JPH0260668B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 5-substituted hydantoins and methods for their production. Encyclopedia of Chemical Technology, edited by Kirk-Othmer.
Technology) (2nd edition, 1966, Volume 11, 144-145
According to p. 1: The reaction of hydantoins with aromatic or heterocyclic aldehydes occurs at the 5-position to yield unsaturated hydantoins: In the formula, R is phenyl, substituted phenyl,
Furyl, pyryl, pyridyl, quinolyl or indolyl. 2. The reaction of hydantoins with aliphatic aldehydes serves various purposes. 3 Various cyclic ketones or keto compounds include cyclohexanone, isisane and parabanic acid (2,
4,5-imidazolidinetrione),
Condensation advantageously with hydantoins gives products analogous to (D). 5-iso-propylidenehydantoin of formula K0346 has been described by Tatsuoka et al., J.Pharm.Soc.Japan, 1949, 69 , 294~
297, Chemical Abstracts 1950, 44 , 2513e, by boiling S-benzyl-dl-penicillamine hydantoin with 15% sodium hydroxide and neutralizing with HCl. U.S. Patent No. 2,861,079 (Britton et al.) shows a method for producing certain unsaturated hydantoins, in which (a) water or lower alcohols, or water and such alcohols; The hydantoin is reacted with an aldehyde having at least 4 carbon atoms per molecule in the presence of a monoalkanolamine having 2 to 4 carbon atoms. Doyle et al., J.Chem.Soc. 1955 , 2265
~73 (Chemical Abstracts1956, 50 , 8602g~
8603b) is a method in which acetone and 2-
A method is shown in which 5-isopropylidene-2-thiohydantoin is produced by reaction with thiohydantoin, and then desulfurized with chloroacetic acid to produce 5-isopropylidenehydantoin. The 5-secondary alkylidenehydantoin of the present invention is utilized in the production of α-ketocarboxylic acids according to the method of patent application (2) of the same date filed by the present applicant. alpha-ketocarboxylic acids (also referred to herein as "alpha-keto acids" and "keto acids")
has many uses, including but not limited to those listed below. 1 Keto acids are utilized as starting materials for the synthesis of amino acids (Yakabson et al.
Biokhimya.1946, 14 , 14-19, Chemical
Abstracts, 1949, 43 , 5084d; Sakurai, J.
Biochem. (Tokyo), 1958, 45 , 379-85,
Chemical Abstracts, 1958, 52, 18537h; Japanese Patent No. 18711 (1962), Chemical
Abstracts, 1963, 59 , 11660p; and Japanese Patent No. 6884 (1963), Chemical Abstracts,
1963, 59 , 11662d). 2 Keto acids are used as drugs for uremia by promoting protein synthesis and suppressing urine production [Walser,
German Patent Application Publication No. 2335215 (1974)]. 3 Keto acids are used as catalysts in the copolymerization of unsaturated monomers [Netherlands Patent Publication No. 298715]
No., Chemical Abstracts, 1966, 64 , 6842d,
and British Patent Specification No. 1018109 (1966)]. 4 Keto acids are used as hair treatment agents to protect hair against hydroperoxides [German Patent Application No.
No. 1158213 (1963)]. The present invention relates to novel hydantoins of the formula K0347, in which R is methyl and X is phenyl, or R is ethyl and X is hydrogen or phenyl, especially novel hydantoins of the formula K0347

【formula】

[Formula] and provides a compound of Further, the present invention uses ammonia or 3 as a catalyst.
In the presence of a primary amine having a pKb value between 1 and 5, a hydantoin of the formula K0351, in which X is hydrogen or phenyl, and a hydantoin of the formula K0352, in which R is an alkyl group having 1 to 2 carbon atoms, Provided is a method for preparing a compound of formula K0353, wherein R and X are as defined above, by condensing a ketone of. The catalyst employed is, of course, present in an effective amount to promote the formation of the desired hydantoin product. The hydantoin can be separated (for example by filtration, centrifugation or decantation after crystallization), dried (if necessary) and recovered. Preferably the catalyst is ammonia or 4 to 4.6
or amines having at least one primary amino group per molecule and at least one secondary or tertiary amino group per molecule. Particularly suitable catalysts are ammonia, ethylamine, isopropylamine, monoethanolamine, ethylenediamine or trimethylenediamine (1,3-propane-diamine). Other amines that can act as catalysts in the process of the invention include, but are not limited to: methylamine, n-propylamine, n-butylamine, iso-butylamine, sec. -butylamine, tert-butylamine, n-amylamine, iso-amylamine, diethylenetriamine, benzylamine, allylamine, amylamines (isomer mixture), cyclohexylamine, 1,3-dimethylbutylamine, 2-aminoheptane, 2-amino-4 -Methylhexane, 1,4-dimethylpentylamine, 2-ethylhexylamine, 1-cyclopentyl-2-aminopropane, 1,1,3,3,-tetramethylbutylamine, Primene 81-R (mainly t −
C ₁₂ H ₂₅ NH ₂ to t-C ₁₄ H ₂₉ NH ₂ ), Premen JM-T (mainly t-C ₁₈ H ₃₇ NH ₂ to t
_{-C22H45NH2 )} , 1-amino-2-propanol, 2-amino-1-butanol, 2-amino-2-methyl-1 _- propanol, 2-amino-2-methyl-1,3-propane Diol, 2-amino-2-ethyl-1,3-propanediol, N-aminoethylethanolamine, 2-amino-2-(hydroxymethyl)-1,3
-Propanediol, dimethylaminopropylamine, diethylaminopropylamine, triethylenetetramine, tetraethylenepentamine, propylenediamine, imino-bis-propylamine, primary octylamine, primary decylamine, primary dodecylamine, Primary tetradecylamine, primary hexadecylamine, primary octadecylamine. The process of the invention can be carried out in the presence of liquid polar diluents such as, for example: water, glycerin, dimethylformamide, dimethyl sulfoxide, liquid alkanols (1), liquid glycols (2), liquid ethers (3). , liquid ester (4),
triethanolamine, diethyl sulfoxide,
A mixture of diethylformamide, water and alkanol (5). (1) Examples of such alkanols are methanol, ethanol, propyl alcohol and butyl alcohol. (2) Examples of such glycols are ethylene glycol, propylene glycol or butylene glycol. (3) Examples of such ethers are 1,4-dioxane or liquid glycol ethers such as diethylene glycol and dipropylene glycol. (4) Examples of such esters are ethyl acetate, propyl acetate or butyl propionate. (5) Preferably, but not necessarily,
Water-soluble alkanol. For the purposes of this invention, a polar diluent is defined as a free-flowing liquid at 60-80°C (or 65-70°C), even though it is a solid at low temperatures.
It is a "liquid". Other available liquid polar diluents include approximately 60 to
Included are secondary and tertiary amines that are liquid at 80°C or 65-75°C and do not contain primary amine groups (including secondary and tertiary alkanol-amines). Such amines include, but are not limited to: pyridine, piperidine, diethanolamine, triethanolamine, N-methylethanolamine,
N,N-dimethylethanolamine, N,N-diethylethanolamine, N,N-diisopropylethanolamine, N-methyldiethanolamine, diisopropanolamine, triisopropanolamine, N-ethyldiethanolamine, N-butylethanolamine, N, N-dibutylethanolamine, N,N-dibutylisopropanolamine, N,N-di(2-ethylhexyl)-ethanolamine. In addition, in the method of the present invention, the polar diluent does not contain a primary amino group and is about 60 to 80°C or
Secondary and tertiary aromatic amines that are liquid at 65-75°C can be used. Water, dimethylformamide, mixtures of water and lower alkanols (ie, alkanols with 7 or fewer carbon atoms per molecule), and piperidine are suitable polar diluents. The weight ratio of water to lower alkanol is not critical, approximately 1:
10000 (or less) or about 1:0.0001
(or larger) range.
However, diluents are not necessary in the method of the invention. The process of the present invention can be carried out under reduced pressure (i.e. if highly volatile materials are not present (or the equipment is such that volatile materials are recovered and recycled).
can be performed at pressures lower than 760 mmHg). The reaction can also be carried out under elevated pressure, such as about 1.2 to 4 or 5 atmospheres, or higher. Increased pressure is particularly desirable when volatile diluents such as diethyl ether or volatile catalysts such as ammonia or methylamine are used. However, the reaction was carried out at near atmospheric pressure (approximately
760 mm Hg pressure) is generally preferred. When operating under atmospheric pressure, it is desirable to include a reflux device to prevent loss of diluent or at least one reactant. When polar diluents are used in the process of the invention, the molar ratio of reactants hydantoin to catalyst (ammonia or a primary amine having a pKb value of about 3 to 5) to ketone is generally from 1:0.1 to 10:0.5. ~4, preferably 1:0.1~2:0.8~2. However, these values are not critical. As used herein, the term "mole" has its commonly used meaning. 1 mole of substance is pure ¹³ C
If an atom weighs 12g, it is the amount that contains the same number of molecules of a substance as there are atoms. If no polar diluent is used, the molar ratio (hydantoin reactants to catalyst to ketone) is generally from 1:4 to 10:0.5 to 4; however, this value is not critical. The residence time (so-called reaction time) is approximately 1 to 8 hours, preferably 1.5 to 3 hours at the abovementioned reaction temperatures. Reaction temperatures can be operated at 50-150°C or somewhat higher; preferred reaction temperatures are 80-150°C.
100°C; this temperature is not critical. When liquid polar diluents are used in the process of the present invention, generally 150 to 1000 ml of such diluent are used per mole of reactant hydantoin, and it is preferred to use about 200 to 500 ml of diluent per mole of reactant hydantoin. However, these amounts are not critical. In the process of the present invention, the product hydantoin generally precipitates from the reaction mixture that gave rise to the product hydantoin when the reaction mixture is cooled (e.g. 5-35°C, preferably 15-25°C). do. The precipitated product is separated (e.g. by filtration,
(by decantation or centrifugation) and can be recovered. If only a portion of the product hydantoin precipitates, it can be separated from the mother liquor in which it has precipitated, and the mother liquor can be acidified to precipitate a second amount of product hydantoin. . Alternatively (and especially if the product hydantoin does not precipitate when the reaction mixture is cooled), the cooled reaction mixture can be acidified directly;
The product hydantoin can be precipitated. The reaction mixture or product recovered liquid or centrifuged liquid (for example, Examples 3, 4, 5, etc. described below)
8, 10, 12 and 13) can be made acidic by adding hydrochloric acid or sulfuric acid (or other strong acids); pH values from 0.5 to 5, preferably from 2 to
Add water before, during or after adding acid to adjust to 4. [The term "strong acid" as used herein means an ionization constant Ka of at least about
10 ⁻³ ]. If the system to which the acid is added already contains water, further addition of water can be omitted. During acidification, approximately 150 to 1000 ml of water is present for each mole of hydantoin in the reactant fed.
(preferably 200 to 500 ml); however, it is possible to operate in the presence of larger and smaller amounts of water. The acid can be added as an aqueous solution to provide acid and water simultaneously if necessary. The following examples further illustrate the invention. Example 1 3.0 g (0.052 mol) acetone and 5.5 g (0.055 mol) hydantoin containing 3.7 g (0.050 mol) 1,3-propanediamine in a reactor equipped with a reflux condenser connected to the reactor. Mixed with 10ml piperidine. The mixture was heated to reflux temperature (approximately 70°C). Continue heating for 2 hours, during which time the temperature reaches 100
The temperature rose to ℃. Bring the reacted mixture to room temperature (approximately 25℃)
200 ml of water was added to this. Next, the PH value
The required amount of concentrated hydrochloric acid was added to bring the concentration to 0.6. Boil the resulting slurry to dissolve all solids;
It was then cooled to about 20°C to crystallize the product. The crystallized product was filtered, washed with water and dried at 55°C. A quantity of 2.3 g of the desired product has the formula K0354 Melting point: 274-277°C IR (KBr): ν _nax (cm ^-1 ) = 1764 ((2)C=O); 174
1
((4)C=O); 1677 (C=C), ^1H NMR (DMSO- _d6 ): δ=1.8 and 2.1 (s,
It was identified as 5-isopropylidenehydantoin with C H ₃ ); 9.7 and 10.7 (S, NH's ). This is approximately based on the acetone supplied.
It showed a conversion rate (transient yield) of 33%. Example 2 The method of Example 1 was repeated. However, in this example, the method was modified by using 3.6 g (0.50 mol) of methyl ethyl ketone instead of acetone. The mixture thus formed was heated to 90-140°C under reflux for 2 hours. Upon addition of water, acidification, boiling and cooling as in Example 1, a crystalline product was obtained. The product was filtered, washed and dried as in Example 1. 1.5 g of product is obtained, which has the formula K0355 Melting point: 178-181°C IR (KBr): ν _nax (cm ^-1 ) = 1749 ((2)C=O); 172
3
((4)C=O); 1674 (C=C), ¹ H NMR (DMSO-d ₆ ): δ=1.0 (t, C H
₃ CH ₂ ); 1.8 and 2.1 (s, CH ₃ −C=C); 2.65 and 2.1 (q, CH ₃ C H ₂ C=); 9.7 and 10.8 (s, N
H's), was identified as 5-sec-butylidenehydantoin. This amount represents a conversion of 19.5% of the theoretical amount, based on the methyl ethyl ketone fed. Example 3 In a reactor equipped with a reflux condenser and a stirring device, 7.5 g (0.13 mol) of acetone and 10.0 g of hydantoin were added.
(0.10 mol), 50 ml of water and monoethanolamine
9.2g (0.15mol) was added. The resulting solution was heated to 78-85° C. with stirring under reflux for 5 1/4 hours. After the mixture was refluxed for about 4 minutes, a precipitate was observed in it. At the end of the reflux period, the mixture was cooled to about 20°C and filtered. The precipitated fine white crystals were washed with water and dried at 55°C. 7.4 g of the desired product was identified as 5-isopropylidenehydantoin with the properties described in Example 1. The solution from which the precipitate was removed is diluted with concentrated hydrochloric acid.
The pH value was made acidic to 2.0. This resulted in the precipitation of an additional 0.5 g of product (5-isopropylidenehydantoin). The total conversion rate was 56.4% of the theoretical amount based on the hydantoin fed. Example 4 The method of Example 3 was repeated. However, in this example, 9.3 g (0.13 mol) of methyl ethyl ketone was used instead of acetone. The resulting solution was heated to 78-81°C under reflux for 5 1/4 hours. In this example, the product did not precipitate until the solution was cooled to 45°C. The product (white precipitate) was separated from the cooled (45°C) slurry and dried at 55°C. 5-sec- with the properties described in Example 2
3.1 g of butylidenehydantoin was obtained. Similarly to Example 3, the solution was made acidic and the product was further reduced to 1.5
g (total 4.6 g), representing a conversion of approximately 30% based on the hydantoin fed. Example 5 In a reactor equipped with a reflux condenser and a stirring device,
8.8 g (0.05 mol) of 3-phenylhydantoin, 5.03 g (0.09 mol) of acetone, 2.3 g (0.04 mol) of monoethanolamine and 50 ml of water were mixed. The resulting mixture was heated with stirring to 75-85°C for 5 hours. The product precipitated during heating. After a 5 hour heating period, the mixture was cooled to about 20°C and filtered. The precipitate was separated, washed with water and dried at 55°C. 1.1 g of dried precipitate has the formula K0356 Melting point: 229-231℃ IR (KBr): ν _nax (cm ^-1 ) = 1761 ((2)C=O); 170
Five
((4)C=O); 1674 (C=C); 1697 and 1502 (phenyl), ¹ H NMR (DMSO-d ₆ ): δ = 1.9 and 2.25 (s,
C H ₃ ); 7.5 (s, aromatic H ); 10.3 (s, (1)N H )
, was identified as 3-phenyl-5-isopropylidenehydantoin. The liquid from which the precipitated product was separated was made acidic with hydrochloric acid to a pH value of 0.5, and boiled.
It was then cooled to 20°C. A precipitate formed upon cooling. This precipitate was separated from the mother liquor. The separated precipitate was washed with water, dried at 55°C and weighed. It weighed 5.5 g and was identified as 3-phenylhydantoin, the unchanged starting material. Example 6 In a reactor equipped with a stirring device and a reflux condenser,
Hydantoin 10.0g (0.1mol), acetone 7.5g
(0.13 mol), 50 ml of water and 28 wt% ammonia water
9.2 g (0.15 mol) were mixed. The resulting mixture was heated to about 85° C. for 5 hours with stirring under reflux;
Then it was cooled to 20°C. The resulting precipitate was separated from the mother liquor, washed with water and dried at 55°C. 2.0 g of the dried product was 5-
It was identified as isopropylidenehydantoin. Example 7 The method of Example 6 was repeated. However, in this example, 4.5 g (0.07 mol) of ethylenediamine was used instead of ammonia, and the heating time was 2.
It was time. The product (precipitate) became visible when heating continued for about 20 minutes. After heating for 2 hours, the reaction mixture was cooled to 20°C and processed as described in Example 6. The cooled reaction mixture was filtered to recover 7.3 g (52% conversion) of 5-isopropylidenehydantoin with the properties described in Example 1. Example 8 The method of Example 6 was repeated. However, in this example, 9.0 g (0.15 mol) of isopropylamine was used instead of the ammonia aqueous solution. The heating time was 5 hours, and the reflux temperature was about 76°C. Upon cooling, 2.3 g of product precipitated. This product was separated. The solution was made acidic with hydrochloric acid to a pH value of 1, and 1.4 g of product was recovered. This product was identified as 5-isopropylidenehydantoin with the properties described in Example 1. The conversion rate is 26.4% of the theoretical amount based on the supplied hydantoin.
It was hot. Example 9 The general procedure of Example 6 was repeated. However, in this example, 5.5 g (0.08 mol) of trimethylene diamine was used instead of the ammonia solution. The reflux temperature was about 80°C and the heating time was 2 hours. After heating for 35 minutes, precipitated product was visible in the reaction mixture. The reaction mixture was cooled to 20°C, filtered, the precipitate was washed with a small amount of water, and the washed product was dried at 55°C to give 5-isopropylidenehydantoin with the properties described in Example 1. 6.6 g of the identified product (corresponding to a conversion of 47% of theory, based on the hydantoin fed) was obtained. Example 10 The method of Example 6 was repeated. However, in this example, a 70% aqueous solution of ethylamine was used instead of the ammonia solution. The reflux temperature was about 89°C and the heating time was 2 hours. A precipitated product appeared in the reaction mixture after 1 hour of heating. At the end of the heating period, the reaction mixture was cooled to 20° C. and the precipitated product (3.6 g) was collected by filtration. The solution was made acidic (PH value 1) with concentrated hydrochloric acid, thereby precipitating 2.4 g of product. The conversion (based on the weight of product recovered after drying at 55°C) was 42% of theory based on the hydantoin fed. The product was identified as 5-isopropylidenehydantoin with the properties described in Example 1. Example 11 The general procedure of Example 6 was repeated. However, in this example, 50 ml of dimethylformamide was used instead of 50 ml of water, and 9.2 g (0.15 mol) of monoethanolamine was used instead of the ammonia solution. The resulting mixture was heated to about 110°C for 5 hours. A precipitate formed when the reaction mixture was cooled to 20°C. The precipitate was separated, washed with a small amount of water, and dried at 55°C. The product weighed 4.5 g and was identified as 5-isopropylidenehydantoin with the properties described in Example 1. 200ml water
mixed with ml. This resulted in the precipitation of an additional 2.0 g of product (5-isopropylidenehydantoin). The conversion was 46% of the theoretical amount, based on the hydantoin fed. Example 12 In a reactor equipped with a stirring device and a reflux condenser,
50 g (0.5 mol) of hydantoin, 75 g (1.04 mol) of methyl ethyl ketone, 75 ml of water and 45.5 g (0.75 mol) of monoethanolamine were mixed. This mixture was refluxed for 2 hours. Until cooled to about 20℃,
No product (precipitate) could be seen in the reaction mixture. Cooling caused the product to precipitate, which was filtered, washed with a little water and dried at 55°C. The product (32.9 g after drying) was identified as 5-sec-butylidenehydantoin. The solution and washing water were combined and acidified to a pH value of 4 with concentrated hydrochloric acid.
This results in the precipitation of a second product, which is 55
After drying at ℃, the weight was 16.2 g. A second product was also identified as 5-sec-butylidenehydantoin with the properties described in Example 2. The conversion rate is 64.5% of the theoretical amount based on the supplied hydantoin.
It was hot. Example 13 In a reactor equipped with a stirring device and a reflux condenser,
Monoethanolamine 26.6g (0.44mol), hydantoin 10g (0.1mol) and acetone 7.5g
(0.13 mol) were mixed. The resulting mixture was heated to approximately 105℃
The mixture was heated under reflux for 2 hours. This treatment resulted in a thick oily solution. The oily solution was cooled to approximately 20°C and mixed with 50ml of water. The resulting aqueous solution was treated with 37% hydrochloric acid solution to a pH value of 1.5. This required 25 ml (0.35 mol) of hydrochloric acid. This treatment immediately precipitated the product. The resulting slurry was stirred at 25°C for 1 hour and then filtered. The precipitate was washed with a small amount of water, dried at 65°C and weighed. 4.5 g of product identified as 5-isopropylidenehydantoin with the properties described in Example 1 were obtained. This represents a conversion of 32.1% based on the hydantoin fed. The 5-substituted hydantoins produced by the method of the invention were identified by infrared spectroscopy. It is believed that the method described in the above example can be modified as described in the following method with satisfactory results. Method 1 The method of Example 5 is repeated, with the exception that instead of acetone, 0.09 mol of methyl ethyl ketone is used. The results show that the product has the formula K0357 Melting point: 183-186°C IR (KBr): ν _nax (cm ^-1 ) = 1762 ((2)C=O); 170
8
((4)C=O); 1669 (C=C); 1600 and 1500 (phenyl), ¹ H NMR (DMSO-d ₆ ): δ = 1.0 (t, CH
₃ CH ₂ ); 1.8 and 2.1 (s, CH 3 -C=C); 2.65 and 2.1 ( _q , CH ₃ C H ₂ C=); 7.5 (s, aromatic H ), 3-phenyl-5 of It is substantially the same as that obtained in Example 5, except that it is -sec-butylidenehydantoin. Method 2 The method of Example 2 is repeated, but can be modified by using 3-phenylhydantoin instead of hydantoin. The results show that the product is 3-phenyl-5 with the properties described in Method 1.
It is substantially the same as that obtained in Example 2, except that it is -sec-butylidenehydantoin. Method 3 The method of Example 10 is repeated, with the exception that sulfuric acid is used instead of hydrochloric acid in that example. The results are substantially identical to those obtained in Example 10. Method 4 The method of Example 8 is repeated, with the exception that nitric acid is used instead of hydrochloric acid in that example. The results are substantially identical to those obtained in Example 8. Method 5 The method of Example 8 is repeated, but can be modified by substituting phosphoric acid for the hydrochloric acid in that example. The results are substantially identical to those obtained in Example 8. Method 6 The method of Example 8 is repeated, with the exception that the hydrochloric acid of Example 8 can be replaced with phosphorous acid. The results are substantially identical to those obtained in Example 8.

Claims (1)

Claims: 1. A compound having the formula K0340, where R is methyl and X is phenyl, or R is ethyl and X is hydrogen or phenyl. 2 Ammonia or 3 to 5 as a catalyst
In the presence of a primary amine having a pKb value of A method for producing a compound of the formula K0343, wherein R and X are as described above, characterized by condensation. 3. The method of claim 2, wherein the catalyst is an amine having at least one primary amine group per molecule and at least one secondary or tertiary group per molecule. 4. The method according to claim 2 or 3, wherein the catalyst is ammonia, ethylamine, isopropylamine, monoethanolamine, ethylenediamine or trimethylenediamine. 5. The method according to any of claims 2 to 4, wherein the reactant hydantoin is condensed with a ketone in the presence of a polar diluent. 6. The method of claim 5, wherein the polar diluent is water, lower alkanol, dimethylformamide, piperidine or a mixture thereof.