Piperidinols

When the terminal anilino moiety of the 4-substituent of 30 is replaced by methylaminocyclohexane, a compound as active as morphine results (ED50 3.2 mg/kg) the dextro antipode (ED50 42 mg/kg) is distinctly less active than the racemic mixture, but the levo form (ED50 3.8 mg/kg) does not show the expected doubling of potency. The more potent members of the group effectively displace [3H]naloxone from rat brain membranes provided NaCl is absent, while theN-propyl analog of 30 (a typical member) produced mydriasis accompanied by a Straub tail response and CNS depressant effects 

Synthesis routes used in the work involved condensation of l-benzyl-4-piperidone with an appropriately substituted propionamide promoted by a strong base (lithium diisopropylamide, LDI), with subsequent alkylation of anilino nitrogen (if necessary) and replacement of N-benzyl by the 2-arylethyl substituent. Direct use of the N-arylethyl-4-piperidone was also made. 

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A mixture of 46 grams of Tmethyl-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... 

A mixture of 6.33 parts of 4-(p-chlorophenyl)-4-piperidinol, 8 parts of sodium carbonate,... 

Chemical Name 1 -[4,4-Bis(4-fluorophenvl)butyl] -4-[4-chloro-3-(trifluoromethyl)phenvl] -4-piperidinol... 

Bls(p-fluorophenyl)butyl chloride 4-(4-Chloro-o ,a,a-trifluoro-m-tolyl)-4-piperidinol... 

A mixture of 24 partsof 4,4-bis(p-fluorophenyl)butyl chloride, 20.9 partsof 4-(4-chloro-aXX,a-trifluoro-m-tolyl)-4-piperidinol, 135 partsof 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 partsof water is added. The organic layer is separated, dried, filtered and evaporated. The oily residue is crystallized from diisopropylether, yielding 4-(4[Pg.1172]

Sodium amide Sodium hydroxide 1-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 chioride with thionyl chloride and the acid chloride is in turn reacted with 1-methyl-4-piperidinol. Finally dimethyl sulfate is reacted with the ester. 

Chemical Name 1-[3-(2-methoxyphenothia2in-10-yl)-2-methylpropyl] -4-piperidinol Common Name —... 

When primary amines are employed, the initially formed 3-butenylamine undergoes a further reaction forming 4-piperidinols.122... 

Benzilate esters of piperidinols, as well as those of acyclic aminoalcohols, show similar anticholinergic activity. For example, ester interchange between methyl benzilate and N-methyl-4-piperidinol, followed by quaternization of the resulting ester... 

Base-catalyzed condensation between phenylacetic acid and phthalic acid produces enol lactone 78, which is reduced to benzoate 79 with HI and phosphorous. Friedel-Crafts cyclization by polyphosphoric acid followed by reduction produces alcohol 80. This alcohol forms ethers exceedingly easily, probably via the carbonium ion. Treatment with N-methyl-4— piperidinol in the presence 6f acid leads to the antidepressant hepzidine (81). 

Thomsen, C., Sprensen, P. 0., and Egebjerg, J. (1997) l-(3-(9H-carbazol-9-yl)-l- propyl)-4-(2-methoxyphenyl)-4-piperidinol, a novel subtype selective inhibitor of the mouse type II GABA-transporter. Br. J. Pharmacol. 120,983-985. 

Penfluridol Penfluridol, 4-(4-chloro-3-trifluoromethylphenyl)-l-[4,4-Z M-(p-fluorophenyl) butyl]-4-piperidinol (6.6.12), is synthesized implementing a Grignard reaction between l-carbomethoxypiperidin-4-one and 4-chloro-3-trifluoromethylphenylmagnesium bromide, giving l-carbomethoxy-(4-chloro-3-trifluoromethylphenyl)-4-piperidinol (6.6.10). Upon alkaline hydrolysis of the carbomethoxy group, it turns into (4-chloro-3-trifluo-romethylphenyl)-4-piperidinol (6.6.11), the alkylation of which with l,l-( ti(4-fluo-rophenyl)butyl bromide (6.6.3) gives penfluridol (6.6.12) [67-69],... 

We now turn to the remaining two hydroxylamines that are N-hydroxylated derivatives of 2,2,6,6-tetramethyl-4-piperidone and -4-piperidinol. The enthalpies of formation of some simple 4-piperidones and their corresponding 4-piperidinols have recently been determined. The values of gaseous N-methyl-4-piperidone and Af-methyl-4-piperidinol are —160.7 1.7 and —226.8 1.8 kJmol (also see Reference 18). The difference between these contemporary values is — 66.1 2.5 kJmol while for the hydroxylated and methylated counterpart species the difference is —47.0 4.8 kJmoH. For comparison, the formal enthalpy of reduction of 3-hexanone to 3-hexanol is ca —54 kJmoH. As has been discussed earlier, reduction enthalpies are not necessarily constant . Relatedly, reaction 8 that exchanges N-methyl and N-hydroxy and parent and tetramethylpiperidines is endothermic by 19.1 5.4 kJmol . The deviation from thermoneutrality is more... 

Replacement of the hydrazine function by a substituted 4-piperidinol leads to a compound that has been investigated as a cardiotonic agent that acts by increasing the contractile force of cardiac smooth muscle. The preparation is quite analogous to those above. The key step involves the displacement of chlorine from the substituted chlorophthalazine (68-1) with the ethyl carbamate from 4-piperidinol (68-2) to afford the alkylation product carbazeran (68-3) [77]. 

Synthesis (Kleemann et al. 1999, Janssen (Janssen), 1973 Janssen et al. (Janssen), 1973, Stokbroekx et al., 1973, Niemegeers et al., 1974) ) Treatment of 2-oxo-3,3-diphenyl-tetrahydrofuran, synthesized by treatment of diphenyl-acetic acid ethyl ester with ethylene oxide, with HBr(gas) yields bromo derivative i, which is then converted into butyryl chloride derivative ii by means of thionyl chloride in refluxing chloroform. Reaction of derivative ii with dimethylamine in toluene affords dimethyl (tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide, which is then condensed with 4-(4-chlorophenyl)-4-piperidinol by means of Na2C03 and Kl in refluxing 4-methyl-2-pentanone to provide loperamide. 

Hydrogen bromide 2-Oxo-3,3-diphenyl-tetrahydrofuran Thionyl chloride 4-(p-Chlorophenyl)-4-piperidinol... 

A mixture of 6.33 parts of 4-(p-chlorophenyl)-4-piperidinol, 8 parts of sodium carbonate, 0.2 part of potassium iodide and 240 parts of 4-methyl-2-pentanone is distilled azeotropically. Then there are added 12.12 parts of dimethyl-(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide (from the preceding step) and the whole is stirred and refluxed for about 15 hours. The reaction mixture is filtered hot and the filtrate is evaporated. 

Diphenylchloroacetyl chloride Silver bromide N-Methyl-4-piperidinol HCI... 

N-methyl-4-piperidyl benzilate and the methiodide An intimate mixture of 0.1 mol of N-methyl-4-piperidinol hydrochloride and 0.1 mol diphenylchloroacetyl chloride is heated at 160°C to 180°C until the evolution of hydrogen chloride ceases (usually about 4 to 5 hours). The melt is then dissolved in 500 ml of water and the resultant mixture heated on a steam bath for about Vi hour, after which time complete solution is effected. The acid solution is cooled and rendered alkaline with ammonium hydroxide solution whereupon the ester is precipitated. The ester is purified either by removal by filtration and recrystallization from benzene petroleum ether or by extracting the mixture with benzene and precipitating the ester by the addition of petroleum ether. After recrystallization there is obtained about 0.06 mol of N-methyl-4-piperidyl benzilate, melting point 162°C to 163°C. 

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. 

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