JP5546372B2 - Process for producing benzylhydantoin compounds - Google Patents

Description

  The present invention relates to a method for producing a benzylhydantoin compound useful as an intermediate for producing pharmaceuticals, agricultural chemicals, various amino acids and the like.

  Benzylhydantoin compounds are useful as intermediates for the production of pharmaceuticals, agricultural chemicals and various amino acids, and are also useful as optical materials, electronic materials and the like.

  As a method for producing a benzylhydantoin compound, a method of reducing a benzylidenehydantoin compound obtained by dehydration condensation of an inexpensive benzaldehyde compound and hydantoin is widely employed. And as the reduction method of the said benzylidene hydantoin compound, the method of carrying out electrolytic reduction in an alkaline solvent (nonpatent literature 1), and the method of making a catalytic reduction and formic acid react in presence of catalysts, such as Raney nickel and palladium (patent literature 1). ~ 3) is known.

JP 61-167669 A JP 05-255273 A JP 05-345713 A

Bulletin of the Chemical Society of Japan, 59 (11), 3690-2 (1986)

  However, the electrolytic reduction method has a problem that the apparatus is special and the operation becomes complicated. On the other hand, the catalytic reduction method uses hydrogen gas and a metal catalyst, and sometimes requires high pressure and high temperature conditions, and therefore requires pressure resistance and heat resistance equipment. Hydrogen gas is flammable and explosive, and the metal catalyst used is usually itself ignitable. The catalyst is an expensive noble metal catalyst sometimes containing palladium and platinum. From the above, the contact reduction method has a problem in terms of safety and cost.

  Accordingly, an object of the present invention is to provide a method for producing a benzylhydantoin compound in a safe and industrially advantageous manner.

  Therefore, as a result of examining the reduction reaction of benzylidenehydantoin, the present inventor used sodium borohydride that is used for the reduction of ketones, aldehydes, nitriles, etc., but is generally not employed for the reduction of carbon-carbon double bonds, It has been found that if a benzylidene hydantoin compound is reduced under alkaline conditions in the presence of an inexpensive cobalt compound and a chelating agent, a benzylhydantoin compound can be obtained safely and industrially advantageously, and the present invention has been completed.

  That is, the present invention provides the formula (1)

(Wherein R ¹ , R ² and R ³ each independently represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, an alkyl group, an alkoxy group, an aralkyl group, an aryl group or a heterocyclic group, or R Two adjacent ones of ^{1 to} R ³ may be combined to form a ring.)
A benzylidene hydantoin compound represented by the formula (2) is reacted with sodium borohydride under alkaline conditions in the presence of a cobalt compound and a chelating agent:

(Wherein R ¹ , R ² and R ³ are the same as above)
The manufacturing method of the benzyl hydantoin compound represented by these is provided.

  According to the method of the present invention, a benzylhydantoin compound can be obtained industrially advantageously in a highly safe facility using inexpensive raw materials.

In formula (1) and formula (2), R ¹ , R ² and R ³ are each independently a hydrogen atom, halogen atom, hydroxy group, amino group, alkyl group, alkoxy group, aralkyl group, aryl group or complex. The ring formula may be shown, or two adjacent R ^{1 to} R ³ may be combined to form a ring. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In addition, examples of the alkyl group include linear or branched alkyl groups having 1 to 8 carbon atoms, specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group. , Tert-butyl group and the like. As an alkoxy group, a C1-C8 linear or branched alkoxy group is mentioned, Specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group etc. are mentioned. Examples of the aralkyl group include a phenyl-C _1-6 alkyl group, and specific examples include a benzyl group and a phenethyl group. Examples of the aryl group include aryl groups having 6 to 14 carbon atoms, and specific examples include a phenyl group and a naphthyl group. Examples of the heterocyclic group include pyrrolyl group, thienyl group, furanyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyridyl group and the like. Examples of the ring formed by combining two adjacent R ^{1 to} R ³ include a cycloalkane ring and a heterocyclic ring. Examples of the cycloalkane ring include a cycloalkane ring having 5 to 7 carbon atoms, specifically, a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring, and examples of the heterocyclic ring include pyrrole, thiophene, furan, imidazole, and oxazole. , Thiazole, pyridine and the like.

When catalytic reduction is employed for the purpose of reducing the benzylidenehydantoin compound (1) in which at least one of R ^{1 to} R ³ is a halogen atom, dehalogenation occurs, but according to the method of the present invention, dehalogenation occurs. Does not occur or little if any. Therefore, the method of the present invention is particularly useful when such a compound is used as a raw material.
More preferably, the substrate of the method of the present invention is a case where ^{two of} R ¹ , R ² and R ³ are chlorine atoms or bromine atoms, more preferably ² of R ¹ , R ² and R ^3. This is the case where one is a chlorine atom or a bromine atom, and one chlorine or bromine is in the 3rd position and the other one chlorine or bromine is in the 4th position.

  The benzylidene hydantoin compound (1), which is a raw material compound, can be easily produced by dehydration condensation of a benzaldehyde compound and hydantoin according to a conventional method. In the dehydration condensation reaction, for example, an organic base such as piperidine, piperazine, morpholine, or an inorganic base such as sodium hydroxide can be used.

  The reducing agent used in the present invention is inexpensive sodium borohydride, and the amount of sodium borohydride used may be about 0.3 mol to 1 mol with respect to 1 mol of the benzylidenehydantoin compound (1). It is not limited to this at all. Sodium borohydride may be added after being dissolved in a solvent, but may be added as it is in a powder state.

  The reduction reaction of the present invention is performed in the presence of a cobalt compound and a chelating agent. Examples of the cobalt compound include cobalt chloride, cobalt nitrate, and cobalt acetate, and cobalt nitrate is particularly preferable. Examples of the chelating agent include dimethylglyoxime, 2,2'-bipyridyl, phenanthroline and the like, and dimethylglyoxime is particularly preferable. Note that the combination of the cobalt compound and the chelating agent described herein can be appropriately changed depending on the substrate of the reaction, the reaction temperature, and the like. The cobalt compound is preferably used in an amount of 0.001 to 0.05 mol, more preferably 0.005 to 0.03 mol, per 1 mol of the benzylidenehydantoin compound (1). Moreover, it is preferable to use a chelating agent 0.01-0.5 mol with respect to 1 mol of benzylidene hydantoin compounds (1), Furthermore, 0.03-0.2 mol. In addition, the ratio with respect to the substrate of a cobalt compound and a chelating agent is not limited to what was described here.

  The process according to the invention is carried out under alkaline conditions. In order to achieve alkaline conditions, the reaction may be carried out in an alkaline solvent, for example, a solvent containing an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogen carbonate or an organic base such as triethylamine or dimethylaniline. . As the reaction solvent, an alcohol solvent such as ethanol and methanol, an ether solvent such as THF and dioxane, or water is used, and methanol is particularly preferable from the industrial viewpoint. A preferred pH is 9-11. The amount of the solvent used is preferably 3 to 10 times (V / W), more preferably 4 to 6 times (V / W), relative to 1 part by weight of the benzylidene hydantoin compound (1). The pH and the amount of the solvent relative to the substrate are not limited to the ranges described here.

  The reaction temperature varies depending on the solvent used, but is preferably 30 to 100 ° C, more preferably 50 to 70 ° C, and particularly preferably 55 to 65 ° C. The reaction time is preferably 1 hour to 12 hours, industrially 3 hours to 5 hours.

  After completion of the reaction, the catalyst and the like are removed by EDTA and activated carbon treatment, and the crystals of the benzylhydantoin compound (2) precipitated after neutralization may be collected. Moreover, you may refine | purify by recrystallization, washing | cleaning, chromatography, etc. as needed.

  According to the method of the present invention, a high yield and high purity benzylhydantoin compound (2) can be produced by a simple operation using an inexpensive raw material without using a special apparatus.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1
90 g (0.35 mol) of 5- (3,4-dichlorobenzylidene) hydantoin, 1.53 g (0.005 mol) of cobalt nitrate hexahydrate, and 4.05 g of dimethylglyoxime as a substrate in 2 L of 4-neck colben (0.035 mol) is added, and 450 mL of methanol and 101.52 g (0.101 mol) of 4% aqueous sodium hydroxide are added. The solution was warmed to 60 ° C. and 6.41 g (0.16 mol) of sodium borohydride was added over 3 hours taking care of foaming. After confirming the disappearance of the raw material by reverse phase HPLC (high performance liquid chromatography), 450 mL of water was added, and 29.6 g of 35% hydrochloric acid was added to adjust the pH to 3.5. The precipitated crystals were filtered and washed with 10 mL of a 10% aqueous methanol solution. After drying, 89.5 g of 5- (3,4-dichloro) benzylhydantoin was obtained. This was 96% pure as analyzed by reverse phase HPLC. (Yield 99%)

Reference example 1
In a 1 L autoclave, 2.0 g (0.0078 mol) of 5- (3,4-dichlorobenzylidene) hydantoin and 1.0 g of Raney nickel were placed as substrates, and a 20% aqueous sodium hydroxide solution 3.1 g (0.0155 mol). 40 mL of water was added and dissolved. Hydrogen gas was sealed at 7.1 kgf / cm ² , the solution was heated to 50 ° C., and then hydrogenation was performed for 6 hours. The reaction solution was analyzed by reverse phase HPLC method every 1 hour, and the substrate, target product and by-products were quantified, and the analysis results as shown in Table 1 were obtained. After 3 hours from the start of the reaction, the substrate material disappears and the desired 5- (3,4-dichlorobenzyl) hydantoin is produced, but at the same time, several by-products presumed to have eliminated chlorine atoms were observed. These were observed to increase over time. One of the by-products was identified as 5-benzylhydantoin from which two chlorine atoms had been eliminated by reverse phase HPLC, which was 9.4% 3 hours after the start of the reaction and 26. Increased to 3%. In addition, other by-products are presumed that the chlorine atom at the 3- or 4-position has been eliminated.

Example 2
In 100 mL of 3-neck Kolben, 5.00 g (18.7 mmol) of 5- (4-bromobenzylidene) hydantoin, 0.16 g (0.55 mmol) of cobalt nitrate hexahydrate, 0.43 g of dimethylglyoxime (3 7 mmol), and 25 mL of methanol and 5.6 mL (5.6 mmol) of 4% aqueous sodium hydroxide solution are added. The solution was warmed to 60 ° C. and 0.65 g (17.2 mmol) of sodium borohydride was added over 1 hour taking care of foaming. After 12 hours, the mixture was concentrated, 20 mL of methanol was added, the solvent was replaced, and the precipitated crystals were filtered and dried to obtain 4.64 g of 5- (4-bromo) benzylhydantoin. This was 95% pure as analyzed by reverse phase HPLC. (Yield 92%)
Incidentally, in the reverse phase HPLC method of the reaction solution, a by-product of 5-benzylhydantoin from which bromine atoms were eliminated was observed, but the by-product rate of this product remained at about 1%.

Reference example 2
In a 1 L autoclave, 2.0 g (0.0075 mol) of 5- (4-bromobenzylidene) hydantoin and 1.0 g of Raney nickel were added, 2.99 g (0.0150 mol) of 20% aqueous sodium hydroxide solution and 40 mL of water were added. In addition, it was dissolved. Hydrogen gas was sealed at 7.1 kgf / cm ² , the solution was heated to 50 ° C., and then hydrogenation was performed for 6 hours. The reaction solution was analyzed every 1 hour (excluding the 5th hour) by the reverse phase HPLC method, and the substrate, the desired product and by-products were quantified, and the analysis results shown in Table 2 were obtained. The substrate disappears in 3 hours after the start of the reaction, and the desired 5- (4-bromobenzyl) hydantoin is produced, but at the same time, a by-product presumed that the bromine atom has been eliminated is observed. It was observed to increase over time. This by-product was identified as 5-benzylidenehydantoin from which a bromine atom was eliminated by reverse-phase HPLC. After starting the reaction, 5.0% of the raw material remains in 1 hour, the ratio of the desired 5- (4-bromobenzyl) hydantoin is 38.9%, and 5-benzylhydantoin from which bromine atoms are eliminated is 55.3. % By-product was observed.

As shown in the above Examples and Reference Examples, in the reaction in which it was difficult to obtain the target product due to side reactions in the conventional catalytic reduction method, the high purity target product was obtained in a high yield by the method of the present invention. It became possible to get in.
That is, in the reduction reaction of a benzylidenehydantoin compound having a halogen such as a chlorine atom or a bromine atom on the benzene ring, the catalytic reduction method proceeds with a hydrogenation reaction to the original carbon-carbon double bond, but with time. The phenomenon of halogen elimination occurs. In 5- (3,4-dichlorobenzylidene) hydantoin, about 10% of by-products from which chlorine atoms have already been eliminated are generated at the time when the raw material almost disappears, and further increases with time. On the other hand, with 5- (4-bromobenzylidene) hydantoin, this tendency is even more pronounced, and in only 1 hour after the start of catalytic reduction, the yield of the desired reductant is about 40% while the bromine atom has been eliminated. It was confirmed that about 55% of organisms were generated.
On the other hand, according to the method of the present invention, it was found that with 5- (3,4-dichlorobenzylidene) hydantoin, only the desired reductant can be obtained almost quantitatively. Further, although 5- (4-bromobenzylidene) hydantoin produces a by-product from which a bromine atom is eliminated, its production rate is suppressed to a very low level, and the target product can be obtained with high purity by a purification step or the like.

Claims (6)

Formula (1)

(Wherein R ¹ , R ² and R ³ each independently represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, an alkyl group, an alkoxy group, an aralkyl group, an aryl group or a heterocyclic group, or R Two adjacent ones of ^{1 to} R ³ may be combined to form a ring.)
A benzylidene hydantoin compound represented by the formula (2) is reacted with sodium borohydride under alkaline conditions in the presence of a cobalt compound and a chelating agent:

(Wherein R ¹ , R ² and R ³ are the same as above)
The manufacturing method of the benzylhydantoin compound represented by these.   The process according to claim 1, wherein the cobalt compound is cobalt chloride or cobalt nitrate and the chelating agent is dimethylglyoxime, 2,2'-bipyridyl or phenanthroline.   The production method according to claim 1 or 2, wherein the alkaline condition is an alkaline solvent. The production method according to claim 1, wherein at least one of R ¹ , R ² and R ³ is a halogen atom. The production method according to claim ¹ , wherein ^{two of} R ¹ , R ² and R ³ are chlorine atoms or bromine atoms. 2. Of R ¹ , R ² and R ³ , two are chlorine or bromine atoms, one chlorine or bromine is at the 3-position, and the other one chlorine or bromine is at the 4-position. 4. The production method according to any one of 3 above.