US1497253A - Process of alkylating organic compounds - Google Patents

Description

Application filed Jul-y To all whom vii-may concern:

' Be it known that I, EUGENE Tinnitus, a citizen of the United 9" in the county and rotate Jersey, have inv "ed. certain new improvement in Processes oi" Qompounds; and do i 116 following to he a lull, clear, and description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

This intention relates to processes of allrylating organic compounds, more particularly compounds of the paraminophenol type; and it has to do especially With the preparation of methyl phenacetin from phenacetin.

ill

In prior copencling applications, Serialhlos. 259,722, filed September 5, 1918, and 301.58%, filed June 4: 1919, I have disclosed and claimed novel methods of alkylating compoundshaving the type formula E I (R1 being an Elkylgroup and Bi an acidyl group) n Ra hy the successive action of an alkali metal, such as sodium, and an alkylating agent, such as an alkyl halid. Examples of this class of compounds, to alkylation of which said methods are especially applicable, are phenacetin (acetphenetidin), acetanisidm, iormyl anisidin, formyl phenetidin, etc. As stated in said prior applications, during the first stage of the allrylation as ordinarily conducted by prior methods, the mass resulting from the reaction of the alkali metalon the compound to be allrylated tends to congcal even Where the reaction is conducted. n the presence of a large amount of a suitable solvent liquid such as xylol. This is an un-- desirable condition and unfavorable for the subsequent treatment with an allryl 'halid, especially Where the latter is a gas like methyl hromid for example. In order to have the reaction mass in the form of a homogeneous liquid mixture for treatment with the alkylating agent, special measures are taken, in accordance with the inventions i919. Eerie! fie. $14,155".

of said prior applications, to attain this result. This can be accomplished, for example, by ensuring the presence, in the re action mixture resulting from the all;

treatment, of a suitable quantity of later stage product, added prior the treatment with an alkylating' agent. it such addition he made prior to the alkali metal treatment, congelation can he entirely prevented; or if made after congclatioi has oc- 1 curred, the congealed mass is thereby liquelied without diiliculty.

In general, the objects of the present invention are similar to those of the inventions disclosed in said prior applications, as are also the classes of compounds treated and the resultant products; but the desired results are achieved in a different and, in some respects, a distinctly more advantageous manner, as will hereinafter appear.

According to the present process the starting material, that is, the compound to he alkylateii, is brought into solution or homogeneous liquid mixture with. an inert solvent or vehicle, such as xylol; and this mixture is first subjected to the action of: an agent comprising an alkali metal i n avail able form, the free alkali metal itself being suitable, in amount materially less than is required to convert all of said compound into the intermediate alkali metal derivative. Moreover, in allq lating a given quantity of the starting material, it is most desirable not to introduce the entire quantity into the initi al mixture, but to use somewhat less, say about two-thirds, for example, with the full proportion of inert solvent or vehicle, the rest. of the starting material and of the al lrali metal being added at a later stage, as will heexplained hereinatter. By proceeding' in this manner. tendencyoi? the intermediate derivative to separate out may he overcome and a homogeneous liquid reaction mixture continuously maintained. While the proportion of alkali metal initially used may vary somewhat. only so much should be used as Will yield a noncongealing mixture of said compound with the intermediate derivative and the inert menstruum or vehicle. The resultant liquid mass is then subjected to the action of the desired alkylating agent to convert the intermediate derivativeinto the desired alkylated compound, which remains after formation in liquid mixture with unchanged well as of that added at this stage.

starting compound and inert menstruum.

At this stage there is added more of thestarting material, specifically the remainder 0 the aforesaidgiven quantity thereof, and also a further amount of alkali metal sufiicient to ensure conversion into the alkali metal derivative of any unaltered portion of the starting material initially usedi as onversion of the resultant intermediate compound into the desired alkylated compound can be effected with the aid of a further quantity of the alkylating agent.

very slowly, making it ordinarily desirable to use somewhat less than the theoretical proportion in order to ensure complete solution. This precaution is rendered unnecessary by the present invention, with the further result that there need be practically no unchan ed starting com ound to separate from the esired alkylate product. -The whole procedure is thus simplified, expedited, and rendered smoother.

In order to afford a fuller understanding of the underlying principles of the invention,

' a particularly desirable embodiment thereof as applied to the manufacture of methyl henacetin from phenacetin will be described in detail by way of an illustrative example.

S ecific quantities of the materials em-- oyed will be mentioned, but it will be unerstood that these may be varied not only in absolute amount but also in proportions, although the pro ortions hereinafter specified are those w ich at present are considered best. 1

In a typical procedure within the invention, where it is desired to convert say 117 pounds of phenacetin into methyl phenacetin, only 80 pounds of phenacetin are initially mixed with 100 pounds of warm xylol to give a homogeneous liquid mass. These proportions give a mixture of such density that metallic sodium will float upon it, which is highly desirable. The amount of xylol used is therefore always best limited accordingly. To the warm mixture or solution, contained in a suitable reaction vessel, is added metallic sodium in amount equal in this specific example to about one-half that theoretically necessary for combination with all of the phenacetin present. An addition of about, 5 pounds of S dium at Furthermore,

Lamas this stage in the present example is good practice. The reaction proceeds vigorously with eneration of considerable heat and evolution of hydrogen, the sodium floating on the mixture until completely dissolved, so that the end of the reaction is readily observed. Some of the xylol distils ofi and may be recovered with the aid of a condenser. The mass resultin from the reaction is a homogeneous liquid which exhibits no tendency toward crystallization and is in pounds of methyl bromid, whereas theory requires but 20.65 pounds. It is found that the use of the small excess of meth l bromid which the reaction mixture will take up at this stage, about 5 per cent in this instance, has a desirable efiect in the remaining stages of the process, particularly in facilitating and expediting complete solution of the second portion of metallic sodium which is now added, after adding the remaining 37 pounds of phenacetin, without its being necessary first to separate the sodium bromid present in the reaction mixture as a result 0 In the present specific example, this second portion of sodium amounts to ten pounds. As before, the reaction proceeds ex editiously and smoothly to completion, t e sodium floating until it has all gone into solution, and. moderate external heating being resorted to toward the last if necessary, but the heat of the reaction itself ordinarily suflicing to carry it through. The reaction mass shows no tendency to solidify or crys' tallize, remaining perfectly liquid throughout. Xylol is best added in suflicient quantity to make up the loss by distillation, as before, and methyl bromid gas is again led into the mass until no longer taken up there;- by. A volume of gas equivalent to 40.75 pounds of methyl bromid is sufiicient in this instance. The entire amount of phenacetin originally present in the starting batch has now been converted into methyl phenacetin. The xylol solution of methyl phenacetin is next decanted from the accompanying so-. dium bromid which settles out rapidly under phenacetin by distillation at ordinary presthe treatment with methyl bromid.

i the described conditions of operation, the

sure, the distillation being materially exthe scope of the invention as defined in theappended claims.

claim:

1. The process of alkylating'acylamine organic compounds capable of alkylation by the action of alkali metal and an alkylating agent, which comprises subjecting an acylamine organic compound in liquid condition to the successive action of an alkali metal in available form and an alkylating agent, in quantit insufiicient to bring about congelation of t e reaction mass or to effect complete alkylation, and thenefiecting more complete alkylation by further treatment with alkali metal and alkylating agent. 2. The process of alkylating organic compounds having the type formula (B being an alkyl group and R: an acidyl group) larly equivalent to said compound to avoid congelation of the reaction mixture, treat ing the resultant intermediate product in liquid condition with an alkyl halid, and then repeating the treatment with alkali metal and alkyl halid to effect further alkylation.

3. The processvof preparing methyl phenacetin which comprises subjecting a liquid mixture of phenacetin and a diluent vehicle to tire action of an alkali metal in available form and in amount sufiiciently less than that molecularly equivalent to the phenacetin to avoid congelation of the reaction mixture, subjecting the resultant mixture to the action of an alkyl halid, and then effecting further alkylation bysuccessive treatment with more alkali metal and alkyl halid;

4. The process of preparing methyl phe-' nacetin which comprises subjecting a liquid mixture of phenacetin and xylol to the action of about one-half the amount of metallie sodium molecularly equivalent to the phenacetin, passing methyl bromid into the resultant liquid mass, adding to the mass more phenacetin and a further amount of metallic sodium sufiicient to react with substantially all the phenacetin present in the mixture, completing the methylation with methyl bromid, and obtaining methyl phenacetin from the mixture finally obtained.

5. The process of preparing methyl phenacetin which compr1ses subjecting a liquid mixtu re of phenacetinand a diluent vehicle to the action of an alkali metal in amount sufliciently less than that molecularly equivalent to the phenacetin to avoid congelation of the reaction mixture, subjecting the resultant mixture to the action of an ,r alkyl halid in excess of that theoretically required for complete reaction with all the intermediate alkali compound of phenacetin present, and then efiecting further alkylation by successive treatment with more alkali metal and alkyl halid.

6.. The process of preparing methyl phenacetin which comprises subjecting a liquid mixture of phenacetin and xylolto the action of about one-half the amount of metal- ,lic sodium! molecularly equivalent to the phenacetin, passing an excess of 'methyl bromid into the resultant liquid mass, adding to the mass more phenacetin and a further amount of metallic sodium. suflicientto react with substantially all the phenacetin present in the mixture, completing the -.methylation with methyl bromid, and I I obtaining methyl phenacetin from the mixture finally obtained.

7. The process of preparing methyl phe-.

nacetin which comprlses mixing with an inert liquid vehicle a quantityof phenacetin less than a given amount which is to be methylated but suflicient to give a liquid mixture dense enough to float metallic sodium, subjecting the mixture to the action of -metallic sodium in quantity less than is molecularly. equivalent to the phenacetin present, treating the resultant mass with a methylating agent, adding the remainder of said given amount of phenacetin, repeating the successive treatments with metallic sodium and methylating agent, and separatingmethyl phenacetin from the reaction mixture.

' In testimony whereof I hereunto afix my signature. 7

EUGENE THEIMER.