US618045A - Xemil f fischer - Google Patents

Description

Unirnn stares Par-est since,

nMIL risonnn, or BERLIN, GERMANY, ASSIGNOR TO 0. r. BOEHBINGER a sonnnn, or WALnnor, GERMANY.

KtLKYL-HYi QXANTHiN AND PRQCESS OF MAKING SAME.

. 'srncrrrcn'rron forming part of Letters Eatent at. 618,045, dated January 17, 1899.

Original application filed September 7, 1397, Serial No. 6 ii 0,826. Divided and this application filed January 3,1898. Serial v No. 665 463. (Specimena) .To all whom it may concern: tion with theobromin, the primary starting Be it known that I, EMIL FISCHER, a citizen. material-employed in my process, and of the of the German Empire, residing at Berlin, in hypoxanthins will be apparent and readily 55 the Empire of Germany, have invented cerunderstood. tain new and useful improvements in the Art The structural formula and consequent ad of Preparingwhlethylized Hypoxanthins; and dition al designations which may be attached I do hereby declare the following to be a full, to these compounds are the following: 6 clear, and exact descri tion of the invention, w L T; Q such as will enable otiiers skilled in the art flush Theobmmm H IO to which it appertains to make and use the S31E18. r' 1 I 1 T This invention relates to the preparation 01 3 dimethyixamh? Ob I\\CH3 of alkylized oxypnrins, and more particu- CH 65 larly the synthetical production of methyl: orgfiflimeth ,1 c 6 di V ized hypoxanthins which have been recog 3 u niied'as methylined oxypurins as the result Faun & of recent investigations. V F F T Dimethyl-hypoxanthin has hitherto been Xanthm 7 obtained only by methylation of hypoxanthin 2o (Kriiger, Zet'tschmflf. Phys. Chem. 18, 436.) y y Q a As to monomethyl-hypoxanthin I am the first CH to obtain the same in any manner. r [I My present invention consists in the meth- O I\ 75 ods of synthetically preparing these methyl- Third. 1 7 -dimethyl- CH NCO ized hypoxanthins, inthe rhonomethyl-hypm hypoxanthin Xanthin, and in such further features and subprocesses as will be hereinafter disclosed or 1-7-dimethyl-6=oxy- HO O-N.CH and pointed out in the claims. purin l' H 80 In explaining my invention the nomenclal ii 3o tnre recently proposed -by me (Sitzmzgs-Be- N-O-N riohte der Kon'igl. Preu-ssischen '.A7CCZ677Li-, 1897, No. 1, January 8, 1897, and Beriohfc d61- Deutschen Ohe-mischen Gesellschcgft, Vol. 30,

In preparing the hypoxanthins I start-from theobromimwhich is the same as 3-7-dimethyl- Xanthin or 3-7-dimethyl-2-6-dioxypurin and 5 Whoseiormnla is given above, treating the same with a phosph'orus-oxyhalogencom-- pound, snch as phosphornsoxychlorid. Under this treatment the oxygen atoms are replaced by chlorin and one methyl radical is split oh, the resultant body being 'Z-noethyl- 2-(i-dichloropurin:

No. 5, page 557) and the structural formulae,

adopted as the result of the most recent in- V vestigations, will be adopted. According to this nomenclature the various atoms of the purin molecule, which forms the basis of the uric acidand xanthin molecules and many others, are numbered as follows:

(1)N-o(6) N20. n

I 9S (2)U(5)UN(7) 01.0 (Jr-11011 l I an I I H a N-;o n 9 7 NU-N l4) The two chlorin atoms of this new body,

5o Bearing these numerals and their relative methyl-dichloropnrin,are verymobile, ,-They positions in mind, the designations of the may be eliminated and replaced byhydroxyl' equivalent terms hereinafter used in connecsimultaneously or separately. For the/prim 2 k 6is,o45

poses of the present invention I remove one only of the chlorin atoms. This substitution gives rise to the following reactions leading to the methylized hypoxanthins:

5 First. 7-methyl-2-6-dichloropurin on being treated with alkali exchanges only one chlorin atom for hydroxyl, the resultant body being 7-'methyl-6-oxy-2-chloropurin I I 1 g 7 y N- -N Second. 7-methyl 6 oxy 2 chloropurin is converted into 7 methylhypoxanthin or 7 as hydriodic. acid methyl-G-oxypurin by a reducing agent, such In the detailed description which is now to follow I will divide the subject into four heads, arranged in the order above indicated, giving a disclosure, first, of the method of converting the startingmaterial, theobromin, into 7-methyl-2-(i-dichloropurin; sccondly,thc method of preparing the TunethyLG-oxy-Q- chloropurin; thirdly, the method of converting this into 7-methyl-hypoxanthin, and, fourthly, the preparation of I-7 -din1etl1yl- 7o hypoxanthin.

F 'rst. Preparation of 7methyZ-2-6-d'ichloropurin -I take ten parts of theobromin and heat the same under pressure-e. g., in a digester-together with one hundred parts of phosphorus-oxychlorid,-to a temperature of 140 centigrade, this temperature being maintained for threeh'ours and the mass constantlyagitated. A clear liquid havinga pale bjrown color results. From this liquid"8o the remaining phosphorus-oxychlorid is removed by-distilling m vacuo. One hundred and fifty parts of cold water, having a. temperature of between 0 and 5 centigrade preferably, are then poured over the amorphous 8 residue. Under this treatment the massis gradually converted into almost colorless crystals. This change is hastened by shaking. The generation of heat in the mass is obviated by cooling with ice or other refrigerant 9o agency. The mass after having been finally cooled thoroughly is put on the filter and washed with ice-water. The crude product so obtained is contaminated with a substance which is soluble in alkali. The same is hence dissolved out with an alkaline solution, pref= erably very dilute, soda-lye .o about one-percent. strength. The solid residue is then drained on a filter and well washed thereon and redissolved in hot water and recrystallized therefrom. The new compound 7-methyl'- 2-.6-dichloropurin so obtained crystallizes in fine colorless needles, which melt at about 196 to 197 centigrade. It is soluble with difficulty in cold water and soluble in about seventy parts hot water and in about thirty parts boiling alcohol. Its composition is indicated by the formula (J lI N Ol or the structural formula: t I

Nicol ill) ()N.CH I I; l N(JN The reaction taking place in preparing the a same from theobromin"ifs-vindicated. in the stirred untila clear solution is formed, whereby-theend at the preeess-isindieated The reaction takes place according to the followin g equation:

l o-NoH,+2Nton= n I ii 1 N-C-N NaN-CO The liquid is then cooled and the same is then supersaturated with acetic acid, whereby the methyl-oxypurin is precipitated in crystalline form. This precipitate after being separated is boiled in one hundred and fifty parts of Water, and after boiling it is filtered and the filtrate allowed to cool, when the new product will be thrown down in the form of columnar crystals of a yellow color. To completely purify the product, it is first converted into its barium salt, which forms fine crystals, and then reconverted into the methyl-oxychloropurin by redissolving the barium salt in fifty to sixty part-s of hot water and supersaturating with acetic acid.

The analysis of the new product shows that its formula is U H NfiCl and that its structure corresponds to the formula:

Pure methyl-oxychloropurin attains a yellow color when heated to about 310 centigrade. At a higher temperature its color becomes more and more dark, this darkening being attended by continuing decomposition.

heated to from to centigrade, after having first added a halt part'of phosphoniumiodid,and maintained at this temperature and frequently shaken until a clear colorless solution results. The liquidis then evaporated, when the hydriodate of the 7-methyl-hypoxanthin or 7-methyl-6-oxypurin remains as a colorless crystalline mass, which is readily soluble in water. The reaction proceeds according l l ll ll swan mceo II it 7 l l N- G-N This new base, 7-methyl-hypoxanthin, is liloerated from the above salt by dissolving the latter in water and boiling the same, then adding carbonate of lead to the boiling solution, and then filtering. Any traces or small quantities of lead rem ainingi nthe filtrate are then HN-CO l l 1-1 no c N.cu, I 1 H ll N-o-n 7 enethyhhypoxanthin when rapidly heated assumes a brown color at about 340 centigrade and melts at about 353 centigrade. The melting-point, however, is not quite fixed. It is readily soluble in water. 0n adding nitrate of silver to an aqueous solution of the same a white precipitate is formed, which on being dissolved in warm dilute nitric acid is obtained as a white crystallinepowder.

1 'o'urtlz. Preparation of 1-'7-(ZimethyZ-hypoa anthin .'lwe parts of -7-methyl-hypoxanthin, which has been described, are mixed with twenty parts of water, twenty parts of methyl alcohol, two parts of methyl io'did, and 0.3 parts of sodium dissolved in methyl alcohol, (a quantity suflicient to replace the hydrogen represented by the one imido group IOO IIO

in the formula of 7methyl-hy poxanthin.) The mixture is then heated in a closed vessel to from 75 to 80 centigrade, this temperature being maintained for three hours. The

resulting liquid is then highly concentrated and allowed to cool. On cooling, the sodiumiodin compound of l-7-dimethyl-hypoxanthin, which has been described by Kriiger (Berichte de'rDeutschen Uhem-ischen Gesellschafi, 10 Vol. 26, page 1921) and having the formula C,H N,O. NaI+ 3aq. is separated from the liq- HN- CO Dimethyl-hypoxanthin begins to soften at about 243 centigrade and melts at 246 centigrade without decomposition. Heated in small quantities it distils over without decomposition for the greater portion. From hot alcohol it crystallizes in the form of fine needles, which for the most part are massed together. vIn other respects this base is distinguished by the characteristicproperties set forth by Kruger.

The 7-methyl-Q-G-dichloropurin herein described, together withits method of manufacturc,for1ns the subjcct-matterof the claims of my application, Serial No. 650,826, filed September 7, 1897, (of which this is is a divisional application,)-and is there shown to be the startingmaterial for the series of processes and compounds described in illustration of the invention. 'Itis hence not claimed herein, being merely-described for the purpose of a full and snflicient disclosure of my present invention.

Having thus fully described my invention, what I clain1,and desire to secure by Letters Patent of the United States, is

l. The process of preparing methyl-hypoxanthin which consists in treating T-methyl- 6-oxy-2-cliloropurin with a reducing agent.

2. The process of preparing methyl-hypoxanthin which consists in heating 7-methyl- 6-oxy-2=chloropurin together with hydriodic acid and phosphonium iodid.

3. The process of preparing methyl-hypo-- xanthin which consists in adding hydriodic acid to 7 -methyl-6-oxy-2-chloropurin and heating the mixture after first adding phosphonium-iodid to the same, all in the proportions and under the conditions substantially as set forth. a v

4. The process of preparing methyl-hypoxanthin which consists in adding hydriodie acid to 7 -m ethyl-6oxy-2-chloropurin and heating the mixture after first adding phosphonium-iodid to the same, all in the proportions and under the conditions substantially as set forth and then separating the resultant hydriodate of the monomethyl-hypoxanthin and Treating the said hydriodate with carbonate of 5. The process of preparing methyl-hypoxanthin which consists in adding hydriodic acid and phosphonium-iodid to 7methyl=6= oxy-2chloropurin and heating and shaking the same, then evaporating and dissolving the residue in water and boiling, then adding carbonate of lead and boiling.

6. The process for the manufacture of monomethyl-hypoxanthin which consists in the following steps: treating theobromin with a phosphorus-oxyhalogen compound and isolating the resultant 7 methyl 2 6 diehloropurin; treating the latter with an alkali and their isolating the resultant 7 -methyl-6-oxy-2- chloropnrin and treating the latter with a reducing agent.

7. As a new chemical compound, 7-methyl-.

hypoxanthin, which has the formula hereinabove stated, whose melting-point is about 353" centigrade, which is readily soluble in water and which assumes a brown color when rapidly heated to about 340 centigrade.

S. The process in the manufacture of dimethyl-hypoxanthin which consists in treating 7-methyl-hypoxanthin with a methylating agent.

9. The process for the manufacture of dimethyl-hypoxanthin which consists in treating 'T-methyl-hypoxanthin with methyl alcohol, methyl iodid, and sodium methylatc.

10. The process for the manufacture of dimethyl-hypoxanthin which consists in mixing 7-methyl-hypoxanthin with water, methyl alcohol, methyl iodid and sodium niethylate, heating the mixture under pressure, concentrating the resulting liquid and cooling, all in the proportion and under the conditions substantially as specified.

11. The process for the manufacture of dimethyl-hypoxanthin which consists in treatin g 7-inethyl-G-oxy-fi-chloropurin with a red ucing agont and isolating the resultant 7 -methylhypoxanthin and then methylating the latter. l

12. The process for the manufacture of dimethyl-hypoxanthin which consists in the following steps: treating Z-methyl-i2-6-dichloropurin with an alkali and isolating the resultant 7-methyl-6-oxy-2-chloro )urin; treating 10 isolating the resultant 7-methyl-6-oxy-2-ehloropurin, then treating the latter with a reducing agent and separating the resultant 7- methyl-liypoxanthin, and methylating the latter.

In testimony whereof I affix my signature :5

in presence of two witnesses.

.EMIL FISCHER.

itnesses:

CHAS. H. DAY, HENRY HASPER.