Meperidines

Fig. 1. Conformational representation of the piperidine ring of morphine (1) and analogues meperidine (7, R = H, R = COOC2H ) and alphaprodine (7, R = R = 0CC2H ). The chiral center of interest in stmcture (7) is starred (see text).

Exploratory research on structure activity relationships in the meperidine series revealed the interesting fact that the oxygen atom and carbonyl group of this molecule could often be interchanged. That is, the so-called "reversed meperidine" (C) still exhibits analgesic activity in experimental animals. (Note that, except for the interchange, the rest of the molecule is unchanged.)... 

Further chemical modification of the phenylpiperidine moiety has proven unusually fruitful in producing medicinal agents that affect the central nervous system. First, a series of compounds loosely related to the reversed meperidines produced several drugs with important antipsychotic activity. Further discussion of this pharmacologic activity, often referred to as major tranquilizer activity, will be found in the section on phenothiazines. The group led by Janssen took advantage of the chemistry of the... 

Still further simplification of the structural requirements for central analgesic activity came from the serendipitous observation that the simple phenyl pi peri dine, meperidine... 

The search for opioid analgesics which show reduced addiction liability ha.s centered largely on benzomorphan and morphinan derivatives. Some research has, however, been devoted to derivatives of the structurally simpler meperidine series. The preparation of one such compound, picenadol (59), starts with the reaction of N-methyl-4-piperidone with the lithium derivative from m-methoxybromobenzene. Dehydration of the first formed carbinol 51 gives the intermediate 52. Deprotonation by means of butyl lithium gives an anion which can be depicted in the ambident form 53. In the event, treatment of the anion with propyl bromide gives the product 54 from reaction of the benzylic anion. Treatment of that product, which now contains an eneamine function. 

A mixture of 23 parts of the ethyl ester of 4 phenylisonipecotic acid and 15 parts of 2,2-diphenyl-4-bromobutyronitrile in 19 parts of xylene is heated for 24 hours at 100°-120°C and then cooled and filtered to remove the precipitate of the hydrobromide of the ethyl ester of 4-phenylisonipecotic acid. The filtrate is then extracted with dilute hydrochloric acid and the extract is rendered alkaline by addition of concentrated aqueous potassium hydroxide and extracted with ether. This ether extract is treated with gaseous hydrogen chloride. The resulting precipitate is collected on a filter. The hydrochloride of the ethyl ester of 2,2 diphenyl-4-(4 -carboxy-4 -phenyl-1 -piperidino) butyronitrile thus obtained melts at about 220.5-222°C. See Meperidine hydrochloride for synthesis of 4-phenyl-isonipecotic acid ethyl ester. 

Benzyl chlorocarbonate Ampicillin Benzyl cyanide Meperidine HCI Tolazoline... 

Examples narcotics such as meperidine, methadone, morphine, oxycodone amphetamines and barbiturates... 

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