Cyclohexylidenecyanoacetic Acid and-Cyclohexenylacetonitrile
Organic Syntheses, Coll. Vol. 4, p. 234 (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0234)
(http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0234)
I guess that 1-cyclohexenylacetonitril might easily be converted (LiAlH4?) to 2-(1-cyclohexenyl)-ethylamine, which is in turn useful for making racemorphan/levorphanol (cf. Post 319328 (https://www.thevespiary.org/talk/index.php?topic=6858.msg31932800#msg31932800)
(blondie: "TITLE Preparation of useful intermediates of ...", Chemistry Discourse)). I saw an Indian company offering both the amine and nitrile on the web today and I figured that they make the amine from the nitrile, I never heard of any other way of making it anyway.
Linking to individual preparations at the Organic Syntheses website is easy as soon as you understand their URL logic, see here:
Org. Syn. Coll. Vol. 4, p. 234: 1-Cyclohexenylacetonitrile (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0234)
(http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0234)
Note the last part of the URL: prep=cv4p0234 - corresponds to - Coll. Vol. 4, p. 234
Thanks for your attention, Rhodium. The rest of the synth basically follows DopaMan's outline https://www.thevespiary.org/rhodium/Rhodium/chemistry/levorphanol.html (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-morphinane
phenylacetic acid-(cyclohexenyl-ethyl)-amide
To 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-isochinoline
243 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-morphinane
The 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)-amide
a) 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-isochinoline
273 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-isochinoline
From 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-morphinane
The 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 8) , at least in animals. Not harder to make, most likely too.
This is from
MEDICINAL CHEMISTRY
A Series of Monographs
Volume 5: George DeStevens (Ed.). Analgetics. 1965
ACADEMIC PRESS New York and London
pages 142-143
A book that I cited before (cf. Post 456856 (missing)
(Pimpo: "2-aminoindane as analgetic", General Discourse)). It is definately on of the best concerning analgesics, which have read!
TABLE III
ANALGETIC ACTIVITY OF N-METHYLMORPHINANS WITH SUBSTITUENTS IN THE AROMATIC PORTION
Mouse, subcutaneous (mg/kg)
---------------------------
R Salt ED 50 LD 50
----------------------------------------------------
H(a) H3PO4 11.3 92
3-OH(b) tartrate 0.5 365
3-OCOCH3(b) tartrate 2.2 -
3-OCH3(b) HBr 3.0 260
3-OH, 2-CH3(b) HCl inactive 200
Morphine HCl 2.1 576
Codeine HCl 14.0 270
TABLE IV
ANALGETIC ACTIVITY OF (-)-3-HYDROXY-N-SUBSTITUTED MORPHINANS
Mouse, subcutaneous (mg/kg)
---------------------------
N-Substituent Salt ED 50 LD 50
--------------------------------------------------------
H HBr 60.2 222
CH3 tartrate 0.5 365
CH2CH3 HBr 9.5 243
CH2CH2CH3 HBr inactive 530
CH2(CH2)2CH3 tartrate 1.1 -
CH2(CH2)3CH3 HCl 0.4 158
CH2(CH2)4CH3 HCl 0.5 -
CH2Ph HBr inactive -
CH2CH2Ph HBr 0.14 -
CH2COPh HCl 0.10 > 400
CH2CH(OH)Ph HCl 0.09 225
CH2(CH2)2Ph HBr 25.4 > 400
CH2(CH2)3Ph tartrate 3.6 > 400
CH2CH2-cyclo-C6H11 HCl 2.6 > 750
CH2CH2-4-pyridyl tartrate 0.09 500
CH2CH2-4-piperidino H2SO4 inactive -
CH2CH2-N-morpholino salicylate 70.1 > 600
CH2CH2-2-furyl HCl 0.01 250
CH2CH2-2-thienyl HCl 0.02 502
CH2CH2-Ph-p-NH2 base 0.02 111
CH2CH2-Ph-m-NH2 HCl 0.04 176
CH2CH2-Ph-o-NH2 base 0.7 665
CH2CH2-Ph-p-OH HCl 0.2 675
CH2CH2-Ph-p-OCH3 tartrate 0.2 > 400
CH2CH2-Ph-p-NO2 HCl 0.04 > 600
CH2CH2-3,4-methylene- HCl 0.07 > 800
dioxyphenyl
CH2CH2-Ph-p-SCH3 base 0.05 > 600
My conclusion: The 3-hydroxy substituent on the aromatic ring seems to be by far the most active substituent on this portion of the molecule. We can clearly see, that there are a lot of possibilities to make more effective yet less toxic derivatives by changing the N-substituent. I think the synthesis wouldn't be much harder in some intersting cases.
Patent US4194044 (http://l2.espacenet.com/dips/viewer?PN=US4194044&CY=gb&LG=en&DB=EPD)
: Process for preparing 3-phenoxy-morphinans
EXAMPLE 6
N-[2-(1-Cyclohexen-1-yl)-ethyl)-4-phenoxyphenyl acetamide
A mixture of 1.26 g (0.01 mol) of cyclohexen-(1)-yl-ethylamine and 1.9 g of 4-phenoxyphenylacetic acid in 20 ml of xylene was heated at reflux for 16 hrs with removal of the water by means of a Dean-Stark apparatus. After evaporation of the solvent, the crude product was crystallized from cyclohexane-hexane mixture to give 2.6 g (76%) of pure N-[2-(l-cyclohexen-l-yl)-ethyl]-4-phenoxyphenyl acetamide, mp 74°-75".
EXAMPLE 7
(±)-1-(p-Phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
A mixture of 2.5 g (0.01 mol) N-[2-(l-cyclohexen-l-yl)ethyl]-4-phenoxyphenyl acetamide, 5.0 ml of POCl3 and 20 ml of toluene was heated at reflux under nitrogen for 2 hrs. After evaporation of the solvent and excess reagent there was obtained (±)-1-(p-phenoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline as residue. The residue was triturated with pet ether (2 * 10 ml). The pet ether insoluble hexahydro compound was dissolved in methanol and immediately reduced by portionwise addition of 1.0 g of sodium borohydride. The reaction mixture was stirred at room temperature for 4 hrs. The methanol was distilled off and the residue was partitioned between ether (60 ml) and dilute aqueous ammonium hydroxide. The ether solution was washed with water, dried and evaporated to give 1.6 g (69%) of crude (±)-l-(p-phenoxybenzyl)-l,2,3,4,5,6,7,8-octahydroisoquinoline.
For purification, 1.5 g (0.005 mole) of the above crude (±)-l-(p-phenoxybenzyl)-l,2,3,4,5,6,7,8-octahy-droisoquinoline in 5 ml of acetone was treated with 0.42 g of oxalic acid and allowed to crystallize. The crude oxalate was recrystallized from ethanol (30 ml) to give 1.61 g (84%) of pure (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline oxalate, mp 176°-178°.
EXAMPLE 5
(±)-1-(p-Phenoxybenzyl)-2-formyl-l,2,3,4,5,6,7,8-octahydroisoquinoline
To a solution of 0.78 g (0.002 mol) of (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 5 ml of chloroform was added 0.42 g of chloral in 1 ml of chloroform dropwise. After the mixture had been stirred at room temperature for 3 hrs it was diluted with IS ml of chloroform and washed with 4 N hydrochloric acid (10 ml) and water (10 ml). After drying, the solvent was removed under reduced pressure to give 0.81 g (96%) of crude (±)-1-(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For characterization, a sample of this compound was distilled, bp 225°-227° (0.08 mm Hq).
EXAMPLE 8
(±)-3-Phenoxy-N-formylmorphinan
(±)-1-(p-Phenoxybenzyl)-2-formyl-l,2,3,4,5,6,7,8-octahydroisoquinoline, 24.5 g (0.07 mol), was combined under stirring with 120 g of phosphoric acid which had been mixed with 1.0 g of concentrated sulfuric acid and the mixture was heated in a nitrogen atmosphere to 70°. The resulting homogeneous solution was kept at 70° for 48 hrs. The mixture was cooled in an ice bath and ice-water was added. The resulting suspension was extracted with ethyl acetate (100 ml). The ethyl acetate solution was washed with water and dried. Removal of the solvent gave 23.3 g (95%) of crude (±)-3-phenoxy-N-formylmorphinan.
For characterization a sample of the morphinan was isolated from the above mixture by preparative tlc on silica gel (eluted with ethyl acetate) and distilled, bp 210°-220°(0.1 mm Hg).
EXAMPLE 9
(± )-3-Phenoxy-N-methylmorphinan
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenyl-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hg) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
This crude morphinan, 7.6 g (0.02 mole) on treatment with oxalic add (2.4 g) in ether (40 ml) afforded 6.8 g of crude oxalate mp 110°-120°. Several recrystallizations from acetonitrile gave 3.6 g (37%) of pure (±)-3-phenoxy-N-methylmorphinan oxalate, mp 144°-146°.
Your last ref was a bit off, but I found the review anyway:
Benzomorphans: synthesis, stereochemistry reactions, and spectroscopic characterizations
David C. Palmer and Michael J. Strauss
Chem. Rev. 77, 1-42 (1977) (https://www.thevespiary.org/rhodium/Rhodium/pdf/benzomorphan.review.pdf)
(https://www.thevespiary.org/rhodium/Rhodium/pdf/benzomorphan.review.pdf)
Abstract
The problems of prolonged physical pain and mental anguish, the efficacy of opiates in ameliorating these experiences, and the consequent difficulties of physical dependence and addiction associated with opiate use have been the subject of extensive study by chemists, biochemists, pharmacologists, and physicians for many decades. The problems of opiate addiction in the United States and the associated social trauma have served, in part, to intensify efforts directed toward understanding the basic mechanisms of the action of these drugs and to intensify the search for a better analgesic which has no harmful side effects and does not induce physical dependence. The detailed mechanisms of action are still in large part unknown and the ideal analgesic has not yet been found, but substantial progress is being made.