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.