Patented Oct. 18, 1949 2,485,236 UNITED STATES PATENT OFFICE 2,485,236 PREPARATION OF METEONNE AND PRECURsoRs THEREOF William F. Gresham and Carl E. Schweitzer, Wi mington, Del, assignors to E. I. du Pont de Nemours & Company, Wilmington, Del, a cor poration of Delaware No Drawing. Application October 24, 1945, Serial No. 624,328 4 Claims. (C. 465-5) 1. This invention relates to improvements in the of methionine is accomplished in overal yields synthesis of methionine, and to novel composi of about 70%. tions of matter employed in the said synthesis. The first step in the synthesis, namely, the re This application is a continuation-in-part of our action between methyl mercaptain and acrolein, now-abandoned copending application S. N. is best performed at a temperature of about 0 to 522,966, filed February 18, 1944. 20° C., in the presence of 0.05 to 5.0%, preferably The classical method for the Synthesis of 0.1 to 0.5%, of pyridine, based on the weight of methionine is the method disclosed by Barger and the methyl mercaptain used. As the reaction Coyne (Biochem. J. 22, 1417-25 (1928)). Accord proceeds, the temperature may be allowed to in ing to that well-known procedure, beta-methyl O crease somewhat, but it should not be allowed mercapto-propionaldehyde is subjected to a to rise above about 50° C., else excessive poly Strecker synthesis, by means of which methionine merization of the acrolein Will occur. The methyl is obtained in about 6% yield (cf. Organic Syn mercaptain preferably should be present in ex theses, volume XIV, page 60). cess of the amount theoretically required. In An object of the present invention is to provide 15 fact, about 2 mols of methyl mercaptain per mole a commercially feasible process for the manu of acrolein is usually desirable. One reason for facture of methionine in good yields from readily this is to permit control of the reaction tempera available starting materials. Another object is ture, since the exothermic heat of the reaction to provide an inexpensive and continuous process can be dissipated conveniently as heat of vapor for the synthesis of methionine. A still further 20 ization of methyl mercaptan. Accordingly, the object is to provide novel compositions of matter reaction vessel is generally equipped With a re which are especially adapted for use in the Syn fiux condenser operated at a temperature of 0° thesis of methionine. Another object is to pre C. Or lower for return of vaporized mercaptain pare methionine nitrile as a novel composition of to the reaction. If desired the heat may be with matter. Other objects of this invention Will ap 25 drawn by external cooling. In carrying out the pear hereinafter. reaction between acrolein and methyl mercaptain, These and other objects are accomplished in care must be exercised to prevent excessive poly accordance with this invention by means of a merization of the arcolein before it has had a series of coacting and interdependent Opera chance to react With the mercaptain. This is tions comprising the following steps: (1) reac 30 achieved by inhibiting the acrolein with about tion between methyl mercaptain and acrolein to 0.1% of hydroquinone, and by very efficient form beta-methylmercaptopropionaldehyde in stirring of the mercaptain while adding the the presence of an alkaline or non-acidic (pref acrolein thereto. It is important that the erably an amine) catalyst; (2) addition of hydro acrolein be introduced directly into the mercap gen cyanide to the resultant beta-methylmer 35 tan and not, for example, along the inner walls captopropionaldehyde, preferably also in the of the reaction vessel, where polymerization of presence of an alkaline catalyst, such as pyridine, the acrolein may occur because of the alkaline to form alpha-hydroxy-gamma-methylmercapto catalyst present. Towards the end of the reac butyronitrile; (3) reaction of alpha-hydroxy tion, which usually requires from 0 to 30 minutes, gamma-methylmercaptobutyronitrile with excess 40 the temperature is preferably allowed to reach ammonia under high pressure to form alpha-ami about 20° C. After the reaction is complete, no - gamma - methylmercaptobutyronitrile; and, the excess methyl mercaptain may be stripped (4) hydrolysis of the said alpha-amino-gamma off, and, if desired, the residue may be distilled methylmercaptobutyronitrile to form methionine. to yield as the almost exclusive product, beta Equations illustrating the reactions may be Writ 45 methylmercaptopropionaldehyde. This novel pro ten as follows: cedure gives beta-methylmercaptopropionalde hyde in very high yield (98%). 1. CHSH-CH2=CHCHO->CH3SCH2CH2CHO The next step in the process of this invention 2. CHSCH2CH2CHO--HCN-> is the preparation of the cyanohydrin of beta CHSCH2CH2CH(OH) CN 50 methylmercaptopropionaldehyde, namely, alpha 3. CHSCH2CH2CH(OH) CN--NH3) hydroxy- gamma - methylmercaptobutyronitrile, CHSCH2CH2CH(NH2)CN--HaO which is prepared also by the use of pyridine as 4. CHSCH2CH2CH(NH2)CN--2H2O-> the preferred catalyst. Consequently, the beta CHSCH2CH2CH(NH2)COOH--NH3 methylmercaptopropionaldehyde obtained in the (Methionine) 55 preceding step need not necessarily be distilled In accordance with this invention, this synthesis or otherwise freed of pyridine, hence acrolein 2,485,286 3 4. methyl mercaptain addition product, containing ent 2,432,478, and 618,783, now U. S. Patent pyridine, may be treated directly with hydrogen 2,432,429, fled September 28, 1945. The success cyanide. In the second step of this invention, full preparation of the aminonitrile in accordance hydrogen cyanide, preferably in about 10% ex with the invention, is probably due to the fact cess, based upon the beta-methyl-mercaptopro that the cyanhydrin is first obtainable, as stated pionaldehyde is added to the reaction product above, in isolable form, and is thereafter treated of the first step at a temperature in the range with high pressure ammonia. Ordinary am of about 15° to 75° C. (preferably 35 to 55° C.) moniation does not give a satisfactory result. In with 0.1 to 0.5% of an amine catalyst, such as fact, unless very large excess, or high pressure, pyridine. The formation of the cyanhydrin 10 of ammonia is used, preferably above about 30 takes place very easily, yield after about 30 atmospheres, a mixed product containing appre minutes reaction time being practically quantita clable amounts of the unreacted cyanhydrin is tive. obtained. The purest aminonitrile is thus pre In a specific embodiment, this cyanhydrin, pared at high ammoniation pressures. This is which is alpha-hydroxy-gamma-methylmercap 15 important since the separation of the aminoni tobutyronitrile may be isolated in pure form, and trile from the cyanhydrin by physical methods thereafter aminated as hereinafter set forth. is quite difficult or virtually impossible. This is This alpha-hydroxy-gamma - methylmercapto due in part to the thermal instability of the butyronitrile is a novel composition of matter aminonitrile, and to the fact that the aminoni which is particularly useful in, and especially 20 trile and the cyanhydrin are similar in structure adapted for, the herein described process for and molecular weight, being representable by the making methionine. Prior investigators in this formula field have never succeeded in isolating this ma CH3SCHCHCHXCN terial, or even obtaining it in crude or transitory form, and, consequently, these prior processes for 25 in which X represents amino or hydroxyl groups. making methionine from beta-methylmercapto Because of the almost quantitative yield in the propionaldehyde without obtaining this interme amination step, the hydrolysis of alpha-amino diate have invariably given low yields. gamma-methylniercaptobutyronitrile to meth The third step of the process of this invention ionine may be effected without intermediate steps is the amination of alpha-hydroxy-gamma 30 or processing of materials. In continuous opera methylmercaptobutyronitrile, by treatment with tion, the product of the preceding step is pumped high pressure ammonia. It is not necessary to through a reaction vessel along with hot aqueous separate the pyridine or other amine catalyst acid, such as Sulfuric acid of about 10 to 70% con from the product of the preceding step prior to centration, preferably about 50%. A preferred carrying on this amination, but such separation 35 procedure is to mix the alpha-amino-gamma may be effected if desired. The reaction of alpha methylmercaptobutyronitrile with 50% sulfuric hydroxy- gamma - methylmercaptobutyronitrile acid, and to heat the mixture at a temperature with ammonia is preferably accomplished by close to the boiling point for about an hour or processing alpha-hydroxy-gamma - methylmer longer. Thereafter the mixture is cooled to about captobutyronitrile at a temperature in the range 40 room temperature, and the sulfuric acid is neu of 10° to 150° C., preferably 75 to 90° C., with a tralized with ammonia. In certain instances the large excess of ammonia (at least 5 moles of am product at this stage has a rather dark color, monia per mole of cyanhydrin, preferably 10 to which can be removed by means of decolorizing 30 moles), at a superatmospheric pressure of 5 charcoal. To isolate methionine from the re to 1000 atmospheres, preferably about 10 to 100 45 Sultant solution, any of the conventional tech atmospheres. At about room temperature the niques for Separating a solute from a solvent may reaction may require up to 12 to 15 hours or more be employed. The water may be removed at low for completion, but at 80 to 90° C., the reaction pressure, and the methionine can be extracted is complete in 15 to 20 minutes. The yield of from the ammonium sulfate in the resulting resi alpha-amino-gamma - methylmercaptobutyroni 50 due by a suitable solvent. Alternatively, the sol trile (i. e., methionine nitrile) under these con vent may be evaporated and the product isolated ditions is virtually quantitative. by fractional crystallization. The yield in the This aminonitrile (i. e., methionine nitrile) is hydrolysis step generally is within the range of a novel composition of matter. Prior attempts 70 to 75%, calculated on the basis of the pure re to obtain either this aminonitrile or a salt there 55 crystallized product. of have invariably met with failure. For example, This Synthesis yields dil-methionine of excellent Barger and Coyne (loc. cit., pages 1420-1) re quality as shown by its high melting point (283°, ported that attempts to obtain the hydrochloride with decomposition). The invention is illus of this aminonitrile have not been successful. trated in greater detail in the following example. None of the other investigators in the methionine 60 Eacample 1.-Into a 200 cubic centimeter 3 field, although numerous efforts have been made necked flask equipped with a stirrer, a Dry-Ice to improve the process of Barger and Coyne, have reflux condenser, a thermometer and a dropping ever succeeded in preparing this aminonitrile. funnel is placed a mixture of 96 grams of methyl The Success of the present methionine synthesis mercaptain and 0.3 gram of pyridine. With rapid is due, in large measure, to the fact that the cy 65 stirring, acrolein (56 grams) containing 0.1% hy anhydrin, and the aminonitrile, are both obtained droquinone is introduced dropwise through the in isolable form. The pure aminonitrile, which is dropping funnel, initial temperature being 5° C. described in detail below, is a thermally unstable As the reaction proceeds it is necessary to absorb compound, which cannot be distilled under ordi part of the reaction heat by surrounding the re nary conditions, i. e. at pressures above a few O action Wessel with an ice water bath. The reac millimeters. It can be hydrolyzed, however, to tion continues for about one hour, during which give methionine in good yields. Specific methods time the reaction mixture is allowed to warm up for the hydrolysis of this nitrile are set forth in to 20 C. The unreacting mercaptain (52 grams) the copending applications, Serial Nos. 618,781, and acrolein (3.6 grams) are recovered by distill now U. S. Patent 2,443,391, 618,782, now U. S. Pat 5 lation at low pressure, the receiver being a cold 2,485,286 trap at -80° C. There remains a residue which at ordinary pressures without decomposition. It distis quite completely at 60° C., 12 mm, which had a density of about 1.129 at 25 C., and an is the boiling point of beta-methylmercaptopro index of refraction of 1.498 at 29.5 C. On pionaldehyde (weight of beta-methyl-mercapto standing, this material tended to develop Color, propionaldehyde, 96 grams). hence it was desirable to store it at relatively low This aldehyde is returned to the reaction ves temperatures, suitably about -10° C. Or lower. sel and a little pyridine (0.3 gram) is added. Into The purified product analysed as follows: free the mixture is introduced 27.2 grams of liquid HCN, 0.0%; total N, 10.38, 10.45% (theory, hydrogen cyanide. By suitable cooling, the tem 10.7%); total S, 23.8% (theory, 24.4%). These perature of the mixture is maintained at 40 to 0 analyses identify the material as alpha-hydroxy 45° C. for about 20 minutes. The formation of gamma-methylmercaptobutyronitrile. the cyanhydrin takes place quite Smoothly. Eacample 3.-A mixture composed of 59.5 grams When the reaction is complete the excess hydro of alpha-hydroxy-gamma-methylmercaptobutyr gen cyanide is removed by low pressure distilla onitrile (0.454 mole) and 155 grams of NH3 tion into a cold trap. There remains 118 grams 5 (nole ratio 1:20) was allowed to stand at room of the cyanhydrin, i. e. alpha-hydroxy-gamma temperature in a closed vessel under autogenous methylmercaptobutyronitrile. This is transferred pressure for 18 hours. Wolatiles were stripped to a pressure resistant silver-lined vessel of about from the product using a stream of CO2 at 900 cc. capacity, and ammonia (300 grams) is 2 mm, and 25 to 30° C.; the remaining product injected. The vessel is then agitated and heated 20 (alpha -amino-gamma-methylmercaptobutyroni to a temperature of 80 to 90° C., the contents trile) weighed 56.0 grams (free NH3, 0.0%); total being under an autogenously developed pressure N=21.16, 21.22% (theory 21.5%); total S-22.4, of about 40 atmospheres. After 15 minutes at 22.6% (theory 24.6%). This aminonitrile was this temperature the reaction mixture is cooled, . a reddish brown liquid, having a density of 1.085 and then withdrawn from the reaction vessel. 25 at 25 C. It was thermally unstable, being even Upon evaporation of the ammonia, there remains more difficult to distil than its parent cyanhydrin. a residue which is a mixture of water and alpha Like the cyanhydrin, this aminonitrile had to be amino-gamma-methylmercaptobutyronitrile. An Stored at relatively low temperatures, suitably aliquot portion of this residue is placed in a dis about -10° C. or lower, to avoid excessive dete tilling flask and water is removed therefrom by 30 rioration. w evaporation at low pressure. The remaining resi One of the significant advances made by the due, which is alpha-amino-gamma-methylmer present invention is its adaptability to operation captobutyronitrile, is obtained in quantity cor in a continuous manner, since no other methi responding to nearly quantitative yield. This onine synthesis lends itself to practical continu residue is thereafter added to the main portion 35 ous operation. Some of the outstanding charac of the aqueous aminonitrile. teristics of the present invention which make con Without separating the water from this amino tinuous operation feasible are: (1) the yield in nitrile, the mixture is added dropwise to a soul all steps except the final hydrolysis is nearly tion containing 180 grams of concentrated sul quantitative, hence complicated purification furic acid and 180grams of water. The resulting 40 Operations after each step, which would make mixture is boiled for 1.5 hours. Thereafter, it is continuous operation infeasible are avoided; and cooled to room temperature, and neutralized (2) the catalyst, which is introduced in the first With aqueous ammonium hydroxide. The solu step (addition of methylmercaptan to acrolein), tion thus obtained is decolorized by boiling with a is effective in the second step (addition of HCN few grams of decolorizing charcoal. After re 45 to the product of the first step), hence may be moval of the charcoal by filtration, the Solution allowed to remain in the reaction mixture is placed in an evaporator, and water is removed throughout steps (1) and (2). In fact, since at diminished pressure until there remains a solid the catalyst is one which does no harm in the mixture of methionine and ammonium sulfate. Subsequent amination and hydrolysis operations, By repeated extraction with liquid ammonia, the 50 it may be allowed to remain in the system methionine is removed from the annonium Su throughout the entire synthesis. fate. The methionine is isolated by evaporation In carrying out the synthesis of methionine in of ammonia from this extract. There is obtained a continuous manner, the conditions of tempera crude methionine which on recrystallization from ture, pressure, and reaction time employed in water yields 112 grams of pure methionine, melt 55 each step are similar to the corresponding condi ing at 283 C, tions used in the batch process described in the Eacample 2.- To 75.5 grams (0.725 mole) of example above. freshly distilled gamma-methylmercaptopropion It will be understood that the present inven aldehyde (B. P. 51° C./7 mm.) containing 0.5 cc, tion is not limited to the particular embodiments of pyridine catalyst there Was added, with stir 60 which are hereinbefore used as illustrations. For ring and cooling to prevent a temperature in example, it is not essential that the same catalyst, excess of 45° C., 40 cc. (1.04 mole) of liquid HCN; pyridine, be employed in the first two steps in this addition required 15 minutes and the mixture the Synthesis, although generally there is an ad was allowed to react for an additional 15 min vantage in doing so. If desired, other non-acidic utes. The product was then placed on a vacuum 65 catalysts may be employed for the reaction be pump and volatiles were removed, the final tem tween acrolein and methyl mercaptain. Thus, perature and pressure being 40 C. at 2 mm. charcoal, amines (piperidine, quinoline, tri (product weights-84.8 grams). This product was ethanolamine, etc.), lime, alkalimetal alcoholates further purified by dissolving it in ether, extract and the like are operative as catalysts in the ing the ether solution with water, and removing 70 first step. If desired, the product obtained in volatile components from the ether layer by step (2), (alpha-hydroxy-gamma-methylmercap means of a stream of CO2 (40 C./2 mm.). The . tobutyronitrile) may be neutralized or acidified resulting purified alpha-hydroxy-methylmercap prior/to the amination, because its storage prop tobutyronitrile was a virtually colorless thin erties are better in the absence of alkali. Other liquid, which could not be satisfactorily distilled acids besides sulfuric acid may be employed in 2,485,286 7 the hydrolysis of the aminonitrile to methionine, has been substantially all converted to an although comparatively poor results are obtained with hydrochloric acid. The oxygen-containing aminonitrile of the formula . . . acids, other than the strong oxidizing agents are Satisfactory catalysts in this hydrolysis step. These catalysts include phosphoric acid, benzene and thereafter stripping ammonia from the re sulfonic acid, oxalic acid, hydroxyacetic acid, Sulting reaction mixture and recovering the methoxyacetic acid, and the like. Promoters for aminonitrile of the formula the hydrolysis of the aminonitrile may be em CHSCH2CH2CHNH2CN ployed, but are generally unnecessary. These O promoters include mercury salts, copper salts, therefrom. zinc salts, and the like. Neutralization of the 3. The process for the preparation of hydrolyzate may be effected with alkaline ma methionine which comprises preparing alpha terials other than ammonia, if desired, although amino - gamma - methylthiol -butyronitrile by ammonia is preferred because it permits easy 5 bringing alpha-hydroxy- gamma - methylthiol isolation of the methionine (an "inner salt') butyronitrile into intimate contact with am without Saponification thereof. After evapora monia and thereafter hydrolyzing the alpha tion of the solvent from the neutralized amino - gamma - methylthiol - butyronitrile to hydrolyzate, and extraction of methionine from form methionine. the resultant residue, the ammonia recovered 20 4. The process for the preparation of alpha from the extraction may be recycled for use in amino - gamma - methylthiol - butyronitrile, an the amination, neutralization, or extraction intermediate which may be hydrolyzed to form operations. methionine, which comprises bringing alpha The compounds of the formula hydroxy-gamma-methylthiol - butyronitrile into 25 intimate contact with ammonia. CH3SCH2CH2CHOHCN WILLIAM. F. GRESHAM. and CH3SCH2CH2CHNH2CN, which are prepared CAR.L. E. SCHWEITZER. as herein disclosed, are useful as precursors of methionine, and of other biologically active com REFERENCES CTED pounds related thereto. 30 The following references are of record in the Since many different embodiments of this in file of this patent: vention may be made without departing from the Spirit and Scope thereof, it will be understood that UNITED STATES PATENTs We do not limit ourselves except as set forth in the appended claims. 35 Number Name Date We claim: 1984,415 Macallum ------Dec. 18, 1934 1. A process which comprises Subjecting a com 2,163,176 KeySSner ------June 20, 1939 pound of the formula CH3SCH2CH2CHOHCN to 2,392,294 Rust et al. ------Jan. 1, 1946 the action of from 10 to 30 mols of ammonia per FOREIGN PATENTS mol of CH3SCH2CH2CHOHCN, at a pressure of 5 O to 1000 atmospheres and a temperature of 10° to Number Country Date 150° C., continuing the resulting reaction until 436,692 Great Britain ------Oct. 16, 1935 substantially all of the compound of the formula 511,841 Great Britain ------Aug. 25, 1939 CH3SCH2CH2CHOHCN has been converted to an 655,563 Germany ------Jan. 18, 1938 aminonitrile of the formula 45 OTHER REFERENCES Barger et al.: "Biochem. Jour.' vol. 22 (1928), and thereafter Separating the said aminonitrile pp. 1420-1421. from the resulting mixture. Sidgwicks: Organic Chemistry of Nitrogen, 2. A process which comprises subjecting a com Taylor and Baker (1937), Oxford University pound of the formula CH3SCH2CH2CHOHCN to Press, New York, page 117. the action of from 10 to 30 mols of ammonia per Keneko et al.: "Chemical Abstracts,' vol. 33, mol of CH3SCH2CH2CHOHCN at a temperature (1939), p. 2106 (abstract of Journal of Chemical of 10° to 90° C. under a pressure of 10 to 1000 Society of Japan, vol. 59 (1938), pp. 1382-1384). atmospheres, continuing the resulting reaction iss Rothstein: "Jour. Chem. Society' (London) until the compound of the formula. (1940), pp. 1562-1563. CH3SCH2CH2CHOHCN