JPH0827082A - Method for producing alpha-dehydroamino acid ester - Google Patents

Abstract

PURPOSE:To simply obtain the subject compound useful as an intermediate for physiologically active peptide antibiotics such as antibacterial agents from easily available raw materials by a step comprising reacting a specific alpha,beta-unsaturated ester with a specific O-alkylhydroxylamine. CONSTITUTION:(A) A compound of formula I [R1,R2 are H, 1-4C (branched)alkyl, (inactive group-substituted)phenyl; R3 is 1--4C (branched)alkyl] such as methyl crotonate is reacted with a compound of formula II [R4 is 1-4C (branched)alkyl] such as Omethylhydroxylamine in the presence of (C) a base such as an alkyl lithium compound or alkali metal alkoxide to obtain the objective compound of formula III. The component (C)is used in an amount of 0.8-2 molar times that of the component (A).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an α-dehydroamino acid ester from an α, β-unsaturated ester in one step using O-alkylhydroxylamine.

[0002]

2. Description of the Related Art Conventionally, .alpha.-dehydroamino acid esters are extremely important compounds as intermediates of peptide antibiotics having various physiological activities such as antibacterial activity, antitumor activity, antiviral activity and enzyme inhibitory activity. It has been known. In addition, this compound is also optimal as a prochiral substrate for asymmetric reduction and asymmetric addition reactions, and has various optically active α
-The utility value is very high, such as the ability to induce amino acids. Conventionally, as a method for producing such α-dehydroamino acid ester, a method via azlactone produced by condensation of aldehyde and acylglycine, β-
Method by β-elimination reaction of hydroxy-α-amino acid derivative, method by condensation reaction of α-ketocarboxylic acid and amine, or method by Wittig reaction [Synth
esis, 159 (1988)] is known.

However, all of these methods are multi-step reactions and have many problems such that the reaction substrate is limited to a specific compound, so that they cannot be said to be industrially advantageous production methods.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present inventor has made it simple to use α as a raw material from a wide range of reaction substrates.
As a result of studying a method for producing a dehydroamino acid ester, it was found that by reacting an easily available α, β-unsaturated ester with an O-alkylhydroxylamine, an α-dehydroamino acid ester can be obtained in one step. The present invention has been reached.

[0005]

That is, the present invention provides a general formula (2) (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aryl group, and R ₃ represents a lower alkyl group. Here, the lower alkyl group means a straight chain or a branched chain. The aryl group means an phenyl group which may have a substituent which does not inhibit the reaction, and an α, β-unsaturated ester represented by Below, the general formula 3 (Wherein R ₄ represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms) and is reacted with an O-alkylhydroxylamine. (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above.)
The present invention provides a method for producing an α-dehydroamino acid ester represented by

In the present invention, the α, β-unsaturated ester represented by the general formula 2 used as a raw material is
For example, methyl acrylate, ethyl acrylate, t-butyl acrylate, methyl crotonate, ethyl crotonate,
T-Butyl crotonate, methyl 3,3-dimethyl acrylate, methyl cinnamate, methyl 2-chlorocinnamate, methyl 3-chlorocinnamate, methyl 4-chlorocinnamate, methyl 2-methoxycinnamate, 3-methoxy Examples include methyl cinnamate, methyl 4-methoxycinnamate and the like.

Examples of the O-alkylhydroxylamine represented by the general formula 3 used in the present invention include O-methylhydroxylamine, O-ethylhydroxylamine, Ot-butylhydroxylamine and the like. The amount of the O-alkylhydroxylamine used is usually 0.8 to 5 mole times, preferably 0.8 to 2 times the amount of the α, β-unsaturated ester as a raw material.
The molar ratio is more preferably 1 to 1.5.

The reaction is carried out in the presence of a base, and as such a base, for example, an alkyllithium compound, an alkali metal amide, an alkali metal alkoxide, etc. are preferably used. Specific examples of such a base include n-butyllithium, lithium diisopropylamide, potassium-t-butoxide, and the like. The amount of base used is
The amount is usually 0.8 to 5 times, and preferably 1 to 3 times the amount of α, β-unsaturated ester.

A solvent is usually used in the reaction, and examples of such a solvent include aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, ether solvents such as diethyl ether, tetrahydrofuran and ethylene glycol dimethyl ether, n
-Hexane, n-heptane, and other aliphatic hydrocarbon solvents can be used, and these can be used alone or as a mixed solvent of two or more thereof. The amount of such a solvent used is not particularly limited, but is usually 1 to 100 times by weight with respect to the α, β-unsaturated ester.

The reaction temperature is usually in the range of -100 to 100 ° C, preferably -80 to 0 ° C.

The target compound produced by such a reaction is
From the reaction mixture after the completion of the reaction, the usual means, for example distillation,
It can be easily isolated and purified by operations such as extraction, recrystallization or various chromatographies.

[0012]

According to the method of the present invention, an α-dehydroamino acid ester can be produced in a single step from various α, β-unsaturated esters that are easily available. Further, since the O-alkylhydroxylamine used as an aminating agent in the present invention can be easily obtained from hydroxylamine at a relatively low cost, the present method is industrially extremely advantageous.

[0013]

The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited thereto.

Example 1 7 ml of dry tetrahydrofuran and 118 g of O-methylhydroxylamine were placed in a flask which had been thoroughly purged with nitrogen.
After adding mg (2.5 mmol) and cooling to −70 ° C., 1.56 ml (2.5 mmol) of a hexane solution of 1.6 Mn-butyllithium was added at the same temperature and then dissolved in 3 ml of dry tetrahydrofuran. 200 mg (2.0 mmol) of methyl crotonate was added. -70 ° C
After stirring for 30 minutes, a saturated aqueous ammonium chloride solution was added, and methylene chloride was further added for extraction treatment. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was isolated by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1). Purify (Z)-
127 mg of methyl 2-aminocrotonate (yield 55
%) Was obtained. ¹ H NMR (270 MHz) spectrum (CDCl ₃ ) δ 1.87 (d, 3H, J = 6.60 Hz), 3.77 (s, 3H), 5.90 (br.s, 1H)
, 6.96 (m, 1H), 9.92 (br.s, 1H) ¹³ CNMR (270MHz) spectrum (CDCl ₃ ) δ 17.9, 64.2, 121.2, 141.0, 164.5 mass spectrum m / z 115 (M +), 69, 41 , 39

Example 2 324 mg (2.0 mmol) of methyl cinnamate and O-
Dissolve 118 mg (2.5 mmol) of methylhydroxylamine in 2 ml of dry tetrahydrofuran and -70
673 mg of potassium-t-butoxide cooled to ℃
8 m of dry tetrahydrofuran containing (6.0 mmol)
1 solution was added dropwise at the same temperature over 5 minutes. After completion of the dropping, the mixture was stirred at -70 ° C for 20 minutes, saturated aqueous ammonium chloride solution was added, and methylene chloride was further added for extraction treatment. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the product was isolated and purified by silica gel thin layer chromatography (developing solution: ethyl acetate / hexane = 1/1) to purify (Z) -2- 47 mg of methyl amino-3-phenylacrylate was obtained. ¹ H NMR (270 MHz) spectrum (CDCl ₃ ) δ 3.84 (s, 3H), 6.55 (br.s, 1H), 7.34 (m, 3H), 7.51
(m, 2H), 7.76 (d, 1H, J = 15.84Hz), 9.28 (br.s, 1H) ¹³ CNMR (400MHz) spectrum (CD ₃ OD) δ 65.3, 118.8, 129.7, 130.8, 131.9, 136.8, 143.5,
166.8 Mass spectrum m / z 177 (M +), 176, 146, 131, 103, 77, 51

Claims (5)

[Claims] 1. A general formula 2 (In the formula, R ₁ and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aryl group, and R ₃ represents a lower alkyl group. Here, the lower alkyl group means a straight chain or a branched chain. The aryl group means an phenyl group which may have a substituent which does not inhibit the reaction, and an α, β-unsaturated ester represented by Below, the general formula 3 (Wherein R ₄ represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms) and is reacted with an O-alkylhydroxylamine. (In the formula, R ₁ , R ₂ and R ₃ have the same meanings as described above.)
The manufacturing method of the alpha-dehydro amino acid ester shown by these. 2. An O-alkylhydroxylamine is O-
Α- according to claim 1, which is methylhydroxylamine.
Process for producing dehydroamino acid ester. 3. The base is an alkali metal compound.
The method for producing an α-dehydroamino acid ester according to 1. 4. The method for producing an α-dehydroamino acid ester according to claim 3, wherein the alkali metal compound is an alkyllithium compound or an alkali metal alkoxide. 5. The method for producing an α-dehydroamino acid ester according to claim 1, wherein the amount of O-alkylhydroxylamine used is 0.8 to 2 mole times that of the α, β-unsaturated ester.