WO2002008170A1 - PROCESS FOR PRODUCING α-AMINO-α', α', α'-TRIHALOKET0NE DERIVATIVES, α-AMINO-α', α', α'-TRIHALOALCOHOL DERIVATIVES AND α-HYDROXY-β-AMINOCARBOXYLIC ACID DERIVATIVES - Google Patents

Abstract

A process for producing optically active α-hydroxy-β-aminocarboxylic acid derivatives. α-Aminoketone derivatives (4) are successively halogenated, reduced and hydrolyzed to thereby efficiently produce α-amino-α', α', α'-trihaloketone derivatives (3), α-amino-α', α', α'-trihaloalcohol derivatives (1) and α-hydoxy-β-aminocarboxylic acid derivatives (2).

Description

 CK-Amino ', α', 'Trihaloketone Derivatives, α-Amino,', a 'Trihaloalcohol Derivatives and α-Hydroxy-1- / 3-aminocarbonic Acid Derivatives

Technical field

 The present invention relates to a method for producing an optically active α-hydroxyl; 8_aminocarboxylic acid derivative useful as an intermediate of a pharmaceutical 'pesticide'. Background art

 Conventionally, a method for producing an optically active α-hydroxy-1-aminocarboxylic acid derivative includes, for example, a method in which a Ν-protected aldehyde derivative is silylated by reaction with silyl cyanide and then hydrolyzed (Japanese Unexamined Patent Publication No. 2-28). No. 144), a method in which a Ν-protected aldehyde derivative is cyanated and hydrolyzed in the presence of a phase transfer catalyst and acetic anhydride (Japanese Patent Application Laid-Open No. 2-017171), and a Ν-protected aldehyde derivative as well. Isomerization and crystallization in the presence of an amine (Japanese Patent Application Laid-Open No. Heisei 9-1878734), a method of converting a Ν-protected acid chloride into a cyanoketone by reacting with silyl cyanide and further converting the ketone ester into a ketone ester After conversion, reduction with zinc borohydride (Ε Ρ— 5 5 3 3 4

No. 3) is known. However, all of the above methods are highly toxic and require the use of a complexing cyanating agent.

 A method is also known in which 反 応 -protected α-aminoketone is reacted with dalioxylic acid, followed by resolution, crystallization, and catalytic reduction (JP-A-55-79353). Requires complicated steps to obtain a desired isomer from a mixture of four isomers.

 As described above, the conventional method has a major problem in inexpensively producing an optically active α-hydroxy_-aminocarboxylic acid derivative on an industrial scale. Summary of the Invention +

SUMMARY OF THE INVENTION In view of the above, an object of the present invention is to provide an optically active _α -hydroxy with high efficiency and simple operation. An object of the present invention is to provide a method for producing a C / 3 / 3-rubonic acid derivative.

 The present inventors have conducted intensive studies in view of the above-mentioned current situation, and as a result, have completed a production method represented by the following reaction formula.

 (1) (2) That is, the present invention provides the following general formula (1)

.

.

 (1)

(Wherein, R ¹ is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted aralkyl group having 6 to 30 carbon atoms. X represents an unsubstituted aryl group, X ¹ , ² and ^{3 each} independently represent a halogen atom, and one represents a hydrogen atom and the other represents a protecting group for an amino group, Together or each represents a protecting group for an amino group, or each represents a hydrogen atom.) By hydrolyzing an α-amino-, a ', a'-trihaloalcohol derivative represented by The following general formula (2)

 (2)

(Wherein, R ¹ is the same as above. P ³ and P ⁴ are the same as P ¹ and P ² , one of which is the alkyl-type protecting group P ¹ or P ² , and the other is hydrogen A method for producing an α-hydroxy / 3-aminocarboxylic acid derivative, comprising obtaining an α-hydroxy-3-aminocarboxylic acid derivative represented by the following formula:

 In the present invention, the α-amino-o a-trihalo alcohol derivative (1) is represented by the following general formula (3)

 (3)

(In the formula, I ¹ , X ¹ , X ² , X ³ , P ¹ and P ² are the same as described above.) Obtained by reducing a triamino ketone derivative represented by the formula: Can be.

 In the present invention, the α-amino-a ′, a ′ a trihaloketone derivative (3) is represented by the following general formula (4)

 (Four)

(Wherein, I ¹ , syrup ¹ and ² are the same as described above. X ⁴ represents the X ¹ or a hydrogen atom.

X ⁵ represents the X ² or a hydrogen atom. However, X ⁴ and X ⁵ simultaneously represent a hydrogen atom Excluding the case. )) Can be obtained by halogenating the α-aminoketone derivative represented by

Further, in the present invention, the α-aminoketone derivative (4) is represented by the following general formula (5)

(Wherein, I ¹ , Ρ ¹ and Ρ ² are the same as above. R ² represents an ester residue.) And a monohaloacetic acid derivative or a salt thereof, or dihalomethane And can be obtained by the reaction with

The present invention also relates to a method for producing an α-amino-'′, α ′, α′-trihaloketone derivative (3) comprising halogenating an _α -aminoketone derivative (4). The present invention also provides a method for producing an amino-, a ', a'-trihaloalcohol derivative (1), comprising reducing the obtained α-amino_', a ', a'-trihaloketone derivative (3). Further, the present invention provides the above amino-ketone derivative (4) obtained by reacting the amino acid ester derivative (5) with a monohaloacetic acid derivative or a salt thereof, or dihalomethane. The method for producing the α ′, α′-trihaloketone derivative (3) and the method for producing the ο; —amino-, a ′, a′-trihaloalcohol derivative (1) described above are also used.

 Furthermore, the present invention provides the following general formula (6)

(Wherein X ⁶ , ⁷ and ⁸ independently represent a bromine atom or a chlorine atom. P ¹ and P ² each represent a hydrogen atom and the other represents a protecting group for an amino group, Or together Or represents an amino protecting group. _Α -amino ',', a 'monotrihaloketone derivatives represented by the following general formula (7)

(In the formula, X ⁶ , X ⁷ and X ⁸ independently represent a bromine atom or a chlorine atom. P ¹ and P ² each represent a hydrogen atom and the other represents a protecting group for an amino group. , Or together or each represents a protecting group for an amino group.) A monoamino, 1 ',', a 'trihaloalcohol derivative.

 The details of this effort are described below. Detailed Disclosure of the Invention

 First, the compound used in the present invention will be described.

In the compounds (1) and (3), X ¹ , ² and ³ independently represent a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and a iodine atom, and X ² and X ³ are preferably independently a chlorine atom or a bromine atom. In particular, X ¹ is a chlorine atom, X ² and X ³ are independently a chlorine atom or a bromine atom, or X ¹ and X ² are each a bromine atom, and X ³ is a chlorine atom or a bromine It is preferably an atom. Among them, X ¹ , X ² and X ³ are preferably all the same atom, and X ¹ , X ² and X ³ are all chlorine atoms, or X ¹ , X ² and X ³ Are more preferably all bromine atoms. In view of the ease of synthesis of the above compounds (1), (2) and (3), X ¹ is a chlorine atom and ² and ³ are independently a chlorine atom or a bromine atom. It is particularly preferred that all of X ¹ , X ² and X ³ are chlorine atoms. In the compound (4), X ⁴ represents the aforementioned X ¹ or a hydrogen atom, and X ⁵ represents the aforementioned X ² or a hydrogen atom. However, this excludes the case where X ⁴ and X ⁵ simultaneously represent a hydrogen atom. Due to the ease of synthesis of the above compound (4), X ⁴ is a chlorine atom Or X ⁵ is a hydrogen atom (especially when X ⁴ is a chlorine atom and X ⁵ is a hydrogen atom), or X ⁴ and X ⁵ are each a bromine atom Is preferred.

Further, in the compounds (6) and (7), X ⁶ , ⁷ and ⁸ independently represent a bromine atom or a chlorine atom. One of X ⁶ , X ⁷ and X ⁸ is a chlorine atom and the remaining two are each a chlorine atom or a bromine atom, or two of them are each a bromine atom and the other one is a chlorine atom or a bromine atom X ⁶ , X ⁷ and X ⁸ are particularly preferably chlorine atoms or all bromine atoms.

In the compounds (1), (3), (4), (5), (6) and (7), P ¹ and P ² represent a protecting group for an amino group or a hydrogen atom. For protecting groups Amino groups, or other one represents a hydrogen atom P ¹及Pi P ² represents a protecting group of the Amino group, or represents a protecting group together such connexion amino group, or, respectively Amino groups Represents a protecting group. Here, “ ¹ and P ² together represent a protecting group for an amino group” means that the amino group is protected by a bifunctional protecting group such as a phthalyl group.

 The above-mentioned protecting group for the amino group is generally a group having an effect of protecting the amino group, and examples of usable groups include, for example, PROTECT I VE GROUPS IN ORGAN IC SYNTHES IS) [2nd edition, John Wiley & Sons (1991)]. The amino-protecting group is not particularly limited, and examples thereof include a urethane-type protecting group, an acyl-type protecting group, and an alkyl-type protecting group. The urethane-type protecting group is not particularly limited, and includes, for example, a benzyloxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbo group, and the like. The above-mentioned acetyl-type protecting group is not particularly limited, and examples thereof include an acetyl group, a trifluoroacetyl group, a phthaloyl group, a benzoyl group, and a tosyl group. The alkyl-type protecting group is not particularly limited, and examples thereof include a methyl group, a benzyl group, and a dibenzyl group.

An example in which ^{one of} P ¹ and P ² represents a hydrogen atom and the other represents a protecting group for an amino group Are benzyl / reoxy / reponyl, methoxycanoleponyl, ethoxycarbonyl, tert-butoxycarbyl, acetyl, trifluoroacetyl, benzoyl, tosyl, methyl, benzyl, etc. Examples of the group which together form a protecting group for an amino group include a phthaloyl group.

Further, examples of P ¹ and P ² each representing an amino-protecting group include, for example, one of the above-mentioned alkyl-type protecting groups such as a methyl group and a benzyl group, and the other being a benzyloxycarbonyl group or a methoxycarbonyl group. The above urethane-type protecting group such as a group; one is the above-mentioned alkyl-type protecting group such as a methyl group or a benzyl group, and the other is the above-mentioned acyl-type protecting group such as an acetyl group or a trifluoroacetyl group. Or when P ¹ and P ² are independently an alkyl group such as a methyl group or a benzyl group; or when both are the same alkyl group (for example, a dimethyl group, a dibenzyl group, etc.) ) And the like.

Among them, a one is hydrogen atom or the alkyl type protecting groups P ¹ and P ^2, is preferably other is the urethane type protecting group, especially, ¹及Pi? ^It is preferable that one of the ^two is a hydrogen atom and the other is a urethane-type protecting group.

In compound (2),? ³ and? ^4, the P ¹ Power \ whereas the same as及Pi P ² is P ¹ or P ² is an alkyl type protecting group other Luca Oh hydrogen atom, or are each hydrogen atom. Among them, or the other is P ¹ or P ² one of P ³ and P ⁴ are alkyl le type protecting group is a hydrogen atom, or, is preferably a hydrogen atom, respectively it, among other things, P ³ And each of P ⁴ is preferably a hydrogen atom. In this case, when one of the above P ¹ and P ² is a urethane type protecting group and the other is a hydrogen atom or an alkyl type protecting group, the above compound (1) is hydrolyzed to obtain the above compound (2). It is preferred to remove the urethane-type protecting group.

In the compounds (1), (2), (3), (4) and (5), R ¹ is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted alkyl group having 7 to 30 carbon atoms or Represents an unsubstituted aralkyl group or a substituted or unsubstituted aralkyl group having 6 to 30 carbon atoms. The above-mentioned substituted or unsubstituted alkyl group having 1 to 30 carbon atoms is not particularly limited, and examples thereof include a meth / yl group, an ethyl group, an isopropyl group, an isobutyl group, a cyclohexylmethyl group, a tert-butyl group, and a hydroxymethyl group. Group, 1-hydroxyxethyl group, mercaptomethyl group, methylthiomethyl group, phenylthiomethyl group and the like.

 The substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms is not particularly limited. Examples thereof include a benzyl group, a p-hydroxybenzyl group, a p-methoxybenzyl group, an a-phenethyl group, and a 3-phenyl group. Examples include an enylpropyl group and a 2-phenylpropyl group.

 The substituted or unsubstituted aryl group having 6 to 30 carbon atoms is not particularly limited. Examples thereof include a pheninole group, a p-hydroxypheninole group, a p-methoxypheninole group, and a p-chlorophene group. Examples thereof include a binore group, a p-funoleolopheninole group, an 11-naphthinole group, and a 2-naphthinole group.

Among them, the above carbon number of 7 to 30 such as a benzyl group, a p-hydroxybenzyl group, a p-methoxybenzyl group, an α-phenyl / ethylene group, a 3-phenylpropyl group, and a 2-phenylpropyl group. And a substituted or unsubstituted aralkyl group is particularly preferable, an unsubstituted aralkyl group having 7 to 30 carbon atoms is particularly preferable, and a benzyl group is particularly preferable. In compound (5), R ² represents an ester residue. The above ester residue, for example, represents a monovalent organic group which may be the Furudo included in the structure represented in one COOR ^2, it acts as an ester-type protective group for carboxyl group. The monovalent organic group is not particularly limited as long as it has an effect of protecting the carboxyl group. For example, PROTECT I VE GROUP SIN ORGAN ICS YN THE SIS ) [Second Edition, John Wiley & Sons (1991)], and can be selected from ester-type protecting groups described in specialized books on the field. Among them, a lower alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted benzyl group is preferable, a lower alkyl group having 1 to 4 carbon atoms is more preferable, and a methyl group and an ethyl group are more preferable. A methyl group is particularly preferred. Next, the details of the reaction will be described.

 First, a method for deriving the compound (1) into the compound (2) by a hydrolysis reaction will be described.

 The compound (1) is hydrolyzed to the compound (2) in the presence of water with steric inversion of the hydroxyl group at the 2-position. The hydrolysis reaction is carried out using a general hydrolysis method, and it is particularly preferable to carry out the hydrolysis under basic conditions (in the presence of a base). The base is not particularly limited, but it is particularly preferable to use an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, and rhodium hydroxide. The equivalent of the base is usually required to be at least about 3 molar equivalents, and preferably about 5 to 10 molar equivalents. However, the type and amount of the base to be used are not limited to these, and can be appropriately determined as necessary by a simple experiment.

 Although the reaction solvent is not particularly limited, for example, a mixed system of water and an organic solvent or an aqueous system is preferable, and an aqueous system is particularly preferable. When an organic solvent is used in combination, it may be water-soluble or water-insoluble, for example, ketones such as acetone, hydrocarbons such as toluene, ethers such as tetrahydrofuran, and polar aprotic solvents such as acetonitrile. Although hydrocarbon can be used, it is preferable to use hydrocarbons, especially toluene, from the viewpoint of economy and availability.

 The reaction temperature is not particularly limited, but generally, a high temperature of 40 ° C. or higher is preferable for terminating the reaction quickly. If a urethane-type protecting group is present on the amino group of compound (1), the urethane-type protecting group is removed by performing a hydrolysis reaction at a high temperature or by increasing the temperature after the hydrolysis reaction. (Desorption) is also possible.

 Next, a method for converting the compound (3) to the compound (1) by a reduction reaction will be described.

The reduction method is not particularly limited. For example, hydrides such as sodium bis (2-methoxy-ethoxy) aluminum hydride, lithium aluminum hydride, sodium borohydride, potassium borohydride, tetramethylammonium borohydride; Minimum triisopropoxide and The aluminum tri alkoxide (§ Rukokishiru group such as an aluminum tree s _e c- butoxide, preferably 1-1 carbon atoms 0, more preferably 1 to carbon atoms

5); lithium aluminum trialkyl hydride such as tert-butoxy hydride (alkoxyl group preferably has 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms); methanesulfonolate Substituted aluminum alkoxides such as oxynoreminidium diisopropoxide ethanesulfonyloxy anoremyium disopropoxide (the substituent preferably has 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms) Which is an alkylsulfonyloxy group). Also, dialkylaluminum hydride (preferably an alkyl group having 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, even more preferably diisobutylaluminum hydride) and an alcohol (preferably an alkyl group having 1 to 10 carbon atoms) To 10, more preferably 1 to 5 carbon atoms, and still more preferably, 2-propanol (see, for example, JP-A-6-206877, JP-A-8-208). —1099-131, JP-A-8-225555, JP-A-198995, Japanese Patent Application No. 9-162505, etc.). Of these, hydrides such as sodium borohydride and aluminum trialkoxides such as aluminum triisopropoxide are preferably used. The reducing agent is generally effective for diastereoselectively producing the compound (1).

 The equivalent of the reducing agent is determined by the type of the reducing agent and the reducing ability per mole of the reducing agent. For example, when sodium polohydride or aluminum triisopropoxide is used, it is generally used in a molar amount of 1 to 2 times.

 The reaction solvent is not particularly restricted but includes, for example, alcohols such as methanol and 2-propanol, hydrocarbons such as toluene, and ethers such as tetrahydrofuran.

 The reaction temperature cannot be uniformly defined depending on the type of the reducing agent, but is generally, for example, preferably in the range of 180 to 110 ° C, and more preferably in the range of 120 to 150 ° C. Can be implemented in

After diastereoselective reduction of the above compound (3) by such a method, The above compound (1) is generally extracted into an organic phase in the range of acidic to weakly basic in the presence of an organic solvent and water. The acidic to weakly basic range is usually from p HO to 9, preferably from pH 1 to 8.

 Acids and / or bases can be used to adjust the extraction operation to acidic to weakly basic. The acid and base are not particularly limited, but the acid is preferably a mineral acid such as hydrochloric acid or sulfuric acid, and the base is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; sodium carbonate, carbonate Alkali metal carbonates such as sodium lime; sodium bicarbonate; and alkali metal bicarbonates such as hydrogen hydride.

 In addition, among the above compounds (1) obtained by the above reduction reaction, the following compounds (7) are particularly novel compounds which have been found to be useful in the production of α-hydroxy-1 / 3-aminocarboxylic acid derivatives by the present inventors. Compound.

(In the formula, X ⁶ , X ⁷ and X ⁸ independently represent a bromine atom or a chlorine atom. Ρ ¹ and Ρ ² each represent a hydrogen atom and the other represents a protecting group for an amino group. , Or together or each represents a protecting group for an amino group).

 • Next, the halogenation reaction for converting the above compound (4) to the above compound (3) will be described.

 The halogenating agent is not particularly restricted but includes, for example, sulfuryl halides such as sulfuryl chloride; _-halosuccinimides such as ク ロ -chlorosuccinimide and ブ ロ モ -bromosuccinimide; halogens such as bromine and chlorine; iron chlorides and the like. Iron halide; hexacrocetone acetone and the like. Among them, N-halosuccinimide such as N-chlorosuccinimide ゃ N-bromosuccinimide is preferably used from the viewpoints of reaction development and simplicity of use.

The equivalent of the halogenating agent is the type of the halogenating agent and 1 mole of the halogenating agent. Is determined by the halogenation ability of For example, when N-halosuccinimide is used, it can be used in an amount of about 1 to 5 mol, more preferably 1.1 to 3 mol, per 1 mol of hydrogen atom to be replaced with halogen.

 The reaction solvent is not particularly limited, and examples thereof include hydrocarbons such as dichloromethane, chloroform, and toluene, and ethers such as tetrahydrofuran. It is preferable to use hydrocarbons, especially toluene, from the viewpoint of economy, safety and availability.

 The reaction can be optionally performed in the presence of an acid or a base to accelerate the reaction. For example, when carrying out the reaction using sulfuryl peroxide, it is preferable to carry out the reaction in the presence of an acid. When the reaction is carried out using N-halosuccinimide, the reaction is preferably carried out in the presence of a base. In this case, the base may be a tertiary compound such as alkali metal carbonate such as potassium carbonate or triethylamine. It is preferable to use a base having relatively low nucleophilicity such as amine. The type and amount of these acids and bases are not particularly limited, but can be easily optimized by simple experiments.

 The reaction temperature must be appropriately determined according to the type of the halogenating agent. In general, the reaction is preferably carried out at 80 ° C. or lower, more preferably at room temperature or lower, in order to suppress side reactions such as excessive halogenation at other sites.

 After the above-mentioned halogenation reaction, for example, water is added to the reaction solution to perform a neutralization operation, and thereafter, ordinary operations such as extraction, washing, and concentration can be performed. In addition, the above compound (using a common separation and purification method such as column chromatography / crystallization operation)

3) can be isolated, but if necessary, it can be used in the next step without isolation.

 Among the above compounds (3) obtained by the halogenation reaction, the following compound (6) is a novel compound which has been found by the present inventors to be useful in the production of α-hydroxy-aminocarboxylic acid derivatives. is there.

(式中、 X⁶、 X⁷及び X^sは、 独立して、 臭素原子又は塩素原子を表す。 P¹及 び P²は、 一方が水素原子を表し他方がァミノ基の保護基を表すか、 又は、 一緒 になって若しくはそれぞれァミノ基の保護基を表す） 。

(In the formula, X ⁶ , X ⁷ and X ^s independently represent a bromine atom or a chlorine atom. P ¹ and P ² each represent a hydrogen atom and the other represents a protecting group for an amino group. , Or together or each represents a protecting group for an amino group).

 The compound (4) may be, for example, a reaction of an o; -haloacetic acid derivative or a salt thereof with an amino acid ester derivative (5) (WO 96/23756), or a dihalomethane and an amino acid ester derivative (WO 96/23756). It can be easily produced by the reaction of 5) (JP-A-8-234728). BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Example 1 Synthesis of (3 S) — 1, 1, 1-trichloro mouth — 2-oxo-l 3- 3- (ethoxycarbinole) amino- 4-phenylbutane

 (3S) 11-chloro-2-oxo-13-Ν- (ethoxycarbonyl) amino

—4—Phenislebutane 1 Suspension of 140 g of Tonolen solution containing 3.5 g (5 Ommo 1) and 20.7 g (15 Ommo 1) of potassium carbonate are suspended in a nitrogen atmosphere while maintaining the temperature at 5 ° C. 20. Og of the acid imide was added in six portions over about 2.5 hours. Then, after stirring at 5 ° C for 20 minutes, 6 Om1 of toluene and 500 ml of water were added. After standing, the aqueous phase was separated, and then 10 Om1 of water was added. Then, ρΉ was adjusted to 2 with concentrated hydrochloric acid, allowed to stand again, and the aqueous phase was separated. The obtained organic phase was washed twice with 10 Om 1 of water, concentrated under reduced pressure at 40 ° C, and (3S) -1, 1, 1-trichloro-1--2-oxo-13-N- (ethoxy) (Carboel) 15.2 g of a yellow oil containing amino-4-phenylbutane was obtained (yield: 90%).

XH-NMR (40 OMHz, CDC 1 3) δ:. 7. 12- 7. 24 (m, 5 H), 5. 38-5 48 (m, 1H), 5. 25- 5. 35 (m, 1H), 3.92-4.02 (m, 2H), 3.26 (dd, J = 5.37Hz, 13.67Hz, 2H), 2.93 (dd, J = 13.92Hz, 2H), 1.76 (m, 3 H) IR (KB r DI SK): 3335, 1696, 1541, 1536, 1262 cm " ¹ Example 2 (2 S, 3 S) — 1,1, 1_Trichloro mouth 1-2—hydroxy 3-N— ( Synthesis of ethoxycarbonyl) amino-4-phenylbutane

 Under a nitrogen atmosphere, 16.1 g (266 mmo 1) of 2-propanol was added to 67 m 1 (1.0 M, 67 mmo 1) of a toluene solution of diisobutylaluminum hydride at room temperature, followed by stirring for 1 hour. Then, 50 g of a toluene solution containing the equivalent of (3S) —1,1,1_trichloro-1--2-oxo-13-N— (ethoxycarbonyl) amino-4-phenylbutane (15.2 g, 45 mmo 1) was added. The mixture was stirred under a nitrogen atmosphere at 35 ° C. for 3 hours. At 5 ° C, a hydrolysis phase composed of 10 Om1 of water and 9.9 g (100 mmo1) of concentrated sulfuric acid was separately prepared, and the resulting reaction solution was added thereto over 20 minutes. After extraction with 200 ml of ethyl acetate, the obtained organic phase was washed twice with 10 Om 1 of water and concentrated under reduced pressure at 40 ° C. The solvent was replaced with toluene, and (2 S, 3 S) —1,1,1-trichloro-2-hydroxy-3-N— (ethoxycarbonyl) amino-4-phenylbutane 14.1 g (41 mmo 1 ) Was obtained in an amount of 50.0 g.

Yield: 92%

^ -NMR (40 OMH z, CDC 1 3) <5: 7. 07- 7. 24 (m, 5 H), 4. 80 (m, 1H), 4. 35 (m, 1 H), 4. 27 (m, 1H), 3.97 (m, 2H), 3.25 (dd, J = 13.18Hz, 13.18Hz, 1H), 2.88 (dd, J = 12.2H z, 12.2H z, 2H), 1.10 (m, 3 H)

IR (KBr DI SK): 3366, 1678, 1643, 1342 cm " ¹ Example 3 Synthesis of (2R, 3S) 1-2-hydroxy-13-amino-4_phenylbutyric acid

(2 S, 3 S) contains 3.4 g (lmmo 1) of 1,1,1,1-trichloro-2-hydroxy-3-N- (ethoxycarbonyl) amino-4-phenylbutane To a toluene solution (10.3 g) was added a 4N lithium hydroxide aqueous solution (22.5 g, 10 mmo 1), and the mixture was heated with stirring at 70 ° C. for 26 hours under a nitrogen atmosphere. After cooling to room temperature, the pH was adjusted to 0.7 with concentrated hydrochloric acid. After standing, the organic phase was separated, the insolubles were removed by filtration, and the aqueous phase was concentrated under reduced pressure. (2R, 3S) — 1.5 g of an oil containing 1.2 g (0.6 mmo 1) of 2-hydroxy-3-amino-4-butyric acid was obtained.

Yield: 63%

Stereoselectivity: (2R, 3S) — 2-hydroxy-3-amino-4-1-phenylbutyric acid / (2S, 3S) — 2-hydroxy_3- 3-amino-1-4-phenylbutyric acid = 85/15 Example 4 Synthesis of (3S) -1, 1, 1 -trib Mouth 2-oxo-l 3-N- (ethoxycarbonyl) amino- 4-phenylbutane

 (3 S) -1, 1-Dibromo_2-oxo-1-N- (ethoxycarbol) amino-4 phenylbutane 8.0 0.5 g (2 Ommo 1) containing toluene solution 80.5 g and carbonic acid Suspension of 6.9 g of potassium (5 Ommo 1), N-bromosuccinimide 8.8 g (5 Ommo 1) is divided into 4 parts under nitrogen atmosphere at 5 ° C for about 1.5 hours. And added. After stirring at 5 ° C for 20 minutes, 20 ml of toluene and 30 Om1 of water were added. After standing, the aqueous phase was separated, and then 15 Oml of water was added. Thereafter, the pH was adjusted to 3 with concentrated hydrochloric acid, and the mixture was allowed to stand still, and then the aqueous phase was separated. After washing with water (15 Om1), the solution was concentrated under reduced pressure at 40 ° C, and (3S) —1,1,1-tribromo-l-2-oxo_3-N— (ethoxycarbol) amino-4— 7.6 g of a yellow oil containing phenylbutane was obtained.

Yield: 80%

'H-NMR (4 0 0MH z, CD C 1 3) δ: 7. 1 4 - 7. 3 5 (m, 5 H), 5. 6 8 (d, J = 5. 3 7H z, 1 H ), 5.24 (d, 9.28, 1H), 4.02 -4.14 (m, 2H), 3.44 (dd, J = 5.37, 13.6) 7H z, 2H), 3.06 (dd, J = 8.3, 13.6 7Hz), 1.16 1 1.20 (m, 3H)

IR (KBr): 3569, 1690, 1541, 1262cm- ¹ Example 5 Synthesis of (2S, 3S) -1,1,1-tripromo 2-hydroxy-3-N- (ethoxycarbol) amino-1-41-butane

 (3S) -1,1,1,1-Tripromo_2-oxo-3-N- (ethoxycarbonyl) amino-4-phenylbutane 3.8 g (8 mmo 1) was dissolved in 100 ml of methanol and placed under a nitrogen atmosphere. At 5 ° C., 0.3 g (8 mmo 1) of sodium borohydride was added thereto. Then, after stirring at 5 ° C for 1 hour, 90 ml of 1 N hydrochloric acid and 100 ml of toluene were added. After standing, liquid separation was performed to remove the aqueous phase, and the organic phase was washed with 300 ml of water. The resulting solution is concentrated under reduced pressure at 40 ° C to give (2S, 3S)-1,1,1-tribromo-12-hydroxy-1-N- (ethoxycarbonyl) amino-14-phenylbutane 2.7 g of a yellow oil containing

Yield: 7 1%

'H-NMR (40 0MH z , CD C 1 3) δ 7. 20- 7. 3 5 (m, 5 H), 5. 00 - 5. 30 (m, 1H), 4. 9 6 (d, 8.78, 1 H), 4.2 1-3.96 (m, 4 H), 2.82-3.22 (m, 2 H), 1.27-1.19 (m , 3H)

IR (KB r): 342 5, 170 1,1 578 cm— ¹ Reference example 1 (3S) —1-Chloro-2-oxo-1-N— (ethoxycarbonyl) amino-4-phenyl Synthesis of Lobutane

Under a nitrogen gas atmosphere, 40.1 g of a toluene solution containing 20.0 g of (S) -2-N- (ethoxycarbyl) amino-3-methyl phenylpropanoate, 17.5 g of sodium acetate sodium Tert-butylmagnesium chloride (1.75 mol / L) 2 28.9 g at an internal temperature of 10 ° C or less over about 3 hours. The mixture was further stirred at the same temperature for 12 hours. Separately, a container containing 100 g of water was prepared, and the reaction solution was added thereto over 1 hour while maintaining the pH at 1 to 8 with concentrated hydrochloric acid. After standing, liquid separation was performed to remove the aqueous phase, and the obtained organic phase was washed with 100 ml of saturated aqueous sodium hydrogen carbonate and then twice with 100 ml of water. Quantitative analysis of the obtained organic phase by HP LC showed (3 S) — 1— Oxo _3— N— (ethoxycarbonyl) amino-4 phenylbutane 21.

3 g had been produced.

Yield: '85% Reference Example 2 Synthesis of (3 S) — 1, 1-dibutene 2-oxo-1 3-N— (ethoxycarbonyl) .amino-4 phenylbutane

 In a nitrogen gas atmosphere, at 40 ° C, 34.2 g of diisopropylamine was added to 152.5 g of n-butylmagnesium chloride (1.86 mo1 / kg) over 30 minutes, and the same temperature was further added for 2 hours. The mixture was stirred (the obtained slurry was used as solution A). Meanwhile, in a separate container, under a nitrogen gas atmosphere, 35.2 g of a toluene solution containing 17.6 g of methyl (S) —2-N— (ethoxycarbonyl) amino-3-phenylpropanoate, 35.2 g of dibromomethane 24 A solution comprising 6 g and 17.7 g of dimethoxyethane was prepared (this is referred to as solution B). Solution A was added to solution B at an internal temperature of about 10 at an internal temperature of about 10 over 3 hours, and the reaction was further performed after 20 hours. Further, 100 g of water was added to another container, and the resulting reaction solution was added to the mixture while maintaining the pH at 1 to 7, and hydrolyzed. After standing, liquid separation was performed, and 100 g of toluene was added to the obtained organic phase, followed by washing twice with 10 Om1 of water. When the obtained organic phase was quantitatively analyzed by HPLC, it was found that (3S) -1,1-dibromo-12-oxo-1-3-N- (ethoxycarbonyl) amino-

26.5 g of 4-phenylbutane was produced.

Yield: 80% industrial potential

 Since the present invention has the above-described configuration, an optically active α-hydroxy-carboxylic acid derivative can be efficiently produced by a simple operation.

Claims

The scope of the claims 1. The following general formula (1)

(Wherein, R ¹ is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or a substituted or unsubstituted aralkyl group having 6 to 30 carbon atoms. X ¹ , X ² and X ^{3 each} independently represents a halogen atom, P ¹ and P ² each represent a hydrogen atom and the other represents a protecting group for an amino group. , Together or each represents a protecting group for an amino group, or each represents a hydrogen atom.) By hydrolyzing an α-amino-1, a ',' -trihaloalcohol derivative represented by The following general formula (2)

 (2) (Wherein R ¹ is the same as described above.) ^{3 and} glue ⁴ are the same as P ¹ and P ² , one of which is the above-mentioned P ¹ or P ² which is an alkyl-type protecting group, and the other is The force \, which is a hydrogen atom, or each represents a hydrogen atom. ^ A method for producing an α-hydroxy-1-amino-3-aminocarboxylic acid derivative, which comprises obtaining a roxy-l-aminoaminocarboxylic acid derivative. 2. The production method according to claim 1, wherein the hydrolysis is performed under basic conditions. 3. Hydrolysis under basic conditions, using alkali metal hydroxide as base 3. The method according to claim 2, which is performed. 4. α-amino, a ', α'-trihaloalcohol derivatives (1) Force S, general formula (3) below

^{(Wherein, RX 1, X 2, X} 3, E及Pi ^ or, the same??.) Represented by _alpha in - amino-, a ^f, alpha 'obtained by reducing an Toriharoketon derivative 4. The production method according to claim 1, 2 or 3, wherein 5. For reduction, sodium bis (2-methoxy-ethoxy) aluminum hydride, lithium aluminum hydride, sodium borohydride, potassium borohydride, tetramethylammonium borohydride, aluminum trialkoxide are used as reducing agents. 5. The process according to claim 4, wherein the process is performed using lithium aluminum trialkoxy hydride or substituted aluminum alkoxide. . 6. The method according to claim 4, wherein the reduction is performed using a reaction product of a dialkylaluminum hydride and an alcohol as a reducing agent. 7. The method according to claim 6, wherein the dialkylaluminum hydride is diisobutylaluminum hydride, and the alcohol is 2-propanol. 8. α-Amino ο, α ', a' trihaloketone derivative (3) Power General formula (4) ヽ P ^{2 X (4)} (Wherein, I ¹ , P ¹ and P ² are the same as described above. X ⁴ represents the X ¹ or a hydrogen atom. X ⁵ represents the X ² or a hydrogen atom. However, X ⁴ and X ⁵ 8. The production method according to claim 4, 5, 6 or 7, which is obtained by halogenating an _α -aminoketone derivative represented by the following formula: . 9. The production method according to claim 8, wherein the halogenation is carried out using ハ ロ -halosuccinic acid imid as a halogenating agent. 10. The method according to claim 9, wherein the halogenation is performed in the presence of a base. 1 1. a-Aminoketone derivative (4) 1 The following general formula (5)

 (Five) (Wherein, RP ¹ and P ² are the same as above. R ² represents an ester residue.) And an α-haloacetic acid derivative or a salt thereof, or dihalomethane 11. The production method according to claim 8, 9 or 10, which is obtained by: 12. The method according to claim 8, 9, 10, or 11, wherein X ⁴ is a chlorine atom or a bromine atom, and X ⁵ is a hydrogen atom. 13. The production method according to claim 12, wherein X ⁴ is a chlorine atom. ' 14. The production method according to claim 8, 9, 10, or 11, wherein X ⁴ and X ⁵ are each a bromine atom. 15. Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, where X ¹ , X ² and X ³ are independently a chlorine atom or a bromine atom Item 14. The production method according to Item 12, 13 or 14. 16. The production method according to claim 15, wherein X ¹ is a chlorine atom, and X ² and X ³ are independently a chlorine atom or a bromine atom. 17. The production method according to claim 16, wherein X ¹ , ² and ³ are all chlorine atoms. 18. The production method according to claim 15, wherein X ¹ and X ² are each a bromine atom, and X ³ is a chlorine atom or a bromine atom. 19. The production method according to claim 18, wherein X ¹ , X ² and X ³ are all bromine atoms. 20. Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 wherein P ¹ is a urethane-type protecting group and P ² is a hydrogen atom or an alkyl-type protecting group. , 12, 13, 14, 15, 16, 17, 18 or 19. 21. The method according to claim 20, wherein the urethane-type protecting group is a benzyloxycarbonyl group, a tert-butoxycanoleponyl group, a methoxycanoleponinole group, or an ethoxycanolepo-norle group. 22. P ³及Pi: or P ⁴ are each hydrogen atom, or, first the claims P ³ is a hydrogen atom P ⁴ is an alkyl type protecting group, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 16, 17, 18, 19, 20, or 21. 23. Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1, 12, 13, 14, 15, 15, 16 wherein R ^{1 is a} benzyl group 1 7, 18, 19, 20, 2 23. The production method according to 1 or 22. 24. The following general formula (3)

 (3) (Wherein, R ¹ is a substituted or unsubstituted alkyl group having 1 to 30 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 30 carbon atoms, or substituted or unsubstituted having 6 to 30 carbon atoms. X represents a substituted aryl group, X ¹ , ² and ^{3 each} independently represent a halogen atom, and one represents a hydrogen atom and the other represents a protecting group for an amino group. Or each represents a protecting group for an amino group, or each represents a hydrogen atom.) A method for producing a monotrihaloketone derivative represented by the following general formula ( Four)

 (Four) (Wherein, RP ¹ and: P ² are the same as above. X ⁴ represents the aforementioned X ¹ or a hydrogen atom. X ⁵ represents the aforementioned X ² or a hydrogen atom, provided that X ⁴ and X ⁵ represent At the same time, hydrogen atoms are Excluding the case. A) a-α, α ′, α ′ monotrihaloketone derivative, characterized by halogenating the α-aminoketone derivative represented by the formula (1). 25. The method according to claim 24, wherein the halogenation is performed using ハ ロ -halosuccinic acid imide as a halogenating agent. 26. The method according to claim 25, wherein the halogenation is carried out in the presence of a base. 27. The monoamino, a ', a' trihaloketone derivative (3) obtained by the method according to claims 24, 25 or 26 is reduced to give the following general formula (1)

(Wherein, RP ¹ , P ² , X ¹ , X ² and X ³ are the same as described above.) A monoamino-α ′, a ′, a ′ trihaloalcohol derivative represented by the formula: A method for producing a triamino alcohol derivative. 28. In the reduction, sodium bis (2-methoxy-ethoxy) aluminum hydride, lithium aluminum hydride, sodium borohydride, potassium borohydride, tetramethylammonium borohydride, aluminum are used as reducing agents. 28. The production method according to claim 27, wherein the production method is performed using a trialkoxide, a lithium aluminum trialkoxide hydride, or a substituted aluminum alkoxide. ' 2 9. Reduction consists of dialkylaluminum hydride and alcohol as reducing agents. 28. The production method according to claim 27, wherein the reaction is performed using the reactant. 30. The process according to claim 29, wherein the dialkylaluminum hydride is diisobutylaluminum hydride and the alcohol is 2-propanol. 31. Hi-aminoketone derivatives (4) Power The following general formula (5)

 (Five) (Wherein, RP ¹ and P ² are the same as described above. R ² represents an ester residue.) And an α-haloacetic acid derivative or a salt thereof, or dihalomethane 31. The production method according to claim 24, 25, 26, 27, 29, 29 or 30, which is obtained by: 32. The method according to claim 24, 25, 26, 27, 28, 29, 30, or 31, wherein X ⁴ is a chlorine atom or a bromine atom, and X ⁵ is a hydrogen atom. 33. The production method according to claim 32, wherein X ⁴ is a chlorine atom. 34. The production method according to claim 24, 25, 26, 27, 28, 29, 30, or 31, wherein X ⁴ and X ⁵ are each a bromine atom. 35.Claims 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34 where X ¹ , X ² and X ³ are independently chlorine or bromine Production method as described. 36. X ¹ is a chlorine atom, and X ² and X ³ are independently a chlorine atom or a bromine atom 36. The production method according to claim 35, which is a child. 37. The production method according to claim 36, wherein X ¹ , X ² and X ³ are all chlorine atoms. 38. The production method according to claim 35, wherein X ¹ and X ² are each a bromine atom, and X ³ is a chlorine atom or a bromine atom. 39. The method according to claim 38, wherein X ¹ , X ² and X ³ are all bromine atoms. 40. The claim 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, wherein P ¹ is a urethane-type protecting group and P ² is a hydrogen atom or an alkyl-type protecting group. 35. The production method according to 35, 36, 37, 38 or 39. 41. The production method according to claim 40, wherein the urethane-type protecting group is a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a methoxycarbonyl group, or an ethoxycarponyl group. 42. The claim 24, wherein R ^{1 is a} benzyl group; 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or 41. The production method described in the section. 43. The following general formula (6)

(In the formula, X ⁶ , X ⁷ and X ⁸ independently represent a bromine atom or a chlorine atom. P ¹ and P ² each represent a hydrogen atom and the other represents a protecting group for an amino group. Or together or each represents a protecting group for an amino group.) An a-amino-α ', α', a'-trihaloketone derivative represented by the formula: 44. The compound according to claim 43, wherein X ⁶ , X ⁷ and X ⁸ are all bromine atoms or all chlorine atoms. 45. The compound according to claim 43, wherein P ¹ is a urethane-type protecting group, and P ² is a hydrogen atom or an alkyl-type protecting group. 46. The compound according to claim 45, wherein the urethane-type protecting group is a benzyloxycarbonyl group, a tert-butoxycarbonyl group, a methoxycarbonyl group, or an ethoxycarbonyl group. 47. The following general formula (7)

(Wherein X ⁶ , X ⁷ and X ⁸ independently represent a bromine atom or a chlorine atom. P ¹ and P ² each represent a hydrogen atom and the other represents an amino group-protecting group. Or together or each represents a protecting group for an amino group.) 0; —amino-a ′, ′, a′-trihaloalcohol derivative. 48. The compound according to claim 47, wherein X ⁶ , X ⁷ and X ⁸ are all bromine atoms or all chlorine atoms. 4 9. P ¹ is urethane-type protecting groups, compounds ranging fourth 7 or 4 8 claim of claim P ² is a hydrogen atom or an alkyl type protecting group. 50. The compound according to claim 49, wherein the urethane-type protecting group is a benzyloxycarbonyl group, a tert-butoxycarbol group, a methoxycarbonyl group or an ethoxycarbonyl group.