JP2002308841A - Method for producing optically active 3-amino-3-(2- hydroxyaryl)propionic acid and its ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply and efficiently producing optically active 3-amino-(2-hydroxyaryl)propionic acids and their esters which are useful as pharmaceutical intermediates, particularly as the inhibitors of integrin reptors. SOLUTION: The optically active 3-amino-(2-hydroxyaryl)propionic acids and their esters are produced from a 3-(2-hydroxyaryl)-3-oxopropionic acid or its ester and an optically active 2-amino-2-substituted arylphenylethane compound by four steps of (a) imination or enamination, (b) stereoselective reduction, (c) elimination of the substituent on nitrogen, and (d) hydrolysis or transesterification.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active 3-amino- (2-hydroxyaryl) propionic acid and its ester, which are useful as pharmaceutical intermediates, especially as integrin receptor inhibitor intermediates. .

[0002]

2. Description of the Related Art Heretofore, as a method for producing optically active 3-aminopropionic acid and its ester, (1) diamines are obtained by diastereoselectively reducing enamine synthesized from 3-oxopropionic acid ester and optically active phenethylamine. Method for removing a substituent on a nitrogen atom (Tetrah
edron Lett. 40, 7721, 1999, W
O0056716) is known, and 2-position is 3-position.
As far as the method for producing a 3-arylpropionic acid derivative having a hydroxyaryl group is concerned, (2) an imine synthesized from an aldehyde and an optically active phenylglycinol may have a Ref
A method of removing a substituent on a nitrogen atom by diastereoselective addition of an ormatsky agent (WO994499)
4) is known.

[0003]

However, the method (2) requires a large amount of zinc as a reformatsky agent and a large amount of a lead compound for elimination of a substituent on a nitrogen atom. From the viewpoint of load, implementation on an industrial scale is extremely difficult.

In the method (1), a heterogeneous palladium catalyst is used for the diastereoselective reduction reaction. However, the palladium catalyst is hardly inexpensive, has an ignitability, a nitro group or a nitro group. Since halogen atoms and the like are easily reduced, there are many problems such as limitations on applicable compounds. Furthermore, the present inventors have proposed that 3-
3-aminopropionic acid having a 2-hydroxyaryl group at the 2-position and its ester are unstable, and in this method, in the step of removing the substituent on the nitrogen atom, the amino is removed through an intramolecular cyclization reaction (lactonization). It has been found that the conversion reaction occurs very easily.

[0005]

SUMMARY OF THE INVENTION In view of the above-mentioned problems of the conventional method, the present inventors can operate safely on a large scale using raw materials and reagents that are industrially easy to handle. As a result of intensive studies on a method for producing high-purity optically active 3-amino-3- (2-hydroxyaryl) propionic acid and its ester in which by-products of impurities are suppressed as much as possible, the deamination side reaction was minimized. Incorporating a step of eliminating a substituent on the nitrogen while suppressing it, further efficiently esterifying or transesterifying to a desired ester form, and using only a simple and easy operation, high-purity optically active 3-amino-3- A method for producing and obtaining (2-hydroxyaryl) propionic acid and its ester has been developed. In particular, the present invention is effective for producing 3-aminopropionic acid and its ester having a halogen atom or a nitro group, preferably a halogen atom, on the 3-position 2-hydroxyaryl group.

That is, the present invention provides (a) the following formula (1):

[0007]

Embedded image (Wherein R ¹ represents a 2-hydroxyaryl group; R ² represents a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group).
3-oxopropionic acid or an ester thereof is converted to a compound represented by the following formula (2):

[0008]

Embedded image (Wherein, R ³ and R ⁴ represent a hydrogen atom, an alkyl group, or an alkyloxy group; * represents an asymmetric carbon center) by reacting with an optically active 2-amino-2-substituted phenylethane compound represented by the formula: Formula (3) below;

[0009]

Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as described above), and / or the following formula (4);

[0010]

Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as above), and (b) is then reduced with a metal hydride compound in the presence of a carboxylic acid to obtain the following compound: (5);

[0011]

Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as those described above).
(C) treating the compound (5) with a carboxylic acid to give a (2-hydroxyaryl) propionic acid derivative;

[0012]

Embedded image (Wherein R ¹ , R ² , and * are the same as described above), leading to an optically active 3-amino-3- (2-hydroxyaryl) propionic acid derivative, and further, if necessary, in the presence of thionyl chloride or an acid. ^By esterification or transesterification with an alcohol represented by ⁵ OH (wherein R ⁵ represents an alkyl group or an aralkyl group), a compound represented by the general formula (7):

[0013]

Embedded image (Wherein R ¹ , R ⁵ , and * are the same as described above), or lead to an optically active 3-amino-3- (2-hydroxyaryl) propionic acid ester represented by the formula (5): By hydrolyzing the compound to be obtained, the following formula (8):

[0014]

Embedded image (Wherein R ¹ , R ³ , R ⁴ , and * are the same as above), and then converted to an optically active 3- (1-arylamino) -3- (2-hydroxyaryl) propionic acid, followed by carboxylic acid. By processing, the following formula (9);

[0015]

Embedded image (Wherein R ¹ and * are the same as described above)
An alcohol represented by R ⁵ OH (wherein R ⁵ represents an alkyl group or an aralkyl group) in the presence of thionyl chloride or an acid if necessary. An optically active 3-amino-ester characterized by being converted into an optically active 3-amino-3- (2-hydroxyaryl) propionic acid ester represented by the formula (7) by esterification.
This is a method for producing 3- (2-hydroxyaryl) propionic acid or an ester thereof.

[0016]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS First, 3-
(2-hydroxyaryl) -3-oxopropionic acid or an ester and an optically active compound represented by the formula (2):
A process for producing an imine compound represented by the formula (3) or an enamine compound represented by the formula (4) by reacting an amino-2-substituted phenylethane compound will be described.

The compound (1) used in this step is, for example, a readily available salicylic acid ester derivative Clais
It can be produced by an en condensation reaction. Where R ¹
Represents a 2-hydroxyaryl group, and may have a substituent other than the 2-position hydroxyl group.

When the compound has a substituent other than the 2-position hydroxyl group,
Examples of the substituent include an alkyl group, an aralkyl group, an aryl group, a hydroxyl group, -OR ⁶ (R ⁶ is a hydrogen atom, an alkyl group, an aralkyl group, an aryl group), - C (O) R
⁷ (R ⁷ represents a hydrogen atom, an alkyl group, an aralkyl group, an aryl group), -COOR ⁸ (R ⁸ represents a hydrogen atom, an alkyl group, an aralkyl group, an aryl group), -NR ⁹
R ¹⁰ (R ^9, R ¹⁰ each independently represent a hydrogen atom, an alkyl group, an aralkyl group, an aryl group), - NHCO
R ¹¹ (R ¹¹ represents a hydrogen atom, an alkyl group, an aralkyl group, an aryl group), —NHCOOR ¹² (R ¹² represents an alkyl group, an aralkyl group, an aryl group), a halogen atom, a nitro group, a cyano group, etc. No.

The alkyl group is a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. And the like. The aralkyl group has 7 carbon atoms.
And 30 to 30 substituted or unsubstituted groups, for example, benzyl group, 4-methylbenzyl group, 4-methoxybenzyl group, 3-phenylpropyl group, 2-phenylpropyl group and the like. The aryl group is a substituted or unsubstituted one having 6 to 30 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group and a 4-methoxyphenyl group. Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

In any position of the 2-hydroxyaryl group, a group independently selected from the above-mentioned substituent groups is 1
May be substituted, preferably 3,5-dichloro, 3,5-dibromo, 3-bromo-5-chloro, 3-
It is a substitution pattern of chloro-5-bromo. According to the present invention, an optically active 3-amino-3-amino-3-substituted compound such as a nitro group or a halogen atom is not impaired.
(2-Hydroxyaryl) propionic acid or its ester can be derived.

R ² represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group. The alkyl group has 1 carbon atom
~ 20 substituted or unsubstituted ones, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and particularly preferred. Is ter
t-butyl group.

The aralkyl group may be a substituted or unsubstituted one having 7 to 30 carbon atoms, such as benzyl, 4-methylbenzyl, 4-methoxybenzyl,
Examples thereof include a 3-phenylpropyl group and a 2-phenylpropyl group. Examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group, and a 4-methoxyphenyl group.

[0023] In the optically active 2-amino-2-substituted phenylethane compound represented by formula (2), R ^3, R ₄ are each independently a hydrogen atom, an alkyl group, an alkyl group, preferably R ^3, One of R ⁴ is an alkyloxy group and the other is a hydrogen atom, or both are alkyloxy groups, more preferably one of R ³ and R ⁴ is an alkyloxy group and the other is a hydrogen atom .

The alkyl group is a substituted or unsubstituted alkyl group having 1 to 20 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. And the like. As the alkyloxy group, a substituted or unsubstituted one having 1 to 10 carbon atoms is shown, for example,
Examples include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, and an isobutoxy group, and a methoxy group is preferable.

Some of the optically active compounds represented by the above formula (2) are commercially available, and can be obtained, for example, by optical resolution of a racemate obtained by reductive amination of the corresponding arylmethyl ketone.

The amount of compound (2) to be used is generally at least 1 mol, preferably at least 1.0 mol to 2.5 mol, per mol of (1). The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include toluene, xylene, tetrahydrofuran, diethyl ether, methanol, ethanol, isopropyl alcohol, DMF, DMSO, and a mixed solvent thereof. , Preferably toluene.

[0027] The reaction temperature is usually from 25 ° C to 100 ° C, preferably from 60 ° C to 90 ° C. The reaction time varies depending on the reaction temperature and the amount of (2) used, but is usually 1 hour to 24 hours, preferably 4 hours to 15 hours.

The resulting compound (3) and / or compound (4) can be obtained by extraction with an organic solvent such as ethyl acetate or ether after the reaction, and can be obtained by a method such as column chromatography or crystallization. Can be purified accordingly. Further, without extraction, the reaction solution may be dehydrated or dehydrated and concentrated as needed, and the reaction solution may be used in the next step. In general, a method of dehydrating or dehydrating and condensing as necessary and using the reaction solution in the next step without extraction is preferably carried out.

Next, the step of producing compound (5) from compound (3) or compound (4) will be described. In this step, compound (5) is produced by stereoselectively reducing compound (3) and / or (4) with a metal hydride compound in the presence of a carboxylic acid.

Examples of the metal hydride compound include sodium borohydride, lithium borohydride, zinc tetraboron,
Sodium cyanoborohydride, L-Selectric
e, K-Selectride and the like, and preferably sodium borohydride.

The carboxylic acid coexisting is not particularly limited, but is preferably an aliphatic carboxylic acid, more preferably an aliphatic carboxylic acid having 2 to 20 carbon atoms, and particularly preferably a carboxylic acid having 2 to 5 carbon atoms. For example, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid and the like can be mentioned, and acetic acid and pivalic acid are particularly preferable.

The solvent used for the reaction is not particularly problematic as long as it does not inhibit the reaction. For example, toluene, xylene, tetrahydrofuran, diethyl ether, methanol, ethanol, isopropyl alcohol, DMF, D
Examples thereof include MSO and a mixed solvent thereof, and preferred are tetrahydrofuran and toluene.

The amount of the metal hydride compound to be used is generally from 0.5 to 10.3 based on the compound (3) or the compound (4).
The molar amount is 0 times, preferably 2.0 to 5.0 times. The amount of the carboxylic acid to be used is generally not less than 1.0 times mol, preferably not more than 3.0 times mol, of the metal hydride compound.
30.0 times mol. The reaction temperature is usually -78 ° C to 5
0 ° C., desirably −30 ° C. to 25 ° C., and the reaction time is 0.5
２４24 hours, preferably 1.0-5.0 hours.

The resulting compound (5) can be obtained by extraction with an organic solvent such as ethyl acetate and ether after the reaction, and can be purified by column chromatography, crystallization or the like, if necessary. .

The compound (5) is usually produced as a diastereomer mixture, and the diastereomer excess can be suitably increased by crystallization. Here, the diastereomer excess is: (abundance of diastereomer A−abundance of diastereomer B) / (abundance of diastereomer A + abundance of diastereomer B) * 100%. Defined. 3-amino-3- (2-
In order to obtain (hydroxyaryl) propionic acid or an ester thereof, the diastereomer excess of the compound (5) is preferably as high as possible.
0% or more is preferable, and 98% or more is more preferable.

The solvent used for crystallization is not particularly limited. For example, pentane, hexane, heptane, octane,
Water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Butanol, benzene, xylene, trimethylbenzene, tetrahydrofuran, tetrahydropyran, 1,3
-Dioxane, 1,4-dioxane, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, n formate
-Butyl, isobutyl formate, t-butyl formate, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, dimethyl ether, t-butyl methyl ether, acetonitrile, Propionitrile, butyronitrile, t
-Butyronitrile, formic acid, acetic acid, propionic acid, butyric acid,
Examples thereof include isobutyric acid, acetone, DMF, DMSO, NMP, and a mixed solvent thereof.

Compound (5) obtained as described above
Is a compound (6) obtained by removing a substituent on the nitrogen atom,
Either esterify or transesterify as necessary to give compound (7), or hydrolyze compound (5) to give compound (8), and if necessary, esterify to give compound (7) At the desired 3-amino-3- (2-
(Hydroxyaryl) propionic acids or their esters.

The step of hydrolyzing compound (5) to compound (8) will be described. This step can be performed using a general method used for the hydrolysis reaction of the ester (for example, acid hydrolysis or alkali hydrolysis). The generated compound (8) can be crystallized in the same manner as in the compound (5) to increase the diastereomer excess.

Next, the step of converting compound (5) to compound (6) or compound (8) to compound (9) will be described. In this step, the compound (5) or the compound (8) is treated with a carboxylic acid to remove a substituent on the nitrogen atom. The carboxylic acid used is not particularly limited, and trifluoroacetic acid or formic acid is generally preferred. When formic acid is used, hydrochloric acid or hydrogen chloride is more preferably added.

The amount of the carboxylic acid used is not particularly limited as long as the reaction mixture can be efficiently stirred.
Usually, the amount is 1.0 ml or more, preferably 1.0 to 5.0 ml, per 1.0 g of the compound (5) or the compound (8). When formic acid is used and hydrochloric acid or hydrogen chloride is added, the addition amount is 1 wt% or more, preferably 5 wt% to 15 wt%, as hydrogen chloride with respect to formic acid. The reaction temperature and time vary depending on the carboxylic acid used. For example, when trifluoroacetic acid is used, the temperature is 50 ° C to 100 ° C, preferably 60 ° C to 90 ° C, and 1 hour to 24 hours.
Preferably, it is 4 to 8 hours. When formic acid is used, the temperature is 80 ° C to 120 ° C, preferably 90 ° C to 110 ° C.
C. for 1 to 48 hours, preferably 3 to 24 hours.

The resulting compound (6) or compound (9) can be obtained by extraction with an organic solvent such as ethyl acetate. This can be further purified, if necessary, by column chromatography, crystallization, or the like.

Next, the step of producing compound (7) from compound (6) or compound (9) will be described. This step
The reaction is carried out by heating the compound (6) or the compound (9) and the alcohol represented by the formula R ⁵ OH together with thionyl chloride or an acid.

Here, R ⁵ represents an alkyl group or an aralkyl group. Examples of the alkyl group include substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group.
Examples include an ethyl group, an n-propyl group, and an isopropyl group, and an ethyl group is preferable. The aralkyl group is a substituted or unsubstituted one having 7 to 15 carbon atoms, and examples thereof include a benzyl group, a 4-methylbenzyl group, a 4-methoxybenzyl group, a 3-phenylpropyl group, and a 2-phenylpropyl group. Can be.

When thionyl chloride is used, it is generally used in an amount of at least 1 mole, preferably from 1.1 to 3.0 moles, per mole of Compound (6) or Compound (9).

The acid is not particularly limited as long as it can be generally used for esterification, and examples thereof include those defined as protonic acids. Specific examples include hydrogen chloride, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferred are methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Preferably, it is p-toluenesulfonic acid.

The amount of the acid to be used is generally 0.001 times or more, preferably 1 time or more, relative to compound (6) or compound (9). In general, it can be suitably carried out at 1 to 3 moles. When the generated 3-aminopropionate is obtained as a sulfonate, the compound (6)
Alternatively, the sulfonic acid may be used in an amount of 1 mole or more with respect to the compound (9), and preferably 1.01 to 3 moles.

The solvent is not particularly limited as long as it does not inhibit the reaction, and toluene, tetrahydrofuran, D
Examples of the solvent include MF and DMSO, but the alcohol selected for the esterification, that is, R ⁵ OH may be used as it is as the solvent. Generally, from the viewpoint of the reaction rate and the conversion, a method in which an alcohol is used also as a solvent is often carried out preferably. The amount of alcohol used is usually
It is 1.0 to 100.0 moles, preferably 1.2 to 50.0 moles, based on Compound (2). The reaction temperature is usually 30 ° C to 100 ° C, preferably 50 ° C to 80 ° C. The reaction time is generally 0.5 hour to 24 hours, preferably 1 hour to 5 hours.

The resulting (7) can be neutralized by adding alkaline water after the reaction to neutralize the acid used in the reaction and extracted from an organic solvent such as acetate (eg, ethyl acetate). By substituting the solvent with another organic solvent as necessary, crystallize as a hydrochloride when thionyl chloride is used, or as a sulfonate when using sulfonic acid, and this is filtered. Can be obtained.

In the case of sampling as sulfonic acid, the organic solvent used for the crystallization is not particularly limited as long as the produced sulfonic acid salt is not completely dissolved.
For example, aliphatic hydrocarbons (eg, hexane, pentane),
Examples thereof include aromatic hydrocarbons (for example, toluene and benzene), acetic esters (for example, ethyl acetate and methyl acetate), and a mixed solvent of two or more kinds. In order to obtain a sulfonate of high yield, it is preferable to crystallize using an acetate ester. In this case, in order to minimize the undesired by-product of the ester, the esterification or transesterification is carried out. An acetic acid ester of alcohol R ⁵ OH used in the reaction, that is, CH ₃ COOR ⁵
It is best to use the following acetate.

[0050]

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

Example 1 N-[(R) -1- (4-meth
Xyphenyl) ethyl] -3-amino-3- (3-bro
Mo-5-chloro-2-hydroxyphenyl) propion
Acid t-butyl ester 3-oxo-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid t-butyl ester 2.0 mmol (0.7 g), (R) -1- (4-methoxy) Phenyl) ethylamine 2.4 mmol (0.37
g), a mixture consisting of 10 ml of toluene at 80 ° C. for 15 minutes.
Allowed to react for hours. On the other hand, sodium borohydride 6.0
Under ice-cooling, 18.0 mmol (1.84 g) of pivalic acid was added dropwise to a mixture of 20 mmol (0.12 g) and THF (20 ml). After stirring was continued for 10 minutes, the above toluene solution was added dropwise under ice-cooling, and then stirred for 2 hours. 30 ml of a saturated aqueous solution of ammonium chloride and 30 ml of ethyl acetate were added, and the reaction product was extracted. Isolation was performed by silica gel column chromatography, and N-[(R) -1- (4-
Methoxyphenyl) ethyl] -3-amino-3- (3-
0.70 g (72%) of bromo-5-chloro-2-hydroxyphenyl) propionic acid t-butyl ester was obtained ((R, R) :( S, R) = 88: 12). ¹ H-NMR (400 MHz, CDCl ₃ ) (R, R) form δ 1.40 (s, 9H), 1.41
(D, J = 6.8 Hz, 3H), 2.35-2.40
(M, H), 2.67-2.74 (m, 1H), 3.3
0 (brs, 1H), 3.73-3.80 (m, 1
H), 3.82 (s, 3H), 4.15-4.21
(M, 1H), 6.70 (s, 1H), 6.78-6.
90 (m, 2H), 7.10-7.42 (m, 4H); (S, R) form δ 1.40 (s, 9H), 1.49
(D, J = 6.8 Hz, 3H), 2.52-2.57
(M, 1H), 2.68-2.77 (m, 1H), 3.
30 (brs, 1H), 3.82 (s, 3H), 4.1
6-4.21 (m, 1H), 6.70 (s, 1H),
6.78-6.90 (m, 2H), 7.10-7.41
(M, 4H).

Example 2 N-[(R) -1- (4-meth
Xyphenyl) ethyl] -3- (3-bromo-5-chloro
(R-2-hydroxyphenyl) propionic acid t-butyl
Ester 3-oxo-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid t-butyl ester 2.0 mmol (0.70 g), (R) -1- (4-methoxyphenyl) ethylamine 2 0.4 mmol (0.3
7 g) and 10 ml of toluene at 80 ° C. for 1 hour.
The reaction was performed for 5 hours. On the other hand, sodium borohydride6.
90.0 mmol (5.40 g) of acetic acid was added dropwise to a mixture of 0 mmol (0.12 g) and 20 ml of THF under ice-cooling. After stirring was continued for 10 minutes, the above-mentioned toluene solution was added dropwise under ice-cooling, and after completion of the addition, the mixture was stirred for 2 hours. 30 ml of a saturated aqueous solution of ammonium chloride and 30 ml of ethyl acetate were added, and the reaction product was extracted. Quantitative analysis is performed by HPLC, and N-[(R) -1- (4-methoxyphenyl) ethyl] -3-amino-3- (3-bromo-5-chloro-2
0.79 g (81%) of -hydroxyphenyl) propionic acid t-butyl ester were obtained ((R, R):
(S, R) = 86: 14).

Example 3 N-[(R) -1- (4-meth
Xyphenyl) ethyl] -3-amino-3- (3-bro
Mo-5-chloro-2-hydroxyphenyl) propion
N-[(R) -1- (4-methoxyphenyl) ethyl] acid
-3-Amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid t-butyl ester ((R, R) :( S, R) = 87: 13) 13.3 mm
ol (6.46 g) and 30 ml of trifluoroacetic acid were reacted at 0 ° C. for 2 hours. After the reaction, 100 ml each of water and ethyl acetate were added, and the aqueous layer was adjusted to pH = 6.5 to 7.5 with 10% NaOH, and the ethyl acetate layer was separated. Further, the organic layer was washed twice with water.
= 6.5-7.5). After drying the organic layer, the ethyl acetate was distilled off under reduced pressure to give N-[(R) -1- (4-methoxyphenyl) ethyl] -3-amino-3- (3-bromo-
5-chloro-2-hydroxyphenyl) propionic acid was obtained as crystals (yield 5.87 g, 99%, (R,
R): (S, R) = 87: 13). ¹ H-NMR (400 MHz, DMSO-d ₆ ) (R, R) form δ 1.44 (d, J = 6.8 Hz, 3
H), 2.46-2.52 (m, 1H), 2.81-
2.85 (m, 1H), 3.72 (s, 3H), 3.7
3-3.75 (m, 1H), 3.81-3.83 (m,
1H), 6.77-6.95 (m, 3H), 7.14-
7.37 (m, 3H); (S, R) body δ 1.37 (d, J = 6.8 Hz, 3
H), 2.53-2.59 (m, 1H), 2.71-
2.77 (m, 1H), 3.51-3.55 (m, 1H)
H), 3.79 (s, 3H), 4.24-4.27
(M, 1H), 6.77-6.95 (m, 3H), 7.
14-7.37 (m, 3H).

Example 4 N-[(R) -1- (4-meth
Xyphenyl) ethyl] -3-amino-3- (3-bro
Mo-5-chloro-2-hydroxyphenyl) propion
8.60 g of concentrated hydrochloric acid was added dropwise to 30.0 g of formic acid under ice-cooling, followed by N-[(R) -1- (4-methoxyphenyl) ethyl] -3-amino-3- (3- Bromo-5-chloro-2-hydroxyphenyl) propionic acid t-butyl ester ((R, R) :( S, R) = 83: 17)
10.3 mmol (5.01 g) were added. The temperature was raised to room temperature, and the mixture was further stirred for 2 hours. 50 ml each of water and ethyl acetate were added, and the reaction product was extracted. HPLC
Quantitative analysis was performed using N-[(R) -1- (4-methoxyphenyl) ethyl] -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid ((R , R): (S, R) = 83: 17) 3.97 g
(90%). This diastereomer mixture was dissolved in a mixed solvent consisting of 30 ml of hexane and 30 ml of ethyl acetate at 60 ° C., allowed to cool to room temperature, and further cooled to 5 ° C.
And cooled. The precipitated white crystals were collected by filtration (2.42).
g, (R, R): (S, R) = 99.6: 0.4).

Example 5 (R) -3-amino-3- (3
-Bromo-5-chloro-2-hydroxyphenyl) pro
Acid N - [(R) -1- ( 4- methoxyphenyl) ethyl]
0.24 mmol of -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid
(0.11 g) and a mixture of 2.0 g of trifluoroacetic acid were reacted at 100 ° C. for 4 hours. The reaction mixture is HP
Analysis by LC revealed that (R) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid was produced at 68% and 6-bromo-4-chlorocoumarin at 26%. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 2.9
2-2.98 (m, 1H), 3.03-3.08 (m,
1H), 4.80-4.85 (t, 1H, J = 6.8H)
z), 7.57-7.60 (m, 2H).

Example 6 (S) -3-amino-3- (3
-Bromo-5-chloro-2-hydroxyphenyl) pro
Acid N - [(S) -1- ( 4- methoxyphenyl) ethyl]
-(S) -3-amino-3- (3-bromo-5-chloro-2-hydroxy) propionic acid 0.23 mmol
(0.1 g) and a mixture of 2.0 g of trifluoroacetic acid were reacted at 60 ° C. for 40 hours. The reaction mixture is HPL
Analyzed at C, 74% of (S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid was obtained, and 6-bromo-4-chlorocoumarin was 1%.
0% was formed.

Example 7 (S) -3-amino-3- (3
-Bromo-5-chloro-2-hydroxyphenyl) pro
Acid N - [(S) -1- ( 4- methoxyphenyl) ethyl]
-(S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid 0.24m
mol (0.11 g), formic acid 2.58 g, concentrated hydrochloric acid 0.7
A mixture consisting of 7 g was reacted at 100 ° C. for 24 hours.
The reaction mixture was analyzed by HPLC, and (S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid was produced in 67% and 6-bromo-4-chlorocoumarin in 28%. did.

Example 8 (S) -3-amino-3- (3
-Bromo-5-chloro-2-hydroxyphenyl) pro
Acid N - [(S) -1- ( 4- methoxyphenyl) ethyl]
1.06 mmol (0.52 g) of-(S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid t-butyl ester;
A mixture of 5 ml and 0.83 g of concentrated hydrochloric acid was added at room temperature for 24 hours.
Allowed to react for hours. When analyzed by HPLC, the t-butyl ester form of the raw material completely disappeared and N-[(S) -1-
The formation of (4-methoxyphenyl) ethyl]-(S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid was confirmed. Next, the reaction solution was heated to 100 ° C. and reacted for 6 hours.
By PLC analysis, (S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid was obtained in a yield of 63%, and 6-bromo-4-chlorocoumarin was obtained in 14%. % Produced.

Example 9 (S) -3-amino-3- (3
-Bromo-5-chloro-2-hydroxyphenyl) pro
Pionic acid isopropyl ester N-[(S) -1- (4-methoxyphenyl) ethyl]
-(S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid isopropyl ester 1.07 mmol (0.51 g), formic acid5.
A mixture consisting of 0 g was reacted at 100 ° C. for 5 hours. The reaction mixture was analyzed by HPLC, and (S) -3-amino-
Isopropyl 3- (3-bromo-5-chloro-2-hydroxyphenyl) propionate 44%, 6-
Bromo-4-chlorocoumarin 14% was produced. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.10
(D, J = 6.8 Hz, 6H), 2.92-2.97
(M, 1H), 3.01-3.04 (m, 1H);
12-4.14 (m, 1H), 4.80-4.82
(M, 1H), 7.57-7.61 (m, 2H).

Example 10 (S) -3-Amino-3-
(3-bromo-5-chloro-2-hydroxyphenyl)
N-[(S) -1- (4-methoxyphenyl) ethyl propionate ]
-(S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid 21 mmol
1 (9.0 g), formic acid 120.0 g, concentrated hydrochloric acid 34.5 g
Was heated to reflux for 7 hours. After the reaction, the reaction solution was distilled off under reduced pressure, 60 ml of water was further added to the residue, and the mixture was again distilled under reduced pressure. 100 ml of toluene and 50 ml of water were added to the residue, and after separating the aqueous phase, 60 ml of ethanol was added.
H was adjusted to 6.2. After that, hold at 5 ° C for 1 hour,
The precipitated crystals were collected by filtration. The crystals collected by filtration were washed with 10 ml of a water-ethanol (1: 1) solution, dried under reduced pressure, and (S)
3.67 g of 3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid (57
%)Obtained.

Example 11 (S) -3-Amino-3-
(3-bromo-5-chloro-2-hydroxyphenyl)
Ethyl propionate / p-toluenesulfonate (S) -3-amino-3- (3-bromo-5-chloro-
2-Hydroxyphenyl) propionic acid 10 mmol
(3.0 g), p-toluenesulfonic acid (monohydrate) 1
A mixture consisting of 5 mmol (2.9 g) and 60 ml of ethanol was heated under reflux at 85 ° C. for 2 hours. Ethanol 30
Then, add 30 ml of ethanol and add another 2 ml.
Time processed. After ethanol was distilled off under reduced pressure, about 40 ml of ethyl acetate was added and the mixture was kept at 80 ° C. for 30 minutes. The mixture was naturally cooled to room temperature, and the precipitated crystals were collected by filtration.
Washed with ml and dried. (S) -3-amino-3-
(3-bromo-5-chloro-2-hydroxyphenyl)
4.7 g of white crystals of ethyl propionate / p-toluenesulfonate were obtained (96%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.0
8 (t, J = 6.8 Hz, 3H), 2.28 (s, 3
H), 2.94-2.96 (m, 2H), 4.08
(Q, J = 6.8 Hz, 2H), 4.89-4.91
(M, 1H), 7.08-7.12 (m, 1H), 7.
85-7.89 (m, 1H), 7.70-7.73
(M, 1H), 8.30 (brs, 2H).

Example 12 (S) -3-Amino-3-
(3-bromo-5-chloro-2-hydroxyphenyl)
Ethyl propionate / hydrochloride Thionyl chloride 36mm in ice-cooled ethanol 30ml
ol (4.28 g) was added dropwise, and the mixture was further stirred for 1 hour.
Next, 11.9 (S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionic acid.
mmol (3.5 g) was added and reacted at 60 ° C. for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, and ethyl acetate (50 ml) was added to the residue to give ethyl (S) -3-amino-3- (3-bromo-5-chloro-2-hydroxyphenyl) propionate hydrochloride in white. The crystals were collected by filtration (4.1
8g, 98%). ¹ H-NMR (400 MHz, CD ₃ OD) δ 1.22
(T, J = 6.8 Hz, 3H), 3.02-3.08
(M, 1H), 3.13-3.19 (m, 1H), 4.
18 (q, J = 6.8 Hz, 2H), 4.85-4.8
9 (m, 1H), 7.38-7.39 (m, 1H),
7.61-7.63 (m, 1H).

[0063]

According to the present invention, 3-oxo-3- (2
Optically active 3-amino-3- (2-hydroxyphenyl) propionic acid ester can be efficiently produced from (-hydroxyphenyl) propionic acid ester.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Kazumi Oguro 1-11-1, Gakuen Nishimachi, Nishi-ku, Kobe City, Hyogo Prefecture Aoso 1217 (72) Inventor Kenji Inoue 82-2-501 Awazu, Kakogawa City, Hyogo Prefecture (72) Inventor Yasuyoshi Ueda 140-15 Kazuhisa, Aboshi-ku, Himeji-shi, Hyogo F-term (reference) 4H006 AA02 AC11 AC46 AC48 AC52 AC59 AC61 AC81 BA50 BA52 BA66 BD70 BE01 BE22 BE23 BE60 BJ50 BM30 BN30 4H039 CA12 CA71 CF10 CF40

Claims (43)

[Claims] (A) The following formula (1): (Wherein R ¹ represents a 2-hydroxyaryl group; R ² represents a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group).
3-oxopropionic acid or an ester thereof is converted to a compound represented by the following formula (2): (Wherein, R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group, or an alkyloxy group. * Represents an asymmetric carbon center.) An optically active 2-amino-2-substituted phenylethane compound represented by the formula: By reacting with the following formula (3); (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as described above), and / or the following formula (4): (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as above), and (b) is then reduced with a metal hydride compound in the presence of a carboxylic acid to obtain the following compound: (5); (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as above.) 3- (1-arylethylamino-3-)
(C) treating the compound (5) with a carboxylic acid to give a (2-hydroxyaryl) propionic acid derivative; (Wherein R ¹ , R ² , and * are the same as defined above) to an optically active 3-amino-3- (2-hydroxyaryl) propionic acid derivative, and further, if necessary, in the presence of thionyl chloride or an acid. ^By esterification or transesterification with an alcohol represented by ⁵ OH (wherein R ⁵ represents an alkyl group or an aralkyl group), a compound represented by the general formula (7): (Wherein R ¹ , R ⁵ , and * are the same as described above), or lead to an optically active 3-amino-3- (2-hydroxyaryl) propionic acid ester represented by the formula (5): By hydrolyzing the compound to be obtained, the following formula (8): (Wherein R ¹ , R ³ , R ⁴ , and * are the same as above). 3- (1-arylethylamino) -3- (2
-Hydroxyaryl) propionic acid, followed by treatment with carboxylic acid to give the following formula (9): (Wherein R ¹ and * are the same as described above), leading to an optically active 3-amino-3- (2-hydroxyaryl) propionic acid, and further, if necessary, in the presence of thionyl chloride or an acid, R ⁵ OH ( Wherein R ⁵ represents an alkyl group or an aralkyl group) by esterification with an alcohol represented by the formula (7).
A process for producing optically active 3-amino-3- (2-hydroxyaryl) propionic acid or an ester thereof, which leads to amino-3- (2-hydroxyaryl) propionic acid ester. 2. R ¹ is independently selected from a halogen atom and a nitro group at any position of an aryl group.
The method according to claim 1, wherein the four groups are substituted 2-hydroxyaryl groups. 3. R ¹ is ¹ to 1 at any position of an aryl group.
The method according to claim 1, wherein the halogen atom is a 2-hydroxyaryl group substituted with four halogen atoms. 4. The method according to claim 1, wherein R ¹ is a 2-hydroxyphenyl group substituted with the same or different halogen atoms at the 3- and 5-positions. 5. The method according to claim 1, wherein R ² is a t-butyl group.
The production method according to any one of the above. 6. The method according to claim 1, wherein at least one of R ³ and R ⁴ is an alkyloxy group. 7. The production method according to claim 1, wherein R ³ is a methoxy group and R ⁴ is a hydrogen atom. 8. The production method according to claim 1, wherein R ³ is a hydrogen atom and R ⁴ is a methoxy group. 9. The method according to claim 1, wherein R ³ and R ⁴ are both methoxy groups. 10. The production method according to claim 1, wherein sodium borohydride is used as the metal hydride compound in the production step of the compound (5) from the compound (3) and / or (4). Law. 11. The method according to claim 1, wherein an aliphatic carboxylic acid is used as a carboxylic acid to coexist in the step of producing the compound (5) from the compound (3) and / or (4). The production method described in the section. 12. A process for producing a compound (5) from a compound (3) and / or (4), wherein an aliphatic carboxylic acid having 2 to 10 carbon atoms is used as a carboxylic acid to coexist. 12. The production method according to any one of Items 1 to 11. 13. A process for producing a compound (5) from a compound (3) and / or (4), wherein at least one of acetic acid and pivalic acid is used as an aliphatic carboxylic acid to coexist. The method according to claim 12. 14. The method according to claim 1, wherein the diastereomer excess of the compound (5) or the compound (8) is 90% or more. 15. The production method according to claim 1, wherein the diastereomer excess of the compound (5) or the compound (8) is 98% or more. 16. The process according to claim 14, wherein the diastereomer excess is increased by crystallizing the compound (5) or the compound (8) from a solvent. 17. The process for producing a compound (6) from a compound (5) or a compound (9) from a compound (8), wherein trifluoroacetic acid is used as a carboxylic acid. Or the production method according to item 1. 18. A process for producing a compound (6) from a compound (5) or a compound (9) from a compound (8),
The method according to any one of claims 1 to 16, wherein formic acid is used as the carboxylic acid. 19. The method according to claim 18, wherein the method is carried out by adding hydrochloric acid or hydrogen chloride. 20. The method according to claim 1, wherein R ⁵ is an alkyl group.
10. The production method according to any one of 9 above. 21. The method according to claim 20, wherein R ⁵ is an ethyl group. 22. The process according to claim 1, wherein a protic acid is used as the acid in the step of producing the compound (7) from the compound (6) or the compound (9). 23. The method according to claim 22, wherein sulfonic acid is used as the protic acid. 24. The method according to claim 23, wherein p-toluenesulfonic acid is used as the sulfonic acid. 25. The method according to claim 23, wherein the compound (7) is obtained as a sulfonic acid salt by using a sulfonic acid in an amount of at least one mole of the compound (6) or the compound (9). . 26. The method according to claim 25, wherein the compound (7) is obtained as a p-toluenesulfonic acid salt. 27. The conversion of compound (6) or compound (9) into compound (7), wherein esterification is carried out using thionyl chloride to obtain compound (7) as a hydrochloride. 22. The production method according to any one of 1 to 21. 28. The following formula (6): (Wherein R ¹ , R ² , and * are as defined above), or an optically active 3-amino-3- (2-hydroxyaryl) propionic acid derivative, or the following formula (9): (Wherein R ¹ and * are the same as described above), by converting the optically active 3-amino-3- (2-hydroxyaryl) propionic acid into a compound having a molar ratio of at least 1 times as large as that of compound (6) or compound (9). In the presence of an acid, esterification or transesterification with an alcohol represented by R ⁵ OH (wherein R ⁵ represents an alkyl group or an aralkyl group) results in the following formula (7): Wherein R ¹ , R ⁵ , and * are the same as defined above, and the compound (7) is an aliphatic hydrocarbon or an aromatic compound. A method for obtaining a sulfonate of compound (7), characterized by crystallizing using at least one solvent selected from hydrocarbons and acetates. 29. The method for obtaining a sulfonate according to claim 28, wherein an acetate is used as the solvent. 30. The method for obtaining a sulfonate according to claim 28, wherein an acetate ester which is an ester of alcohol and acetic acid used in the esterification or transesterification is used as the solvent. 31. The method for obtaining a p-toluenesulfonic acid salt according to any one of claims 28 to 30, wherein p-toluenesulfonic acid is used as the sulfonic acid. 32. The following formula (5): (Wherein R ¹ , R ² , R ³ , R ⁴ , and * are the same as above). 3- (1-arylethylamino) -3-
By treating a (2-hydroxyaryl) propionic acid derivative with a carboxylic acid, the following formula (6): (Wherein R ¹ , R ² , and * are the same as described above). 33. R ¹ is any position of an aryl group,
1 independently selected from a halogen atom and a nitro group
33. The production method according to claim 32, wherein ~ 4 groups are substituted 2-hydroxyaryl groups. 34. R ¹ is ¹ at any position of the aryl group.
33. The production method according to claim 32, wherein two to four halogen atoms are substituted 2-hydroxyaryl groups. 35. The method according to claim 32, wherein R ¹ is a 2-hydroxyphenyl group substituted with the same or different halogen atoms at the 3- and 5-positions. 36. The method according to claim 32, wherein R ² is a t-butyl group.
36. The production method according to any one of -35. 37. The method according to claim 32, wherein at least one of R ³ and R ⁴ is an alkyloxy group.
The production method described in the section. 38. The production method according to claim 32, wherein R ³ is a methoxy group and R ⁴ is a hydrogen atom. 39. The production method according to claim 32, wherein R ³ is a hydrogen atom and R ⁴ is a methoxy group. 40. The production method according to claim 32, wherein R ³ and R ⁴ are both methoxy groups. 41. The method according to claim 32, wherein the method is carried out using trifluoroacetic acid as the carboxylic acid. 42. The process according to any one of claims 31 to 40, wherein the process is carried out using formic acid as the carboxylic acid. 43. The method according to claim 42, wherein hydrochloric acid or hydrogen chloride is added.