Racemorphan

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Racemorphan
Racemorphan.svg
Systematic (IUPAC) name
(±)-17-methylmorphinan-3-ol
Clinical data
Legal status
?
Identifiers
CAS number 297-90-5
5985-35-3 (HBr)
ATC code ?
ChemSpider 16736212
UNII V7R79HN3XD YesY
Chemical data
Formula C17H23NO 
Mol. mass 257.37 g/mol
Not to be confused with Morphan.

Racemorphan is the racemic mixture of the two stereoisomers of 17-methylmorphinan-3-ol, each with differing pharmacology and effects:

Synthesis[edit]

Racemorphan synthesis:[1][2]

One of the syntheses starts by the Knoevenagel condensation of cyclohexanone with ethyl cyanoacetate, hydrolysis of which leads to the corresponding cyano acid. The latter loses carbon dioxide under reaction conditions to give 1-cyclohexenylacetonitrile.[3] The out-of-conjugation shift of the olefin is a direct consequence of the mechanism of the decarboxylation reaction.

Treatment of the nitrile with lithium aluminium hydride then leads to the primary amine, or alternatively the nitrile can be selectively reduced with hydrogen over Raney cobalt.

Acylation with p-anisoyl acetyl chloride adds the aromatic ring required for the morphinan.

The use of the Bischler–Napieralski cyclodehydration of phenylacetamides of arylethylamines constitutes one of the standard methods for synthesis dihydroisoquinolines; the reaction interestingly works well when the benzene ring in the cyclization is replaced by cyclohexane. Thus reaction with polyphosphoric acid or POCl3 gives the hexahydroisoquinoline via the enol form of the amide.

Exposure to sodium borohydride or hydrogenation over Raney nickel leads to selective reduction of the imine bond and formation of the morphinan precursor.

There are two ways to proceed with the next stage:

(1): Treatment with strong acid leads proceeds to the morphinan. Acylation with ethyl chloroformate followed by reduction of the intermediate urethane leads to Methorphan. Cleavage of the methyl ether then leads to racemorphan.

(2): The 2° amine is N-methylated by treatment with paraform and reduction over Raney-nickel. The cyclization and O-demethylation step is performed concomitantly with polyphosphoric acid.

See also[edit]

References[edit]

  1. ^ Schnider, O.; Grüssner, A. (1949). "Synthese von Oxy-morphinanen". Helvetica Chimica Acta 32 (3): 821. doi:10.1002/hlca.19490320325. PMID 18129560.  edit
  2. ^ Schnider, O.; Hellerbach, J. (1950). "Synthese von Morphinanen. (2. Mitteilung)". Helvetica Chimica Acta 33 (6): 1437. doi:10.1002/hlca.19500330606.  edit
  3. ^ Submitted by A. C. Cope, A. A. D'Addieco, D. E. Whyte, and S. A.Glickman. Checked by T. L. Cairns and R. E. Heckert. (1951). "CYCLOHEXYLIDENECYANOACETIC ACID AND 1-CYCLOHEXENYLACETONITRILE [Δ1,α-Cyclohexaneacetic acid,α-cyano-, and 1-Cyclohexene-1-acetonitrile]". Organic Syntheses 31: 25. doi:10.15227/orgsyn.031.0025.  edit