Patented Oct. 27, 1936 2,058,521 UNITED STATES PATENT OFFICE 2,058,521 ETHERS OF MORPHINE AND ITS DHYDRO. GENATED: DERVATIVE, AND METHODS OF PRODUCTION Lyndon Frederick small, Charlottesville, Wa, as signor to the Government of the United States, represented by the Secretary of the Treasury No Drawing. Application October 22, 1935, Serial No. 46,215 18 Claims. (CI. 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 cess of hydrogen peroxide and water is removed factured and used by or for the Government of under diminished pressure at a temperature of the United States for governmental purposes only 40° to 50° C. The frothy glass-like mass is Without payment of any royalty, thereon. treated with about 200 cc. of hot acetone in which The present invention includes new ethers of it dissolves readily. The walls of the vessel are morphine and of its dihydrogenated derivative, gently rubbed with a glass rod, whereupon crys dihydromorphine, which are superior in certain tallization takes place; the crystalline product is respects to morphine, and which may serve to practically insoluble in acetone, and is Washed replace morphine or its previously known de thoroughly on the filter with cold acetone. This 0. rivatives in pharmaceutical preparations and in product is the hitherto-unknown crystalline form medical applications. The subjects of the inven of methoxymethylmorphine-N-oxide, and con 10 tion show a higher degree of physiological activ tains one molecule of acetone of Crystallization. ity than morphine, and possess the advantage of The yield is 116.5 grams of pure white crystals. a greater margin of Safety than morphine. The One hundred and Sixteen grams of methoxy 15 product of the invention is intended to be ad methylmorphine-N-oxide acetone compound is 15 ministered through the mouth or rectum or by dissolved in 100 cc. of water in a vessel equipped injection, and thus, obviously while the terms with an efficient stirring device, and an excess “morphine' and “dihydromorphine' or ethers of of diethyl sulfate (about 180 cc.) and of 10-nor these, are used herein as representative for pur mal sodium hydroxide solution (about 180 cc.) 20 poses of definition, they are intended to be in added dropwise over a period of five to six hours, terpreted as including compounds. Such as the in such manner that the solution remains always 20. Salts of these basic Substances with inorganic or alkaline; during the operation, the containing organic acids. vessel is cooled in an ice bath, and the reaction Accordingly, while specific salts are mentioned mixture stirred vigorously. The solution is 25 in the illustrative examples of the invention here stirred for a further period of four hours at room inafter, these are only representative of the nu temperature, acidified immediately with 25% sul 25 merous posssible salts commonly employed for phuric acid solution, and the acid Solution ex medical use, and the use of the basic terms in tracted with ether, to remove unused diethyl the appended claims is likewise to be interpreted. Sulfate. The aqueous layer, usually containing 30 as inclusive of Such salts. some oily methoxymethylmorphine ethyl ether 30 The invention comprises three new ethers of . N-oxide sulfate, at a temperature of about 60° C., morphine and dihydromorphine, in which the is treated. With gaseous Sulfur dioxide during alcoholic hydroxyl group of the parent sub several hours, cooled, made ammoniacal, and ex stances (morphine and dihydromorphine) has tracted many times with ether. The yield of 35 been etherified, viz: ... - crude crystalline morphine, alcoholic ethyl ether 35 1. Morphine alcoholic ethyl ether (heterocod obtained by distillation of the ether is about 51 ethylin or heteroethylmorphine). - - grams. The base may be purified as such by 2. Dihydromorphine alcoholic ethyl ether (di Crystallization from Organic Solvents, most ad hydroheterocodethylin, heteroethyldihydromor vantageously ethyl acetate, or may be purified 40 phine). by crystallization of its sparingly soluble salts, 3.Dihydromorphine alcoholic methyl ether (di notably the salicylate, the hydrochloride, the hy 40 hydroheterocodeine). drobromide, the hydriodide, and the perchlorate. The first product of the invention mentioned Morphine alcoholic ethyl ether is found by an above, morphine alcoholic ethyl ether is attained alysis to have the formula C19H23O3N--H2O; it 45 as follows: ...'", melts, at 110-112 C., and has the Specific rotation One hundred and eight grams of the well 45 known methoxymethyl ether of morphine (see (a - 178.8° Mannich, Archiv der Pharmazie, vol. 254, page 349, of 1916; German Patent No. 280,972) is (alcohol, c=1,012). Its hydrochloride, (hetero 50 treated with 65 cc. of 30%. hydrogen peroxide, dionin) of formula C19H24O3NC1--3H2O melts at whereupon a vigorous reaction takes place and 241-243°C. in an evacuated tube, and has the 50 the methoxymethylmorphine goes into Solution; specific rotation most suitably the temperature is not allowed to rise above 50°C. The frothy mobile liquid is (a)- 134.9° 55 then Warmed at 50° C. for 20 minutes. The ex in aqueous solution. 2 2,058,521 phine alcoholic methyl ether (dihydroheteroco AS Variations of this process, various ethyl deine) is attained as follows: halides, as ethyl iodide, ethyl bromide, or ethyl Five grams of the well-known morphine alco); chloride may be substituted for diethyl sulfate. holic methyl ether (Heterocodeine; see Mannichi, Furthermore, in place of morphine methoxy Archiv der Pharmazie, vol. 254, page 439 of 1916) methyl ether, the well-known morphine benzyl. dissolved in a convenient quantity of methanol. ether may be used. This variation has the ad ethanol, ethyl acetate, dilute acetic acid, dilute: vantages that morphine benzyl ether is much hydrochloric acid, dilute sulfuric acid, etc. is agi cheaper to prepare and is obtained in better yields tated in an atmosphere of hydrogen in the fires than morphine methoxymethyl ether. In this ence of a small quantity (80 mg.) of platinuns or. 103 O modification, the product of ethylation carried out palladium catalyst, whereby one mole of hydro as described above, namely, benzylmorphine ethyl gen is absorbed; nickel catalysts may likewise be ether-N-oxide is first reduced in acid solution with employed. The product, isolated in the usual way, sulfur dioxide, and the resulting benzylmorphine is 5g. of dihydromorphine alcoholic methyl ether, ethyl ether is then heated with acids (preferably and is purified by crystallization from alcohol, 15 5 3-normal hydrochloric acid) until an alkali-solu ethyl acetate, or other organic solvent. It has the ble product is obtained; this is morphine alcoholic melting point 216-217 C. and the specific rotation ethyl ether, identical with that described above. The second product of the invention, dihydro morphine alcoholic ethyl ether is attained as (a) - 178.0° 20 20 follows: (alcohol, c=1.000). Analysis shows the formula Seventeen grams of the above-described mor to be C18H23O3N. The hydrochloride is prepared phine alcoholic ethyl ether hydrochloride (hetero in alcohol with alcoholic hydrogen chloride, and dionin) Suspended or dissolved in a Convenient has the Specific rotation amount of water (about 200 cc.) is agitated in 25 25 an atmosphere of hydrogen in the presence of One gram of palladium-barium Sulfate catalyst, (a):- 1369 whereby about one mole of hydrogen is absorbed. (Water, c=3.247), the melting point 299-299.5° C. After removal of the catalyst, the solution is con in Vacuo, and the formula C18H24OgNC. centrated under diminished pressure at about 60° The third product of the invention may lice 30 30 C.; the hydrochloride of dihydromorphine alco Wise be advantageously prepared by methylation: holic ethyl ether separates crystalline in nearly of the hitherto-unknown methoxymethyldihy quantitative yield. On cautious addition of dilute dromorphine-N-oxide, or of the hitherto-un ammonia to an aqueous Solution of the above hy known benzyldihydromorphine-N-oxide with di drochloride (most advantageously in the presence methyl Sulfate or methyl halides in alkaline so 35 of a trace of ether) the dihydromorphine alco lution by a procedure parallel to that described holic ethyl ether separates as fine white crystals, under the first product of the invention. In this and may be further purified by crystallization case the products resulting from the methylation, from ethyl acetate or other Organic solvent. The methoxymethyldihydromorphine alcoholic meth hydrogenation may also be accomplished using yl ether-N-oxide, and benzyldihydromorphine al 40 40 Solutions of morphine alcoholic ethyl ether in coholic methyl ether-N-oxide respectively, are dilute acids, as acetic, tartaric, hydrochloric, sul reduced at the N-oxide group with sulfur di furic, etc., or in Organic media, as methanol, oxide and the methoxymethyl group and benzyl ethanol, ethyl acetate, etc., and with other noble group in the resulting respective products is re metal catalysts, or nickel catalysts. moved by hydrolysis with hot dilute acids. The 45 As a variation of this process, the hitherto-un product is dihydromorphine alcoholic methyl known methoxymethyl ether of dihydromorphine ether identical with that described above. In the (having the formula C19H25O4N, the melting point methods for producing the products of the in 102-104° C. and the specific rotation vention the amounts of the catalysts and solvents - re- O above mentioned may be varied within wide lim 50 (e)o D 155.8 its without greatly changing the result. What I claim as new is: (absolute ethanol, c=1.219)) or the hitherto-un 1. A morphine derivative in which the hydro known benzyl ether of dihydromorphine (having gen atom of the alcoholic hydroxyl group of mor the formula, C24H2O3N, the melting point 95-97 phine has been replaced by an ethyl group.