17-(Cyclopropylmethyl)-6-oxamorphinan-3-ol or (1S,9R,10R)-17-(cyclopropylmethyl)-13-oxa-17-azatetracyclo[7.5.3.0~1,10~.0~2,7~]heptadeca-2,4,6-trien-4-ol
Starting material for this preparation is ketoester 1, available by one of the classical benzomorphan syntheses.[7] Condensation with the
ylide from
Triethyl phosphonoacetate (
HWE reaction) affords diester 2.
Catalytic hydrogenation proceeds from the less hindered face to afford the corresponding saturated diester (3). The esters are then reduced by means of
LiAlH4 to give the
glycol (4); this undergoes internal ether formation on treatment with acid to form the
pyran ring of 5.
Von Braun reaction with
BrCN (or
ethyl chloroformate) followed by
saponification of the intermediate leads to the 2° amine (6). This is converted to the cyclopropylmethyl derivative 8 by acylation with
cyclopropylcarbonyl chloride[8][9] followed by reduction of the thus formed amide (7) with LiAlH4. Cleaving off the O-methyl ether with sodium
ethanethiol affords proxorphan (9).
^Hayes AG, Birch PJ (August 1988). "Reversal by beta-funaltrexamine and 16-methyl cyprenorphine of the antinociceptive effects of opioid agonists in the mouse and guinea-pig". Neuropharmacology. 27 (8): 813–816.
doi:
10.1016/0028-3908(88)90096-2.
PMID3216959.
S2CID54433737.
^Barltrop JA (March 1947). "Syntheses in the morphine series; derivatives of bicyclo [3 : 3 : 1]-2-azanonane". Journal of the Chemical Society. 169: 399–401.
doi:
10.1039/JR9470000399.
PMID20240573.