JPH09143131A - Production of 3-amino-2-oxo-1-hydroxypropane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To realize an industrially short-cut process for producing 3-amino-2- oxo-1-hydroxypropane derivative in high yield, from a compound obtained by an α-amino acid via a novel intermediate to this derivative which is important as an intermediate for a variety of HIV protease inhibitors. SOLUTION: A compound of formula (Rs are H, an alkyl, an aryl, an aralkyl; P1 and P2 are H, amino-protecting group; E1 is phenoxy, benzyloxy) is allowed to react with an alkali metal enolate derived from a glycolic ester of formula II (R1 is an alkyl, an aryl; R2 is H, an alkyl, aryl) to give a new compound of formula III, 4-amino-3-oxo-2-hydroxybutanoic ester derivative, followed by hydrolysis of the ester group and decarboxylation to give an optically active 3-substituted-3-amino-1,2-epoxypropane derivative as an equivalent of α- aminoalcohol derivative which is important as an intermediate for HIV protease inhibitor or a kind of enzyme inhibitor.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an HIV protease inhibitor,
Alternatively, α-, which is important as an intermediate for certain enzyme inhibitors
The present invention relates to a method for producing a 3-amino-2-oxo-1-hydroxypropane derivative which can be easily converted into an optically active 3-substituted-3-amino-1,2-epoxypropane derivative which is an equivalent of an aminoalcohol derivative.

[0002]

2. Description of the Related Art Optically active 3-substituted-3-amino-1,2
An α-amino alcohol derivative which can be easily converted from an epoxypropane derivative is Ro31-8959 (Park).
es, K.E. Roche, J. et al. Org. Che
m. , 1994, 59, 3656. ), SC-5215
1 (Getman, DP, et al. (Monsanto),
J. Med. Chem. , 1993, 36, 28
8. ), VX478 ((Vertex) WO94056
39), AG1343 ((Lilly) WO95211)
64) and many other HIV protease inhibitors are used as synthetic intermediates.

Although several methods for producing 3-amino-1,2-epoxypropane derivatives are known, for example, stereoselection of the 2-position of N-protected 3-amino-2-oxo-1-halogenopropane. Method of dehydrohalogenation and epoxidation after reduction of alcohol to alcohol (Getma)
n, D. P. J. et al. Med. Chem. , 1993,
36,288. Etc.), a method for oxidatively asymmetric epoxidation of N-protected 3-amino-1-propene (Luly,
J. R. J. et al. Org. Chem. , 1987, 5
2,1487. Et al., Method of inserting methylene into N-protected 3-amino-1-propanal (Searle,
G. FIG. D. , WO93 / 23388. Etc.).

In the first method, the key intermediate N
It is important how industrially and inexpensively the protected 3-amino-2-oxo-1-halogenopropane or its equivalent can be produced. However, in the methods known so far, the auxiliary raw material is extremely explosive. Due to the need to use diazomethane, which is highly toxic, there is a limit to the industrialization of these processes (eg Getman, DP.
J. et al. Med. Chem. , 1993, 36, 28
8. , Okada, Y et al., Chem. Pharm. B
ull. , 1988, 36, 4794. , EP346
867. Raddatz, P. et al. Med. Che
m. , 1991, 34, 3267. ). In addition, there is a method of allowing a halomethyl anion to act on an N-protected amino acid ester, but using a very unstable halomethyl anion and the halogen to be introduced at the 1-position are not known from general knowledge about chemistry. There is a limit to the industrialization of this method because it is supposed that it can be limited to chlorine or fluorine (Barluenga et al., J. Chem. Soc.,
Chem. Commun. , 1994. ). Further, as an existing technique related to the present case, a method of activating the C-terminal of an N-protected amino acid and then decarboxylating it by reacting a fluoromalonic acid half ester (EP44275)
4) can be mentioned, but this is limited to a special element in which halogen is fluorine and cannot be applied to a system for achieving this object such as chlorine and bromine. In the second method, the Wittig reaction of expensive aldehyde (3-amino-1-propanal) is used to prepare the key intermediate N-protected 3-amino-1-propene, which is extremely difficult. It is a high-cost manufacturing method.
Furthermore, in the third method, not only the method for producing the N-protected aldehyde, which is the same intermediate as above, is expensive, but it is necessary to generate carbene at a low temperature in the insertion reaction of methylene, which is industrially suitable. It is not a manufacturing method.

It should be noted that 3-amino-2-oxo- which is an equivalent of 3-amino-2-oxo-1-halogenopropane.
As a method for producing 1-hydroxypropane, there is a method in which a chloride of an N-protected amino acid is reacted with tris ((trimethylsilyl) oxy) ethane and the trimethylsilyl group is hydrolyzed with an acid (Parkes et al., J. Org.
Chem. , 1994, 59, 3656. However, there are problems that the reaction yield is low because a side reaction that produces a dimer-like compound proceeds, and that the reagents used are expensive.

[0006]

The problem to be solved by the present invention is as follows.
An object of the present invention is to provide an industrial production method of a 3-amino-2-oxo-1-hydroxypropane derivative which can be easily converted into an amino-1,2-epoxypropane derivative.

[0007]

DISCLOSURE OF THE INVENTION As a result of studies to solve the above-mentioned problems, the present inventors have found that 3-amino-1,2-epoxypropanes or their equivalents correspond to 3-amino-2- Focusing on the fact that it can be produced from an oxo-1-hydroxypropane derivative in a high yield, a novel 4-amino-3-oxo-2-hydroxybutanoic acid ester derivative which is a precursor thereof and a production method thereof have been found, and the present invention Has been completed.

That is, the present invention provides a compound represented by the following general formula (I):

[0009]

[Chemical 6]

(In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, and 6 carbon atoms.
To an aryl group having 15 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a substituent containing a hetero atom in these carbon skeletons, P ₁ and P ₂ are each independently a hydrogen or amino protecting group, or P ₁ and P ₂ has a bifunctional amino-protecting group as a unit, E ₁ has an activated carboxy terminus as an alkoxy ester residue having 1 to 10 carbon atoms, and each has a substituent on the ring. Phenoxy group or benzyloxy group, N-oxysuccinimide or 1
An active ester residue of oxybenzotriazole, an active thioester residue, an imidazolyl group, an acid halide,
It represents a residue capable of forming an acid anhydride or an acid azide. )

By reacting an alkali metal enolate derived from an ester of glycolic acid represented by the following general formula (II),

[0012]

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(Wherein R ₁ is an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, and R ₂ is And hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or an acyl group having 1 to 20 carbon atoms).

4-amino-represented by the following general formula (III)
Synthesizing a 3-oxo-2-hydroxybutanoic acid ester derivative,

[0015]

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(Rs, P ₁ , P ₂ , R ₁ and R ₂ in the formula have the above meanings.)

Further, the following general formula (IV) is characterized in that the ester group is hydrolyzed and decarboxylated.

[0018]

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(Rs, P ₁ , P ₂ and R ₂ in the formula have the above-mentioned meanings.)

3-amino-2-oxo-1-
Process for producing hydroxypropane derivative or salt thereof and 4-amino-3-oxo-2 which is an intermediate for producing the same
A hydroxybutanoic acid ester derivative.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of formula (I) used in the present invention has a functional group in which the amino group of a natural or unnatural α-amino acid is protected by a protecting group and the carboxyl group is capable of reacting with a nucleophilic reagent. It is a type of protected amino acid that has been converted to a group. The compound represented by the formula (I) has an optical activity due to the steric carbon atom at the base of the amino group, and for example, by selecting an optically active amino acid as a starting material, the compound having the optical activity can be easily synthesized. Applicable.

In the formula (I), Rs represents hydrogen or a general substituent such as alkyl, aryl and aralkyl. For example, a methyl group is a compound having an alanine skeleton, and a benzyl group is a compound having a phenylalanine skeleton. P ₁ and P ₂ represent a commonly used amino protecting group, either P ₁ or P ₂ may be a hydrogen atom, and P ₁ and P ₂ may be a combined bifunctional amino protecting group. Examples include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl,
It may be any of formyl, benzoyl, dibenzyl, phthaloyl, etc., and may be determined in consideration of the functional group selectivity in the hydrolysis and decarboxylation of the ester group (R ₁ ) described later. E ₁ represents a carboxy-terminal functional group capable of reacting with a nucleophile, and includes residues such as lower ester, active ester, acid halide and acid anhydride. Examples are methoxy, ethoxy, benzoxy and substituted benzoxy, phenoxy and substituted phenoxy, N-oxysuccinimide, 1-oxybenzotriazole, imidazolyl, chlorine, bromine, methoxycarboxy, isobutoxycarboxy, tert-butylcarboxy and the like. To specifically exemplify the compound represented by formula (I), N-benzyloxycarbonyl-L-phenylalanine methyl ester, N
-Benzyloxycarbonyl-L-phenylalanine-
N-oxysuccinimide ester, N, N-dibenzyl-L-phenylalanine p-nitrophenyl ester, N-benzyloxycarbonyl-S-phenyl-L
-Cysteine methyl ester and the like.

The compound represented by the formula (I) is prepared by protecting the amino group of a natural or unnatural α-amino acid by a method commonly used in peptide synthesis, and then esterifying the carboxyl group by a method commonly used in peptide synthesis. Or halogenated.

The conversion of the formula (I) into the formula (III) is carried out by using an alkali metal derived from an ester of the formula (I) or an acid halide or an acid anhydride of the ester of glycolic acid of the formula (II). React with enolate to 4-amino-3
It is a reaction that produces an oxo-2-alkoxybutanoic acid ester derivative. The glycolic acid ester used in this reaction is preferably a hydroxyl group-protected one, and examples thereof include ether-protected ones such as tert-butyl and benzyl. Further, the ester represents an ester of a carboxylic acid which is usually used, for example, alkyl ester,
It is an aralkyl ester, a silyl ester or the like, and specifically, any hydrolyzable ester group such as methyl, ethyl, tert-butyl, benzyl, trimethylsilyl and the like may be used. The enolate refers to an alkali metal salt, and a lithium salt is most preferable. The preparation of these enolates is
It can be carried out by adding a glycolic acid ester to a solution of a base such as lithium amide, lithium diisopropylamide, or lithium tert-butoxide. Glycolic acid enolate is required in an amount of 1 equivalent or more with respect to the compound represented by the formula (I), but 1 equivalent of a base is necessary for forming an enolate of a 4-amino-3-oxo-2-alkoxybutanoic acid ester derivative of the product. Usually 2 from being offered
The reaction proceeds in good yield by using an equivalent amount or more of glycolic acid enolate. This reaction rapidly proceeds at a temperature of about −100 ° C. to room temperature. The optimum temperature varies depending on the compound, but as a typical example, minus 75
The reaction is completed in 5 to 60 minutes at about -30 degrees. As the reaction solvent, hydrocarbon, ether, etc. are used,
Tetrahydrofuran, hexane, toluene and a mixed solvent thereof may be mentioned as an example. The reaction concentration is not particularly limited and may be determined according to the solubility of the reaction product. After completion of the reaction, the reaction solution is treated with an acid to protonate the product alkyl metal salt to give a 4-amino-3-oxo-2-hydroxybutanoic acid ester derivative represented by the formula (III). . The product obtained by using a glycolic acid ester having a protected hydroxyl group gives a 4-amino-3-oxo-2-alkoxyoxybutanoic acid ester derivative.

This compound can be easily purified by means such as silica gel chromatography and recrystallization, if necessary, but can also be used as a raw material for the next reaction in an unpurified state. In the course of the reaction, due to its selectivity, diastereomers are produced, and these can be separated by thin layer chromatography or silica gel column, but the separation is not required for the purpose of this production process.

The structure of the product 4-amino-3-oxo-2-hydroxy (or alkoxy) butanoic acid ester derivative (III) is novel and is a compound which is an important intermediate in the present invention. Is. The structure of this compound is taken to include the corresponding enol form as tautomers. For example, other tautomers include the following general formula (V)

[0027]

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(In the formula, R _S , P ₁ , P ₂ , R ₂ and R ₂ have the above meanings.)

4-amino-2,3-dihydroxybut-2-enoic acid ester derivative represented by
-Oxo-2-alkoxybutanoic acid ester derivative, 4
-Amino-3-hydroxy-2-alkoxybut-2-
Enoic acid ester derivative, 4-amino-3-oxo-2-
Acyloxybutanoic acid ester derivative, 4-amino-3-
Examples thereof include a hydroxy-2-acyloxybut-2-enoic acid ester derivative.

Conversion from formula (III) to formula (IV) involves hydrolysis of the 4-amino-3-oxo-2-hydroxy (or alkoxy) butanoic acid ester derivative of formula (III),
It is carried out by decarboxylation at the same time. As a hydrolysis method, any method usually used in organic chemistry may be used, such as alkali hydrolysis of a lower alkyl ester, acid hydrolysis of a tertiary alkyl ester, catalytic hydrogenation of a benzyl ester, weak acidity to medium of a silyl ester. Hydrolysis by nature can be applied. Optimum conditions differ depending on the structure of the compound, but often give good results in the system of tertiary alkyl ester or silyl ester. 4-amino-3-oxo-2-hydroxy (or alkoxy) represented by formula (III)
The butanoic acid ester derivative can be selectively reacted by combining the types of the hydroxyl protecting group and the carboxyl protecting group. That is, this includes a method of simultaneously conducting hydrolysis of an ester and removal of a hydroxyl-protecting group to lead to hydroxymethylketone, and a method of selectively performing only hydrolysis of ester to lead to a hydroxymethylketone having a protected hydroxyl group. As a typical example of the conditions of this reaction, when R ₁ and R ₂ are each benzyl, hydrolysis is carried out for several hours by contacting with hydrogen (1 atm) at room temperature under a palladium carbon catalyst in a solvent such as alcohol, The decarboxylation reaction is complete. By further increasing the pressure of hydrogen, the benzyl group attached to the hydroxyl group is also deprotected and 3-amino-2-
The reaction concentration of the oxo-1-hydroxypropane derivative is not particularly limited and may be determined according to the solubility of the reaction product. The desired product can be extracted and isolated from the reaction solution in an organic solvent, and can be purified by means such as silica gel chromatography and recrystallization if necessary.

The 3-amino-2-oxo-1-hydroxypropane derivative represented by the formula (IV) obtained by these methods is as described in the literature (for example, (Parkes
J. et al. Org. Chem. , 1994, 59, 365
6. )) Known compounds useful as intermediates for HIV protease inhibitors.

The compound represented by the formula (IV) is a more advanced intermediate as an intermediate of an HIV protease inhibitor by undergoing several steps of existing reactions such as reduction of a carbonyl group, and the following general formula (VI) ) Can be derived to the 1,2-epoxy compound.

[0033]

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(Rs, P ₁ and P ₂ in the formula have the above meanings.)

In the reduction reaction of the carbonyl group, it is possible to carry out a stereoselective reduction with respect to the stereo bond of the bond of the substituent represented by Rs at the 3-position, and is represented by, for example, sodium borohydride. It can also be achieved by using such conventional reducing agents. For example, Rs is a benzyl group, the 3-position is an S-form, and a compound in which a urethane-type protecting group is selected as an amino-protecting group is reduced with sodium borohydride to give a hydroxyl-group to the S-form. Further, when the compound having the dibenzyl protecting group as the amino-protecting group is subjected to the same reduction reaction, the stereochemistry at the 3-position is the S-form, and the stereotype of the hydroxyl group gives the R-form predominantly. When the hydroxy group of hydroxymethyl ketones is protected by a protecting group represented by R2, 3-amino-1 represented by the following general formula (VII) can be obtained by carrying out a deprotection reaction before or after this reduction reaction. , 2-diol.

[0036]

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(Rs, P ₁ and P ₂ in the formula have the above meanings.)

The above-mentioned 1,2-diol is a chemical equivalent to a 1,2-epoxy compound, and is converted into an epoxy group by a method of converting a hydroxyl group into a leaving group such as paratoluenesulfonylation, methanesulfonylation, halogenation and the like. It is inducible to the body, and as an example, an alkoxyhalidene derivative obtained by the reaction with an orthoacetic acid ester is reacted with an acid halide to obtain a compound represented by the general formula (VIII),

[0039]

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(In the formula, Rs, P ₁ and P ₂ have the above meanings, R ₃ represents an acyl group, and X represents halogen.)

Hydrolysis of the acyloxy group leads to the desired epoxy compound (VI). Furthermore, since it is possible to select the 1-position and 2-position when introducing a leaving group, it is possible to separately prepare an epoxy having an arbitrary relative arrangement from a diol having an arbitrary relative arrangement. For example, by introducing a leaving group into the 1-position hydroxyl group of (2S, 3S) -diol, (2S, 3S) -epoxy is introduced into the 2-position hydroxyl group (2R, 3S)-. The epoxy can be selectively formed.

The flow from the starting compound (I) of the present invention to the objective compound (IV) and the above epoxidized compound (VI) is shown below.

[0043]

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(Wherein E ₁ , Rs, P ₁ , P ₂ ,
R ₁ and R ₂ have the above-mentioned meanings. )

[0045]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the invention thereto. Temperatures are given in degrees Celsius unless otherwise noted.
Proton Nuclear Magnetic Resonance (NMR) spectrum is Varian 3
Recorded on a 00 MHz spectrometer; chemical shifts (δ) are given in ppm. The abbreviations used in the examples are Boc: tertiary butoxycarbonyl; Z:
Benzyloxycarbonyl; THF: tetrahydrofuran; LDA: lithium diisopropylamide; NCS:
N-chlorosuccinimide; NBS: N-bromosuccinimide is included.

Production Example 1 Production of N, N-dibenzyl-L-phenylalanine paranitrophenyl ester (Ia) N, N-dibenzyl-L- in chloroform (50 ml).
Phenylalanine hydrochloride (7.64 g, 20.0 mmo
1) was added, and 10% aqueous ammonia (20.
(0 ml) was added dropwise to neutralize. Separate the organic layer and add water (2
(0 ml), dried over magnesium sulfate, and filtered.
The residue obtained by concentrating the filtrate was chloroform (50 m
l) and dissolved in para-nitrophenol (2.8
9 g, 20.4 mmol) and N, N'-dicyclohexylcarbodiimide (4.13 g, 20.0 mmo)
1) were sequentially added and reacted overnight. Ethyl acetate (30 ml) was added to the reaction solution, the precipitated N, N′-dicyclohexylurea was filtered, and the filtrate was washed with 10% aqueous potassium carbonate solution. The organic layer was separated and concentrated, and the resulting residue was redissolved in ethyl acetate (30 ml), and the precipitated insoluble material was filtered off. The crude product obtained by concentrating the filtrate was purified by silica gel column chromatography to give the title compound.
(Ia) (7.77 g, 16.65 mmol) was obtained. 1H-NMR (300MHz, CDCl3) δ: 3.13 (dd, J = 7.4,13.7Hz, 1H),
3.26 (dd, J = 8.2,13.9Hz, 1H), 3.72 (d, J = 14.0Hz, 2H), 3.96
(dd, J = 7.4,8.2Hz, 1H), 4.06 (d, J = 14.0Hz, 2H), 7.14 (d, J =
9.2Hz, 2H), 7.06-7.37 (m, 15H), 8.26 (d, J = 9.3Hz, 2H) Mass spectrum (FAB) 467 (MH +)

Production Example 2 N, N-dibenzyl-L-phenylalanine N-oxysuccinimide ester (Ib)
Preparation of N, N-dibenzyl-L- in methylene chloride (50 ml)
Phenylalanine hydrochloride (5.0 g, 13.09 mmo
1) and 10% aqueous ammonia (30.
(0 ml) was added dropwise to neutralize. After stirring for 30 minutes, the layers are separated,
It was dried over sodium sulfate, filtered, and concentrated. The concentrated residue was dissolved in chloroform (50 ml), and N-hydroxysuccinimide (1.52 g, 13.09 mmol) and N, N′-dicyclohexylcarbodiimide (2.
70 g, 13.09 mmol) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (150 ml) was added to the reaction solution, the precipitated N, N′-dicyclohexylurea was filtered, and the filtrate was concentrated. The concentrated residue was redissolved in ethyl acetate (50 ml) again, the insoluble material was filtered off, and the crude product obtained by concentration was purified by silica gel column chromatography to obtain the title compound (Ib) (4.22 g, 9.54 mmol). It was

Production Example 3 Production of t-butoxyacetic acid t-butyl ester (IIa). tert-Butyl alcohol (100 ml) with potassium tert-butoxide) 8.21 g, 73.20 mmo
l) was added and stirred for 30 minutes, and then chloroacetic acid tert
-Butyl (10.0 ml, 69.72 mmol) was added, and the mixture was reacted at room temperature for 2 days. The reaction solution was mixed with hexane (1
(00 ml) and water (100 ml), and the mixture was stirred for 10 minutes and separated into layers. The aqueous layer was further mixed with hexane (20 m
l), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. Vacuum distillation of the residue (boiling point 87 ° C 1
0 mmHg) to give the title compound (IIa) (5.89 g, 3
1.29 mmol) was obtained. 1H-NMR (300MHz, CDCl3) δ: 1.23 (s, 9H), 1.47 (s, 9H), 3.9
1 (s, 2H)

Production Example 4 Production of benzyloxyacetic acid benzyl ester (IIb) Sodium hydride (798 mg, 19.95 mmol) was added to benzyl alcohol (20 ml) under ice cooling.
The mixture was stirred for 20 minutes while warming to room temperature, then benzyl chloroacetate (3.0 ml, 19.70 mmol) was added, and the mixture was stirred for 1 hour. This reaction solution was mixed with hexane (20 m
The mixture was poured into a mixed solution of 1), ethyl acetate (20 ml) and water (20 ml), the layers were separated, and the mixture was further extracted with ethyl acetate (10 ml). The organic layers are combined, dried over sodium sulfate, filtered,
Concentrated. Benzyl alcohol was further distilled off from the obtained oily substance under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (IIb) (1.
28 g, 4.99 mmol) was obtained. 1H-NMR (300MHz, CDCl3) δ: 4.14 (s, 2H), 4.64 (s, 2H), 5.2
0 (s, 2H), 7.27-7.42 (m, 10H)

Example 1 (4S) -4- (N, N-dibenzylamino) -4-benzyl-3-oxo-2-t-
Production of butoxybutanoic acid t-butyl ester (IIIa) Anhydrous THF (12.5 m
1) and LDA in heptane, THF, and ethylbenzene solution (2.0M) (1.33 ml, 2.66 mmol) were mixed. It was synthesized there in Production Example 3 at -70 ° C (IIa).
(500 mg, 2.66 mmol) in THF (2.6 m
The solution dissolved in l) was added dropwise and stirred for 10 minutes. Next, a THF solution of (Ia) synthesized in Production Example 1 (0.25
M) (4.4 ml, 1.1 mmol) was added dropwise, and the mixture was reacted for 1 hour while raising the temperature. The reaction solution was citric acid (600 m
g, 3.12 mmol) was poured into a mixed solution of an aqueous solution in which water (10 ml) was dissolved and ethyl acetate (10 ml), and the mixture was stirred for 10 minutes and then separated into layers. The organic layer was washed with 10% aqueous potassium carbonate solution, dried over sodium sulfate, and filtered.
The crude product obtained by concentrating the filtrate was purified by silica gel preparative thin layer chromatography to give the title compound (2
A mixture of S, 4S)-(IIIa) and (2R, 4S)-(IIIa) (263.8 mg, 5.12 mmol) was obtained. Mass spectrum (FAB) 516 (MH +)

Example 2 Preparation of (4S) -4- (N, N-dibenzylamino) -4-benzyl-3-oxo-2-benzyloxybutanoic acid benzyl ester (IIIb) Anhydrous THF ( 15.0 ml) and L
DA in heptane, THF, ethylbenzene solution (2.0
M) (2.0 ml, 4.0 mmol) was mixed at -70 ° C. This solution was synthesized in Production Example 4 at -70 ° C (IIb).
(1.01 g, 3.95 mmol) in THF (8.0 m
The solution dissolved in l) was added dropwise and stirred for 15 minutes. Then, a THF solution of (Ib) synthesized in Production Example 2 (0.25
M) (7.9 ml, 1.98 mmol) was added dropwise, and the temperature was raised to 0 ° C. over 2 hours. The reaction solution was citric acid (1.0
g, 5.21 mmol) was poured into a mixed solution of an aqueous solution of water (20 ml) and ethyl acetate (20 ml), and the mixture was stirred for 15 minutes and then separated. The organic layer was washed with a 10% aqueous potassium carbonate solution and further washed with saturated saline. The crude product obtained by drying over sodium sulfate, filtering, and concentrating was purified by silica gel column chromatography to give the title compounds (2S, 4S)-(IIIb) and (2R, 4).
S)-(IIIb) mixture (646.0 mg, 1.11 mm
ol).

Example 3 Preparation of (3S) -3- (N, N-Dibenzylamino) -3-benzyl-3-oxo-1-benzyloxypropane (IVb) (IIIb) ( 646.0 mg, 1.11 mm
ol) was dissolved in ethyl acetate (11 ml), and the system was replaced with an argon stream. 5% palladium carbon (water content 5
(3.5%) (152.4 mg, 0.033 mmol) was added, and then argon in the system was replaced with a hydrogen stream, and the mixture was stirred overnight at room temperature and atmospheric pressure under a hydrogen atmosphere. The reaction solution was filtered through Celite, and the residue obtained by concentrating the filtrate was purified by silica gel preparative thin layer chromatography to obtain the title compound (IVa) (206.4 mg, 0.459 mmol). 1H-NMR (300MHz, CDCl3) δ: 2.92 (dd, J = 4.1,13.2Hz, 1H),
3.21 (dd, J = 9.4,13.2Hz, 1H), 3.57 (dd, J = 4.2,9.3Hz, 1H),
3.59 (d, J = 13.9Hz, 2H), 3.70 (d, J = 17.6Hz, 1H), 3.81 (d, J = 1
7.6Hz, 2H), 4.35 (d, J = 10.5Hz, 1H), 4.36 (d, J = 17.6Hz, 1H),
4.49 (d, J = 12.0Hz, 1H) Mass spectrum (FAB) 450 (MH +) Mass spectrum (ESI) 370 (MH +) Compounds used or synthesized in the above Production Examples and Examples are shown below.

[0053]

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[0054]

INDUSTRIAL APPLICABILITY According to the present invention, 3-amino-1, which is an important unit as an intermediate for pharmaceuticals including various HIV protease inhibitors or certain enzyme inhibitors,
It has become possible to industrially produce a 4-amino-3-oxo-2-hydroxybutanoic acid ester derivative that can be easily converted into 2-epoxypropanes in a high yield in a short process and in a safe process. .

Claims (6)

[Claims] 1. A compound represented by the following general formula (I): (In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a carbon skeleton thereof. A substituent containing a hetero atom therein, P ₁ ,
P ₂ is independently of each other hydrogen or an amino protecting group, or P ₁ and P ₂ are taken together to form a bifunctional amino protecting group,
E ₁ is an activated carboxy terminus and has 1 to 1 carbon atoms.
0 alkoxy ester residue, phenoxy group or benzyloxy group each optionally having a substituent on the ring, N-oxysuccinimide or 1-oxybenzotriazole active ester residue, active thioester residue, Imidazolyl group, acid halide, acid anhydride,
Alternatively, it represents a residue capable of forming an acid azide. ) By reacting with an alkali metal enolate derived from an ester of glycolic acid represented by the following general formula (II), (R ₁ in the formula has 1 to 1 carbon atoms which may have a substituent.
An alkyl group of 0, an aryl group of 6 to 15 carbon atoms or an aralkyl group of 7 to 20 carbon atoms, R ₂ is hydrogen, an alkyl group of 1 to 10 carbon atoms which may have a substituent, or 6 carbon atoms.
Represents an aryl group having 15 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an acyl group having 1 to 20 carbon atoms. ) 4-amino-3-oxo- represented by the following general formula (III)
A 2-hydroxybutanoic acid ester derivative was synthesized and (Rs, P ₁ , P ₂ , R ₁ and R ₂ in the formula have the above-mentioned meanings.) Further, the ester group is hydrolyzed and decarboxylated, and the following general formula (IV): ] (In the formula, Rs, P ₁ , P ₂ and R ₂ have the above-mentioned meanings.) A method for producing a 3-amino-2-oxo-1-hydroxypropane derivative or a salt thereof. 2. The method according to claim 1, wherein the carbon atom at the base of the amino group of the compound represented by formula (I) has S configuration. 3. The method according to claim 1, wherein the base carbon atom of the amino group of the compound represented by formula (I) has D configuration. 4. A 4-amino-3-oxo-2-hydroxybutanoic acid ester derivative represented by the following general formula (III) or a salt thereof. Embedded image (In the formula, Rs is hydrogen, an alkyl group having 1 to 10 carbon atoms which may have a substituent, an aryl group having 6 to 15 carbon atoms or an aralkyl group having 7 to 20 carbon atoms, or a carbon skeleton thereof. A substituent containing a hetero atom therein, P ₁ ,
P ₂ is independently of each other hydrogen or an amino protecting group, or P ₁ and P ₂ are taken together to form a bifunctional amino protecting group,
R ₁ is an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms or 7 to 2 carbon atoms.
0 represents an aralkyl group, R ₂ represents hydrogen, an optionally substituted alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or 1 carbon atom. Represents an acyl group of 20. ) 5. The compound according to claim 4, which has a (4S) configuration. (Except when Rs is hydrogen.) 6. The compound according to claim 4, which has a (4R) configuration. (Except when Rs is hydrogen.)