Cyclohexenylacetonitrile for Morphinans

[Pimpo]

Recently I found some more interesting stuff about my favourite field of research in the library:

Helvetica Chimica Acta, 40 (1957), p. 1232-1441, and J. Hellerbach and O. Schnider - '138. Hydroxy-morphinane (11. Mitteilung)'

It contains experimental procedures for N-arylalkyl-morphinanes, as well as some physical data and confirms the high activity of the N-phenethyl compounds (up to 50 - 70 x morphine). N-phenylpropyl compounds are stated to have weak effects, the phenylbutyl compounds being somewhat more active. All this confirms the activity data posted recently. I will translate the more interesting parts now, starting from p. 1235 - all elemental analysis data is omitted:

Experimental Part

For each method only one method is described in detail.

Method A (-)-3-Hydroxy-N-phenylethyl-morphinane. 70 g (+)-1-p-Hydroxybenzyl-1,2,3,4,5,6,7,8-octahydro-isochinoline are dissolved in 350 ml DMF and after addition of 40 g anhydrous K2CO3, 53.2 g beta-phenylethyl-bromide are added dropwise with stirring. The reaction product is stirred overnight in an oil bath having a temperature of 100 °C, mostly freed of DMF at waterpump-pressure and dissolved in ether. The ethereal solution is washed with water, dried with anhydrous Na2SO4 and the ether is distilled off. The remaining base (ca. 100 g), dissolved in acetone, immidiatelly yields (-)-1-p-Hydroxybenzyl-2-phenylethyl-1,2,3,4,5,6,7,8-octahydro-isochinoline oxalate upon addition of oxalic acid, and melts at 158 - 159 °C from i-PrOH. [alpha]22D = - 55 ° (c = 1 in MeOH).
Hydrobromide: mp 203 - 205 °C (from EtOH-ether), [alpha]21D = - 47.3 ° (c = 1 in MeOH)

100 g (-)-1-p-Hydroxybenzyl-2-phenylethyl-1,2,3,4,5,6,7,8-octahydro-isochinoline oxalate are heated with stirring with 500 g 99 % crystalline H3PO4 at 140 °C (reaction temperature) for 72 h, carefully diluted with 1200 ml water afterwards and then boiled for another hour. The reaction mixture is cooled,  600 ml n-BuOH are added on top ['überschichten'] and conc. NH3 is added dropwise with stirring until the mixture is slightly alkaline to phenolphtaleine at such a rate that the neutralization temperature is 50 - 60 °C. After cooling ca. 400 ml benzene are added, the aqueous phase is removed from the benzene-butanol layer and the latter is washed neutral with water. Upon distilling off the benzene-butanol mixture in vacuo the base crystallizes. Recrystallized from DMF the (-)-3-Hydroxy-N-phenylethyl-morphinane melts at 243 - 245 °C.
Hydrobromide: mp. 300-301 °C (from water-EtOH), [alpha]20D = - 63.12 °, (c = 3,27 in MeOH).
[? can't read if D or L]-tartrate. 1 H2O: mp. 125 - 126 °C (from i-PrOH), [alpha]20D = - 42.75 ° (c = 0.983 in water).
Phosphate: mp. 190 - 192 °C (from water)
Camphorsulfonate: mp. 218 - 220 °C (from water)
Methyl-'onium-bromide: mp. 239 - 240 °C (from EtOH), [alpha]20D = - 42.81 ° (c = 1.155 in MeOH)



This is it for now, more will bee presented some other day. I think the use of p-hydroxybenzyl-1,2,3,4,5,6,7,8-octahydro-isochinoline instead of the methoxy-derivative as starting material has mainly to do with chirality, the latter should work too, shouldn't it? That would make phenomorphan just as accessible as dromoran .

P.S.: I just noticed that I have been promoted to hive bee from new bee, that's very nice !

[Pimpo]

There follows on pages 1236 - 1239 a table of physical data of various derivatives. Onfortunately most of the mp.s are unreadable in my copy. On inquiry I could (might take a while) look that data up in the library. The only thing to report at this point is that 3-hydroxy-N-phenethylmorphinane has mp 300 - 301 °C from EtOH-water too, so this might be an alternative for recrystallizing the product.

So here comes p. 1240 - 1241:

Method B (-)-3-Hydroxy-N-(p-nitro-beta-phenylethyl)-morphinane. 8.2[the last figure I can't read, I think it's 8.25 or 8.26, gonna check that] (-)-3-hydroxy-morphinane are heated with 7.8 g p-nitro-beta-phenylethyl-bromide and 5 g anhydrous K2CO3 in 100 ml DMF with stirring for 6 h in an oilbath heated to 100 °C. The reaction product is poured in water and extracted with ether. After washing and drying the ethereal solution and evaporating the solvent the residue is converted with ethanolic HCl to the hydrochloride, which on rubbing['anreiben'] with acetone crystallizes immidiatelly and melts at 247 °C from EtOH. [alpha]13D = - 84.6 ° (c = 1 in MeOH)

(-)-3-hydroxy-N-(p-amino-beta-phenylethyl)-morphinane. When reducing 36.5 (-)-3-hydroxy-N-(p-nitro-beta-phenylethyl)-morphinane in 300 ml MeOH in the presence of 20 g 5 % Pd on charcoal the calculated amount of hydrogen is absorbed rapidly. (-)-3-hydroxy-N-(p-amino-beta-phenylethyl)-morphinane crystallizes already while evaporating the methanolic solution. From acetone it melts at 196 - 199 °C, [alpha]20D = - 107.6 °

Method C 3-Hydroxy-N-(3',4'-methylenedioxy-phenylethyl)-morphinane. 12.15 g (-)-3-hydroxy-morphinane are dissolved in 160 ml DMF with stirring at 100 °C, 7.3 g powdered anhydrous K2CO3 is added and 10.3 g 3,4-methylenedioxy-phenylacetyl-chloride is added dropwise. After 2 h heating at 120 °C (temperature of bath) the mixture is filtrated while hot, and the solution is evaporated at waterpump-pressure. The residue is disolved in butanol-benzene (1 : 1) and the solution is sequentially washed with dil. HCl, water, NaHCO3-solution and finally until neutral with water. The benzene-butanol solution is evaporated in vacuo. The residue is disolved in 80 ml absolute THF and at 50 °C slowly added to a stirred suspension of 5.7 g LAH in 250 ml THF. After 3 h water is added while cooling with ice until the excess LAH is destroyed. The THF solution is decanted, the residue extracted with ether, the THF- and ether solution is dried with K2CO3, filtrated and evaporated. The residue which melts at 176 - 178 °C from MeOH, is disolved in 80 ml MeOH and made slightly acidic against congo red with methanolic HCl. 18 g of the hydrochloride crystallize, mp. 290 - 292 °C. [alpha]10D = - 75.53 ° (c = 1.0428 in MeOH).

Method D is omitted, it describes the preparation of (-)-3-hydroxy-N-(gamma-phenylpropargyl)-morphinane from (-)-3-hydroxy-morphinane, HCHO and PhCCH and it's reduction to the phenallyl compound.

Method E. (-)-3-Hydroxy-N-phenacyl-morphinane. To the solution of 12.15 g (-)-3-hydroxy-morphinane im 150 ml DMF is added while stirring 7.3 g finely powdered K2CO3 and 11 g bromo-acetophenone. CO2 and heat are evolved. After stirring for 1/2 h the mixture is evaporated and the residue recrystallized from EtOH. Yield 14 g (78 %), mp. 173 - 175 °C.
Hydrochloride: mp. 278 - 279 °C (from EtOH - ether), [alpha]20D = - 71.91 ° (c = 1.022 in MeOH)

(-)-3-Hydroxy-N-(2'-hydroxy-2'-phenylethyl)-morphinane. 2 g (-)-3-Hydroxy-N-phenacyl-morphinane is disolved in 100 ml MeOH and reduced in the presence of 5 g 5 % Pd on charcoal. After filtrating and evaporating the MeOH in vacuo the hydrochloride is obtained from EtOH - ether [?]. mp. 244 - 245 °C, [alpha]20D = - 70.6 ° (c = 1.024 in MeOH).

[summary omitted]


So that's it, hope it will help somebee some day   .