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Synthesis and Pharmacology

General Information

Anileridine is an analog of pethidine, where the methyl group on the nitrogen is replaced by a p-aminophenethyl group. Ehyl 1-(4-aminophenethyl)-4-phenylisonipecotate is prepared by reacting ethyl 4-phenylisonipecotate and p-aminophenethylchloride.HCl in alcohol with sodium bicarbonate1. The freebase can be precipitated from ether solution by gassing it with HCl. The dihydrochloride can be purified by crystallization from methanol - ether, which can be further purified by crystallization from methanol, M.P.: 280-287°C.

The N-acetyl monohydrochloride can be prepared by treatment of the free base (M.P.: 83 °C) with acetic anhydride - acetic acid at 90 - 100 °C. (M.P. of the N-acetyl monohydrochloride = 264 - 265 °C).

Anileridine, is a potent analgesic with high oral activity and relative mild side reactions. Mild anti-acetylcholine and antihistaminic activity has been observed in both isolated organs and in intact animals. In animals, the compound approaches morphine in analgesic potency and is several times more active than pethidine (ethyl 1-methyl-4-phenylisonipecotate). Unlike pethidine, it is a good antitussive agent against experimental cough in guinea pigs and dogs. The side reactions in such animals such as general depression and sedation, depression of respiratory and lowering of blood pressure, are considerably milder than those produced by morphine, and somewhat milder than those of pethidine. Anileridine does not produce nausea, vomiting or constipation in animals.

The acute oral and subcutaneous toxicity of the compound, as measured in mice, is of the same order as pethidine, but it is somewhat more toxic on intravenous administration. After subcutaneous injection into rats, a bound form, probably the N-acetyl derivative, was found in the tissues. The N-acetyl derivative has analgesic activity of the same order as the parent compound when tested in rats. Preliminary results in man by oral and parenteral administration indicate an analgesic potency at least twice that of pethidine.

The more systematic name of anileridine is 1-para-aminophenethyl-4-phenylpiperidine-4-carboxylic acid ethyl esther. Dose: 25 - 50 mg, every 6 hours.


Anileridine Pharmacology

Anileridine Hydrochloride2

The drug is rapidly absorbed from the gastrointestinal tract and provides analgesia for 2-4 h. The usual oral dosage is 25 mg every 6 h, if necessary. A dosage of up to 50 mg, or more frequent doses, may be desirable for more severe pain.

Anileridine Phosphate2

Anileridine Phosphate is a synthetic analgesic compound closely related in chemical structure and pharmacological action to meperidine hydrochloride. Its analgesic potency lies between that of meperidine and morphine; on the basis of its ability to relieve pain in man, anileridine appears to be about two and onehalf times as potent as equal amounts of meperidine and approximately one-quarter as potent as the same weight of morphine. Iike meperidine, anileridine exerts mild antihistaminic and spasmolytic effects, but it does not produce the constipating effect of the opiates. In the usual range of analgesic doses, sedative and direct hypnotic effects are minimal, being about the same as with meperidine but somewhat less than with morphine. Anileridine also exerts an antitussive effect, but this has not been evaluated clinically. It is similar to meperidine in that it does not produce as much dizziness, nausea and vomiting as morphine in patients confined to bed. The incidence of such effects is probably increased by ambulation as with all other narcotic analgesics, thus limiting its use in ambulatory patients. In equianalgesic doses the degree of respiratory depressant effect of anileridine is not significantly different from that of meperidine, but it is apparently of shorter duration. Circulatory depression is less than with meperidine. As with all narcotics, anileridine potentiates the action of the ultrashortacting barbiturates and other central nervous system depressants. The drug is promptly absorbed after parenteral administration, and peak plasma levels are reached within 1 hour. Its duration of action is slightly less than that of meperidine; analgesic effects persist for about 0.5 to 1 hour after intravenous administration, 1 to 2 hours after intramuscular administration and 3 to 4 hours after subcutaneous injection. Animal experiments indicate that the kidney and the liver are the principal sites of degradation and excretion.

Anileridine phosphate is useful for the relief of moderate to severe pain. It may be used as an analgesic adjunct in general anesthesia in the same manner as meperidine to reduce the amount of anesthetic needed. to facilitate relaxation and to reduce laryngospasm. The drug is also useful postoperatively for the relief of wound pain. Anileridine has also been employed for obstetric analgesia, both alone or in combination with scopolamine or barbiturates. The results have been satisfactory, as a rule, for the mother, but some degree of fetal respiratory depression has been observed. There are also indications that the drug may slow labor. In general, anileridine appears to have the same usefulness and the same limitations as meperidine and is considered a satisfactory substitute for meperidine in all conditions in which that drug may be indicated. It will not relieve the most severe pain as effectively as morphine.

Anileridine has an addiction liability equivalent to that of morphine and is subject to the federal narcotic law. It suppresses morphine abstinence completely, whereas meperidine does not; in this sense, it has an addiction liability greater than that of meperidine. On the other hand, the dose of anileridine required to sustain addiction is about the same as that of meperidine, even though two and a half times as much meperidine as anileridine is needed to produce equal analgesic effects.

Respiratory depression and, to a somewhat lesser degree, circulatory depression are the chief hazards attending the use of anileridine. These effects are particularly prone to occur in elderly patients or in patients in whom the drug is administered too fast by the intravenous route. Special caution should be observed when the drug is used in conjunction with other narcotics, sedatives or anesthetics, since these agents enhance respiratory depression. Should significant respiratory depression occur, this can be reversed by administration of nalorphine. Side effects with anileridine are no more troublesome than with meperidine and include occasional nausea and vomiting, dizziness, perspiration, feeling of warmth, xerostomia, restlessness, nervousness and excitement. Except in high concentration, parenteral injection causes little tissue irritation.


Anileridine phosphate is administered by subcutaneous, intramuscular or intravenous injection. Dosage varies according to severity of pain and response of the patient. For single subcutaneous or intramuscular injection in adults, the usual initial dose is 25 to 50 mg. This may be repeated at intervals of 4 to 6 hours as required. The usual dose for obstetric analgesia is 50 mg. repeated in 3 to 4 hours. For intravenous use in support of anesthesia, the drug should be well diluted and administered slowly. For adults, 50 to 100 mg. is diluted with 500 cc, of 5 per cent dextrose in water for injection. Enough of this diluted solution to provide 5 to 10 mg. is then infused slowly. Analgesia is maintained by slow intravenous drip at a rate adjusted to provide about 0.6 mg. per minute, depending on individual need and response. Direct intravenous injection of the concentrated commercial solution should not be attempted except under grave emergency situations when time or facilities do not permit dilution of the drug. If used under these conditions, the rate of injection should be extremely slow, so that the injection takes at least several minutes. It should be borne in mind that the sudden intravenous injection of an amount greater than 10 mg may cause apnea.



N-[beta-(-p-aminophenyl)ethyl-4-phenyl-4-carboethoxypiperidine, Salts Thereof and Processes of Preparing the Same3

Notes Relating to Meperidine (of the family discussed in this patent): Meperidine is an analgesic that has the unfortunate property of becoming toxic at low levels. The larger the analog made, the less analgesic properties are available and the more toxic the compound becomes. N-benzyl-4-phenyl-4-carboethoxypiperidine only has ½ the analgesic activity of meperidine. Compounds of the title’s nature and their N-acyl analogues and salts thereof are only about 1/3 as toxic as meperidine and are more active. N-[beta-(p-aminophenyl)-ethyl]-4-phenyl-4-carboethoxypiperidine is less than 1/10th as toxic as meperidine.

Preparation of beta-(p-aminophenyl)ethyl chloride HCl

A mix of 111g acetic anhydride and 66g of acetic acid is cooled to 0*C. 69g of fuming nitric acid is added slowly and the mix is cooled to -5*C. To the cold mix, a dropwise addition with stirring is begun for 101g of beta-phenylethylbromide over about 2 hours. The temperature should be maintained at -10 –0*C. The nitration mix is stirred for an additional 2-3 hours below 0*C. The mix is then poured into a suspension of 145g sodium carbonate 1100cc of ice water. The yellow product is extracted from the aqueous mix with benzene, the benzene extract is washed with excess sodium bicarbonate solution, then with water, and the dried over anhydrous Mg sulfate. The benzene is evaporated from the solution using vacuum. The residue is recrystallized with pet. Ether to give about 55g of beta-(p-nitrophenyl)ethyl bromide; MP: 65-67*C. To a solution of 172g stannous chloride in 430 cc concentrated aqueous HCl is added portionwise with shaking 43 g of b-(p-nitrophenyl)ethyl bromide over a period of 45 minutes. The resulting mixture is warmed for an additional 45 minutes on a steam bath, then the aqueous solution is decanted from the oil material. The resulting solution is cooled, 750cc of 30% aqueous NaOH is added, the resulting cold aqueous alkaline solution is extracted with 400cc of ether and then with two 200c portions of ether. The combined ether extracts are washed with two 300cc portions of water and the washed ether solution is shaken with 95cc of 3.5N aqueous HCl causing an immediate precipitation. The crystalline slurry is cooled to about 0*C; allowed to stand to complete crystallization, the slurry is filitered, and the crystals are washed with three 25cc portions of ice water and dried in vacuo to give about 30g of a mix of beta-(p-aminopheny)ethyl bromide hydrochloride and beta-(p-aminophenyl)ethyl chloride hydrochloride.

Example 1

A mix of 7.8g (0.05mol) of beta-(p-aminophenyl)ethyl chloride hydrochloride, 12.5g (0.025 mol) of 4-phenyl-4-carboethoxypiperidine carbonate, 10.5g (0.125mol) sodium bicarbonate, and 100cc of anhydrous ethanol are mixed, stirred and heated under reflux for a period of approximately 40 hours. And then concentrated in vacuo to dryness. Thre residue is triturated with 50cc of water, decanted, washed an additional 50cc of water (then decanted) and then dried in vacuo to give N-[beta-(p-aminophenyl)-ethyl]-4-phenyl-4-carboethoxypiperidine.

The product compound from the previous step is dissolved in 50cc of hot anhydrous ethanol, an excess (about 20cc) of 20% alcoholic hydrochloride acid solution is added; upon scratching the side of the container, crystals form. 100cc of ether are then added to the mix and the ether is then cooled. The mix is filtered to recover the precipitate which is washed with ether and dried to give 12.g of N-[beta-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine dihydrochloride. This can be further purified by recrystallization from ethanol or methanol to give substancially pure material; MP: 275-277*C. Given for C22H28N2-2HCl.

Example 2

1g of N-[beta-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine dihydrochloride prepared as described in Example 1 is dissolved in 25cc of water, excess sodium hydroxide solution is added, and the aqueous mix is extracted with two 50cc portions of ether. The extracts are combined, dried over Mg sulfate and evaporated to dryness under vacuum to give the freebase. This material is mixed with 2cc of glacial acetic acid and 2cc of acetic anhydride, the mix is then heated on a steam bath for a period of about one hour, and then allowed to stand at RT overnight. The reaction mix is diluted with 25cc of water, an excess of sodium bicarbonate is added whereupon a gummy precipitate forms. The aqueous layer is decanted from this precipitate and the latter is washed by decantation with three 15cc portions of water. The compound is then dried in vacuo to give N-[beta-(p-aminophenyl)ethyl]-4-phenyl-carboethoxypiperidine base.

The base is dissolved in 10cc of anhydrous ethanol, a trace of salt which forms is removed by filtration and to the filtered solution is added an excess (2cc) of 20% alcoholic HCl solution. The crystallization takes place immediately and the slurry is cooled to 0*C then filtered. The material is washed with four 3cc portions of cold anhydrous ethanol and dried to give about 0.5g of N-[beta-(p-aminophenyl)ethyl]-4-phenyl-4-carboethoxypiperidine hydrochloride; MP: 264-265*C.


  1. JACS (1956) vol 78 p 2342 - 2343
  2. New and Non-Official Drugs (1963)
  3. US patent 2,966,490