US patent 2498433 - Prodine
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US patent 2498433
Notes on Use as Pharmaceuticals:
It has been found that those compounds, as described in this patent, that do not have a 3-methyl substituent are drastically less toxic and causing no spasticity in animal experiments. They also have a high analgesic effect. The compounds of this document are also much more stable in aqueous solution.
In a RB flask provided with a stirrer, dropping funnel, condensor and a gas outlet for keeping the system under nitrogen, 200cc of dry ether is placed and 4.6g of Li metal cut into thin strips is added. 52g of bromobenzene in 50cc of dry ether are added dropwise and after addition, the mixture is refluxed for 2 hours. This procedure results in the formation of phenyl-Li. Other aryl-Li compounds can be prepared in a similar manner by reacting Li metal or a lithium compound capable of exchangeable halogen group as, for example, bromonaphthalene.
The solution of phenyl-Li is cooled to –20*C and to this a solution 12.7g of 1,3-dimethyl-4-piperidone, prepared according to the method of Howton, JOC 10, 277 (1945), in ether is added dropwise with stirring. After the addition, the stirring is continued for a further 2 hours at –20*C. The Li-complex, 1,3-dimethyl-4-phenyl-4-oxylithium piperidine, which forms is soluble in ether and can recovered therefrom. To prepare the piperidinol, the Li-complex, while in the reaction mixture is decomposed by the addition of an ice and hydrochloric acid mixture. The acidified layer is separated, basified and extracted with ether. After drying the ether solution, and removing the solvent, the residue on distillation in vacuum distill chiefly at 155*C/10mmHg, yielding the product 1,3-dimethyl-4-phenyl-4-hydroxypiperidin
3g of 1,3-dimethyl-4-phenyl-4-hydroxypiperidin
The salt obtained above is dissolved in water, made alkaline with sodium hydroxide and the resultant base is extracted with ether. The ether is dried with sodium sulfate and then the solvent removed. The free base is dissolved in 10-cc of propionic anhydride and 1 drop of sulfuric acid as a catalyst. The mixture is refluxed on a steam bath for 3 hours. The larger part of the anhydride is removed in a vacuum. The residue is poured onto an ice bath. This is extracted with ether and dried over sodium sulfate for 12 hours then filtered. HCl gas is then passed through the ether to form the HCl salt of the freebase, which will be recrystallized from ethyl acetate to give colorless, shiny crystals of 1,3-dimethyl-4-cyclohexyl-4-propionoxy piperidine HCl that have; MP: 205-206*C.
300g of benzyl amine (Post 399055 (Aurelius: "Preparation of Benzylamine", Methods Discourse)) and 420g of methyl methacrylate are mixed with 300cc of methanol and allowed to stand for 4 days at RT. The methanol and excess methyl methacrylate are removed in vacuo and the residue is distilled in vacuo to obtain (beta-methyl-beta-carbomethoxy)-ethyl-be
289g of (beta-methyl-beta-carbomethoxy)-ethyl-be
In a flask equipped with stirring apparatus, reflux condensor and dropping funnel is placed 1500cc of toluene and 25.3g of sodium shot is added. The mixture is brought, with stirring, to 100*C and the diester is added gradually. After the addition is completed, the flask is heated for a further 2 hours with stirring and then cooled to RT. 1000cc of water is added through a dropping funnel and the solid which separates is redissolved by the further addition of 400cc of conc. HCl acid. The toluene layer is separated and the aqueous layer is heated under reflux to saponify the 1-benzyl-3-methyl-5-carboethoxy-4-piperi
3.7g of Li metal wire is cut into small pieces and added to 300cc of dry ether in a reaction vessel equipped with stirring, dropping funnel, reflux condensor and the capability to form a stream of N2. After the addition, stirring is continued for 1 hour; 100cc of water is then added in small portions. The ether layer is separated and dried over potassium carbonate. The ether is filtered from the potassium carbonate and the ether removed under vacuum. The residue on fractionation yields 1-benzyl-3-methyl-4-phenyl-4-hydroxypipe
The piperidinol so obtained may transformed into esters such as the propionate, benzonate and the like, as such in previous examples.
In an apparatus for performing Grignard reactions, 2.4g of Mg metal is added to 100cc of dry ether. To this, 15.7g of bromobenzene is added dropwise with stirring. After this addition, the ether is refluxed for 1 hour when the formation of the reagent is complete. The flask and the contents are cooled in an ice bath and a solution of 20.3g of 1-benzyl-3-methyl-4-piperidone in 100cc of ether is added dropwise. After the addition, the reaction mixture is refluxed for 2 hours, the flask cooled by means of an ice bath and 50cc of saturated ammonium chloride is added in portions with stirring followed by the addition of 100cc of water. The ether layer is separated, dried over potassium carbonate, filtered and the ether removed in vacuo. This yields 1-benzyl-3-methyl-4-phenyl-4-hydroxypipe
Other References Mentioned:
JACS 53, 1017 (1931)
CA 33, 5403 (1939)
CA 36, 2853 (1942)
CA 37, 5053 (1943)
JOC 10, 277 (1945)
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