Patented Dec. 11, 1951 2,577,948 fJ-IjUNITED STATES PATENT v- OFFICE New York Quinine and Chemical Works, Incor porated, Brooklyn, N. Y., a, corporation of New York No Drawing. Application October 28, 1950, Serial No. 192,813 3 Claims. _(Cl. 260-285) 1 ., . 2 ' _My invention relates‘ to the manufactureof with reference to its addiction liability. Where; dihydroisocodeine, hereinafter conveniently re-. as ‘DHIC is rather‘ expensive when madefby ferred to as. DHIC. the method of the prior art, it is produced'by' DHIC has previously been made by a process my new method in a much less expensive and which involves converting codeine to alpha 5 more convenient manner, since the' yield is chlorocodide (SmallCohen, J. A. C. S. 52, 2214, greatly improved and no extensive separation 1931) and. treating the latter with acetic acid and puri?cation is required. Thus, DHIC will which gives a mixture of pseudocodeine, allo now be readily available for us in clinical trials. pseudocodeine, and isocodeine. The mixture is The following examples illustrate my inven laboriously separated into its components by 10 means of appropriate salts, and the isocodeine' tion: ' is then hydrogenated and yields DHIC (Speyer ‘ Example 1 and Krauss, Ann. 432, 233, 1923). A mixture of 5.00 g. dihydrocodeinone, 7.50 The overall yield of this method is only 22.3% g. aluminum isopropoxide and 150 cc. dry tol of the theory based on codeine. In another ex 15 uene was heated under a re?ux condenser con periment (Rapoport and Payne, J. Org. Chem. nected to a sulfuric acid trap for 24 hours. The 15, 1097, 1950) the overall yield obtained by the. 1 mixture was cooled and extracted ?rst with 80, same method was only 6%. then with 50 and ?nally with 35 cc. of 10% In an effort to improve the yield, I have now hydrochloric acid. The acid extracts were discovered that a far superior yield of DHIC 20 made strongly alkaline with sodium hydroxide in the order of about 60% can be obtained by and extracted four times with 100 cc. each of a procedure which is very different from the 7 chloroform. The chloroform extracts were one referred to above. washed, dried and evaporated to dryness. The My new process involves the reduction of di residue, 4.75 g., was dissolved in 60 cc. of ethyl hydrocodeinone with the aid of metallic al 25 ene dichloride and passed by gravity through koxides in an anhydrous organic solvent. a column of activated alumina 6 inches high Aluminumfor carbonyl alkoxides compounds are knownbut have reducing never agentsbefore and three-quarter of an inch in diameter. The column was then washed by gravity with por ‘been applied to keto opium alkaloids. The re-‘ 1 tions of ethylene dichloride _and the effluents duction fails with some alkaloids such as quin 31) collected in 50 cc. fractions. The first four ef inone and even with some simpler amino-ke ?uents contained a total of 1.12 g. of a mixture tones, and it usually gives mixtures of isomers of dihydrocodeinone and dihydroisocodelne. which are di?icult to separate. Where one of i The alkaloid remaining on the alumina was re-' two possible epimers is favored in this reaction, moved by 5% sulfuric acid. The acid solution the possibility of predicting the outcome is very was made alkaline and extracted with chloro small at present. Jackman et al. (Journ. form. Evaporation of the chloroform gave 3.05 Chem. Soc. 1949, 2642) attempted to develop g. (about 60%) of alkaloid which after recrys a hypothesis as to which epimer would be fav tallization from alcohol melted at 195—198° and ored. 0n the basis of that hypothesis, Rapoa; .. yielded a picrate and acetyl derivative whose port et al. (J. Org. Chem. 15, 1103, 1950) inter melting points of 235-236° and 165~168° respec preted their own data on the oxidation of di-" ' tively agreed well with those reported in the hydrocodeine and of DHIC in the Openauer re literature for the corresponding derivatives of action as indicating that dihydrocodeine and dihydroisocodeine. (Cf. Small’s “Chemistry of not DHIC should be the primary reduction prod the Opium Alkaloids” published by the U. 8. uct of dihydrocodeinone in a reaction catalyzed 5 Treasury Department, Public Health Service. by metallic alkoxides. Supplement No. 103, page 224.) I have found that the DHIC obtained by my new method is not admixed with any sig Example 2 ni?cant quantity of its epimer, dihydrocodeinee. CR A mixture of 5.00 g. dihydrocodeinone, ‘7.50 g. the crude dihydroisocodeine of my process yields aluminum isopropoxide, 50 cc. dry isopropyl alco derivativeswhose melting such pointsas the arepicrate in goodand methiodideagreement _> 'I_ hol and 150 cc. dry toluene was heated under partial re?ux with slow take-01f. The distillate with those reported in the literature. was tested from time to time for acetone. About DHIC has been extensively investigated clini-_l I 55 60 cc. of dry isopropanol was added dropwise in cally as an analgesic and antitussive agent. and the course of the reaction to compensate for 10st 9,677,948 3 ‘ . 4 . solvent. When no further acetone was formed which comprises heating a mixture of 5.00 a. di in the distillate, the reaction mixture was heated hydrocodeinone, 7.50 g. aluminum isopropoxide, to about 107° (vapor temperature) cooled and ex 150 cc. dry toluene under re?ux with exclusion tracted ?rst with 50, then with 20 and ?nally of moisture, extracting the cooled reaction mix with 10 cc. of 10% HCl. The continued acid ex ture with 10% hydrochloric acid, adding'sodium tracts were made strongly alkaline with 40% hydroxide to the extract to make it strongly sodium hydroxide. The . precipitated alkaloid alkaline, extracting it with chloroform evaporat was removed ?ltration, washed with water and ing the chloroform extract, chromatographing dried. Yield 4.38 g. (87.6%), M. P. 180-193". A the residue dissolved in ethylene dichloride on ac sample after recrystallization from alcohol melted tivatedalumina, washing the alumina with dilute at 194-199° and gave no depression in melting sulfuric acid to remove the dihydroisocodeine point when admixed with authentic dihydro therefrom, making the acid solution strongly isocodeine. - alkaline, extracting it with chloroform and evap The solvent employed in this reaction is an an orating the ‘chloroform solution to obtain the hydrous organic liquid such as benzene and tolu crude dihydroisocodeine. ene selected primarily for its ability to dissolve 2. In the process of reducing dihydrocodeinone substantial amounts of the aluminum salt of an to dihydroisocodeine the improvement which alcohol capable of being oxidized to its carbonyl comprises performing the reduction with alumi derivative. The reaction is conveniently per nuinisopropoxide in an anhydrous organic sol formed at re?ux temperature of the solvent and 20 vent. proceeds to completion within a reasonable time. ' -3. The improvement of claim 2 in which tolu The reaction conditions such as temperature, ene is used as the organic solvent. duration, relative proportions of the reactants MANUEL M.'BAIZER. and of the solvent, can be modi?ed in various ways to strengthen the e?lciency of the process REFERENCES CITED and further increase the yields. These modi?ca The following references are of record in the tions are intended to be included in the scope of ?le-‘of this patent: this invention and of the appended claims. ' What I claim is: Rapoport et al.: J. Org. Chem., vol. 15, pp. '1. The process of making dihydroisocodeine 30 1103-1107 (September 1950). .