Patented Mar. 14, 1950 2,500,444 UNITED STATES PATENT OFFICE 2,500,444 URAMIDOHOMOMEROQUINENE Robert Burns Woodward, Cambridge, Mass., and William von Eggers Doering, New York, N. Y., assignors to Polaroid Corporation, Cambridge, Mass., a corporation of Delaware No Drawing. Application October 10, 1944, Serial No. 558,080 Claim. (C. 260-294) 2 This invention relates to the synthesis of Which stereoisomers may be isolated as chemical quinine and cinchona-like alkaloids. individuals and then subjected to further trans The present application is a continuation-in formation. It is preferable, however, instead of part of our copending applications Serial No. 508,- isolating the stereoisoners from their mixture, to 954, filed November 4, 1943, now Patent No. 2,475,- Oxidize the latter and thus form a mixture of the 932, entitled "7-hydroxyisoquinoline derivatives Corresponding ketones, i. e., the stereoisomers of and method of preparing the same,' and Serial 2-acetyl-7-keto - 8-methyldecahydroisoquino No. 523,940, filed February 25, 1944, now Patent line, and to isolate from the latter mixture the No. 2,395,526, entitled “Isoquinoline derivatives Stereochemically homogeneous products. The and methods of preparing the same.' 10 carbocyclic ring of each stereoisomeric ketone may It is one object of the present invention to pro then be cleaved to give the corresponding N vide a novel process of synthesizing homonero acetyl - 10 - oximinodihydrohomomeroquinene quinene from isoquinoline derivatives. ethyl ester having the formula Another object is to provide novel quinine and cinchona-like alkaloids, and particularly al H. kaloids having the structural formula of quinine 5 /\H NoH and quinotoxine, derived from 1-cis-homonero CH3CON 5C-C-CE quinene and racemic-cis-homomeroquinene and O from one of the trans-homomeroquinenes. 7 8 9 Still another object is to provide novel 7-hy C2 4C-CICEICO OEt; droxyisoquinoline derivatives and Specifically the 20 N3/ N - acetyl - 10 - aminodihydrohomomeroquinene ethyl esters, the salts of Said esters, the N-acetyl 10 - trimethylammonium - dihydrohomomero The latter compound is catalytically hydrogenated quinene ethyl ester iodides and uranidohomo 25 to transform the oximino group to an amino meroquinenes. group. The hydrogenation may be carried out According to the method of the present inven without a solvent to give the corresponding amino tion, 7-hydroxyisoquinoline ester, but is preferably performed in an acidic Sol vent, such as acetic acid, whereby the correspond E. E. 30 ing amino salt, N - acetyl - 10 - aminodihydro N34in Yo1 /w w o O homomeroquinene ethyl ester acetate, having the formula, Hc & 4. 5 CH E. SH NH-HOAC is transformed to 7-hydroxy-8-methylisoquinoline 35 chicoy (-CH-CH, C C-CECCO OEt and the latter is converted to its tetrahydro deriv N/H. ative, 1,2,3,4-tetrahydro - 7 -hydroxy - 8 - meth C ylisoquinoline, from which the N-acetyl derivative, 2 - acetyl-1,2,3,4 - tetrahydro - 7 - hydroxy - 8 is formed. The amino compound is methylated, methylisoquinoline, having the formula for example with methyl iodide, to give N acetyl - 10 - trimethylammoniumdihydrohomo meroquinene ethyl esteriodidehaving the formula

45 NH N(CH)32 CaCO (-CH-CH, H. g-CH,Chicooet is obtained. The latter product is then converted C into a mixture of stereoisomers of 2 - acetyl-7- 50 EI hydroxy-8-methyldecahydroisoquinoline having which can be decomposed to homomeroquinene, the formula the latter being isolated as its uramido derivative.

55 NOC-N /SHC-CeCe. H. (-CHCH.cooH CSf 2,500, 444 3 4. The uramidohomomeroquinene is hydrolyzed to 7-hydroxyisoquinoline derivative having an N obtain the free racemic homomeroquinene Substituted-aminomethyl group, i.e., -CH2-N <, attached to the eight position of the isoquinoline C ring, the Specific amino Substituent depending B on the one of the primary and secondary annines HN/ YE-CH=CH, which is used as a reaction ingredient. The 7 H2C (-CHCH.cooH hydroxy-8-N-substituted aminomethylisoquino N/H line is thereafter reduced by reacting Said product Ea with an alkali methoxide, such as sodium methox The racemic homomeroquinene thus obtained will 10 ide or potassium methoxide, preferably in a hy have a cis Cr trans configuration, depending upon droxylic Solvent, such as methanol. The reduc the configuration of the stereoisomer of 2-acetyl tion may be carried out in an autoclave and pre 7 - keto - 8 - methyl decahydroisoquinoline from ferred temperature and time ranges therefor are Which the homomeroquinene is synthesized. between 200 and 250° C. and from six to sixteen Either of these racemic mixtures of homomero- 5 hours. The reaction products comprise the alkali quinene can be converted by esterification and Salt, e. g., the Sodium or potassium Sait, of 7-hy benzoyiation to N-benzoylhomomeroquinene ethyl droxy-8-methylisoquinoline, and Said salt is neu ester, and the latter can be condensed with ethyl tralized by acidification to free the 7-hydroxy-8- quininate, as by following the general methods methylisoquinoline, the latter compound being of Rabe disclosed in Berichte der Chemischen ( thereafter isolated from the reaction products, Gesellschaft 51, 1360 (1918); ibid., 52, 1842 (1919), preferably by Sublimation and crystallization. and of Prostenik and Prelog disclosed in Helvetica The 7-hydroxy-8-methylisoquinoline Inay be Chemica Acta, 26, 1965 (1943), to form the cor purified, for example, by forming the oxalate of responding racemic mixtures having the struc said co:npound, crystallizing Said oxalate and tural formula of quinotoxine. The l- and d 2: then liberating the pure 7-hydroxy-8-methyliso isomers of these quinotoxine-like compounds may quinoline. be resolived, as for example, by means of diben The 7-hydroxy-8-methylisoquinoline is hydro ZOyl-d-tartaric acid, d-quinotoxine-dibenzoyl-d- genafed over a suitable catalyst, as for example tartrate being less soluble in water than 1-quino platinum, being thus smoothly and quantitatively toxine-di-dibenzoyl-d-tartrate. From any of 30 converted to the tetrahydro-derivative, 1,2,3,4- these isomers, or either of the racemic mixtures tetrahydro-7-hydroxy-8-methylisoquinoline. It thereof, the corresponding cinchona-like alkaloids is to be expressly understood that while platinum having the Structural formula of quinine, includ is the preferred catalyst for this purpose, other. ing the novel racemic quinine and d-quinine, may hydrogenation catalysts, Such as nickel, may be be obtained, for example, by means of the con S 5 enployed. The tetrahydro-derivative is there version reported by Rabe in Berichte der Chem after converted into the corresponding N-acetyl ischen Gesellschaft, 51, 466 (1918). To make d derivative, 2-acetyl-1,2,3,4-tetrahydro-7-hydroxy quinine the starting material is liquinotoxine 8-methylisoquinoline, by reaction With acetic an Which is converted to a mixture of stereo-isomeric hydride in ethanol and this N-acetyl-derivative is quinines according to the method described by 40 hydrogenated, as for example, over Raney nickel Rabe and analogous to the method described to give a practically quantitative yield of a rix herein, followed by resolution of the optical ture of stereoisoners of 2-acetyl-7-hydroxy-8- isomers to give d-quinine. The l-quinotoxine is methyldecahydroisoquinoline. A certain propor employed to make d-quinine. tion of each of the stereoisomers in this reaction. The method of the present invention is pref 4. mixture can be isolated as a chemical individual erably carried out with 7-hydroxyisoquinoline as and when so isolated may thereafter be subjected the Starting material and the latter is reacted to the following transformation in the pure form. With formaldehyde and a compound from the However, it is preferable to oxidize the crude inix class consisting of primary and secondary amines, ture of the stereoisomers to produce the cor these ingredients being preferably mixed in a ii responding stereoisomeric ketones, since this proc hydroxylic Solvent, such as ethanol, methanol and ess reduces by one the number of asymmetric Water, or in a mixture of said solvents, as for centers in the molecule. From the mixture of . example, aqueous ethanol and aqueous methanol. ketones thus obtained the crystalline site:eochein The formaldehyde may be obtained from any ically homogeneous cis ketone may be isolated as suitable Source and may be conveniently intro- 55 a hydrate. This form of stereochemical indi duced into the reaction mixture in aqueous solu vidual has the same configuration as the cor tion. The primary or secondary amine may, for responding atoms of the quinine molecule. example, be any one of the following: piperidine, The stereoisoner of 2-acetyl-7-keto-3-innethyl morpholine, aniline and its homologues, and the decahydroisoquinoline thus obtained is cleaved alkyl and dialkyl amines, such as methylamine, 80 between the 7- and 8-positions of its carbocyclic ethylamine, dimethylamine, diethylamine, neth ring to give the N-acetyl-10-oximinodihydro yethylaxine, propylamine, dipropylamine, homomeroquinene ethyl ester. The cleavage is methylpropylamine, ethylpropylamine, ethyl accomplished by reacting the ketone with ethyl butylamine, isopropylbutylamine, as Well as aryl nitrite and Sodium methoxide, best results being Substituted derivatives of said alkyl and of said 65 obtained during this step of the giocess by ex dialkylamines. The completely aromatic second cluding moisture from the reaction. To accorn alry amines, as for exaltaple diphenylanine, and plish this all of the materials are preferably puri the aromatic heterocyclic amines such as indole fied just prior to use and are handled in vessels and thiazole, are less preferred than the non equipped, for example, with calcium chloride aromatic heterocyclic secondary amines, such as 70 tubes in order to obtain a complete exclusion of morpholine and piperidine and the noia-cyclic moisture. A rigid exclusion of moisture is also amines having, at least one alkyl group attached effected during the reaction. to the nitrogen, such as the alkyl and dialkyl The N-acetyl- 10 - OXininodihydrohonomero amines. quinene ethyl ester. is then catalytically hydro The product of the above reaction comprises a 5 genated, for example, in the presence of platinum, 2,500,444 5 6 and in a suitable solvent, preferably an acidic of 2 - acetyl-7-keto - 8 - methyldecahydrois0 solvent, such as acetic acid, to give the corre quinoline, relates to materials having a cis Con sponding salt of the amino ester, as for example, figuration. It is to be understood, however, that N-acetyl - 10 - aminodihydrohomomeroquinene the stereoisoner of 2-acetyl-7-keto - 8 - methyl ethyl ester acetate. The acetic acid is preferably decahydroisoquinoline, having a trans configura at least partially removed after this reduction and tion, may also be subjected to a similar synthesis care is taken during the removal to avoid conden to give the trans forms of honomeroquinene and sation between the amino and the ester groups the corresponding quinotoxine-like compounds, between or within molecules. A Satisfactory i. e., compounds having the structural formula of method of carrying out the removal is by distilling O quinotoxine, and quinine-like compounds, i. e., off the acetic acid in vacuo at room temperature. compounds having the structural formula of The N-acetyl-10 - aminodihydrohomoneroqui quinine. nene ethyl ester acetate in pure form, or in mix The following examples are given to illustrate ture with a slight amount of acetic acid, is then the novel processes of the present invention treated with a weak base, preferably, potassium 15 whereby the novel products of the invention are carbonate, and with a methylating agent, such as obtained, but it will be understood that the in methyl iodide, in alcohol solution and this reac Wention is not limited to the details given therein tion mixture is refluxed for a sufficient time to except as indicated by the appended claim. effect complete methylation. The product of the Eaccinaple 1 reaction, N-acetyl - 10 - trimethylammoniumdi 20 hydrohomomeroquinene ethyl ester iodide, is then Twenty grams of 7-hydroxyisoquinoline are isolated, the excess potassium carbonate and po dissolved in 500 c. c. of boiling methanol contain tassium iodide being removed, for example, by ing 12 grams of piperidine. To the cooled solu filtration, and the alcohol being removed, for ex tion are added fourteen grains of 35%. Formalin ample, by distillation in Vacuo. To remove the 25 Solution. After standing for two and one-half inorganic salts the residue is taken up in chloro hours at room temperature, the solvent is blown form. To insure purification the procedure may Off and the residual Oil is dried in vacuo. The be repeated. dried oil is taken up in 550 c.c. of absolute meth The N-acetyl - 10 - trimethylammonium dihy anol and One hundred thirty grams of sodium drohomomeroquinene ethyl ester iodide is then 30 methoxide are added. The Solution is heated in decomposed to the Sodium salt of honomero the autoclave at 220° C. for twelve hours. quinene, as for example, by being heated with The reaction mixture is diluted with 40 c. c. concentrated sodium hydroxide Solution. The of Water and partially neutralized with 150 c. c. reaction starts at 140 to 200° C. and evolves tri of concentrated hydrochloric acid. The solution methylamine. When trimethylamine is no longer is boiled down to 400 c. c. at which time 300 c. c. evolved, the inmiscible sodium hydroxide a queous additional Water is added and boiling is con layer is mechanically separated from the semi tinued till the vapors no longer burn. The cooled solid mass of organic material which consists solution is neutralized with hydrochloric acid and principally of the sodium salt of honomero buffered with sodium bicarbonate. The precipi quinene, the separation being preferably per tate of 7-hydroxy-8-methylisoquinoline is col formed While the materials are still hot. The lected and dried. decanted material is dissolved in Water and the The crude material is Sublined and the Sub solution is brought to neutrality by the addition innate is dissolved in 400 C. c. of methanol. After of acid. Potassium cyanate is then added, pref concentrating the Solution to 200 c.c. and cooling, erably in slightly more than equivalent quantity, i 10.3 grams of Shiny platelets of 7-hydroxy and the solution is heated for a short time, for 8-methylisoquinoline having a melting point of example, 20 to 30 minutes. It is then cooled and from 230 to 232 C., are obtained. acidified to Congo, crystallizing out uramidoho moneroquinene which has a neiting point of Eacample .. 2 65.2 to 165.8° C. Ten grams of 7-hydroxy-8-methylisoquinoline The uranidohomoneroguinene is then hydro and 0.50 gram of platinum oxide are suspended lyzed, as by boiling, with hydrochloric acid to give in 100 c. c. of glacial acetic acid. After shaking the racemic honomeroquinene hydrochloride and for three hours with 60 lbs. of hydrogen, the aminonium chloride, Which mixture is Worked up theoretical quantity of hydrogen is taken up. in the usual way to obtain the free racemic ho No additional hydrogen is taken up On Shaking momeroquinene having a melting point of 215°C, for a longer time. The catalyst is renoved by The racenic-cis-homonerodinene thus ob filtration and the solvent by distillation in vacuo. tained may be converted by esterification and The product remaining is dissolved in 100 c. c. of benzoylation to benzoylhomoneroGuinene ethyl methanol and treated with 8.0 c.c. of acetic anhy ester and condensed with ethyl quininate by the t dride. A first crop of 11.4 grams of pure 2-acetyl methods of Rabe or Prostenik and Preliog to form 1,2,3,4-tetrahydro-7-hydroxy-8-methylisoquino racemic-cis-quinotoxine. The optical isoners of line, having a melting point of from 187 to 198 this racemic mixture of quinotoxines may be re C., is obtained. A Second crop of .9 grania is ob Solved by means of dibenzoyl-d-tartaric acid, tained on concentrating the mother liquor. The d-quinotoxine - dibenzoyl - d - tartrate being less total yield is 94.5% of the theoretical. soluble in Water than I-CLinotoxine-dibenzoyl-d- tartirate. Either of the optical isomers of quino Eacample 3 toxine or their raceinic mixture may be trans Four grams of 2-acetyl-1,2,3,4-tetrahydro formed to the corresponding compounds having 7-hydroxy-8-methylisoquinoline and three grams the structural formula of quinine including the of Raney nickel catalyst are Suspended in 20 C. c. novel d-quinine and dil-guinine, the transforma of absolute ethyl alcohol and hydrogenated at a tion being carried out, for example, by the starting pressure of 3000 lbs. for ten hours at method disclosed by Rabe in Berichte der 150° C. Chemischen Gesellschaft, 51, 466 (1918). On cooling, the solution is washed from the The above Synthesis, Starting with the hydrate 5 vessel and filtered. Evaporation to dry gives an 2,500,444 7 8 oil which is a mixture of the stereoisoners of 2-acetyl-7-hydroxy-8-methyldecahydroisoquin Eacample 5 line. i.00 gram of N-acetyl-10-oximinodihydroho he oil is dissolved in 40 c. c. of glacial acetic nomeroquinene ethyl ester is placed, together acid and cooled to -5° C. To the solution is with 0.300 gram of platinum oxide catalyst, in added a Solution of 1.50 grams of chronic anhy 30 c. c. of glacial acetic acid (purified by distilla dride in 5 c. c. of water and 20 c. c. of acetic acid tion. Over potaSSium permanganate) and hydro also cooled to -5° C. A dark brown precipitate genated at atmospheric pressure or a pressure up appears which dissolves slowly at the ice bath to three to four atmospheres. In twenty to forty temperature after three hours. The reaction O hours the hydrogenation is completed, the re mixture is then allowed to stand at room temper action taking up the theoretical two moles of ature for six hours and then heated at 50° C. for hydrogen (plus that required for reduction of the three more. catalyst). The acetic acid is removed in vacuo. The re The platinum catalyst is removed by filtration sidual oil is shaken vigorously with 100 c.c. of and the acetic acid Solution distilled in vacuo at ether. The chromic salt precipitate and the 25 to 30° C. until a syrup of the N-acetyl-10 ether Solution is decanted. The chromic salts are aminodihydrohomomeroquinene ethyl ester ace then dissolved in 10 c. c. of methyl alcohol; to tate remains. No attempt need be made to remove the solution 200 c. c. of ether are added with the last exceSS of acetic acid, and the syrup may Vigorous shakilag. The Supernatant Solution is be immediately taken up in 50 c.c. of commercial united with the first ether extraction. absolute ethyl alcohol and methylated. Evaporation of solvent leaves an oil containing Small announts of chronic SaltS. The oil is dis Eaccian pile 6 tilled in a modified Hickman still. 2.50 grains The alcoholic solution of the N-acetyl-10 of colorless oil are obtained. It is analytically 25 a?hinodihydrohonomeroquinene ethyl ester ace pure 2-acetyl-7-keto-8-methyldecahydroisoquin tate is poured over 15 grams of commercial anhy oline. It is dissolved in an equal woline of ether. drcus potassium carbonate, five grams of methyl 0.20 gran of water is added with Shaking. On iodide (freshly purified by distiliation over mer seeding with the crystalline ketone-hydrate, 1.00 cury) are added, a reflux condenser fitted, and gram of pure ketone-hydrate, having a melting 30 the mixture refluxed over a free flane. Another point of 82° C., is obtained. The nother liquor ten grams of potassium carbonate are added containing other Stereoisoners is saved. The after about twenty-four hours, and another fifteen ketone-hydrate is boiled with benzene until no to twenty grains of methyl iodide in five gram por more Water is driven off and then the benzene is tions in intervals over forty-eight hours, at which completely evaporated to give the anhydrous 35 tine the reaction is completed. ketone. The reaction mixture is filtered to remove the bulk of inorganic salts, and the ethyl alcohol is Eacample 4 renoved by distillation in vacuo at 40°C. The 3.75 grams of 2-acetyl-7-keto-8-methyldeca residue is eluted with about 50 c. c. of chloroform hydroisoquinoline hydrate, obtained in accord 40 and again filtered to remove the last traces of in ance with the process of Example 3, are dehy organic salts. The chloroform is removed in drated by boiling with benzene. The freshly ob vacuo at 40 to iO0°C. leaving a hard, yellow glass tained anhydrous ketone, whose dryneSS is thus of N-acetyl-10-trimethylammoniundihydroho assured, is then dissolved in a Small amount of moneroquinene ethyl ester iodide. The yield is absolute alcohol, which is freshly distilled, for 1.45 grains (94% of the theoretical). example, from magnesium ethoxide, in order to be completely dry. Eacample 7 3.84 grams of metallic sodium are also dis The glass of the 1-acetyl-10-trimethylam solved in dry absolute alcohol and then mixed monium dihydrohomomeroquinene ethyl ester With the Solution of the ketone. The mixture is iodide is dissolved in 2 c. c. of water, transferred to cooled to 0° C., and there is added to the mixture a platinum crucible together with 2.5 c. c. of a 1.24 gians of ethyl nitrite, which is preferably 5:4 Sodium hydroxide aqueous Solution, and grad freshly prepared and freshly distilled after being ually heated to 180° C. with vigorous stirring (sil dried over potassium hydroxide. The reaction wer Spatula). Trimethylamine is copiously mixture is then allowed to stand in a cold room, evolved and the reaction is compieted in one to for example at a temperature of 5° C., With pre two hours." Another c. c. of water is added in cautions taken to exclude moisture. There may intervals during the heating to maintain the re be added to the mixture, at predetermined inter action mixture in the liquid phase. When tri vals, Sinal quantities of freshly prepared ethyl Inethylamine is no longer evolved the lower, the nitrite to replace any ethyl nitrite Which may be inniscible, Sodium hydroxide aqueous layer is lost by evaporation. renoved, while still hot, by pipette, leaving the After the mixture has stood for eighteen hours, Sennisolid maSS of light brown homoneroquinene carbon dioxide is passed in for approximately Sodium Salt behind. three hours, the precipitate is filtered off, and This material is taken up in two to three c.c. the solution is decolorized by treatinent with of water, transferred to a small flask, and neu charcoal. The solution is then evaporated to tralized to pH 7 with concentrated hydrochloric dryness, ether is added, and the mixture is again acid. The solution is clarified by boiling five to evaporated to dryness. The dry residue is dis ten lininutes With active charcoal and filtered, Solved in 10 C. c. of ether and 2.62 grains of cry A Solution of 0.35 gram of potassium cyanate in stalline N-acetyl-10-oximinodihydrohomonero O C. C. of Water is added and the reaction Solu quinene ethyl ester separated from the liquid. tion gently warned on the steam bath for thirty From the mother liquor a further group of crys ninutes, then removed and acidified to Congo tals is obtained. The crystals have a neiting red with concentrated hydrochloric acid. On point of 94° to 96° C. and can be recrystallized further cooling in an ice bath, and scratching, from ether. - . . . s colorleSS crystals of uramidohomoneroquinene 2,500,444 separate. These are filtered, washed with one or evident is obtained. Benzoyl chloride odor is two small portions of cold water and dried. very faint. This is taken at about 129° C. and The yield is 0.30 gram (38% of the theoretical at a pressure of 0.2 to 1.1 mm. from the N-acetyl-10-oximinodihydrohonomero Fraction. V.-2.87 g. of absolutely clear, color quinene ethyl ester). The crystals have a melt. less, Odorless heavy viscous liquid are obtained. ing point of 66° C. Fraction W is taken during eight to nine hours and the bath temperature rises very gradually Eacan pile 8 during this time from 134° C. (initial) to 145° C. Eighty Initigrams of crystalline uramidoho. (final), While the pressure falls from 0.08 mm. monerocuinene are heated under reflux with 13 O (initial) to 0.01 mm. (final). c. c. of 0.1 normal hydrochloric acid for thirty-six 2.70 grams of N-benzoylhomomeroquinene ethyl hours. After removal of exceSS hydrochloric acid, ester (0.0086 mole) from fraction Ware mixed with the crystalline residue, consisting of dl-homo 4.0 g. of ethyl quininate (0.0173 mole=100% meroquinene hydrochloride and annonium exceSS). 1.4 g. of absolutely dry pulverulent sodi chloride, may be worked up directly by treatment 5. un ethoxide (0.0207 mole=140% excess, based With Silver oxide followed by hydrogen Sulfide On N-ben ZOylhomomeroquinene ethyl ester) is to obtain the free dil-honomeroquinene, having added, and the reaction mixture is heated to a melting point of 25 C. Alternately, the mix about 80° C. with continuous stirring. As the ture of chlorides may be separated by treatment ethyi quininate melts, and the materials become with hot absolute alcohol, in which the di-homo 20 thoroughly mixed, the initial yellow color changes moneroquinene hydrochloride alone is soluble, to brown and then gradually to deep red. The and from which the pure crystalline material may reaction mixture is maintained at about 82° C. be recovered on evaporation. The yield in the for fourteen hours With continuous stirring. It cleavage reaction is quantitative. is then cooled, and the resulting very hard, dark red mass is decomposed with ice Water and ben Eacample 9 Zene. The (not entirely clear) combined aqueous After the removal of the hydrochloric acid in layerS are extracted with a small amount of the method outlined in the preceding example, ether. The clear, deep red, aqueous layer is then instead of isolating homomeroquinene the crude made just acid to litmus. The precipitated oil hydrochloride remaining is converted directly 30 is taken up in ether. Evaporation of solvent, into its ethyl ester by evaporating three times finally in vacuo, gives 2.56 g. of a red glass. The With about 4% absolute ethanolic hydrogen chlo combined benzene and ether extracts from above, ride (6.5 g, dry hydrochloride in 153 g. alcohol). Containing largely neutral material, are extracted The residue is treated with 20 cc. of Warm chloro With 10% aqueous sodium hydroxide. The alka form, the undissolved annonium chloride being line extract is made just acid to litmus, and ex Washed several times with 5-10 cc. portions of traction with ether followed by removal of sol Warm chloroform. The weight of dry ammonium vent gives a further small quantity of 6-keto chloride is 0.62 g. (theoretical Unit=0.60 g.). 7 g. ester, 0.16 g. of anhydrous potassium carbonate are made into Total weight of N-benzoylquinotoxine carbox a mush with 3.5 cc. of water (1.7 cc. excess over 40 ylic acid ethyl ester thus obtained was 2.72 g., the quantity necessary to convert the anhydrous equivalent to 63.4% of the theoretical, carbonate into K2CO32H2O). The combined 2.72 grams of N-benzoylquinotoxine carbox chloroform extractS containing the homomero ylic acid ethyl ester are dissolved in 30 cc. of 1:1 quinene ester hydrochloride are poured over the aqueous hydrochloric acid (from 15 cc. concen carbonate mush, and Stirred Vigorously and boiled trated hydrochloric acid and 15 cc. water). The under reflux for one-half hour. To the cooled Clear, reddish-Orange Solution is then boiled un reaction mixture, 2.0 cc. of freshly distilled ben der reflux for four hours. The very dark red zoyl chloride (2.4 g. =50% excess over the theo dish-brown Solution is extracted with ether (from retical amount) in 4 cc. chloroform are added this extract 0.50 g. of benzoic acid is obtained on dropwise during ten minutes. The reaction mix 50 evaporation). The aqueous solution is then made ture, which warmS Somewhat Spontaneously, is strongly alkaline, and extracted with ether. 0.23 then boiled under reflux with vigorous stirring for g. Of ether-insoluble interface material is dis about two hours. The chloroform Solution is de Solved in benzene and set aside. Removal of sol canted, the inorganic SaltS are washed with chlo vent from the above ether extract gives 1.39 roforn, and the combined chloroform extracts are 55 g. of Crude quinotoxine as a dark red viscous oil. evaporated to Small Volume and transferred to Eacample 10 the molecular still. The remainder of the chlo roform is removed, and the still is left under a 0.56 g. of the crude synthetic racemic quino Water-pump vacuum for seven hours at 50° C. to toxine is converted to the acid tartrate and frac remove the last traces of low-boiling material. 60 tionally crystallized from equal volume of Water The Still is then put on a high vacuum pump, and by seeding. The resulting material is more solu the temperature is raised gradually. The follow ble and less easily crystallized than natural d ing fractions are taken: quinotoxine-d-tartrate. After four crystalliza Fraction. I.-0.08 g. of red oil is carried over tions the salt melts from 40° to 55° C., melting mechanically before start of molecular distilla lower than the natural material. Regeneration tion, during removal of chloroform. gives quinotoxine with al--13°. When the Fraction II.-0.07 g. of Crystals and oil is Washed acid tartrate is crystallized from absolute alco from cold finger. There is a strong odor of ben hol, a very Small amount of the anhydrous sait, Zoyl chloride. melting point 149-153 C. is obtained. Fraction III.-0.33 g. of crystals and oil is Froin the mother liquors impure quinotoxine Washed from Cold finger. The odor of benzoyl d-tartrate is recovered and the 44.4 mg. of par chloride is quite strong. After Solution in ether, tially resolved quinotoxine (Eal=-|-13°) regen extraction. With aqueous K2CO3, and evaporation erated therefrom is converted to the neutral di gives 0.24 g. clear oil. benzoyl-d-tartrate. The d-quinotoxine-diben Fraction IV.-0.11 g. in which no crystals are 75 Zoyl-d-tartrate crystallizes well from twice the 2,500,444 2 weight of methyl alcohol, 30.2 mg. of Salt, melt What is claimed is: ing point 175-177° C., being obtained. After one As a new composition, an uramidohomonerd further crystallization, pure d-quinotoxine-di quinene having the formula, benzoyl-d-tartrate, melting point 184-185° C. is obtained (16.6 mg). No depression with natural 5 NE d-quinotoxine-dibenzoyl-d-tartrate is observed. HNO C-N C-C=C From the relatively pure d-quinotoxine-diben Hé ?-CHCH.CooH zoyl-d-tartirate there is obtained, upon regenera N/H. C tion, the pure di-quinotoxine having (al=-44. H All mother liquors are then exhausted of isolat O able d-quinotoxine, and are united and converted ROBERT BURNS WOODWARD. to the dibenzoyl-l-tartrate. After five recrystal WILLIAM WON EGGERS DOERING. Iizations, 34.6 mg. of 1-quinotoxine-dibenzoyl-l- tartrate, melting point 135-186° C., are obtained. REFERENCES CITED The pure -quinotoxine is then regenerated from 5 The following references are of record in the the latter compound, file of this patent: Since certain changes in carrying out the above methods and in obtaining the Various Species of OTHER REFERENCES the invention may be made without departing Chen. Abstracts, vol. 4, pp. 2136-238 (1910). from the scope thereof, it is intended that all Berichte, vol. 51, pp. 466-467, 1360-1365 (Rabe) matter contained in the above description shall (98). be interpreted as illustrative and not in a lin Beilstein: Organische Chennie, Wierte Auflage, iting Sense. vol. 25, pp.39-40 (1927). It is also to be understood that the following Chem. Abstracts, vol. 26, pp. 1935-1936 (1932); claim is intended to cover all the generic. and citing: Annalen, vol. 492, 242-266. specific features of the invention herein described, Karrer: Organic Chemistry, Nordemann Pub. and all statements of the Scope of the invention Co., pp. 798-801 (1938). which, as a matter of language, night to Said to fall therebetween.