Thanks for your attention, Rhodium. The rest of the synth basically follows DopaMan's outline
https://www.thevespiary.org/rhodium/Rhodium/chemistry/levorphanol.html
, but of course there are a lot more details given:
... continuing from p. 1444 - p. 1446, all elemental analysis info omitted
Synthesis of N-Methyl-morphinanephenylacetic acid-(cyclohexenyl-ethyl)-amideTo 125g Cyclohexenyl-ethyl amine (1 mol) in 250 ml absolute benzene is slowly added with cooling in ice and stirring 85 g (0,55 mol) phenylacetyl chloride in 170 ml absolute benzene. The reaction product [?] is allowed to stand for 30 min at RT and is then warmed for another 30 min on a water bath. After filtering off the Cyclohexenyl-ethyl amine hydrochloride the benzene solution is washed with sodium bicarbonate and the benzene is distilled off; the residue (123 g), which solidifies, consists of phenylacetic acid-(cyclohexenyl-ethyl)-amide. Mp 69 - 71 °C from benzene-petrolether. For analysis the product is distilled at high vacuum[is that the right word
? I mean like really low pressure.].
1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline243 g (1 mol) phenylacetic acid-(cyclohexenyl-ethyl)-amide are heated with 730 g P2O5 in 1200 ml benzene for 45 min and then allowed to stand for 2 h at RT. To the reaction product[?] is added ice with strong cooling and the aqueous phase is separated from the benzene, which contains small amounts of the starting material. The base is precipitated from the aqueous phase by addition of solid KOH at 0 °C and extracted with ether and dried. After distilling off the ether there remain 178g of a light yellow oil, to which, dissolved in 80 ml aceton, there is added a solution of 200 g methyl bromide [yuck! the iodide might do too?] in 300 ml anhydrous acetone, and this is allowed to stand for 12 h.
The residue, which remains after removing the acetone in vacuo, is dissolved in little water and extracted with ether. The aqueous solution of the quaternary salt, after addition of 56 g KOH in methanol, is reduced in the presence of Raney-Nickel in an autoclave at 50 atm H2. The reduction product is dissolved is dissolved in benzene, after filtering off the catalyst and removing most of the methanol in vacuo, and then washed with water. After the usual workup the 1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline distills at 106 - 108 °C (0.01 mm). There is obtained 85.8 g of a yellow oil, the hydrochloride of this melts at 195 °C and does not depress the mp in a mixture with benzyl-methyl-octahydro-isochinoline HCl obtained by another method [1,2].
N-methyl-morphinaneThe cyclization of the benzyl-N-methyl-octahydro-isochinoline to N-methyl-morphinane is done as known [1] and yields a base of bp 110 °C (0.04 mm), phosphate mp 141 - 145 °C.
C. Synthesis of 3-Hydroxy-N-alkyl-morphinanes [this is racemorphan]
p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amidea) To 125 g (1 mol) cyclohexenyl-ethylamine in 300 ml benzene is added dropwise at 0 °C with good stirring within 30 min a solution of 92.3 g (0,5 mol) thionyl chloride in 92 ml benzene. The reaction starts imidiatelly and is finished after 2 h standing at RT. After workup as described for phenylacetic acid-(cyclohexenyl-ethyl)-amide the p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide melts at 81 - 82 °C, after crystallization from petrolether. There are obtained 123 g, i.e. 90 % of theory.
b) the same product is obtained in virtually theoretical yield when equimolar [better yield and no waste of precious amine!] amounts of cyclohexenyl amine and p-methoxy-phenylacetic acid are refluxed in xylene, until the calculated amount of water has been removed with a trap [you know what I mean].
1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline273 g (1 mol) p-methoxy-phenylacetic acid-(cyclohexenyl-ethyl)-amide is refluxed in 1000 ml benzene with 307 g POCl3 for 3 h. After cooling the reaction product [?] is poured on ice and the aqueous phase is made alkaline with ca. 30 % NaOH. The precipitated base is extracted with ether and the ethereal solution washed with water and dried. The crude 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline, which remains after distilling off the ether, is dissolved in the five-fold amount of methanol
and reduced at normal pressure in the presence of 50 g Raney-Nickel.
After the calculated amount of hydrogen has been taken up, the catalyst is filtered off, and the alcoholic solution made slightly acidic with 48 % HBr. Then the methanol is removed in vacuo and the residue recrystalized from water. There are obtained 170 g (50 % of theory) 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline hydrobromide, mp 198 - 199 °C.
1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinolineFrom a solution of 338 g (1 mol) methoxybenzyl)-1,2,3,4,5,6,7,8-octahydro-isochinoline in water the free base is precipitated with conc. NaOH and dissolved in 600 ml MeOH. To the solution is added 90 ml of ca. 40 % formaline and this is allowed to stand for 2 h at RT and then reduced after adding 100 g Raney-Nickel. The reduction stops after the calculated amount of hydrogen is taken up. After filtering off the catalyst methanol and water are removed with addition of benzene in vacuo and the residual oil is distilled at high vacuum. The 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydro-isochinoline distills at 117 - 119 °C (0.008 mm). The distillate is dissolved in acetone and the calculated amount of oxalic acid is added. There are obtained 235 g of oxalate, which is recrystalized from water or alcohol, mp 163 - 164 °C. Yield 65 % of theory. Hydrochloride mp 149 - 151 °C. The mixed mp with the hydrochloride from Schnider & Grüssner was not depressed.
3-oxy-N-methyl-morphinaneThe oxalate is converted to 3-oxy-N-methyl-morphinane with 100 % H3PO4 as described in [1] by Schnider & Grüssner, giving the yield stated there, mp 251 - 253 °C; hydrobromide mp. 192 - 194 °C; tartrate mp 147 °C. From the mother liquor there can be obtained in minute amounts a compound of the same ["bruttoformel" = same percentage of elements, I think this might be the corresponding isomorphinane reported in other literature]. The base melts at 202 - 203 °C, hydrobromide mp 282 - 283 °C.
[The rest is about dioxy-morphinans and ethers of morphinans, this is omitted, as far as I know these are not or not very active.]
refs:
[1] 1. Mitt. O. Schnider & A. Grüssner, Helv. Chim. Acta 32, 821 (1949).
[2] R. Grewe and co-workers, Naturwiss. 33, 333 (1946) [couldn't get this, anybee want to try?]; Z. angew.Chemie, 59, 194 (1947) [I got this one too, interesting read, but NO experimentals]; A. [?] 564, 161 (1949).
Great article, unfortunately some steps (e.g. autoclave) seem to bee somewhat a problem for all but the best-equipped bees. Well let's see what comes from this. I'll post something on morphinane SARs soon. I can tell you that much, there are some that let levorphanol look like light-beer compared to whiskey
, at least in animals. Not harder to make, most likely too.