Patented Nov. 13, 1934 1980,972 UNITED STATES PATENT OFFICE

1980,972 DERVATIVE AND PROCESSEs FOR ITS PRE PARATION Lyndon Frederick Small, Charlottesville, War, as signor to Government of the United States, represented by the Secretary of the Treasury No Drawing. Application July 19, 1934, Serial No. 736,108 7 Claims. (C. 260-25) (Granted under the act of March 3, 1883, as amended April 30, 1928; 370 O. G. 757) The invention described herein may be manu more Or leSS, is absorbed. The solution is then factured and used by or for the Government of filtered and the solvent removed by distillation . the United States for governmental purposes only at atmospheric pressure, or preferably in vacuum Without the payment to me...of any royalty thereon. at about 40° C. The resulting material is dis 5 The present invention is a new product of the solved in water and the product precipitated out morphine. Series and is Superior in physiological by slow addition of ammonia, sodiumcarbonate, action to most present known narcotics related or similar precipitants' for phenolic substances, to morphine, and drugs of like action and shaking into ether or other organic solvent, as which may serve to replace morphine, in pharma chloroform, benzene, etc., after each addition. O ceutical preparations, and in medical applications. The organic solvent is distilled to a small volume The invention is more effective in producing and traces of tetrahydrodesoxymorphine filtered analgesia, in effect on respiration and cough, and out. The product remaining in the solvent crys in general depressant action, but relatively free tallizes on rubbing with ethyl acetate. The yield from convulsant, enetic and toxic effects, and is approximately 9.2 grams. The Substance has 5 is designed to replace morphine and other drugs. the melting point 188-189 C. and has the specific O of morphine-like action in therapeutic practice. rotation in absolute methanol It is intended to be administered by mouth, by rectum or by injection. In respect to effective (a)p-76.8° (c=1.614). dose it will be less costly-that is, the amount Analysis shows the composition to be C17HaiO2N. 20 necessary for an effective dose would be less than As variations of this process, under the first 75 morphine or codeine; consequently for an effec example the well-known beta-chloromorphide, tive dose it would be less expensive than the bronomorphide or iodomorphide may be used, equivalent amount of morphine or codeine. and other noble metal catalysts or copper con The methods of producing the present product taining catalysts, or finely divided nickel in vari 25 are simple in operation and relatively economical. ous organic solvents as ethanol, benzene, etc., or 80 The invention, to be known chemically as di in acid solutions, may be employed as well as the hydrodesoxy-morphine-D, represents a dihydro neutral aqueous solution of the salts, or alkaline genated morphine in which the alcoholic hy solution, but in a degree less satisfactory So far droxyl group has been replaced by a hydrogen as experiments have shown, the neutral salts 30 atom. being more satisfactory than the alkaline solu The present product may be attained in three tion. distinct ways: (1) by catalytic hydrogenation of The amounts of catalysts and solvent, above the halogenomorphides; (2) by catalytic hydro mentioned, may be varied within wide limits genation of the halogenocodides, followed by de without greatly changing the result. Also, hy methylation; (3) by catalytic hydrogenation of drogen pressure below and especially above, at 90 35 desoxy-morphine-C (see Journal of American mospheric pressure may be employed. Chemical Society, vol. 55, page 2874 of 1933, par The product may likewise be isolated advan ticularly at page 2881) under special conditions. tageously in the form of Salts, as Oxalate, salicy The applicant is aware that German Patent late, hydrochloride, Sulfate, etc. Dihydrodesoxy #414,598 of Knoll and Company claims the prep morphine-D hydrochloride of formula . 95. 40 aration of a substance of the formula of dihydro desoxymorphine-D. Applicant has, however, demonstrated that the product in the Knoll pat has the specific rotation ent is actually a desoxymorphine which depresses Iolo-66.8 (water, c=0.898). 45, the melting point of dihydrodesoxymorphine-D 100 and is convertible to the latter by addition of two Dihydrodesoxymorphine-D sulfate of formula hydrogen atoms catalytically, and therefore can (C17H2ON) H2SO4-2H2O, has the specific rota not be identical with it. tion In producing the product of the invention by a D-57.9 (Water, Cs1.425). the first examplementioned above: Fifteen grams 105 50 of alpha-chloromorphide, a well-known morphine. These salts as well as numerous others such as derivative, dissolved in 150 cc. of absolute meth the tartrate, phosphate and, acetate are soluble anol is shaken in the presence of 1 gram of palla in water and adapted to medical use. dium on barium sulphate in an atmosphere of In preparing the dihydrodesoxymorphine-D in 55 hydrogen, whereby about 2064 cc. of hydrogen, accordance with the second example: Fifty grams O 2 o 1980,972 of the well-known codeine derivative, alpha here stated, the amounts of glacial acetic acid chlorocodide, is dissolved in 160 cc. of dilute, and catalyst may be varied within wide limits. preferably normal hydrochloric acid, 100 cc. of The precipitate is extracted into ether or other water and 2 grams of palladium on barium, Sul organic solvent as benzene or chloroform, and fate catalyst added, and the mixture shaken un on distillation of the solvent, about 2.2 grams der hydrogen until absorption ceases. The of oily material is obtained his is rubbed with amounts of these reagents and the strength of a little acetone, ethyl acetate or other organic acid may be varied within wide limits without Solvent whereby the tetrahydrodesOxymorphine greatly changing the result. About 7600 cc. of present crystallizes and can be filtered out. The O hydrogen is absorbed. The product of this hy mother liquor yields about 0.75 gram of dihydro drogenation, the known dihydrodesoxycodeine-D, desoxymorphine-D which is purified by one of the is isolated after removal of the catalyst by treat methods described in connection with the first ing the acid solution with excess of sodium car example. bonate, sodium hydroxide or other alkaline agents As a variation of this process, the Well known 15 and extracting into ether or other organic Sol desoxycodeine-C hydrochloride (see Journal vents usually employed for extraction. The American Chemical Society, vol. 53, page 2225 of product is obtained in nearly quantitative yield 1931) or other desoxymorphine-C ethers may be when the organic solvent is distilled off, and is hydrogenated, and the product so obtained de purified by crystallization from alcohol, acetone, etherified as described under the second example. benzene or other solvents, or may be purified ad I have found that in the preparation of the 95 vantageously as salts such as the tartrate, Salicy product of this invention, the first and second late, sulfate and others. As variations of this examples constitute the more feasible and eco process, other known halogenocodides, as beta nomical preparative methods while the third chlorocodide, bromocodide or iodocodide may be process is more difficult and involves considerable used in organic solutions or in acid solutions, and losses in material, giving a lower yield of the 100. alpha-chlorocodide may be used in organic Sol desired product. vents as ethanol, methanol, and others adapted The product of invention has a very great ad as media for hydrogenation. Other catalysts, as Vantage over most narcotics in its extreme stabil the various known active forms of platinum, pal ity, so that solutions of its salts may be sterilized 30 ladium, and nickel, and copper compounds may by boiling without any deterioration. be employed. The dihydrodesoxycodeine-D is What I claim as new is: : 105 demethylated as follows: Ten grams of dihydro 1. A . derivative in which the desoxycodeine-D is dissolved in 50 cc. of hydro alcoholic hydroxyl group of dihydromorphine bromic acid (48% HBr, sp. gr. 1.49) and boiled has been replaced by hydrogen. under a reflux condenser until the product is 2. A new compound having the formula 10 completely soluble in sodium hydroxide Solution, C17HaO2N and wherein two hydrogen atoms have requiring about 15 minutes. The reaction mix been added to the allicyclic unsaturation in more ture is diluted with water, 500 cc. of ether, ben phine and the alcoholic hydroxyl group replaced zene, chloroform, etc., added and Saturated Sodi by a hydrogen atom. um carbonate solution or ammonia in excess 3. The method of preparing a new product of 115. cautiously poured in. The precipitate of dihy the morphine series which includes catalytically. dirodesoxymorphine-D is extracted into the Or hydrogenating a compound selected from the ganic layer. Several more extractions yield a group consisting of halogenomorphides and small additional amount of the drug. During desOxymorphine-C, in the liquid phase. 45 the extraction, traces of tetrahydrodesoxymor 4. The method of preparing a new product of 120 phine, which is almost insoluble in organic Sol the morphine series which includes catalytically vents, are separated by filtration and discarded. hydrogenating a compound selected from the The yield is about 8 grams of pure dihydrodesoxy group consisting of the ethers of the halogeno morphine-D. base. As variations of this de morphides and of desoxymorphine-C in the liquid 50 methylation, concentrated hydriodic acid may be phase, and then de-etherifying the hydrogenation. 125 used, or concentrated hydrochloric acid in a products. sealed tube at temperatures above 100° C. The 5. The method of preparing a new product of. amount and strength of the acids used for the morphine series which includes catalytically demethylation may be varied. The product may hydrogenating solutions of the halogenomor also be isolated as the crystalline hydrobromide phides in the presence of a catalyst selected from 130. or hydriodide salt when the acid solution is a group consisting of nickel, noble metals and diluted. copper-containing hydrogenation catalysts. In accordance, with the third example men 6. The method of preparing a new product of tioned above, of preparing the dihydrodesoxy the morphine series which includes demethylation morphine-D: A suspension of 2.27 grams of the of dihydrodesoxycodeine-D by action of a hot 135. well-known desoxymorphine-Chydrochloride (see concentrated acid selected from the group COn yournal of American Chemical Society, Vol. 55, sisting of hydrobromic, hydriodic, and hydro page 2874 of 1933, particularly at page 2881) in chloric. 10 cc. of glacial acetic acid with 0.05 g. of plati 7. The method of preparing a new product of num oxide or other platinum, palladium, nickel the morphine series which includes catalytic hy 140 or copper containing catalyst is shaken under 'drogenation of organic acid solutions of desoxy hydrogen until absorption ceases, the solution is morphine-C in the presence of a catalyst selected freed from catalyst, diluted and treated with from a group consisting of nickel, noble metals excess of ammonia, or sodium carbonate or bi and copper-containing hydrogenation catalysts. O carbonate or similar precipitants for phenolic substances. While the preferred quantities are LYNDON FREDERICKSMALL. 145

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