Patent GB-816504-A (GB)
Title: Manufacture of new quinuclidine derivatives
Filed: 1955-10-07
Abstract: The invention comprises quinuclidines which are C-substituted only in the 4-position by a free or functionally converted carboxyl group, their salts and quaternary compounds, and a process for the preparation of quinuclidines by reacting a 1-alkyl-4-cyanopiperidine in the form of a metal derivative thereof with a reactive ester of a vic-glycol, and then, if desired, converting the cyano group to carboxyl or a functional derivative thereof, e.g. amide or ester, while at any stage after the condensation with the glycol ester the resulting compound or compounds may be dequaternated and the base or bases so obtained converted, if desired, into a salt or salts or quaternary compound(s), or from a resulting salt or salts the free base or bases may be isolated.  The metal derivatives are formed, e.g. with sodium or lithium amide, potassium in liquid ammonia, lithium diethylamide, or sodium phenyl; the nitriles are converted to carboxylic acids or their derivatives by known methods, e.g. hydrolysis, alcoholysis, esterification, conversion to acid halides and treatment with alcohols or amines; treatment of the 1-alkyl-4-cyanoquinuclidinium halides with alkaline agents yields betaines.  Specified salt-forming acids are hydrohalic, sulphuric, nitric, phosphoric, thiocyanic, acetic, propionic, oxalic, malonic, succinic, malic, methane-, ethane-, and hydroxyethane-sulphonic, benzene and toluene sulphonic acids; quaternizing agents include alkyl halides, dialkyl sulphates, and toluene sulphonic acid.  In examples: (1) 1-methyl-4-cyanopiperidine and sodium phenyl are reacted in benzene and then treated with 1,2-dichlorethane yielding 1 - methyl - 4 - cyanoquinuclidinium chloride, characterized by conversion to the picrate; (2) the chloride from (1) is heated to 260-70 DEG  C. in vacuo, yielding 4-cyanoquinuclidine, which is converted to its picrate and methiodide; (3) saponification of the chloride from (1) with NaOH yields N-methyl-4-quinuclidinium carboxylic acid betaine, which on heating rearranges to the lactone of 1-methyl-4 - (b  - hydroxyethyl) - piperidine carboxylic acid; (4) 4-cyanoquinuclidine is saponified with NaOH and acidified giving quinuclidine-4-carboxylic acid hydrochloride which with silver oxide gives the free acid, characterized as its picrate; (5) treatment of the last-named hydrochloride with thionyl chloride and then methanol gives 4-carbomethoxy-quinuclidine hydrochloride and thence the free base; the 4-carbethoxy compound is similarly prepared.  Starting material.-1 - Methyl - 4 - cyanopiperidine is prepared from isonicotinic acid amide by hydrogenation with Raney nickel to isonipecotinic acid amide, methylation to 1-methyl-isonipecotinic acid amide and dehydration with thionyl chloride.ALSO:Pharmaceutical preparations, suitable for treatment of disturbed peristalsis, comprise quinuclidines which are C-substituted only in the 4-position by a free or functionally converted carboxyl group, their salts and quaternary compounds in admixture with organic or inorganic carriers suitable for enteral, parenteral or local application.  Specified carriers include water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly and cholesterol, and the compositions may further contain preserving, stabilizing, wetting or emulsifying agents, buffer or osmosis controlling salts, and other therapeutic agents.