Pentazocine synthesis

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

Pazoxide, 395 Pemerid, 288 Penfluridol, 334 Pentapiperium methyl-sulfate, 76 Pentazocine, 325 Pentoxifylline, 466 Perhydropyrindene synthesis, 450... 

Scheme 2. Cyclization step in synthesis of pentazocine giving cis and trans isomers.

The synthesis of pentazocine was originally accomplished by Archer and coworkers (5 6,7) and has been reviewed previously (8,9.10,11). The intermediate 1,2,3,4,5,6-hexahydro-8-hydroxy-... 

Geometrical (cis-trans) isomers of benz-omorphans result from the cyclization step in their synthesis when the bond to C-6 is formed (Scheme 2). When this is considered a transaddition to the double bond the preponderance of the cis or form is easily explained (10). Resolution of optical isomers from both cis and trans forms has been reported (7,19.20). The norpentazocine precursor in the cis form crystallized first as the (-) base with (+) tartaric acid which would give the twenty-fold more active (-) pentazocine. The (+) base (-) tartarate was recovered from resolution liquors. Quinic acid salts were formed for resolution of the trans isomers. 

In the morphinan series, the preparation of 3-alkyl-morphinans222 and 3-mercapto-morphinans223 has been described. In the benzomorphan series, a novel cleavage of aryl benzyl ethers and of aryl allyl ethers has been described and used in an improved synthesis of pentazocine. The lactam (162), on hydrogenolysis, gives the benzomorphan (163 R1 = R2 = H). Treatment of this with dimethylallyl... 

A pentazocine (109) synthesis has been reported by Kametani and co-workers(45) from the methyl ester of tyrosine methylether (107) via the piperidinol intermediate 108, according to Scheme 4.16. Other piperidinol syntheses have been published by Kametani(46 49), Janssen,(50) and Henecka and Schubert.(51)... 

Pentazocine (Fortral), manufactured via a modified Grewe synthesis,(61a) behaves pharmacologically in humans like other opiates. At normal doses (30-50 mg parenteral equivalent to 10 mg morphine 50 mg oral, equivalent to 60 mg codeine) it is analgesic, is sedative, and depresses respira-... 

The structure of the rearranged product 114 is very similar to that of the benzomorphan, like pentazocine (Fig. 23) [105, 106], a useful analgesic. Although several papers have previously described the total synthesis of pentazocine, many... 

For synthesis of pentazocine, see [107-111], For synthesis of (-)-pentazocine with optical resolution, see [112, 113]. For the asymmetric synthesis of (-)-pentazocine, see the asymmetric synthesis of (-)-metazocine (an A-methyl derivative of (-)-pentazocine) has also been reported, [114] very recently, the asymmetric synthesis of (-)-9-epi-pentazocine was also reported [115] it has been shown that (-)-pentazocine is more potent than its antipode [116]. 

A classification scheme has been suggested. Those receptors that bind the (-F )-6,7-benzomorphans, such as (-F)-NANM and (-F )-Pentazocine, with high affinity and those which bind these ligands with low affinity are designed as CT, and CTj respectively (Quirion et al., 1992). Other sites with a distinct pharmacological profile versus the previously defined subtypes appear to exist. A series of l-phenyl-3-aminotetralines (PATs), exemplified by Hj-PAT was found to stimulate tyrosine hydroxylase activity and dopamine synthesis through interaction with a novel aj receptor (Wyrick and Booth, 1995). 

Effect of morphine, nalorphine, naloxone, pentazocine, cyclazocine, and oxotremorine on the synthesis and release of acetylcholine by mouse cerebral cortex slices in vitro Howes, John F. Harris, Louis Selig Dewey, William L. 

Cyclization. A key step in a recent synthesis of pentazocine (3), a nonnarcotic analgesic, involved treatment of the carbinol (1) with coned, hydrobromic acid in HOAc for 38 hr. The reaction involves dehydration, ring closure, and O-demethylation. It is noteworthy that only one (2) of the two possible isomers is formed. 

How would you synthesize Pentazocine from 1 -bromo-3 -methyl-2-butene Explain the route of synthesis. 

The effect of opiates on the release of ACh from neuronal stores has been the subject of several detailed studies. Thus, morphine depressed ACh output from the cat cerebrum, whilst nalorphine and naloxone were inactive alone and antagonised the effects of morphine [104]. Similarly, the direct perfusion or intravenous administration of morphine suppressed the release of ACh from the perfused cat lateral ventricle [105]. Much of the in vitro work supports the in vivo studies thus, morphine suppressed the release of ACh from cortical slices [99,106]. Furthermore, nalorphine, pentazocine and naloxone reduced ACh synthesis in rodent cortical slices (even though cyclazocine and oxotremorine increased synthesis under similar conditions [107]). 

The synthesis of pentazocine is comparatively short. The Grignard reaction with a pyridinium salt is followed by partial hydrogenation. Cleavage of the methyl ether is accompanied by acid-catalysed alkylation, which leads to the buildup of the quaternary centre. Finally, the amino-function is demethylated with cyanogen bromide and alkylated with isopentenyl bromide. 

Synthesis of (-)-Metazocine and (-)-Pentazo-cine (—)-Metazocine and (-)-pentazocine termed... 

Base-catalyzed migratory hydroamination has also been used for the synthesis of (—)-pentazocine, where the starting compound 41 is prepared from the route described above. Migratory hydroamination of 41 produces 42, which upon demethylation with NaSEt/DMF generates (—)-pentazocine 43 in 45% overall yield (Scheme 39.12). 

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