US3419551A - Method of preparing 5-(indolyl-3-methylene)-hydantoin - Google Patents

Description

United States Patent 3,419,551 METHOD OF PREPARING 5-(INDOLYL-3- METHYLENE)-HYDANTOIN Yoshioki Komachiya Seiji Suzuki, and Setsuji Sakurai, Kanagawa-ken, Japan, assignors to Ajinomoto Co., Inc., Tokyo, Japan No Drawing. Continuation-impart of application Ser. No. 286,908, June 11, 1963. This application May 18, 1964, Ser. No. 368,409

Claims priority, application Japan, May 17, 1963, 38/24,446 16 Claims. (Cl. 260-240) ABSTRACT OF THE DISCLOSURE The hydrogenation of nitriles in a liquid acidic medium in the presence of a nickel catalyst produces higher yields of aldehyde and smaller amounts of other hydrogenation products (alcohol, amine) when small amounts of lead are simultaneously present in the catalyst or in the medium. The phenylhydrazone of B-(S-hydantoyD-propionaldehyde is thus prepared from S-cyanoethylhydrantoin, and is converted to 5-(indolyl-3-methylene)-hydantoin in good yields by indol condensation in a 0.01 to 0.5 normal solution of a strong acid, thereby providing a tryptophan synthesis starting with readily accessible raw materials.

This application is a continuation-in-part of our copending application Ser. No. 286,908, filed on June 11, 1963, now abandoned.

This invention relates to a method of preparing aldehydes by hydrogenation of nitriles, and more particularly to a method in which aldehydes are prepared from nitriles in a single step.

When nitriles are hydrogenated in the presence of conventional hydrogenation catalysts in a conventional manner, the hydrogenation product largely consists of the corresponding primary amine and the alcohol having the same carbon skeleton as the amine. In many instances, neither the aldimine expected from reaction of one molecule of nitrile with one molecule of hydrogen, nor the aldehyde formed by hydrolysis of the aldimine are found in the reaction product in major amounts.

We have found that the hydrogenation of nitriles in an aqueous acidic medium in the presence of an otherwise known Raney nickel catalyst, and particularly in the presence of metallic lead or lead ions leads directly to aldehydes in high yields. The hydrogenation is readily controlled so that it does not proceed to the amine or alcohol. The mechanism by which hydrogenation in the presence of an acid takes place is not entirely understood, but it is believed that the adsorption afiinity between the catalyst surface and the aldimine and aldehyde is sharply reduced by the presence of the acid. This hypothesis is strengthened by the observation that the yield of aldehyde in the hydrogenation mixture is not improved by the addtion of an equimolecular amount of semicarbazide to the hydrogenation mixture although semicarbazide otherwise eifectively traps aldehydes.

The lead bearing nickel catalysts preferably employed in the method of our invention may be prepared by partial decomposition of an alloy of nickel, aluminum, and lead, such as Raney alloy Type NP which has a nominal compostion of 44.0% Ni, 51.8% A1, 0.8% Fe, and 3.3% Pb. A suitable catalyst is also obtained by decomposition of nickel-aluminum alloys in the presence of lead. Suitable alloys include Raney alloy NDH having a nominal composition of 50.0% Ni, at least 49.5% Al, less than 0.5% Fe, and Raney alloy PL which consists of 30.0% Ni, 66.0% Al, and 4.0% Fe. The catalyst system of the invention may also be prepared by decomposing at alu- 3,419,551 Patented Dec. 31, 1968 minum-nickel alloy and thereafter adding a lead salt or finely distributed metallic lead. The iron is not believed to contribute significantly to the catalytic hydrogenation of the nitriles to the correspoding aldehydes, and the nickel catalyst may be prepared from other materials than the allows mentioned.

In carrying out the method of our invention, we dissolve a nitrile in water or in a medium consisting of a mixture of water and a water-soluble organic solvent, such as methanol, ethanol, or dioxane, which is inert to the reactants of the hydrogenation mixture. The aqueous nitrile solution is acidified with the acid which does not dissolve the finely divided nickel catalyst. lLower alkanoic acids, such as formic, acetic, or propionic acid, and hydroxy acids, such as tartaric acid are typical of the organic acids suitable for the purpose. Phosphoric acid is the strongest inorganic acid that may be employed.

Best results are obtained when the mol ratio of acid to nitrile radical is between 2:1 and 10:1. An acid concentration of about 10% by weight of the hydrogenation mixture is typical of those which give good results. The nickel catalyst is preferably admixed last although the sequence is not critical. If the nickel catalyst does not contain lead, a lead salt or metallic lead are added at this stage or earlier.

The temperature at which the mixture is contacted with hydrogen is not important. Depending on ambient temperature, the hydrogenation may be carried out at 5 C. of at 50 C. or at any temperature therebetween. Hydrogenation between 10 and 25 C. is preferred. The time required for hydrogenation decreases with hydrogen pressure, but the yield decreases with pressure. It is therefore undesirable to hydrogenate at pressures greater than 70 kilograms per square centimeter, and we prefer to operate at a hydrogen pressures lower than 20 kg./cm. At a pressure of 1 kg./cm. the time required for complete hydrogenation is about 50% longer than at 15 kg./cm. but the aldehyde yield is usually superior by 3 to 5 percent.

Three methods are generally available for preparing the preferred lead-bearing hydrogenation catalyst of this invention. The first method (Method A) employs a lead bearing alloy, such as Raney alloy NP which is digested with about twenty parts 15% aqueous sodium hpdroxide solution at C. for 80 minutes in a conventional manner. In the second method (Method B), a Raney alloy free from significant amounts of lead, such as alloys NDH or PL is mixed with 3 to 5 percent lead powder, and the mixture is digested with about twenty milliliters of the 15% NaOH solution per gram of metal mixture. The preferred digestion time and temperature for alloy NDH is 100 minutes at C., for alloy PL 80 minutes at 60 C. The catalyst is washed with Water prior to use. Other methods of developing the nickel catalyst may be used and are well known to workers in this art.

In the third method (Method C), a nickel catalyst free from significant amounts of lead is developed separately, and the nickel catalyst and an amount of lead corresponding to 3 to 5 percent of the original weight of the catalyst alloy are directly added to the hydrogenation mixture. While greater amounts of lead do not interfere with the desired reaction, no advantages are normally obtained by using an amount of lead greater than 5 percent by weight of the nickel alloy from which the nickel catalyst is prepared. Lead salts in equivalent amounts may be substituted for the metallic lead in Method C. Their anions should meet the requirements for the acidifying agent set forth hereinabove.

The method of the invention is applicable to nitriles generally, as is apparent from Table 1 which lists representative nitriles employed as starting materials, the aldehydes obtained therefrom, the solvent and acid mixture in which the nitrile was dissolved, the amount of nickel alloy used for preparing the catalyst, and the yield of aldehyde in mole percent of nitrile converted as will presently be described in more detail AcOH in the table stands for acetic acid.

The table also lists the method of preparing the catalyst. In Method A, the indicated amount of NP alloy was digested 80 minutes at 80 C. in 85 grams of 15% aqueous NaOH solution. In Method B, alloy NDH was digested with an equal amount of caustic soda solution at 90 C. for 100 minutes in the presence of 3% lead powder. In Method C, the NDH alloy was digested as in Method B, but Without lead, and an amount of lead acetate corresponding to lead metal on the weight of the alloy was added to the hydrogenation mixture.

The mixture initially contained 0.1 mole of the nitrile, the hydrogenation was carried out at 2.5 kg./cm. hydrogen pressure and 1820 C. until 0.105 mole hydrogen had been absorbed, with the exception of Run No. which was stopped at a hydrogen absorption of 0.049 mole.

The catalyst was removed from each hydrogenation mixture by filtration, and 0.1 mole 2,4-dinitro phenylhydrazine was added to the filtrate. The yield of the phenylhydrazone is listed under Y in Table 1. Another estimate of aldehyde yield was obtained in a parallel run in which a filtrate free from catalyst was adjusted to pH 10 with sodium hydroxide, and the ammonia liberated was distilled off and determined as a measure of nitrile conversion to aldehyde. The aldehyde yields obtained on this basis are listed in column X.

The following examples are further illustrative of the method of this invention, and it will be understood that the invention is not limited to the examples.

EXAMPLE 1 A catalyst was prepared by developing 4.2 grams of the nickel-aluminum alloy NDH at 90 C. for 100 minutes, and by washing the metallic residue with water. The nickel catalyst was added to a solution of 10.3 g. (0.1 mole) benzonitrile and 230 mg. lead acetate trihydrate in a liquid medium of ml. acetic acid, 80 ml. water, and 50 ml. dioxane. The mixture was hydrogenated in a pressure vessel at 20 C. under a hydrogen pressure of 2.5 l-:g./cm. until 0.100 mole hydrogen had been absorbed (150 minutes).

The catalyst was removed by filtration and washed with 60 ml. water. 11.1 grams (0.1 mole) semicarbazide hydrochloride were added to the combined filtrate and washings, and the mixture was left to stand overnight with external cooling. A crystalline precipitate formed. It was separated from the mother liquor, washed with water, and dried. The dry product melted at 223 C. and was further identified by elementary analysis as the semicarbazone of benzaldehyde. The yield was 11.4 g. (70%).

80 minutes, followed by washing with water. The catalyst was employed in the hydrogenation of benzonitrile in the presence of lead acetate in the same manner as described in Example 1. The absorption of 0.100 mole hydrogen was completed within 140 minutes. 10.5 grams benzaldehyde semicarbazone were recovered from the hydrogenation mixture for a yield of 65%. M.P. 223 C.

EXAMPLE 3 The procedure of Example 2 was repeated, but the acetic acid in the hydrogenation mixture was replaced by an equal volume of propionic acid. The absorption of 0.100 mole hydrogen required 140 minutes. The crystalline product obtained had a melting point of 221222 C. and weighed 10.3 grams (yield: 63%).

EXAMPLE 4 11.7 grams (0.1 mole) p-methylbenzonitrile were hydrogenated in the presence of nickel and lead catalysts and of acetic acid by the method of Example 1. 0.100 mole hydrogen Was absorbed within 150 minutes. The catalyst was filtered off and washed with water. The filtrate and washings were combined, and the mixture was adjusted to pH 7.2 by addition of sodium bicarbonate powder. The aldehyde was extracted from the neutralized aqueous medium with ether, the ether extract was dried with anhydrous magnesium sulfate, and the ether was evaporated. The residue was distilled at low pressure. A fraction distilling at 88 C. at 19 mm. Hg was identified at p-methyl-benzaldehyde. It weighed 8.4 grams (yield 70%).

The aforedescribed hydrogenation of a nitrile to an aldehyde is employed to advantage in a series of reactions which leads from commonly available reactants to tryptophan in very good overall yields.

We have found that 5-(indolyl-3-methylene)-hydantoin, hereinafter referred to as compound (I) and having the formula CID-(J HC 0 H NH N NH-CO can be prepared from fi-cyanopropionaldehyde in a sequence of operations involving the reaction of 15%-cyanopropionaldehyde with hydrogen cyanide, ammonia and ammonium carbonate to S-(fi-cyanoethyl)-hydantoin, hereinafter referred to as com-pound (II).

NC-ClIz-CHrCH-C O The yield of compound (II) in this reaction can be raised to 70 percent or higher if the reaction mixture is TABLE 1 Solvent (ml) Yield Run No. Starting material, nitrile Product, aldehyde Catalyst Method AcOH H2O Dioxane (g) X Y (percent) (percent) 20 80 3. 1 A 79 2O 80 50 3. l B 80 64 20 80 50 3. 1 C 83 65 20 80 100 3. 6 C 79 63 20 80 100 3. 6 C 77 79 20 80 100 3. 6 C 87 82 20 S0 100 3. 6 C 72 20 80 0 3. 1 A 65 44 20 80 0 3. 1 B 75 51 20 0 3. 1 C 77 62 20 80 0 3. 1 C 7' 20 80 0 4. 5 C 98 52 C 20 so 50 4.5 o 63 30 14 (CH3)z=CH-CN (CH3)2=CH- 20 80 O 4.2 C 72 55 15 CHaS-(CHz)z-CN CHnS(CH2)z HO 10 40 50 5.0 C 65 51 LE 2 kept above C., preferably at to C. for 3 A catalyst was prepared from 4.2 grams of the Ni-Al-Fe alloy PL by digestion with 85 grams of an to 15 minutes in an autoclave.

The influence of the reaction temperature on the yield aqueous 15% sodium hydroxide solution at 60 C. for 75 of compound (II) is shown in Table 2. All reaction mixtures consisted of 110 milliliters water, 14.5 g. ammonium carbonate, 10.3 milliliters aqueous 28% ammonium hydroxide solution, 4.1 g. hydrogen cyanide, and 8.3 g. fl-cyanopropionaldehyde. After heating with stirring to the listed temperatures for the periods shown, the reaction mixtures were evaporated to dryness in a vacuum at 30 C. The residues were dissolved in 16 milliliters water and the solutions thus obtained were mixed with enough concentrated hydrochloric acid to make the pH lower than 1 at 90 C To each solution were further added 16 milliliters water and a small amount of activated charcoal to remove impurities. The charcoal was filtered off. Crude crystals of compound (II) were obtained'from the filtrates by concentrating and cooling the same. The crystals, When recrystallized from hot water had a melting point of 109 to 110 C. and an infrared spectrum with absorption bands at 2250 cmr (GEN) and 1710 cm. (0:0 in hydantoin).

Compound (11) was then hydrogenated to transform the nitrile group to a formyl group. The aldehyde obtained was reacted with phenylhydrazine to form the corresponding phenylhydrazone, hereinafter referred to as compound (III).

(III) Compound (III) is converted to compound (I) by heating in a suitable solvent in the presence of an acid catalyst. The conversion of phenyl hydrazones of aldehydes to indol derivatives is known per se, but the known processes have yields of 50 percent or lower. We have found that the yield of compound (I) from compound (III) can be raised to 90 percent or more by modifying the known process.

Compound (I) may be transformed further to tryptophan in a known manner (Majima et al., Chem. Ber 55, 3864, 1922). The overall yield of tryptophan from compound (III) may be maintained at 85 percent, and the instant invention thus provides a synthesis of tryptophan at very good yields from the relatively inexpensive and readily available B-cyanopropionaldehyde.

The influence of such process variables as hydrogen pressure, temperature, and molar ratio of compound (II) to acid in the original hydrogenation mixture on the yield of compound (III) is shown in Tables 3 and 4 which respectively list results of test runs performed with acetic acid and phosphoric acid.

TABLE 3 H2 Press. Temp., Ratio Comp'd Concn 01 Yield Run No. kgJem. C. (II) to acet. seat. 210., percent ac. percent The catalyst employed was -Raney nickel alloy PL in an amount of one half of the weight of compound (II) in the hydrogenation mixture except in Runs No. 9 and 10 when the nickel catalyst weighed A and respectively of the compound (II) originally present.

It is evident from Table 3 that a better yield is not gained by raising the ratio of acetic acid to compound (II) beyond 3.3: l, and that relatively little is lost by reducing the amount of acetic acid to only a slight excess over the compound (II). Best yields are obtained at or near room temperature (approximately 20 C.). The hydrogen pressure at which the most advantageous results are achieved is near 15 kg. per sq. cm. The most favorable weight ratio of compound (II) to catalyst is between 2:1 and 4: 1.

These findings are practically independent of the nature of the acid used in conjunction with the nickel catalyst as is apparent from Table 4 which shows results of eight test runs made in the presence of phosphoric acid under various process conditions. The ratio of compound (II) to Raney nickel alloy PL was 2: 1.

The yield of compound (III) is greatly improved if the hydrogenation mixture contains metallic lead or lead ions in addition to the Raney nickel catalyst and acid. The influence of lead additions by far outweighs the difierences in catalytic effect between different types of Raney metal free from lead and employed for preparing the nickel catalyst.

The test results tabulated in Table 5 were obtained under otherwise identical conditions with the aforementioned types of Raney alloys.

Lead was added to the hydrogenation mixtures in the form of Raney alloy NP (Run No. 1), of lead powder (Runs Nos. 2-4), or of lead acetate trihydr'ate (Runs Nos. 5-12). All hydrogenation mixtures consisted of 0.1 mole of compound (II) dissolved in 100 milliliters 10% aqueous acetic acid and of a Raney nickel catalyst prepared from 4.2 g. alloy. The NP alloy was developed at C. for 80 minutes. The lead powder was added to NDH alloy and the mixture was developed at C. for minutes. The lead acetate was directly added to the hydrogenation mixture. In this case, the NDH alloy was developed at 90 C. for 100 minutes, and the PL alloy at 60 C. for 80 minutes. The hydrogen pressure was 2.5 kg. per sq. cm. and the temperature 20 C. The hydrogenation was stopped after 0.105 moles of hydrogen had been absorbed. The catalyst was removed by filtration, and 0.1 mole phenylhydrazine were added to the filtrate.

No'rE.The ammonia formed was determined by adjusting the pH of the reaction mixture to 10, and distilling the ammonia off. The per centage is indicated relative to moles of compound (II) originally present. The yield is correspondingly calculated.

It is apparent from Table that the yield of compound (III) increases with the amount of lead acetate present in the hydrogenation mixture until the lead acetate amounts to about 3 to 5 percent of the nickel alloy, and that no further improvement is achieved by more than 5% lead acetate. Similarly, no further improvement results from an amount of metallic lead greater than 3% of the nickel catalyst alloy.

For the preparation of compound (III) on a commercial scale, we dissolve the compound (II) in water or an aqueous solution of methanol, ethanol, or dioxane. We then add formic, acetic, propionic, tartaric or phosphoric acid in such amounts that the weight of acid present is about two to ten moles per mole of compound (II), and the concentration of the acid is approximately percent. The catalyst is developed from a. lead bearing Raney alloy and added. If the alloy does not contain lead, either lead powder or a Water soluble source of lead ions such as lead acetate is provided. The hydrogen pressure should be at least one kilogram per square centimeter, and may be as high as 70 kg. per sq. cm. without drastically affecting the yield, but nothing is gained by high pressures except a higher reaction rate. The temperature may be between about 5 and 50 C., and is preferably held at about room temperature, that is, at 10 to 30 C. The working up of the hydrogenation mixture and the recovery of the phenylhydrazone have been described above.

The development of the Raney catalyst may follow any conventional procedure. The developing time and temperature may range from 1 to 2 hours, from 50 to 100 C. respectively. The catalyst is washed with water prior to use in the hydrogenation reaction.

The following examples are further illustrative of the synthesis of compound (III).

EXAMPLE 5 A mixture of 100 milliliters water and 15.3 grams (0.1 mole) S-cyanoethylhydantoin, compound (II), was heated with stirring until the solids dissolved, whereupon the solution was cooled to room temperature. 5 grams PL type Raney alloy were developed in the usual manner and admixed to the aqueous solution together with 90 milliliters aqueous acetic acid. The total volume of the solution was adjusted with water to 200 milliliters. A hydrogen pressure of 15 kg. per sq. cm. and a temperature of C. were maintained in a hydrogenation vessel holding the mixture for 13 minutes after which the amount of hydrogen absorbed reached 0.1 mole.

firmed by elementary analysis as the phenylhydrazone of hydantoylpropionaldehyde.

Calculated for C H N O /2H O: C, 56.50; H, 5.93; N, 21.93. Found: C, 56.85; H, 6.20; N, 22.11.

EXAMPLE 6 The hydrogenation of cyanoethylhydantoin was carried out in the same manner as described in Example 1, but the acetic acid solution was replaced by '90 milliliters 23% aqueous phosphoric acid. The hydrogen absorption reached the desired value after 15 minutes. The crude crystals of the recovered phenylhydrazone weighed 16.1 grams and had a melting point of 108110 C. After recrystallization from 110 milliliters 50% aqueous ethanol they weighed 143 grams, and had a melting point of 125127 C.

EXAMPLE 7 A solution of 15.3 grams (0.1 mole) 5-cyanoethylhydantoin+l00 milliliters 10% aqueous acetic acid was mixed with a catalyst prepared from 4.2 grams of the lead bearing Raney alloy NP by development with 85 grams 15% NaOH at C. for 80 minutes. The hydrogenation was carried out under a hydrogen pressure of 2.5 kg. per sq. cm. at 20 C. 0.105 mole hydrogen Was absorbed in 120 minutes. The catalyst was removed from the remainder of the hydrogenation mixture by filtration, and was washed with 60 milliliters water. 10.8 grams phenylhydrazine were added drop by drop to the combined filtrate and washings with stirring. The mixture was left to stand overnight with external cooling. The crystals formed were separated from the mother liquor, washed with water, and dried. They had a melting point of 114-116 C., and weighed 21.7 grams yield). After recrystallization from 150 ml. of 50% aqueous ethanol, the weight was reduced to 19.7 grams, and the melting point was raised to 126-127 C.

EXAMPLE 8 The run of Example 7 was repeated with a catalyst prepared from type NDH alloy developed at C. for minutes in the presence of 126 mg. lead powder. The adsorption of 0.105 mole hydrogen required 130 minutes. Under otherwise identical conditions, there were obtained 22.4 grams of a crude crystalline phenylhydrazone having a melting point of 115117 C. (88% yield). Purified crystals which weighed 19.8 grams and melting at 126-127 C. were obtained by recrystallization from milliliters 50% aqueous ethanol.

EXAMPLE 9 A hydrogenation solution was prepared from 15.3 grams cyanoethylhydantoin (0.1 mole), 230 milligrams Pb(CH COO) H O, and 100 milliliters 10% aqueous acetic acid. The catalyst was prepared by developing 4.2 grams type NDH alloy at 90 C. for 100 minutes. The hydrogenation was carried out under a hydrogen pressure of 2.5 kg. per sq. cm. at 20 C. The absorption of 0.105 mole hydrogen took 120 minutes. The crude phenylhydrazone crystallized from the hydrogenation mixture after removal of the catalyst weighed 23.8 grams (93% yield) and had a melting point of 115-117 C. When recrystallized from milliliters 50% aqueous ethanol, the crystals weighed 21.7 grams, and melting at 126-127 C.

The elfects of catalyst concentration and reaction time on the amounts of ammonium ions (ammonia) and compound (I) formed from compound (III) are illustrated in Table 6 which lists the results obtained by holding a 3.8% solution of compound (III) in a mixture of equal parts of water and ethanol at 80 C. for the periods indicated in the presence of an amount of hydrogen chloride sufiicient for the indicated HCl concentration. The yield of compound (I) was determined by hydrolysis to tryptophan and biological assay for the L-tryptophan present. The weight yield of the hydrolysis is 90%, and the total amount of tryptophan formed is twice that of the L-tryptophan. The amount of compound (I) was calculated from the L-tryptophan values of the assay by multiplication with 200/90. The amount of ammonium ions (ammonia) formed is expressed as mole percent of the initial amount of compound (III).

It is apparent that the reaction does not proceed substantially beyond the results obtained in the first minutes when the HCl concentration is 2 N, and that the yield under these conditions does not reach When the hydrochloric acid present makes the solution 0.5 normal, the yield reaches within a half hour, and rises to in two hours. At the higher HCl concentration, a substantial amount of compound (III) is lost by transformation into by-products.

Only a small further improvement of the yield was achieved when the reaction was carried out in the presence of phenylhydrazine, as shown in Table 7. The results listed were obtained by holding a 3.8% solution of compound (III) in equal parts of water and ethanol at 80% C. for two hours in the presence of sulficient HCl to make the solution initially 0.5 normal with respect to HCI.

TABLE 7 Mole Ratio of Ammonium ions Yield of phenylhydrazine formed (as N H compound (I), to compound (III) percent percent Optimum reaction conditions were ultimately determined in a series of experiments the results of which are tabulated in Table 8. In these experiments, 20' grams of compound (III) were combined with 660 milliliters water previously mixed with 7 milliliters 5.2 N hydrochloric acid, so that the molar ratio I-IClzcompound (III) was 1.13, and the initial concentration of HCl in the solution was 0.13 normal. After the solution had been held at the listed temperatures for the periods shown, it was filtered, and the filtrate was evaporated to dryness. The residue was washed three times with 30 milliliters cold water.

TABLE 8 Yield of compound (I),

percent Temperature, C. Time, hours medium acidic. When the acid was added drop by drop to satisfy this requirement, but to avoid an excess of free acid present, the maximum yield was raised to 93 percent. The solution was originally made up from 1 mole compound (III), 1.5 moles hydrochloric acid, and enough water to make the solution 0.05 normal with respect to HCl. One additional mole of HCl was added dropwise to the reaction mixture over a period of one hour in the form of a 0.5 normal HCl solution.

Although water gives excellent results when employed as a sol-vent, and is preferred because of its low cost, the reaction of the invention may also be carried out in solvents consisting of lower alkanols, such as methanol or ethanol, lower alkanoic acids such as acetic acid, mixtures of these solvents, and their aqueous solutions.

All strong acids are effective catalysts. Results closely similar to those achieved with hydrochloric acid are available when other strong inorganic acids, such as sulfuric acid, are employed. Strong organic acids, such as benzene or toluene s'ulfonic acids are excellent catalysts, and cation exchange resins that are strongly a-cid have the same effect. Somewhat weaker acids, such as formic or oxalic acid, have relatively weak catalytic effects. The reaction takes place, but only slowly, and does not go to completion until after a long time. The use of ion exchange resins, while feasible, is not economically attractive at this time because of the large amounts of acid solutions required for regeneration. The use of cation exchange resins which retain the ammonia liberated during the reaction and are otherwise as effective as hydrochloric acid leads directly to a pure product, and are highly advantageous for this reason. Suitable cation exchange resins are polystyrene resins of the sulfonic acid type.

For highest yields, the concentration of the acid catalyst in the reaction mixture should not exceed 0.5 gram equivalents per liter, and less than 0 .01 gram equivalents per liter are not usually effective. The preferred range of acid catalyst concentration is between 0.02 N and 0.1 N, and highest yields are obtained in this catalyst range. The acid should preferably be added gradually to the reaction mixture at such a rate as to neutralize the ammonia formed in the reaction and to maintain an excess of free acid within the indicated ranges.

Rapid agitation of the reaction mixture is important to avoid localized higher or lower acid concentration which reduces the yield of compound (I). When the reaction reaches the desired stage, the solvent is evaporated in a vacuum and the residual crystals of crude compound (I) are Washed with small amounts of the solvent originally employed. The crude product so obtained may contain about 95 percent of pure compound (I), and may be purified by recrystallization from 25 weights of a mixture of equal parts of water and ethanol. The purified crystals melt at 214 C. to 215 C. with decomposition.

The following examples are further illustrative of the second stage of the present invention:

EXAMPLE 10 25.5 grams of the phenylhydrazone of B-(S-hydantoyD- propionaldehyde, compound (III), were admixed to 200 milliliters of a 0.2 N solution of hydrogen chloride in a 1:1 mixture of water and ethanol. The mixture was heated to 80 C., and was held at that temperature with vigorous agitation while milliliters 1 N hydrochloric were added drop by drop over a period of two hours. Stirring was then continued at 80 C. for two additional hours.

The reaction mixture was evaporated to dryness is a vacuum, and the residue was mixed with 100 milliliters cold water with external cooling. The crystals of crude 5-(indolyl-3-methylene)-hydantoin, compound (I), which were formed thereby, were collected and washed with water. They weighed 20.5 grams, and melted at 211 C. with decomposition. They contained 95 of the pure compound (I), and the overall yield of the pure compound thus was 85 percent.

After recrystallization from 50% aqueous ethanol, the crystals melting at 214 C. to 215 C. with decomposition.

EXAMPLE 1 l 25 .5 grams of the phenylhydrazone of [3-(5-hydantoyl) propionaldehyde, compound (III), were admixed with vigorous agitation to 840 milliliters 0.14 N aqueous hydrochloric acid. The temperature of the mixture was held at 90 C. for 2.5 hours. It was then evaporated to dryness in a vacuum, and the residue was stirred with 100 milliliters cold water with external cooling. The crystals of compound (I) were collected and washed with water. They weighed 20.8 grams, melted at 212 C. to 213 C. with decomposition and were 99 percent pure. The net overall yield thus was 90 percent.

EXAMPLE 12 25.5 grams of compound (Ill) were mixed with 900 milliliters 0.14 N aqueous sulfuric acid. The mixture was brought to 90 C. and stirred vigorously for three hours. The pH was then adjusted to 3.5 by addition of sodium bicarbonate, and the mixture was evaporated to dryness in a vacuum. The residue was stirred with 100 milliliters cold water as described in Examples 10 and 11, and the crystals of compound (I) were washed with water. They weighed 208 grams, and melted at 210 C. to 212 C. with decomposition. Their purity was 96%, and the total yield 88 percent.

EXAMPLE 13 25.5 grams of compound (III) were mixed with 400 milliliters 0.04 N aqueous hydrochloric acid. The mixture was heated to 90 C., and 100 milliliters 1 N HCl were added drop by drop over a period of two hours. Stirring was continued after completion of acid addition for one hour at 90 C. The reaction mixture was evaporated, and the residue was treated as described in the preceding examples. The crystals obtained weighed 21.8 grams, and melted at 212 to 213 C. with decomposition. Their purity was 98 percent. The overall yield thus was 93 percent.

While the invention has been described with particular reference to specific embodiments, it is to be understood that it is not limited thereto, but is to be construed broadly and restricted solely by the scope of the appended claims.

What we claim is:

1. A method of preparing -(indolyl-3-methylene)hydantoin which comprises heating the phenylhydrazone of fl-(S-hydantoyl)-propionaldehyde in a 0.01 normal to 0.5 normal solution of a strong acid to a temperature between 60 C. and the boiling point of said solution.

2. A method as set forth in claim 1, wherein said acid is selected from the group consisting of hydrochloric acid, sulfuric acid, benzenesulfonic acid, a toluenesulfonic acid, oxalic acid, formic acid and a strongly acid cation-exchange resin.

3. A method as set forth in claim 1, wherein said solution contains as the solvent a member of the group consisting of water, methanol, ethanol, acetic acid, and mixtures thereof.

4. A method as set forth in claim 1, wherein said acid solution is 0.02 to 0.1 normal with respect to said acid.

5. A method as set forth in claim 1, which further comprises hydrogenating 5-cyanoethylhydantoin in the presence of a nickel catalyst in an acidic aqueous medium under a hydrogen pressure between one and seventy kilograms per square centimeter and at a temperature of 5 to 50 C., until fi-(S-hydantoyl)-propionaldehyde is formed; and reacting said fl-(S-hydantoyl)-propionaldehyde with phenylhydrazine to form said phenylhydrazone of 18- S-hydantoyl) -propionaldehyde.

6. A method as set forth in claim 5, wherein said acidic aqueous medium mainly consists of a member of the group consisting of water, a mixture of water with a lower alkanol, and a mixture of water with dioxane, and an acid selected from the group consisting of lower alkanoic acids, tartaric acid, and phosphoric acid, the amount of said acid being between two and ten moles for each mole of said cyanoethylhydantoin; said nickel catalyst contains at least two percent lead and the weight of said nickel catalyst is between one fourth and one half of the weight of said S-cyanoethylhydantoin, and wherein said solution of a strong acid is an aqueous solution of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, benzenesulfonic acid, a toluenesulfonic acid, oxalic acid, formic acid and a strongly acid cation-exchange resin.

7. A method of preparing the phenylhydrazone of ,B- (S-hydantoyl)-propionaldehyde which comprises hydrogenating S-cyanoethylhydantoin in the presence of a nickel catalyst in an acidic aqueous medium under a hydrogen pressure between one and seventy kilograms per square centimeter and at a temperature of 5 to 50 C. until fi-(S-hydantoyl)-propionaldehyde is formed, said catalyst or said medium containing lead; and reacting said ,B-(S-hydantoyl)-propionaldehyde with phenylhydrazine.

8. A method as set forth in claim 7, wherein said acid aqueous medium contains an acid selected from the group consisting of lower alkanoic acids, tartaric acid, and phosphoric acid.

9. A method as set forth in claim 7, wherein said medium mainly consists of a member selected from the group consisting of water, a mixture of water with a lower alkanol, and a mixture of water with dioxane.

10. A methd as set forth in claim 7, wherein said medium contains between two and ten moles acid per mole of said 5-cyanoethylhydantoin.

11. A method as set forth in claim 7, wherein the weight of said nickel catalyst is between one fourth and one half of the weight of said S-cyanoethylhydantoin.

12. A method as set forth in claim 7, wherein said nickel catalyst contains said lead.

13. A method as set forth in claim 12, wherein the lead content of said nickel catalyst is at least two percent.

14. A method as set forth in claim 7, wherein said aqueous medium contains said lead in the form of ions.

15. A method as set forth in claim 14, wherein said aqueous medium mainly consists of a member of the group consisting of water, a mixture of water with a lower alkanol, and a mixture of water with dioxane, and contains an acid selected from the group consisting of lower alkanoic acids, tartaric acid, and phosphoric acid, the amount of said acid being between two and ten moles for each mole of said cyanoethylhydantoin.

16. The phenyl hydrazone of ,B-(5-hydantoyI)-propionaldehyde having the formula /NH NI-I-CO References Cited UNITED STATES PATENTS 2,945,862 7/1960 Mignonac et a1 260297 2,947,757 8/1960 Justoni et al 260326.15 3,037,031 5/1962 Lewis 260-32615 OTHER REFERENCES Ishikawa et al.: Nippon Kagaku Zasshi, vol. 81, pages 1179 to 1191 (1960).

(Other references on following page) Chemical Abs ts., v01. 54, col. 2447IG (1960), Abst. of Ishikawa.

Chemiches Zentralblatt, vol. 134, 19566 (1963), Abst.

of Ishikawa.

JOHN D. RANDOLPH, Primary Examiner.

US. Cl. X.R.