Phenylpiperidines

More radical dissection of the morphine molecule was in progress concurrently with the work above. The chemistry of the series of analgesics that rely on an acyclic skeleton, the compounds related to methadone, is discussed earlier. Suffice it to say that this series of agents, with the possible exception of propoxyphene, seem to share abuse and addiction potential with their polycyclic counterparts. 

Examination of the morphine molecule reveals the presence of a 4-phenylpiperidine fragment within the molecule (A). It was 

The key intermediate, normeperidine (81), is obtained by a scheme closely akin to that used for the parent molecule, Thus, alkylation of phenylacetonitrile with the tosyl analog of the bischloroethyl amine (78) leads to the substituted piperidine 

Alkylation of that amine with p-(2-chloroethyl)aniline affords anileridine (82), an analgesic similar to the parent compound but somewhat more potent. In similar fashion alkylation by means of w-(2-chloroethyl)morpholine gives morpheridine (83), while the use of 2-(chloroethyl)-ethanol yields carbethl- 

Condensation of normeperidine (81) with 3-chloropropan-l-ol affords the compound possessing the alcohol side chain (88). The hydroxyl is then converted to chlorine by means of thionyl chloride (89) displacement of the halogen by aniline yields pimino-dine (90). ° Condensation of the secondary amine, 81, with styrene oxide affords the alcohol, 91 removal of the benzyllic hydroxyl group by hydrogenolysis leads to pheneridlne (92).  

---

On the basis of this retrosynthetic analysis, design a synthesis of A-methyl-4-phenylpiperidine (compound A, where R = CH3, R = CgHj). Present your answer as a series of equations, showing all necessary reagents and isolated intermediates. 

A mixture of 750 grams of 1-methyl-3-benzoyl-4-hydroxy-4-phenylpiperidine and 2,500 cc of 48% hydrobromic acid is refluxed for about 20 minutes. It is then poured into 8 liters of water. An oily precipitate appears which on standing crystallizes. It is filtered and crystallized from about 3.5 liters of alcohol. 2-Methyl-9-phenyl-2,3-dihydro-1-pyridindene hydrobromide, MP 201°-203°C, is obtained. 

The starting materials for the overall process are phenylacetonitrile with bis-chloroethyl toluene sulfonyl amide. These react to give a product which hydrolyzes to normeperidine (4-carboethoxy-4-phenylpiperidine). Condensation of that material with benzoylethylene gives the ketone /3-(4-carboethoxy-4-phenylpiperidino)propiophenone. 

I CN l-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxyIic acid ethyl ester hydrochloride... 

Diethyl A-(4-hydroxy-4-phenylpiperidin-1 -yl)methylenemalonate did not react with ketene in acetone to give a cyclobutanone derivative (64JMC68). 

By conventional tests, secondary amine analogues of 4-phenylpiperidine analgesics lack activity (normorphine is equi-potent with morphine by the intra-cisternal route [48]) many secondary bases of the thebaines,(VII), however, are morphine-like analgesics. These findings lend support to the view that the low potencies reported for many nor-analogues of analgesics are due to distribution factors and not to the failure of such derivatives to associate at the receptor. 

There has been recent interest in 5-phenylbenzomorphans since such derivatives may be thought to combine the diphenylquaternary carbon feature of methadone with the 4-phenylpiperidine unit. The derivatives XVIla displayed... 

The morphine-like potency [100] of the 4-(2-furyl) ether (XXIV) raises the question of the general acceptability or otherwise of a 4-alkoxy group as the C-4 oxygen function in 4-phenylpiperidine analgesics. Comparison of the relative... 

In an analysis of stereochemical factors in narcotic analgesics, Portoghese considers that the conformational requirements for most of the 4-phenylpiperidine analgesics appear to be minimal [282]. His argument was based, in part upon (1) the fact that endo and exo isomeric azabicyclo [2,2,1] heptane analogues (LXXXII) of pethidine have similar orders of potency in mice (benzoquinone... 

The 4-phenylpiperidine unit is common to simple piperidine derivatives such as pethidine and a-prodine, and also to morphine, morphinan, and benzomorphan... 

Transition metals (iron, copper, nickel and cobalt) catalyse oxidation by shortening the induction period, and by promoting free radical formation [60]. Hong et al. [61] reported on the oxidation of a substimted a-hydroxyamine in an intravenous formulation. The kinetic investigations showed that the molecule underwent a one-electron transfer oxidative mechanism, which was catalysed by transition metals. This yielded two oxidative degradants 4-hydroxybenzalde-hyde and 4-hydroxy-4-phenylpiperidine. It has been previously shown that a-hydroxyamines are good metal ion chelators [62], and that this can induce oxidative attack on the a-hydroxy functionality. 

Meperidine Meperidine, the ethyl ester of l-methyl-4-phenylpiperidine-4-carboxyhc acid (3.1.39), is a synthetic opioid analgesic. Its synthesis is accomphshed by the alkylation of benzyl cyanide using Af,Al-fcix-(2-chlorethyl)-iV-methylamine in the presence of sodium amide, which forms l-methyl-4-phenyl-4-cyanopiperidine (3.1.38), and its subsequent acidic ethanolysis into meperidine [30-32]. 

Diphenoxylate Diphenoxylate, ethyl ester of l-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid (3.1.58), is also a drag of 4-phenylpiperidine series. In practice there are two ways of making it. The first way is by the alkylation of the ethyl ester of 4-phenylpiperidine-4-carboxylic acid (3.1.56) with 2,2-diphenyM-bromobutyronitrile, which in turn is synthesized from l-benzyl-4-phenyM-cyanopiperidine. The product undergoes ethanolysis in the presence of acid, followed by benzylation. The second way is a synthesis accomplished by alkylation of diphenylacetonitrile using ethyl ester of l-(2-chloroethyl) -phenylpiperidine-4-carboxylic acid (3.1.57), which is synthesized by... 

---