JPH07149732A - Production of 5-arylhydantoin and its derivatives - Google Patents

Abstract

PURPOSE:To easily obtain compound of high purity which is useful as a synthetic intermediate for semisynthetic penicillin by allowing an inexpensive, readily available hydantoin substituted with a halogen in the 5-position to react with a phenol unsubstituted on the p-position. CONSTITUTION:A hydantoin of formula I (X is Cl, Br, I; R1 is H, an N- protecting group; R2 is H, alkyl, alkenyl, alkinyl, acyl, aryl, aralkyl) is allowed to react with a phenolic compound of formula II (R is H, a phenolic hydroxyl- protecting group; R3-R6 are H, a group substantially not inhibiting the para orientation of RO group) to give a 5-arylhydantoin of formula III. A compound of formula III is preferably 6-[(4-hydroxyphenyl)-alpha-amino-acetylamino]-2,2- dimethylpenam-3-carboxylic acid, particularly amoxicillin. The compound of formula III is useful as an important synthetic intermediate for (D)-arylglycine which is used in the production of semi-synthetic penicillin.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 5-arylhydantoin compounds and their derivatives. The 5-arylhydantoin compound is an important synthetic intermediate for (D) -arylglycines (for example, (D) -p-hydroxyphenylglycine) useful for the production of semisynthetic penicillin (Japanese Patent Laid-Open No. 50-100077). It is the body.

[0002]

BACKGROUND OF THE INVENTION 5-Arylhydantoins are known to be classically synthesized by the Bucherer-Berg method by reacting the corresponding aryl aldehyde with ammonium carbonate and sodium cyanide (J. Prakt. Ch.
em., p291 140 [1934]). Also, a method of reacting glyoxylic acid, urea, and an aryl compound under acidic conditions (JP-A-54-106740) and a method of reacting 5-hydroxyhydantoin and an aryl compound (JP-A-54-1).
38560), and a method of reacting a reduction product of parabanic acid with phenol (Japanese Patent Laid-Open No. 3-206080).

[0003]

The Bucherer-Berg process requires dangerous sodium cyanide, and the resulting crude hydantoin contains a large amount of by-products due to the side reaction of the oxidation of the phenol ring under alkaline conditions. It will also be colored. In addition, the method using raw materials such as glyoxylic acid, 5-hydroxyhydantoin, and parabanic acid is
Raw materials are expensive and not a satisfactory method.

[0004]

As a result of intensive studies to solve these problems, the present inventor found a completely novel method for synthesizing a 5-arylhydantoin compound using an inexpensive hydantoin compound as a raw material, and The invention was completed. Particularly, by reacting inexpensive 5-halohydantoin as a raw material with phenol, the yield of 5- (p-
Hydroxyphenyl) hydantoin is obtained.

That is, the present invention has the general formula (I):

[Chemical 4] (Wherein X represents Cl, Br, or I, R ₁ represents a hydrogen atom or a nitrogen atom-protecting group, and R ₂ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aralkyl group, or a substituted group. Optionally, an aminocarbonyl group, an alkoxycarbonyl group, an aryloxycarbonyl group,
An aralkyloxycarbonyl group, a sulfinyl group, a sulfonyl group or a nitrogen-containing substituent other than the above is shown. ) And a general formula (II):

[0006]

[Chemical 5] (Wherein R represents a hydrogen atom or a protective group for a phenolic hydroxyl group, and R _{3 to} R ₆ represent a hydrogen atom or a group that does not substantially impair the para orientation of the RO group). The general formula (II
I):

[Chemical 6] (Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R
₆ is the same as above. ). The manufacturing method of the 5-aryl hydantoin compound shown by these.

The present invention will be described in detail below. The hydantoin compound in the present invention means a hydantoin compound in which one atom of halogen is introduced at the 5-position which may be substituted with a protecting group at the nitrogen atom at the 1-position of the hydantoin and an organic group at the nitrogen atom of the 3-position. In particular, in order to hydrolyze the obtained 5-arylhydantoins to obtain arylglycine, the 1-position of the hydantoin ring is preferably an unsubstituted or easily removable nitrogen atom-protecting group, and the 3-position is preferably unsubstituted. . From the viewpoint of reactivity, 5-halohydantoin itself which is inexpensive and easily synthesized is particularly suitable.

The phenol compound means a phenol compound in which the para position is unsubstituted and the hydroxyl group may be protected. The compound represented by the general formula (II) is preferable. Phenol itself is particularly suitable for obtaining p-hydroxyphenylglycine, both in terms of reactivity and economy, and also in terms of reactivity and economy.

Although it depends on the hydantoin compound and the phenol compound used in the reaction, the reaction for producing the 5-arylhydantoin compound does not normally produce decomposition products as by-products and does not cause coloration. The by-product of the reaction is a 5- (o-substituted aryl) hydantoin compound in which the ortho position of the phenolic compound and the 5th position of the hydantoin compound have reacted. For example, the main product obtained by reacting 5-halohydantoin with phenol is 5- (p-hydroxyphenyl) hydantoin, and the by-product is 5- (o-hydroxyphenyl) hydantoin. Although it depends on the reaction conditions and the reaction substrate, the production ratio of the target p-form of the 5-arylhydantoin compound to the by-product o-form is in the range of 2: 1 to 8: 1. Although depending on the type of the 5-arylhydantoin compound, the p-form generally has better crystallinity than the o-form, and the p-form can be separated by recrystallization, difference in solubility, or the like. For example, in the case of 5- (hydroxyphenyl) hydantoin as the 5-arylhydantoin compound, if a solvent optimal for the reaction is used, only the desired p-form is precipitated as a solid after the reaction, and 5- (p-hydroxyphenyl) is easily formed. Hydantoin can be isolated.

Although the reaction mechanism of this reaction is not clear, it is considered to be a Friedel-Crafts type reaction of the hydantoin compound (I) and the phenol compound (II). In support of this, 1) a carbon-carbon bond forming reaction between a haloalkane and a phenol compound, 2) a para- or ortho position of R which is particularly activated by a substituent R of the phenol compound (II) (I It is observed that the characteristic feature of the Friedel-Crafts reaction is that 3) the rate of formation of (III) is a quadratic equation proportional to the product of (I) and (II).

Further, as a remarkable feature not seen in other reactions of this reaction, a Lewis acid which is essential in the Friedel-Crafts reaction of a haloalkane and an aromatic compound is unnecessary,
The reaction occurs without a catalyst. That is, in this reaction,
By reacting the hydantoin compound (I) and the phenol compound (II) even in traces in a solvent in which both dissolve, or by mixing both in a heated and molten state, a carbon-carbon bond forming reaction useful in organic synthesis is caused, That is, various 5-arylhydantoin compounds can be easily synthesized in one step. For example, by simply mixing and stirring 5-chlorohydantoin (V) and phenol (IV) at room temperature, a key intermediate (D) -p-hydroxyphenylglycine precursor 5- (of a penicillin antibiotic can be obtained in high yield. p-hydroxyphenyl)
Hydantoin (VI) is obtained.

[0012]

[Chemical 7] This reaction reacts even in the presence of a Lewis acid catalyst, but when the reaction is carried out on an industrial scale, the cost of the Lewis acid catalyst is high, and the use of the Lewis acid causes problems in the equipment such as corrosion prevention. There are problems such as a complicated separation step from the Lewis acid, and the advantage of carrying out the reaction without adding the Lewis acid is extremely high economically.

The protecting group for the nitrogen atom at the 1-position of the hydantoin compound in the present invention is a substituent capable of regenerating the nitrogen-hydrogen bond under appropriate deprotection conditions. The requirements of the protecting group here are in accordance with the concept of the protecting group generally accepted in synthetic organic chemistry and satisfy the following requirements. 1) No change during the reaction, 2) Does not hinder the intended reaction, 3) After the reaction, the protecting group can be deprotected without damaging the part other than the protecting group. For reference, Theodora W. Greene, Peter, the de facto standard for protecting groups.
GM Wuts' Protective Groups in Organic Syn
thesis Second Edition '', JOHN WILEY & SONS, INC.
I will give you.

The protecting group (R ₁ ) includes a methyl group, C3
To C10 alkenyl groups (such as allyl groups), C3 to C1
0 alkynyl group (propargyl group, etc.), C2-C1
0 acyl group (acetyl group, propionyl group, benzoyl group, etc.), C7-C10 aralkyl group (benzyl group, p-methoxybenzyl group, etc.), C1-C10 aminocarbonyl group (N-methylaminocarbonyl group, etc.) , C2-C8 alkoxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, etc.), C7-C
A 10 aryloxycarbonyl group (such as a phenyloxycarbonyl group) and a C8 to C17 aralkyloxycarbonyl group (such as a benzyloxycarbonyl group) are suitable. These protecting groups should not interfere with halogenation and subsequent reaction with the phenol compound, and may be deprotected during the isolation operation after the reaction.

The organic group (R ₂ ) on the nitrogen atom at the 3-position means
C1-C8 alkyl groups (methyl group, ethyl group, octyl group, etc.), C3-C10 alkenyl groups (allyl group, etc.), C3-C10 alkynyl groups (propargyl group, etc.), C2-C10 acyl groups (acetyl group). Group, propionyl group, benzoyl group, etc.), C6 to C10 aryl group (phenyl group, toluyl group, etc.), C7 to C16 aralkyl group (benzyl group, p-methoxybenzyl group, etc.), C1 to C10 aminocarbonyl group. (N-methylaminocarbonyl group etc.), C2-C8 alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group etc.), C7-C10 aryloxycarbonyl group (phenyloxycarbonyl group etc.), C8-C17
Aralkyloxycarbonyl group (benzyloxycarbonyl group, etc.), nitrogen-containing substituent (azo group, etc.), C1-
A C8 sulfinyl group, a C1-C8 sulfonyl group and the like are suitable. Examples of the hydantoin compound include 5-chlorohydantoin, 5-bromohydantoin, 1
-Benzyl-5-bromohydantoin is preferable, but the hydantoin compound applicable to the present invention is not limited to the above hydantoin compound.

The phenol compound represented by the general formula (II) used in this production method will be described. R is a hydrogen atom or a hydroxyl-protecting group, and the protecting group is a substituent capable of regenerating an oxygen-hydrogen bond if appropriate reaction conditions are selected,
The concept of the protecting group described in the description of the hydantoin compound is applied.

R is a C1 to C8 alkyl group (such as a methyl group, an ethyl group, an octyl group), a C3 to C10 alkenyl group (such as an allyl group), a C3 to C10 alkynyl group (such as a propargyl group), and C2. To C10 acyl groups (acetyl group, propionyl group, benzoyl group, etc.), C7 to C16 aralkyl groups (benzyl group, p-
Methoxybenzyl group, etc.), C1-C10 aminocarbonyl group (N-methylaminocarbonyl group, etc.), C3
To C8 alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group and the like), C7 to C10 aryloxycarbonyl group (phenyloxycarbonyl group and the like), C8 to C17 aralkyloxycarbonyl group (benzyloxycarbonyl group and the like), tri Alkylsilyl group (triethylsilyl group, t-butyldimethylsilyl group, etc.), dialkylarylsilyl group (dimethylphenylsilyl group, etc.), alkyldiarylsilyl group (methyldiphenylsilyl group, etc.), triarylsilyl group (triphenylsilyl group) Etc.) and phosphoric acid ester derivative groups (the groups represented by (VII), (VIII), and (IX) below are suitable.

[0018]

[Chemical 8] R _{3 to} R ₆ are hydrogen atoms and halogen atoms (F, Cl, B
r, I) or other substituents, and as long as they do not substantially impair the para orientation of the phenolic compound with respect to RO, those atoms and substituents may be used in any combination. As the substituent, for example, a hydroxyl group, C1 to C
4 alkyl groups (methyl group, ethyl group, etc.), C1 to C
4 alkoxy groups (methoxy, ethoxy, etc.), C
A 2-C4 alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, etc.), an amino group in which a hydrogen atom of an amino group may be substituted (dimethylamino group, etc.), and an amino in which a hydrogen atom of an amino group may be substituted. Examples thereof include a carbonyl group (such as a methylaminocarbonyl group), a nitro group, a nitroso group, a thiol group, and a C1-C4 sulfide group (such as a methylsulfide group). Examples of the phenol compound include phenol, catechol, resorcin, anisole, o-cresol, m-cresol and o.
-Methoxyphenol, m-methoxyphenol, o-
Chlorophenol, m-chlorophenol, o-anisidine, m-anisidine, 2,5-dimethylphenol,
2,5-di-t-butylphenol, or a compound having a protective group on the phenolic hydroxyl group thereof is preferably used, but the phenol compound applicable to the present invention is not limited to the above phenol compound.

The hydantoin compound used in this reaction does not necessarily have to be a high-purity product, and a reaction liquid containing it may be used. For example, 5-chlorohydantoin may be synthesized by reacting 5-hydroxyhydantoin with thionyl chloride (Bu
ll. de la Soc. Chim. de. Fr., p942 No.3 [1971]),
It may be synthesized from the reaction of hydantoin with a halogenating agent such as chlorine in an acetic acid solvent and used without isolation.

In this reaction, the hydantoin compound (I) and the phenol compound (II) react in the molten state and do not necessarily require a solvent, but when the temperature in the molten state is high and the hydantoin compound may decompose, A reaction solvent can be used. As the reaction solvent, an organic solvent is generally used, and a polar nucleophilic solvent having substantially no water is preferred. Particularly, dioxane and acetic acid are preferably used. When water is included in the solvent, hydrolysis of (II) occurs and the reaction yield is generally reduced. The solvent used in this reaction may be a single solvent or a mixed solvent, and is appropriately selected from the reagents used in the reaction, the reaction temperature, and the ease of isolation of the product.

As the reaction solvent, the following solvent systems containing substantially no water are preferably used, but the present invention is not limited to these solvents. Ether system: Dioxane, tetrahydrofuran, dimethoxyethane, diglyme, triglyme etc. Carboxylic acid system: Acetic acid, propionic acid, etc. Nitrile system: Acetonitrile, propionitrile, butyronitrile, adiponitrile, etc. Halogen system: Chloroform, dichloroethane, etc. Aprotic polar solvent: Dimethylformamide , Dimethyl sulfoxide, etc.

The reaction temperature is preferably raised to about -10 to 120 ° C, preferably 0 to 50 ° C. When the reaction temperature is low (less than −10 ° C.), the time required for the reaction to be completed becomes extremely long, and when the reaction temperature is high (more than 120 ° C.), the reaction substrate is decomposed and the yield of the 5-arylhydantoin compound is lowered. The reaction time is preferably 3 to 18 hours. The reaction time depends on the addition amount of the phenol compound and the reaction temperature. When the phenol compound is added in an amount of 1.5 to 3 times the amount of the hydantoin compound charged and the reaction temperature is set to 0 to 50 ° C., the reaction takes about 2 to 12 hours. Complete. Of course, the reaction temperature and the reaction time are appropriately selected depending on the combination of the compounds represented by the general formulas (I) and (II) as the reaction raw materials.

The 5-arylhydantoin obtained by this production method can be mainly derived to arylglycine which is useful as a pharmaceutical intermediate. A representative arylglycine is (D) -p-hydroxyphenylglycine (X), which is a key intermediate for semisynthetic penicillins such as amoxicillin.

[0024]

[Chemical 9] The synthesis from a 5-arylhydantoin compound to a penicillin compound is carried out by 1) deprotection of the phenolic hydroxyl group of 5-arylhydantoin and the protective group at the 1-position of hydantoin, 2) hydrolysis including optical resolution to arylglycine, 3 ) Synthesis of N- (1-alkoxycarbonylpropen-2-yl)-(D) -α-amino-phenylacetic acid alkali metal salt (conventional name Dane salt) from arylglycine, 5) 6-aminopenicillanic acid It is carried out by the condensation reaction of Dane salt. In the above steps, the order of 1) deprotection and 2) optical resolution depends on the method of optical resolution of arylglycine.

The above steps will be described in detail by taking the synthesis of amoxicillin as an example. First, (D) -p-hydroxyphenylglycine is obtained by the method of the present invention.
It is synthesized by asymmetric hydrolysis of an arylhydantoin compound by a microorganism or optical resolution.

In the case of asymmetric hydrolysis of microorganisms, 5- (p-hydroxyphenyl) hydantoin is used as the 5-arylhydantoin compound. In the 5-arylhydantoin compound in which the nitrogen atom at the 1-position of the phenolic hydroxyl group and / or hydantoin is protected, the protecting group is deprotected, and then 5- (p-hydroxyphenyl) hydantoin is introduced, followed by asymmetric hydrolysis. . For example, 5-
(P-Methoxyphenyl) hydantoin is acetic acid-48%
Deprotection of the methoxy group was carried out with an HBr aqueous solution,
It is induced by (p-hydroxyphenyl) hydantoin. Also, although it is not a protective group for phenolic hydroxyl group, it is 5
In order to selectively synthesize-(p-hydroxyphenyl) hydantoin, 5- (p-hydroxy-2,5-) in which detachable substituents were introduced at two ortho positions of phenol was introduced.
The deprotection step also includes the synthesis of 5- (p-hydroxyphenyl) hydantoin by removing the substituent (t-butyl group) on the benzene ring of t-butylphenyl) -hydantoin.

5- (p-Hydroxyphenyl) hydantoin is quantitatively induced to (D) -p-hydroxyphenyl-N-carbamoyl-glycine, accompanied by asymmetric conversion by an enzyme such as hydantoinase [J. .Fermen
t. Technol., 57, p328, (1979)]. Next, the N-carbamoyl group is decomposed with nitrous acid to obtain (D) -p-hydroxyphenylglycine.

In the case of optical resolution, aryl glycine, aryl glycine ester, aryl glycine amide, etc. are used as a substrate for optical resolution, and the optical resolution agent is appropriately selected depending on the properties of each. Synthesis of arylglycine from a 5-arylhydantoin compound is carried out by hydrolysis of the 5-arylhydantoin compound under basic conditions. For example, 5- (p-hydroxyphenyl) hydantoin is hydrolyzed with a concentrated alkaline aqueous solution to obtain p-hydroxyphenylglycine. A 5-arylhydantoin compound in which the nitrogen atom at the 1-position of the phenolic hydroxyl group and / or hydantoin is protected is similarly hydrolyzed in a concentrated alkaline aqueous solution, but it is intentionally used because of the ease of optical resolution of the resulting arylglycines. In some cases, the protecting group is not deprotected.

The phenolic hydroxyl group may be protected,
Aryl glycine ester (p-hydroxyphenyl glycine ethyl ester, etc.) contains an acid (JP-A-49-66651).
No.), and N-acyl-arylglycine (p-methoxyphenyl-N-acetamido-glycine, etc.) are optically resolved by using a base (JP-A-50-52041). Further, the phenolic hydroxyl group may be protected arylglycine (p-hydroxyphenylglycine, p-
(Methoxyphenylglycine, p-benzyloxyphenylglycine, etc.) can be optically resolved by directly adding a resolving agent such as p-toluenesulfonic acid (JP-A-50-111033).

After the optical resolution, the phenol hydroxyl group, the carboxyl group and the amine protecting group are carefully deprotected under conditions without racemization to obtain (D) -p-hydroxyphenylgulincin. For example, (D) -p-benzyloxyphenylglycine obtained by optical resolution is P
deprotecting the benzyl group by hydrogenolysis in the presence of a dC catalyst,
(D) -p-hydroxyphenylgrincin is obtained without racemization.

In the synthesis of antibiotics, first, (D)-
p-Hydroxyphenylglycine is a N- (1-alkoxycarbonylpropene-2 referred to as a dyne salt obtained by condensation of an alkali metal salt of the carboxyl group of (D) -p-hydroxyphenylglycine and acetoacetic acid esters. -Yl)-(D) -α-amino- (p-hydroxyphenyl) acetic acid alkali metal salt (XI) (JP-A-2-49757). As an alkali metal salt,
Sodium, potassium, etc. are used, and as acetoacetic acid esters, acetoacetic acid methyl ester, acetoacetic acid ethyl ester, etc. are used.

[0032]

[Chemical 10] The Dane salt is derivatized and activated to a mixed acid anhydride, and undergoes a condensation reaction with the 6-position amino group of a 6-amino-2,2-dimethylpenam-3-carboxylic acid compound (conventional name: 6-aminopenicillanic acid). Do it. After condensation, the acetoacetic acid ester is deprotected with a thin acid to give a penicillin antibiotic. [J. Chem. Soc. (C) p1920 (1971)]

For the synthesis of amoxicillin, for example, N- (1-methoxycarbonylpropene-
2-yl)-(D) -α-amino- (p-hydroxyphenyl) sodium acetate is used. Dane salts are converted to mixed acid anhydrides by reaction with ester activators such as ethyl chlorocarbonate. Next, a condensation reaction between the mixed acid anhydride and 6-aminopenicillanic acid is performed to form an amide. Finally, the methyl acetoacetate is removed with dilute hydrochloric acid to give amoxicillin (XII).

[Chemical 11]

[0034]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of 5-chlorohydantoin 2.3 g (0.02 mol) of 5-hydroxyhydantoin is heated under reflux in 40 ml of thionyl chloride for 2 hours with vigorous stirring. After cooling, the formed precipitate was washed with anhydrous hexane to obtain 1.9 g of a crude product of 5-chlorohydantoin. Yield 71% m / e = 136.134

Example 1 1.34 g (10 mmol) of 5-chlorohydantoin and phenol
1.88 g (20 mmol) was dissolved in 10 ml of dioxane and heated at 70 ° C. for 6 hours while stirring. After allowing to cool to room temperature, it was further cooled in an ice bath for 2 hours. The precipitated crystals were collected by filtration, thoroughly washed with water, and air-dried to obtain white crystals of p-hydroxyphenylhydantoin (0.93 g, yield 48%). The crystals showed a melting point of 262 to 264 ° C (decomposition). IR spectrum, NMR spectrum, Rf of thin layer chromatography
Values were consistent with those of the separately synthesized grades.

Example 2 1.78 g (10 mmol) of 5-bromohydantoin and phenol
1.88 g (20 mmol) was left at room temperature for 8 hours with mixing and stirring. 10 ml of water was added and the precipitated crystals were collected by filtration, washed thoroughly with water and air-dried to obtain 5- (p-hydroxyphenyl) hydantoin (1.69 g, yield 88%).

Example 3 Hydantoin (2.00 g, 20 mmol) was dissolved in acetic acid (30 ml) and stirred at 80 ° C. for 5 hours while introducing chlorine.
After cooling to room temperature, nitrogen was introduced to remove dissolved chlorine. Add 3.76 g (40 mmol) of phenol to the reaction solution while stirring.
Heated at 70 ° C. for 8 hours. After allowing to cool to room temperature, the reaction solution was concentrated under reduced pressure to remove acetic acid and phenol. 50m of water for residue
l was added and the residue was heated and dissolved and left to stand. The deposited precipitate was collected by filtration, washed with water and dried to give white scale-like crystals of 5- (p-hydroxyphenyl) hydantoin (0.55 g, yield 28.9%).
Got

Example 4 A mixed solution of 4.0 g (40 mmol) of hydantoin, 6.4 g (40 mmol) of bromine, 10 mg (0.1 mmol) of methanesulfonic acid and 30 ml of dioxane was heated and stirred at 100 ° C. for 3 minutes, and then bromine disappeared at 50 ° C. It was stirred until 7.52 g (80 mmol) of phenol was added, and the mixture was further heated and stirred at 50 ° C. for 4 hours. After allowing to cool to room temperature, it was further cooled in an ice bath for 2 hours. The precipitated crystals were collected by filtration, washed thoroughly with water, and air-dried to give white crystals
(P-Hydroxyphenyl) hydantoin (4.69 g, 61% yield) was obtained.

Example 5 A mixed solution of 4.0 g (40 mmol) of hydantoin, 6.4 g (40 mmol) of bromine, 10 mg (0.1 mmol) of methanesulfonic acid and 30 ml of dioxane was heated and stirred at 100 ° C. for 3 minutes, and then bromine disappeared at 50 ° C. It was stirred until 8.64 g of anisole after cooling to room temperature
(80 mmol) was added and the mixture was reacted at 100 ° C. for 6 hours. The formed precipitate was collected by filtration, washed with water and dried to obtain 5- (p-methoxyphenyl) hydantoin (3.96 g, yield 48%).

Example 6 3.8 g (20 mmol) 1-benzyl-hydantoin and 6.4 bromine
A mixed solution of g (40 mmol), methanesulfonic acid 10 mg (0.1 mmol) and dioxane 30 ml was mixed at room temperature and vigorously stirred at 40 ° C. for 4 hours. After cooling to room temperature, phenol 5.7g (60m
mol) was added and the mixture was reacted at 100 ° C. for 6 hours. The formed precipitate was collected by filtration, washed with water and dried to give 5- (p-hydroxyphenyl) -1-benzyl-hydantoin (2.88 g, yield 51
%) Was obtained.

The following examples relate to deprotection and optical resolution to arylglycines. Example 7 10.3 g (50 mmol) of 5- (p-methoxyphenyl) hydantoin obtained in the same manner as in Example 5 was added to acetic acid-48% HB.
The mixture was refluxed in an aqueous solution (1: 1) for 1 hour. The solvent was removed under reduced pressure and recrystallized from water to give 5- (p-hydroxyphenyl) hydantoin (6.0 g, yield 62%).

Example 8 9.5 g (50 mmol) of 5- (p-hydroxyphenyl) -1-benzyl-hydantoin obtained in the same manner as in Example 6
Then, 500 mg of 5% Pd-C and 50 ml of acetic acid were placed in an osmotic medium pressure hydrogen reduction apparatus, and hydrogen was introduced at 80 ° C. for 6 hours. Pd-C
Is filtered, the acetic acid is distilled off, and then recrystallized from water to give 5- (p-
Hydroxyphenyl) hydantoin (8.2g, 85% yield)
Got

The following examples relate to the optical resolution to 5-arylglycines. Synthesis of p-hydroxyphenylglycine from 5- (p-hydroxyphenyl) hydantoin and optical resolution to (D) -p-hydroxyphenylglycine.

Example 9 Synthesis example of p-hydroxyphenylglycine 5- (p-hydroxyphenyl) hydantoin 19.2 g
20% (w / w) aqueous sodium hydroxide solution (100 mmol) 200 ml
Heated at reflux for 24 hours. After cooling to room temperature, the reaction solution was adjusted to pH = 4 with concentrated hydrochloric acid. The product was separated by filtration and washed with 10 ml of water and 10 ml of acetone × 3. The white solid obtained was dried under reduced pressure to obtain crude crystals of p-hydroxyphenylglycine (8.68).
g yield 52%) was obtained. The infrared spectrum and NMR spectrum of the obtained crude crystal were in agreement with those obtained from the standard data of p-hydroxyphenylglycine.

Example 10 Optical Resolution of p-Hydroxyphenylglycine 3.0 g of p-hydroxyphenylglycine and 5.9 g of d-bromocamphorsulfonic acid monohydrate were dissolved in 30 ml of boiling water and stirred at room temperature for 2 hours. . The crystals are collected by filtration, washed with water and dried to give (D) -p-hydroxyphenylglycine.d-
4.0 g of crude crystals of bromocamphor sulfonate were obtained. The crude crystals were recrystallized from 3 ml of d-bromocamphorsulfonic acid, and 3.5 g of optically pure (D) -p-hydroxyphenylglycine.d-bromocamphorsulfonate was obtained by comparing the specific optical rotation with the evaluated product. Obtained. [Α] 25 D-
2.8 ° (c = 1 ； 1N-HCl)

3.0 g of pure (D) -p-hydroxyphenylglycine d-bromocamphorsulfonate was dissolved in 25 ml of boiling water and adjusted to pH = 6 with sodium hydroxide solution, and then the solution was concentrated to 7 g. did. After stirring at 5 ° C for 2 hours, the precipitated crystals were collected by filtration, washed with water and dried,
0.9 g of (D) -p-hydroxyphenylglycine was obtained. [Α] 20 D -158.1 ° (c = 1 ； 1N-HCl)

Example 11 Deprotection of benzyl group after optical resolution 5- (p-benzyloxyphenyl) hydantoin obtained in the same manner as in Example 6 was hydrolyzed with a concentrated sodium hydroxide solution, and then the existing solution was used. Optical resolution using the method,
(D) -p-benzyloxyphenylglycine was obtained.
(D) -p-benzyloxyphenylglycine 5.1 g (2
(0 mmol), 5% Pd-C (200 mg) and acetic acid (30 ml) were placed in an osmotic medium-pressure hydrogen reduction apparatus, and hydrogen was introduced at 80 ° C. for 3 hours. Pd
-C was filtered and acetic acid was distilled off to obtain (D) -p-hydroxyphenylglycine (3.1 g, yield 92%). [Α] 23
D -157.9 ° (c = 1 ； 1N-HCl)

The following examples relate to the synthesis of β-lactam antibiotics. An example of synthesizing a Dane salt is shown below.

Example 12 N- (1-alkoxycarbonylpropen-2-yl)
Synthesis example of potassium (-D) -α-amino- (p-hydroxyphenyl) acetate In a 200 ml flask, 5.82 g (98.5 g) of potassium hydroxide was added.
(95 mmol, purity 95%) and 95 ml of methanol are added, and potassium hydroxide is dissolved at room temperature. Next, after adding (D) -p-hydroxyphenylglycine 16.72 g (100 mmol),
Stir at room temperature for 1 hour. Methyl acetoacetate 12.19 g (1
(05 mmol) is added all at once and heated to reflux for 2 hours. After cooling the reaction solution to 10 ° C., the precipitated crystals are collected by filtration and washed with methanol (10 ml × 3). The obtained crude crystals are dried under reduced pressure to give N- (1-alkoxycarbonylpropene-2-
Il)-(D) -α-amino- (p-hydroxyphenyl) acetate potassium (26.0 g, yield 86%) was obtained.

The synthesis examples of penicillin antibiotics are shown below. Example 13 Synthesis Example of Amoxicillin In a 50 ml round-bottomed flask, 7 ml of acetone and 1.23 g of potassium N- (1-alkoxycarbonylpropen-2-yl)-(D) -α-amino- (p-hydroxyphenyl) acetate.
Add (4.05 mmol) and cool to -10 ° C. 0.50 g (4.50 mmol, purity 97%) of ethyl chloroformate and 10 mg of N-methylmorpholine were added, and the mixture was stirred for 15 minutes. Then, 0.82 g (3.8 mmol) of 6-aminopenicillanic acid prepared in advance was added to 5%.
It was added to a solution obtained by dissolving it in a mixed solution of 4 ml of potassium hydroxide solution and 3 ml of acetone. After stirring at room temperature for 2 hours, the reaction solution was adjusted to pH = 2 with a hydrochloric acid aqueous solution under ice-cooling. 15 ml of cooled methylene chloride was added, and the mixture was stirred for 5 minutes. After separating the aqueous phase, the organic phase was distilled off under reduced pressure with an evaporator attached to a water bath at 10 ° C. The residual liquid was adjusted to pH = 5 with an aqueous solution of sodium hydroxide and stirred at 5 ° C. for 3 hours. The separated crystals were collected by filtration and washed with chilled water (2 ml) and acetone (1 ml) to obtain amoxicillin trihydrate (1.0 g, yield 63%). [Α] 23 D + 293 ° (c = 0.2; H ₂ O)

[0052]

According to the present invention, a 5-arylhydantoin compound having a high purity can be easily obtained by reacting a phenol compound with a hydantoin compound having a halogen at the 5-position. That is, the present invention provides an excellent method for producing 5-arylhydantoins useful for the production of D-arylglycines, which are important synthetic intermediates for semisynthetic penicillin antibiotics. Penicillin antibiotics incorporating this production method into the production process can be industrially produced. By using a substituted phenol compound, it is possible to provide a novel derivative of the above penicillin antibiotic and a method for producing the same.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): (In the formula, X represents Cl, Br, or I, R ₁ represents a hydrogen atom or a nitrogen atom-protecting group, and R ₂ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group, an aralkyl group. , An optionally substituted aminocarbonyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a sulfinyl group, a sulfonyl group, or a nitrogen-containing substituent other than the above. Formula (II): (Wherein R represents a hydrogen atom or a protective group for a phenolic hydroxyl group, and R _{3 to} R ₆ represent a hydrogen atom or a group that does not substantially impair the para orientation of the RO group). The general formula (II
I): [Chemical Formula 3] (Wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R
₆ is the same as above. ) The manufacturing method of 5-aryl hydantoin shown by these. 2. The method according to claim 1, wherein the hydantoin compound is hydantoin and the phenol compound is phenol. 3. The production method according to claim 1, wherein the reaction is carried out in a solvent containing substantially no water. 4. The method according to claim 6, including the following steps.
Method for producing [(4-hydroxyphenyl) -α-amino-acetylamino] -2,2-dimethylpenam-3-carboxylic acid compound: (a) 5 according to the production method according to claim 1 to claim 3
When the 5-arylhydantoin compound obtained in the production step of an arylhydantoin compound, (b) the production step a has a protective group for a phenolic hydroxyl group and / or a nitrogen atom protective group at the 1-position of the hydantoin ring, Deprotection step of protecting group, (c) 5 obtained in production step a or b
By a process for producing an optically active arylglycine compound by a hydrolysis reaction including optical resolution of an arylhydantoin compound, and (d) a condensation reaction between an alkali metal salt of the arylglycine compound obtained in the production process c and an acetoacetic acid ester. Dane salt manufacturing process. 5. 6-[(p-hydroxyphenyl) -α
The production method according to claim 4, wherein the -amino-acetylamino] -2,2-dimethylpenam-3-carboxylic acid compound is amoxicillin.