United States Patent Office Paterated Feb

3,306,895 United States Patent Office Paterated Feb. 28, 1967 1. 2 3,306,895 The compounds of this invention are obtained by treat HETEROCYCLIC DERVATIVES OF TRPHENYL ment of triphenylethylene derivatives of the type: , ETHYLENES, TRIPHENYLETHANES AND TRI PHENYLETHANOLS Edward McCreery Roberts, George Philip Claxton, and 5 Frances Gertrude Fallon, Cincinnati, Ohio, assignors to Richardson-Merrell Inc., New York, N.Y., a corpo ration of Delaware No Drawing. Filed June 27, 1962, Ser. No. 205,551 10 Claims. (C. 260-240) k This invention relates to a series of novel and useful O where R and R' are as previously defined, with an ap compounds and processes for preparing the same. More propriate organometallic derivative such as cy-picolyl particularly, this invention relates to a series of triphenyl lithium (as in Examples 2 and 5), 3-pyridyl lithium (as ethanes, triphenylethylenes, and triphenylethanols, in in Example 6), or 2-pyridyl lithium (as in Examples 1 which one of the phenyl groups is substituted with a pyri and 4). Such treatment is conveniently carried out by dyl or reduced pyridyl ring which is separated from the mixing the reactants in an inert solvent such as ether, aromatic portion of the molecule by an oxygenated alkyl benzene, toluene, or combinations of such inert solvents fragment of one, two or three carbon atoms. The inven at appropriate temperatures chosen in the range of tion also includes nontoxic, water-soluble addition salts, -60° C. to 80° C. The resulting imine is hydrolyzed to quaternary ammonium derivatives and N-oxide deriva the corresponding ketone without being isolated by being tives of the new compounds. Inixed with dilute mineral acid at 25-100 C. The compounds of this invention may be represented The resulting keto-triphenylethylenes, which will here by the following formulas: inafter be referred to collectively as triphenylethylene pyridylalkanones, may be seen to have three reactive centers capable of being reduced. These are the ethylenic double bond, the keto group, and the pyridine ring double bonds. By varying the order and extent of the reduction of these reactive centers, a variety of useful compounds may be obtained. Such reductions and the production of 30 useful derivatives of the reduced compounds are discussed in the numbered sections below. (1) REDUCTION OF THE PYRIDINE RING 35 ( )--CH-( )-(-CH H 4) / O DC { > -- (=CH3:2 . ( >-0-chi-k)--CH-/ Y where: Hydrogenation of the triphenylethylene-pyridyl-alka R and R' are hydrogen, chlorine or methoxyl; nones to the triphenylethylene-piperidylalkanones may be Y is an oxygenated carbon fragment chosen from the effected at room temperature in an acidic medium in the following: presence of platinum oxide catalyst at an initial hydrogen 5 preSSure of 25-125 lbs./sq. in., as in Examples 8 and 9. ? OH QH (H GH The acidic medium may be realized, for instance, by dis -C-, bH , -C-CFI-, -CH-CH-, -C-, g CH Solving or suspending: E CH (a) A mineral acid salt of the triphenyl-ethylene pyridylalkanone in a suitable polar solvent such as meth in which the carbon bearing the oxygen is always attached 60 anol, ethanol, dimethylformamide or acetic acid. to the phenyl ring; (b) The triphenylethylene-pyridylalkanone in acetic Z is a pyridyl ring or a partially or completely saturated acid. pyridyl ring which is attached to Y through a ring-carbon (c) The triphenylethylene-pyridylalkanone in metha atom. The nitrogen of the reduced pyridyl ring bears a nol, ethanol, or dimethylformamide plus enough mineral hydrogen atom or a lower alkyl substituent. 65 acid to more than neutralize the organic base. 3,306,895 3 4. Under the above described conditions, the uptake of (4) REDUCTION OF THE PYRIDINE RING, THE hydrogen slows markedly when the triphenyl-ethylene KETO GROUP AND THE ETHYLENE DOUBLE piperidylalkanone stage is reached, that is, when three BOND molar-equivalents of hydrogen have been consumed. The reaction may be stopped at this point to give the desired 5 Compounds in which all three reactive centers of un products. saturation are fully reduced to produce triphenylethane In a completely analogous manner, the hydrogenation piperidylalkanols may be derived by the further reduc of a quiternary salt of a triphenylethylene-pyridylalka tion of any of the triphenylethylenes above. In practice, they have been obtained by two general procedures: none (such as those in Example 7) may be made to yield (a) The one-step reduction by complete hydrogenation a triphenylethylene-N-alkylpiperidylalkanone (as in Ex O (with five molar-equivalents of hydrogen) of the tri ample 24). phenylethylene-pyridylalkanones (as in Example 14). (2) REDUCTION OF THE KETO GROUP Such reductions may be carried out in methanol, ethanol, The reduction of the keto group, without affecting the acetic acid, or dimethylformamide in the presence of a pyridine ring unsaturation, may be realized in several catalyst, such as platinum oxide or 10 percent palladium ways: to give a secondary alcohol by direct reduction on charcoal, at an appropriate temperature between 25 (as in Example 31); or a tertiary alcohol by alkylative ... C. and 80° C. and at an initial hydrogen pressure of 25 reduction (as in Example 3). That is, mixing a triphenyi 125 lbs./sq. in. The necessary acidic medium is attained ethylene-pyridylalkanone in ethanol or methanol (or a as described above in Section (1). mineral acid salt of such an alkanone in methanol or 20 (b) The hydrogenation of triphenylethylene-piperidyl ethanol plus an equivalent or a slight excess of aqueous alkanols as either a free base or a mineral acid salt, dis base, such as dilute sodium hydroxide) with a complex solved or suspended in methanol, ethanol, acetic acid, or metal hydride, such as sodium borohydride, yields a dimethylformamide, in the presence of 10 percent palladi secondary triphenylethylene-pyridylalkanol (as in Exam um on charcoal at an initial hydrogen pressure of 25-125 ple 31). Similar results may be achieved under anhy lbs./sq. in. Examples of this procedure are shown in Ex drous conditions by mixing absolute ether or tetrahydro amples 15, 16, 27, 28, and 29. furan solutions of triphenylethylene-pyridylalkanones and complex metal hydrides such as lithium aluminum hy (5) PREPARATION OF DERIVATIVES OF dride. Alkylative reductions are brought about by mixing PIPERDYLALKANOLS ether solutions of a triphenylethylene-pyridylalkanone 30 A number of useful derivatives can be made by further and an organo-metallic reagent such as alkyl-lithium or reaction of the triphenylethylene-piperidylalkanols and an alkyl-magnesium halide. This treatment yields a the triphenylethane-piperidylalkanois. These are N-alkyl tertiary triphenylethylene-pyridylalkanol as in Example 3. derivatives, N-alkyl-N-oxides, and N,N-dialkylpiperidini (3) REDUCTION OF BOTH THE PYRIDINE um salts. RING AND THE KETO GROUP The reduction of both the pyridyl ring unsaturation and the keto group of the triphenylethylene-pyridylalka nones leads to triphenylethylene-piperidylalkanols. This (a) N-alkyi Derivatives 4() two-step reduction may be accomplished in either order, N N as can be seen from the discussion in the two preceding OH N sections. That is to say, the further reduction of either O C -9- the triphenylethylene-pyridylakanols or the triphenyleth R-CH-CH / N R-CH-CH / ylene-piperidylalkanones yields triphenylethylene-piper rur-H orCFIIs idylalkanols. The same result may be achieved in one 4: step by allowing the triphenylethylene-pyridylalkanones ) Where R is to take up four molar-equivalents of hydrogen in the initially described hydrogenation. More specifically, these triphenylethylene-piperidylalkanols may be obtained as ( )--CH-KY follows: (a) By hydrogenation of triphenylethylene-pyridylal 50 kanols (as in Example 38) under any of the conditions described in Section (1). (b) By the reduction of triphenylethylene-piperidylal O kanones (as in Examples 12, 13, 34, 37, and the alternate 55 procedure of Example 10) under any of the conditions described in Section (2). ( )-(H-CH-(D- (c) By the hydrogenation of triphenylethylene-pyridyl alkanones with four molar-equivalents of hydrogen (as in Examples 10 and 11) under any of the conditions de scribed in Section (1). In this case, the hydrogen uptake 60 N is simply allowed to proceed until four molar-equivalents of hydrogen have been consumed. A special subclass of this stage of reduction is obtained (as in Example 32) when the keto group is reduced and 65 N-alkyl derivatives which resulted from the reduction the pyridine ring is only partly reduced. These com of triphenyletheylene-pyridylalkanone quaternary salts pounds, triphenylethylene - N-alkyltetrahydro-pyridineal and N-alkyltriphenylethylene-piperidylalkanone are dis kanols, are obtained by mixing a methanol or ethanol cussed in Sections (1) and (3) above. N-methylation Solution of a quaternary salt of a triphenylethylene-pyr of the already-reduced triphenylethylene- and triphenyl idylalkanone with one or slightly more than one equiv ethane-piperidylalkanols may be carried out by heating alent of a base, such as dilute sodium hydroxide, and a at reflux a water suspension of the starting piperidylalka complex metal hydride, such as sodium borohydride, with nol (or its mineral acid salt plus a molar-equivalent of or without isolation of the intermediate quaternary enolate sodium formate) in the presence of formaldehyde and formed by treatment of the triphenylethylene-pyridylal formic acid (as in Examples 18, 19, 20, 21, 25, 26 and kanone quaternary Salt with the dilute sodium hydroxide. 75 30). 3,306,895 5 6 (b) N-Alkyl-N-Oxide Derivatives istered parenterally. In most cases, the compounds of the specific examples have been found to have this physi ological activity. Some of the individual compounds of the specific examples also show additional physiological 5 effects as will be indicated. These include cholesterol depressant, anti-inflammatory, and blood coagulant and anti-coagulant activities.

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