reacting the corresponding tertiary aminoalkyl ketone of formula <FORM:0657301/IV (b)/6> (wherein R1 is alkyl or aryl, optionally containing alkyl or alkoxy groups) and the organo-magnesium derivative of 2-bromo-thiophene or other organo-metallic derivative of thiophene, e.g. 2 - thienyl - lithium and hydrolysing.  Products in which R1 is 2-thienyl, i.e. those corresponding to the compounds of the Complete Specification, are made by the methods disclosed therein, th corresponding tertiaryaminoalkyl thienyl ketone also being obtained.  Dehydration to compounds of formula <FORM:0657301/IV (b)/7> is described by the methods of the Complete Specification as are the salts of the various free bases obtained.  Quaternary ammonium salts of formul <FORM:0657301/IV (b)/8> and <FORM:0657301/IV (b)/9> in which R7 is alkyl or aralkyl and X is an acid radicle such as Cl, Br, I, or methosulphate are made by conventional methods, and in examples (1) b -N-piperidinopropiothienone hydrochloride is reacted in ether with phenyl magnesium bromide and 3-N-piperidino-1-phenyl-1-(2-thienyl)-propan-1-ol isolated after hydrolysis with acetic acid, it is also converted to the hydrochloride and methiodide; (2) 3-diethylamino-1-phenyl-1-(2-thienyl)-propan-1-ol is similarly prepared from diethylaminopropiothienone hydrochloride and its hydrochloride and methiodide made; (3) 3-N-piperidino-1 : 1-di-(2-thienyl)-propan-1-ol is made from b -N-piperidinopropiothienone hydrochloride and a Grignard reagent prepared from magnesium and 2-bromothiophene and its hydrochloride and methiodide made; (4) the product of (1) is made by reacting the Grignard reagent of (3) with b -N-piperidinopropiophenone hydrochloride; (6) 3-N-piperidino-1-phenyl-1-(2-thienyl-prop-1-ene is made by refluxing 3 - N - piperidino - 1 - phenyl - 1 - (2-thienyl)-propan-1-ol with conc.  HCl in acetic acid and its hydrochloride and methiodide made; (7) 3 - diethylamino - 1 - phenyl - 1 - (2-thienyl)-propan-1-ol is similarly dehydrated to 3-diethylamino-1-phenyl-1-(2-thienyl)-prop-1-ene, the hydrochloride and methiodide of which are also made; and in (8) the methiodide of 3 - N - piperidino - 1 : 1 - di - (2 - thienyl) - prop-1-ene is prepared.