Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
  • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Definitions

• This invention relates to new thebaine derivatives as well as to intermediates and processes for preparing them. These new thebaine derivatives have been found to have surprising pharmacodynamic activity.
• the thebeaine derivatives of this invention are represented, for example, by the following structural formula:
• R is lower alkyl of from 14 carbon atoms preferably methyl
• R is lower alkyl of from l-4 carbon atoms preferably methyl
• hydrogen or an acyl residue of a phar maceutically acceptable carboxylic acid having a maximum of 8 carbon atoms such as acetyl, propionyl, benzoyl, isonicotinoyl or preferably nicotinoyl represents an optional single bond at the 8, 14 position and R represents an unsaturated alkane group or a cycloalkyl group of maximum of 8 carbons.
• R represents:
• R R and R represent hydrogen, methyl or chloro atoms.
• the cycloaliphatic rings can also have optional methyl substituents.
• This invention also includes, as well as the basic compounds of Formula I, the N-oxide derivatives thereof and the nontoxic acid addition or quaternary ammonium salts of the thebaine and dihydrothebaine bases or the N-oxides thereof.
• the acid addition salts are those with pharmaceutically acceptable acids such as hydrochloric, imaleic, sulfuric, phosphoric, sulfamic, benzoic, salicylic, acetic, hydrobromic, ethanedisulfonic, etc. acids.
• the pharmaceutically acceptable quaternary ammonium salts are those with active quarternizing agents such as lower alkyl iodides, chlorides or bromides, benzyl chloride, ethylene chlorohydrin, lower alkyl sulfates, etc.
• active quarternizing agents such as lower alkyl iodides, chlorides or bromides, benzyl chloride, ethylene chlorohydrin, lower alkyl sulfates, etc.
• These acid addition or quaternary salts of the the'baine or dihydroethbaine compounds and the N-oxides thereof are prepared by methods well known to the art such as reacting the base in an organic solvent with an equivalent amount of the acid or halide.
• the preferred compounds of this invention are those represented by Formula I in which R is allyl, 3,3-dimethylallyl or cyclopropylmethyl; R is methyl; R is methyl, hydrogen or nicotinoyl.
• the compounds of this invention are generally prepared by treatment of the appropriate N-northebaine with an active alkyl halide in the presence of an acid binding agent such as an alkali metal carbonate or alternatively with an alkanoyl halide to form the N-acyl intermediate followed by reduction to the N-substituted thebaine such as by a bimetallic hydride, for example, lithium aluminum hydride.
• an acid binding agent such as an alkali metal carbonate
• an alkanoyl halide such as by a bimetallic hydride, for example, lithium aluminum hydride.
• the N-alkylation or acylation may be carried out early in the reaction scheme wit-h suitable further reactions to form the desinable thebaine nuclei.
• esters are prepared by reaction of the compounds of Formula VII with a suitable carbamyl chloride in basic media such as in pyridine or benzene-triethylamine. Alternatively the esters are prepared by stepwise reaction of a compound of Formula VII with carbonyl chloride then with an amine.
• N-substituted dihydronormorphinones of Formula VII have been unexpectedly found to form O-carbamate esters such as the 3-O-dimethylcarbamate or die-thylcarbamate which are stable in basic solution and therefore especially suitable for alkylation to the enol ethers as may be desired.
• the desired compounds of Formula I are in general the desmethylthebaine intermediates of For- 35 mula VII in which the final desired N-substitutent has been inserted are obtained (i) by alkylation of dihydronormorphinone, (ii) by alkylation of dihydronorcodeinone followed by demethylation of the resulting product with pyridine hydrochloride, boron tribormide or boron trithen obtained by reduction as described.
• the carbamate 40 chloride, or (iii) preferably by the following scheme:
• RCO is a carbamyl group, usually diethylcarbamyl; the relative stability of the carbamate ester group towards acid permits the preparation of esters of structure XXV in good yield.
• the N-oxide derivatives of this invention are prepared by reacting the base of Formula I with an excess of a peracid or 30% aqueous hydrogen peroxide, usually with gentle heating. These N-oxide derivatives form acid addition or quaternary salts as noted hereabove.
• the nicotinoyl esters are particularly useful.
• Example 1 To a solution of dihydronorcodeinone (3.80 g.) in dioxan (38 ml.) are added magnesium oxide (1.075 g.) and water (38 mL). The mixture is stirred while a solution of t-butyl azidoformate (3.82 g.) in dioxan (15 ml.) is added dropwise. When addition is complete the pale orange mixture is maintained at 4550 C. with stirring for 20 hours, then cooled in ice and filtered using a filtration aid. The filtrate is diluted with saturated aqueous sodium chloride (50 ml.) and water (50 ml.), and extracted with ethyl acetate (3X50 ml.).
• N(t-butoxycarbonyl)-A -dihydronorthebaine (0.900 g.) is dissolved in a mixture of ethanol-free chloroform (11.5 ml.) and anhydrous methanol (45 ml.), and finely divided magnesium oxide (0.073 g.) is added.
• the mixture is cooled in an ice-bath and stirred vigorously while bromine vapour (from 0.375 g. of bromine in a small flask) is drawn through the mixture by means of a slow stream of dry air (dried by passage through concentrated sulphuric acid), using an aspirator pump.
• the rate addition of bromine is such that the reaction mixture remains colorless throughout the addition, which takes 1.5 hours.
• the apparatus is then re-converted for reflux and a solution of 7bromo-N(t-butoxycarbonyl)dihydronorcodeinone dimethyl ketal (0.306 g.) in dry toluene (5 ml.) is added to the potassium alkoxide solution and rinsed in with further toluene 10 ml.).
• the mixture is then heated under reflux in an atmosphere of dry nitrogen for 24 hours, after which the reaction mixture is coo-led and treated with saturated aqueous sodium chloride (20 ml.), and the aqueous layer extracted with ethyl acetate (2X15 ml.).
• a Soxhlet extraction apparatus is set up with toluenep-sulphonic acid monohydrate (0.301 g.) and chloroform (500 ml.) in the boiling flask and a thimble (28x80 mm.) filled with activated calcium sulphate in the extractor.
• the mixture in the flask is heated under vigorous reflux for 1.5 hours, after which time the contents of the thimble have removed all the water present in the mixture.
• This product is dissolved in a mixture of ethyl acetate and ethanol-free chloroform (25 ml.; 1:1), and the solution placed in a separatory funnel and treated portionwise with a mixture of trifiuoracetic anhydride (2.5 ml.) and ethyl acetate (7.5 ml.), with shaking after each addition.
• a mixture of trifiuoracetic anhydride 2.5 ml.
• ethyl acetate 7.5 ml.
• This product is taken up in dry benzene and subjected to chromatography on activated alumina (150 g.; type H). Elution with benzene and evaporation of the eluate give N(trifluoroacetyl)northebaine as a yellow oil.
• N-(trifluoracetyl)northebaine (0.109 g.) is dissolved in a mixture of acetone (3.5 ml.) and methanol (10.5 ml.) and the mixture stirred at 25 C. while 2 N-sodium hydroxide (1.40 ml.) is added dropwise. Stirring is continued for four hours, the temperature being maintained at 2025 C.
• Ten percent aqueous citric acid (14 ml.) is then added slowly with continued stirring, and the mixture, after dilution with water (14 ml.), extracted with ether (3X20 ml.).
• a solution of allyl bromide (0.058 g.) in ethanol (1 ml.) is added to a mixture of northebaine (0.136 g.) and finely powdered sodium bicarbonate (0.057 g.).
• the mixture is diluted with further ehtanol (1 ml.) and is then heated under reflux with stirring for 21 hours.
• the resulting mixture is diluted with methanol (3 ml.) and the solids removed and wished with methanol using a filtration aid.
• the filtrate and washings are evaporated giving a brownish residue which is extracted with boiling ether (2X4 ml.).
• the ether-insoluble residue is digested with hot benzene (4X2 ml.) and the benzene digests filtered using a filtration aid; the filtrate on evaporation gives a brown gum.
• This product is digested with cold benzene (5x2 ml.) and the benzene digests filtered as above, giving, on evaporation of the filtrate, a pale brown foam which is taken up in dry benzene and subjected to chromatography on activated alumina (2.08 g.; type H). Elution with benzene and evaporation of the eluate gives a residue (0.044 g.) which is taken up in light petroleum. A trace of whitish residue is removed using a filtration aid, and the filtrate is evaporated giving N-allylnorthebaine as an almost colorless gum.
• Example 2 N-cyclopropylmethyl-n -dihydronorthebaine (6.00 g., prepared as in Example 3) is dissolved in anhydrous methanol (425 ml.), and finely divided magnesium oxide (0.54 g.) is added. The mixture is cooled in an icebath and stirred vigorously while bromine vapour (from 2.78 g. of bromine in a small flask) is drawn through the mixture by means of a slow stream of dry air (dried by passage through concentrated sulphuric acid), using an aspirator pump. The rate of addition of bromine is such that the reaction mixture remains colorless throughout the addition, which takes 2.5 hours.
• bromine vapour from 2.78 g. of bromine in a small flask
• the apparatus is now re-converted for reflux and a solution of 7-bromo-N-cyclopropylmethyldihydronorcodeinone dimethyl ketal (2.00 g.) in dry toluene (25 ml.) is added to the potassium alkoxide solution.
• the mixture is then heated under reflux in an atmosphere of dry nitrogen for 24 hours, after which the reaction mixture is cooled and treated with water (25 ml.) and the aqueous layer extracted with ethyl acetate (2X25 ml.).
• the combined toluene and ethyl acetate phases are washed with saturated aqueous sodium chloride (2X10 ml.), dried over magnesium sulphate, and evaporated.
• the brown oil so obtained is dissolved in dry tetrahydrofuran (75 ml.) and the solution added to a stirred slurry to lithium aluminum hydride (1.0 g.) in dry tetrahydrofuran (60 ml.).
• the mixture is heated under reflux with stirring in an atmosphere of dry nitrogen for 1.5 hours, and then allowed to stand overnight at room temperature.
• the resulting mixture is decomposed by dropwise addition first of ethyl acetate ml.) and then of water (3 ml.).
• the precipitate is collected using a filtration aid and washed with ethyl acetate (5X20 ml.).
• a Soxhlet extraction apparatus is set up with toluenep-sulphonic acid monohydrate (5.95 g.) and chloroform (480 ml.) in the boiling flask and a thimble (27 100 mm.) filled with activated calcium sulphate in the extractor.
• the mixture in the flask is heated under vigorous reflux for 2 hours, after which time the contents of the thimble have removed all the water present in the mixture.
• the mixture is then cooled in ice, poured into a mixture of 10% aqueous ammonium hydroxide (60 ml.) and saturated aqueous sodium hydrogen carbonate (120 ml.) well shaken (whereupon the precipitate initially formed in the aqueous phase redissolves), and the chloroform layer is separated and washed with saturated aqueous sodium hydrogen carbonate (3X70 ml.), dried over magnesium sulphate, and evaporated under reduced pressure, giving a brown foam.
• aqueous ammonium hydroxide 60 ml.
• saturated aqueous sodium hydrogen carbonate 120 ml.
• the bulicolored product is then collected, washed with absolute ethanol, and dried in a vacuum to give N-cyclopropylmethylnorthebaine salicylate, M.P. 192.5-194.5 C. (decomp. to red-brown melt).
• the filtrate and washings deposit further material, and after 50 hours at 0 C. there is obtained a second crop of the salicylate, needles M.P. 193195 C. (decomp.).
• the combined product is dissolved in a mixture of acetone and ethanol (2:1) and the solution, after filtration, evaporated on the steam-bath with portionwise addition of ethanol until the mixture no longer contains acetone.
• the solution is then concentrated to about 25 ml. and seeded, giving N-cyclopropylmethylnorthebaine salicylate as long pinkish white needles, M.P. 197198.5 C. (decomp.), [a] 102.5 (c., 0.276 in chloroform).
• Example 3 Dihydronorcodeinone (21.10 g.) is dissolved in dioxan (211 ml.) and treated with water (21 ml.) and anhydrous potassium carbonate (21.1 g.). To the stirred mixture is added, dropwise, cyclopropylcarbonyl chloride (14.81 g.), during a period of 45 minutes. Stirring is continued for a further 3 hours at room temperature, after which the mixture is poured into water (1100 ml.). The resulting suspension is made alkaline to pH 11 with 2 N-sodium hydroxide and extracted with chloroform (200 ml., followed by 2 portions of ml.).
• the combined chloroform extracts are washed with N-hydrochloric acid (150 ml.) and with water (150 ml.) and dried over magnesium sulphate. Evaporation of the dried extracts under reduced pressure gives a pale brown viscous oil which crystallizes when rubbed with ether giving prisms of N-cyclopropylcarbonyldihydronorcodeinone (23.70 g.), M.P. 140141 C. Recrystallization from ethanol-ether gives needle clusters, M.P. 143144 C. The product can also be recrystallized from ethyl acetate-light petroleum or from isopropanol-ether-light petroleum.
• the purified material has [a] 295 (c., 0.440 in chloroform).
• the gelatinous precipitate is collected using .a filtration aid and washed with ethyl acetate (300 ml.). The combined filtrate and washings are evaporated to dryness to give a gum (5.5 g.), a portion of which crystallizes when cooled and rubbed with light petroleum. The remainder of the product when dissolved in the minimum volume (about 4 ml. per gram) of methanol and seeded with the foreging crystalline material gives rectangular tablets or rods of N-cyclopropylmethyl-A -dihydronorthe'baine, M.P. 112.5-113 C., 270 (c., 0.432 in chloroform).
• Example 4 Benzyl chloroformate (4.57 g.) is added dropwise with vigorous stirring to .a mixture of dihydronorcodeinone (5.74 g.), potassium carbonate (5.73 g.), and water (5.7 ml.) during a period of 30 minutes. The resulting mixture is stirred for 2 hours at room temperature and then poured into water (300 ml.) containing 2 N-sodium hydroxide (5 ml.).
• the aqueous phase is treated by 6 N-suphuric acid m1.) and set aside for 1 hour after which the resulting oily suspension is extracted with chloroform (3x100 ml.).
• the combined chloroform extracts are washed with water (2x100 ml.), saturated aqueous sodium bicarbonate (50 ml.), and finally again with water ml.), dried over magnesium sulphate, and evaporated. Pure N-(benzyloxycarbonyl)dihydronorcodeinone is thus obtained as a white foam.
• a -dihydronorthebaine (6.00 g.) is dissolved in anhydrous methanol (600 ml.), and finely divided magnesium oxide (0.638 g.) added.
• the mixture is cooled in ice and stirred vigorously while bromine vapour (from 3.241 g. of bromine) is introduced in a current of dry air by the method used in the preparation of the N-cyclopropylmethyl analogue.
• bromine vapour from 3.241 g. of bromine
• the mixture is stirred for a further 15 minutes at 0 C. and then for 2 hours at room temperature.
• the residual magnesium oxide is then removed using a filtration aid and washed with methanol, and the filtrate and washings taken to dryness.
• the residue is treated with water (100 ml.), followed by saturated aqueous sodium carbonate (50 ml.), and the mixture extracted with chloroform (3x100 ml.).
• the combined chloroform extracts are washed with water,
• Potassium (1.41 g.) is dissolved in dry 2-methyl-2- butanol (160 ml.) under reflux and the resulting alkoxide solution distilled through a 30 cm. Vigreux column, dry toluene being added at a rate sufficient to keep the volume of the mixture constant. This process is continued until the distillate consists of pure toluene (as is indicated by the temperature of distillation).
• the apparatus is then re-converted for reflux and a solution of 7bromodihydronorcodeinone dimethyl ketal (7.40 g.) in dry toluene (50 ml.) is added in one portion.
• the mixture is then stirred under reflux in an atmosphere of dry nitrogen for a further 23 hours, then cooled and treated with saturated aqueous sodium chloride (100 ml.).
• the aqueous phase is separated and extracted with ethyl acetate (2X 100 ml.), and the combined toluene and ethyl acetate phases washed repeatedly with saturated aqueous sodium chloride until the aqueous washings have a pH value of less than 9, dried, and evaporated, giving a gum (6.1 g.).
• Pure norcodeinone dimethyl ketal is obtained from a small-scale dehydrobromination, starting from 0.207 g. of the bromo-ketal. Isolation as described above gives a gum (0.160 g.) which is crystallized from 1:1 ether-light petroleum giving the pure ketal as fine cream-colored needles, M.P. 104-l06 C. (0.107 g.).
• a mixture of norcodeinone dimethyl ketal (3.29 g.; containing a small porportion of northebaine), finely powdered sodium bicarbonate (1.26 g.), allyl bromide (1.24 g.), and absolute ethanol (40 ml.) is heated under reflux with stirring for 22.5 hours. The mixture is cooled and the solids removed and washed with methanol. Evaporation of the filtrate and washings gives a gum which largely dissolves on addition of light petroleum, leaving a residue which is collected using a filtration aid and washed with further light petroleum. Evaporation of the filtrate and washings gives crude N-allylnorcodeinone dimethyl ketal (3.329 g.) as an orange oil which is used dlrectly for the next step.
• a Soxhlet extraction apparatus is set up with toluene-psulphonic acid (6.80 g.) and chloroform (500 ml.) in the boiling flask and a thimble (28 x80 mm.) filled with anhydrous magnesium sulfate in the extractor.
• the mixture in the flask is heated under vigorous reflux for 2 hours, and then cooled to 20-25 C.
• This product is purified by chromatography on alumina (60 g.; type H); elution with benzene and evaporation of the eluate gives a residue which largely dissolves on treatment with light petroleum.
• the insoluble material is removed using a filtration aid and washed with light petroleum and the filtrate and washings evaporated giving N-allylnorthebaine base as a pale yellow syrup.
• the base so obtained is dissolved in ether (10 ml.) and the solution added dropwise to a solution of salicylic acid (0.27 g.) in ether.
• the salicylate salt crystallizes out on seeding with a crystal from a previous preparation, and the mixture is set aside overnight at 0 C.
• Collection gives the salicylate salt, M.P. 179-180 C. which on dissolution in acetone, dilution with ethanol, and removal of the acetone under reduced pressure, crystallizes as fine needles, M.P. 186.5l87.5 C. of pure N-allylnorthebaine salicylate, identical (mixed M.P. and infrared spectrum) with the product obtained by alkylation of northebaine.
• Example 5 Dihydromorphinone base (52.33 g.), acetic acid (131 ml.), and acetic anhydride (131 ml.) are heated together under reflux for 1.25 hours. The reaction mixture is then cooled in ice and treated with an excess of saturated aqueous sodium carbonate, and the product isolated by extraction with chloroform (3 X 150 ml.). The combined chloroform extracts are washed with 2 N-sodium hydroxide (200 ml.) and then with saturated aqueous sodium chloride (2x200 ml.), dried (magnesium sulphate) and evaporated. The resulting foam crystallizes on treatment with a mixture of light petroleum and ethyl acetate, giving prisms, M.P. 121.5122.5 C. of acetyldihydromorphinone.
• Acetyldihydromorphinone (50 g.), dissolved in chloroform ml.), is added slowly with stirring during 20 minutes to a solution of cyanogen bromide (16.40 g.) in chloroform. Heat is evolved. After the initial reaction has subsided, the mixture is heated on the water-bath for 2 hours, after which the solvent is removed under reduced pressure. The residue on treatment with hot water gives crude O acetyl N-cyanodihydronormorphinone which is washed with hot water and then with cold wa ter. Recrystallization from methanol gives the pure cyano-compound as yellowish prisms, M.P. 98100 C. (efferv.).
• Dihydronormorphinone (25 g), dioxan (250 ml.), water (25 ml.), and potassium carbonate (25 g.) are stirred together and cyclopropanecarbonyl chloride (18 g.) added. Stirring is continued for 20 hours at room temperature; then 2 N-sodium hydroxide (200 ml.) is added and the mixture stirred for a further 45 minutes. The mixture is extracted with ethyl acetate (4x100 ml.) to remove any cyclopropanecarboxylic ester formed, and the aqueous layer adjusted to pH 2 with 2 N-hydrochloric acid. Collection of the precipitate gives N-(cyclopropanecarbonyl) dihydronormorphinone, M.P. 338340 C. (decomp.).
• N,N-diethylcarbamyl chloride (8 g.) is added dropwise to a solution of N-(cyclopropanecarbonyl) dihydronor- .morphinone (10 g.) in dry pyridine (50 ml.), and the last traces 'of chloride washed in with further pyridine (10 ml.). The mixture is then heated under reflux with stirring for 4 hours, during which time all the solid initially present dissolves. The reaction mixture is cooled in ice, treated with sufficient 6 N-sulph-uric acid to remove the pyridine, and extracted with chloroform (4X 10 ml.). The combined chloroform extracts are washed with 2.5 N'sodium hydroxide (3x100 ml.) and with water (2x100 ml.), dried (magnesium sulphate) and evaporated, giving a brown foam.
• This product is dissolved in absolute ethanol (75 ml.) containing acetic acid (7.5 g.), Girards reagent P (6 g.) added, and the mixture heated under reflux for 1 hour.
• the reaction mixture is cooled and poured into ice-water (500 ml.) containing 0.5 N-sodium hydroxide (225 ml.).
• the aqueous mixture is extracted with ether (4x100 ml.), and the aqueous phase is then treated with 6 N- sulphuric acid (80 ml.) and set aside for 1 hour.
• the resulting aqueous suspension is extracted with benzene (200-
• the residue (8.80 g.) is further purified by chromatography on alumina (type H; 150 g.); elution with benzene containing 0.3% of methanol and evaporation of the eluate give pure N (cyclopropanecarbonyl) O (N'., N diethylcarbamyl) dihydronormorphinone as a colorless glass which subsequently crystallizes as needles on treatment with benzene and then has M.P. 176177 C.
• a solution of dimethyl sulphate (1.82 g.) in t-butanol (25 ml.) is then added dropwise with stirring, and the mixture stirred for 1 hour at room temperature and then for 2 hours under reflux.
• the bulk of the solvent is then removed under reduced pressure and the residue stirred with 1.5% aqueous ammonium hydroxide (300 ml.), extracted with benzene (200-1-2X100 ml.), and the combined benzene extracts washed with saturated aqueous sodium chloride (100 ml.), dried over magnesium sulphate, and evaporated.
• the residue (5.41 g.) is purified by chromatography on alumina (150 g.; type H) and elution with benzene containing 0.1% of methanol. Evaporation of the eluate gives a foam (4.7 g.) which on crystallization from ether gives N-(cyclopropanecarbonyl) O (N,N' diethylcarbamyl) A dihydronoroipavine, needle clusters M.P. 7578 C.
• the mixture is stirred under reflux in an atmosphere of dry nitrogen for 3 hours, after which the mixture is cooled in ice-water and stirring continued while a mixture of ethyl acetate (14 ml.) and ether (30 ml.) is added dropwise, followed by cautious addition of a solution of disodium dihydrogen ethylenediaminetetraacetate (17.5 g.) in water (80 ml.). After addition of benzene (50 ml.), saturated aqueous sodium bicarbonate is added until the aqueous phase has pH 8. The upper phase is separated and the aqueous phase extracted with benzene (2x100 ml.).
• This material (500 mg.) is dissolved in pyridine and reacted with an excess of nicotinoyl chloride. Quenching in water gives the nicotinoyl ester.
• Example 6 A stirred suspension of dihydronormorphinone (30 g.) in dioxan (300ml) is cooled in ice-water and treated successively with potassium carbonate (30 g.), water (30 ml.), and cyclobutanecarbonyl chloride (24.2 g.). The resulting mixture is stirred for 20 hours at room temperature and then treated with 2 N-sodium hydroxide (180 ml.), stirred for a further 45 minutes, and finally extracted with ether (3X60 ml.).
• the aqueous phase is cooled in ice and acidified with 6 N-hydrochloric acid, and the buff colored product collected, washed with water, and dried, giving almost pure N-cyclobutanecarbonyl)dihydronormorphinone, M.P. 285 C. (decomp.).
• the compound is prepared by the same two methods as were used for the preparation of the corresponding N- cyclopropanecarbonyl derivative.
• a -dihydronororipavine (4.85 g.) is reduced with lithium aluminum hydride by the method used for the preparation of the corresponding N-cyclopropylmethyl derivative.
• Isolation gives crude N (cyclobutylmethyl)A -dihydronororipavine (4.25 g.) which is converted to the salicylate salt needle-clusters M.P. 231232 C. (decomp.) from ethanol.
• trituration of the crude reduction product with ether gives the free base as an amorphous solid M.P. 103-104 C.
• Example 7 The process of Example 1 is repeated substituting in equimolar quantities propargyl chloride for allyl bromide to give N-propargylnorthebaine. Substituting 3,3-dimethylallyl gives N 3,3 dimethylallylnorthebaine. 3,3- dichloroallyl bromide substituted in Example 4 using sodium bicarbonate in ethanol give 3,3-dichloroallylnorthebaine. Substituting cyclopentylcarbonyl chloride or cyclohexylcarbonyl chloride for the cyclopropylcarbonyl chloride of Example 5 gives N-cyclopentylmethyl or N-cyclohexylmethyl-M-dihydronororipavine.
• Example 8 A solution of dihydromorphinone base (46.0 g.) in dry pyridine (230 ml.) is stirred while diethylcarbamyl chloride (43.7 g.) is added slowly. The resulting mixture is stirred under reflux for 3 hours, after which the solvent is removed under reduced pressure. The syrupy residue is taken up in warm water (150 ml.) and the solution concentrated to 100 ml. under reduced pressure, treated with charcoal at the boiling point, filtered, and the filtrate cooled and made alkaline with 10 N-sodium hydroxide (30 ml.).
• the oily suspension is extracted with benzene (100+2 50 ml.) and the combined benzene extracts are washed with saturated aqueous sodium chloride (50 ml.), dried over magnesium sulphate (with charcoal), and evaporated.
• the resulting oil is treated with light petroleum (200 ml.) and left overnight at 0 C.
• the crystalline mass so obtained is broken up and the solid collected, washed with 1:1 ether-light petroleum, and dried.
• the product has M.P.
• Example 9 N(3,3 dimethylallyl) A dihydronororipavine (0.5 g.) when treated with nicotinoyl chloride in the presence of pyridine (according to the method used in the preparation of N-cyclobutylmethyl-O-nicotinoyLM-dihydro- 2.1 nororipavine) gives N(3,3-dimethallyl)-O-nicotinoyl-A dihydronoro'ripavine which on treatment with one mole equivalent of hydrobromic acid in methanol at C. gives the hydrobromide salt.
• Example N cyclobutylmethyl A dihydronororipavine (0.50 g.) is added to a solution of nicotinoyl chloride hydrochloride (0.52 g.) in dry pyridine (6 ml.). Some heat is evolved and a clear orange solution results. This solution is stirred at room temperature for 3 days, after which ether (50 ml.) is added and the ethereal solution washed with saturated aqueous sodium carbonate (5 20 ml.) and with Water (2X25 ml.), dried over magnesium sulphate, and evaporated, giving the cmde nicotinoyl ester.
• N-allyldihydronorcodeinone prepared by the method of Clark, Pessolano, Weijlard, and Pfister, J, Amer. Chem. Soc., 1953, 75, 4963] (10.23 g.) is methylated by the same method as that used in the preparation of N-(cyclopropanecarbonyl)-A -dihydronorthebaine. After chromatography on alumina the product is obtained as an oil which on crystallization from light petroleum gives pure N-allyl-A -dihydronorthebaine as cubes, M.P. 6364 C.
• Example 12 N (cyclopropanecarbonyl) O(N',N' diethylcarbamyl)-A -dihydron-ororipavine (4.53 g.) on treatment with methyl hypobromite (by the method used in the preparation of 7 bromo-N cyclopropylmethyldihydronorcodeinone dimethyl ketal) gives 7-bromo-N-(cyclopropanecarbonyl) O(N',N' diethylcarbamyl)dihydrononmorphinone dimethyl ketal.
• N cyclopropanecarbonyl -O(N,N'-diethylcarbamyl) normorphinone dimethyl ketal (2.4 g.) is dissolved in dry tetrahydrofuran (60 ml.) and the solution added to a stirred slurry of lithium aluminum hydride (1.2 g.) in dry tetrahydrofuran (60 ml.). The mixture is then stirred under reflux in an atmosphere of nitrogen for 3 hours.
• N-cyclopropylmet-hylnormorphinone dimethyl ketal (2.0. g.) is treated with anhydrous toluene-p-sulphonic acid in chloroform solution (by the method used in the preparation of N-cyclopropylmethylnorthebaine).
• the crude reaction product (2.1 g.) is dissolved in dry pyridine(20 ml.) and the solution cooled to 0 C. and stirred while a mixture of acetic anhydride (4 ml.) and dry pyridine (6 ml.) is added drop wise. The mixture is kept at roomtemperature for 24 hours, then poured into saturated aqueous sodium bicarbonate ml.).
• the mixture is extracted with chloroform (3 30 ml.) and the combined chloroform extracts are washed with saturated aqueous sodium bicarbonate (3x25 ml.), dried over magnesium sulphate, and evaporated.
• the residue (2.3 g.) is subjected to chromatography on alumina (45 g.; type H); elution with benzene and evaporation of the eluate gave O-acetyl-N-cyclopropylmethylnororipavine.
• R is a member selected from the group consisting of 1 out-out and in which R R and R are members selected from the group consisting of hydrogen, methyl and chloro;
• R is methyl
• R is a member selected from the group consisting of methyl, hydrogen and a lower acyl group derived from a pharmaceutically acceptable carboxylic acid of a maximum of 8 carbon atoms.
• a -dihydronorthebaine comprising reacting N-(benzyloxycarbonyl)-A -dihydronorthebaine with triethylsilane in the presence of triethylamine and palladium chloride to form N-triethylsilyl-A dihydronorthebaine, reacting said N-triethylsilyl-A -dihydronorthebaine with methanol treating the reaction mixture from the methanol treatment with an aqueous citric acid solution to separate the insoluble acid addition citrate salt and neutralizing said salt to form A -dihydronorthebaine.

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  • BE BE638369D patent/BE638369A/xx unknown
• 1963
  • 1963-10-04 US US313793A patent/US3299072A/en not_active Expired - Lifetime

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