L-Methyl-4-piperidinol

A mixture of 46 grams of l-methyl-4-piperidinol (0.4 mol), 49.4 grams of benzhydryl bromide (0.2 mol) and 100 ml of xylene was refluxed for approximately 24 hours. The reaction mixture separated into two phases with the upper phase containing the desired ether compound dissolved in xylene. The lower phase consisted of the hydrobromide salt of the excess l-methyl-4-piperidinol. The upper phase was separated from the lower phase and the desired benzhydryl ether recovered in the crude state by distilling off the xylene under reduced pressure. 

Phenylacetonitrile Thionyl chloride Sodium amide l-Methyl-4-piperidinol... 

Phenylacetonitrile is alkylated with secondary butyl bromide and the resultant nitrile is hydrolyzed to 3-methyl-2-phenylvaleric acid. The acid is converted to the acid chloride with thionyl chloride and the acid chloride is in turn reacted with l-methyl-4-piperidinol. Finally dimethyl sulfate is reacted with the ester. 

A mixture of 46 g of l-methyl-4-piperidinol (0.4 mol), 49.4 g of benzhydryl bromide (0.2 mol) and 100 ml of xylene was refluxed for approximately 24 hours. The reaction mixture separated into two phases with the upper phase containing the desired ether compound dissolved in xylene. The lower phase consisted of the hydro bromide salt of the excess l-methyl-4-piperidinol. The upper phase was separated from the lower phase and the desired benzhydryl ether recovered in the crude state by distilling off the xylene under reduced pressure. The crude benzhydryl ether was a clear reddish oil. It was dissolved in 75 ml of 20% hydrochloric acid and the aqueous acid solution then washed three times with 50 ml portions each of ethyl ether. The aqueous acid solution was then decolorized with activated carbon and thereafter slowly admixed with 75 ml of 28% aqueous ammonia. The benzhydryl ether separated as an oily material and was removed from the aqueous mixture by extraction with three 50 ml portions of ethylether. On evaporation of the ethyl ether from the ethyl ether solution, the benzhydryl ether was recovered as a pale yellow oil. The benzhydryl ether was dissolved in 60 ml of isopropanol and the isopropanol solution acidified to a PH of 3 with dry hydrogen chloride-methanol solution. The acidic propanol solution was then diluted with ethyl ether until a faint turbidity was observed. In a short time, the crystalline hydrochloride salt of the benzhydryl ether separated from the propanol solution. The crystallized salt was recrystallized once from 75 ml of isopropanol with the aid of ethyl ether in order to further purify the material. 

Complete removal of the 4-phenyl substituent of the reversed ester of pethidine results in a drastic fall in potency as judged from tests in mice (see 23, R = Et). However, certain esters of l-methyl-4-piperidinol formed from aromatic acids display antinociceptive activities in the morphine to codeine range of potency (23).<68) A QSAR study of such esters has been made and a substitution pattern of the phenyl group defined for optimal activity/69 The relevance of these compounds to morphine-type analgesics is doubtful since the more active members show marginal or no affinity for opioid receptors of rat brain homogenates and display no physical dependence in monkeys. 

Treatment of l-methyl-4-phenyl-3,4-epoxypiperidine with phenyl-magnesium bromide in refluxing anisole affords a mixture of 1-methyl-4,4-diphenyl-3-piperidinol (27) and l-methyl-4-phenyI-5-hydroxy-3-piperideine (28).21... 

Addition of hypobromous acid to l-methyl-4-phenyl-3-piperideine hydrobromide (127) was accomplished by the action of bromine in aqueous sodium bromide. Treatment of the resulting l-methyl-3-bromo-4-phenyl-4-piperidinol hydrobromide (128) with 10% aqueous sodium hydroxide gave l-methyl-4-phenyl-3,4-epoxypiperidine (129).114 (Compound 128 was formerly given the erroneous structure of l-methyl-5-bromo-4-phenyl-3-piperideine hydrobromide.7)... 

Hydroboration of l-methyl-3-piperideine with (— )-diisopino-camphenylborane (followed by oxidation) gave ( — )-S- 1-methyl-3-piperidinol (132).116 A similar hydroboration of l-methyl-4-phenyl-3-... 

Both exo- and endo-cyclic alicyclic and heterocyclic ketones have been reduced. Important examples are found in the preparations of cyclo-pentanol (95%), cycloheptanol (92%), /S-pyridylmethylcarbinol (85%), and l-alkyl-4-piperidinols (90%). A comparison of four reagents—sodium and alcohol, lithium aluminum hydride, hydrogen and Raney nickel, and hydrogen and copper-chromium oxide—has been made in the preparation of methyl cyclopropylcarbinol. The last method is superior for the preparation of this compound (SH)%). ... 

A mixture of 24 parts of 4,4-bis(p-fluorophenyl)butyl chloride, 20.9 parts of 4(4-chloro-a,a,a-trifluoro-m-tolyl)-4-piperidinol, 13.8 parts of sodium carbonate, a few crystals of potassium iodide in 600 parts of 4-methyl-2-pentanone is stirred and refluxed for 60 hours. The reaction mixture is cooled and 150 parts of water is added. The organic layer is separated, dried, filtered and evaporated. The oily residue is crystallized from diisopropylether, yielding 4-(4chloro-a,a,a-trifluoro-m-tolyl)-l-[4,4-bis(p-fiuorophenyl)butyl]-4-piperidinol melting point 106.5°C. 

Dehydration of l-alkyI-3-methyl-4-aryl-4-piperidinol in hydrochloric acid and acetic acid afforded a mixture of isomeric piperideines (10), (ll).9-10... 

Some l-alkyl-4-aryl-3-piperideines are obtained from a-methyl-styrene and its derivatives by the reaction with formaldehyde and hydrochloride of a primary amine, rearrangement of the resulting oxazine derivative (14) with sulfuric acid or hydrochloric acid to l-alkyl-4-aryl-4-piperidinol, and dehydration of the latter.13-15... 

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