JPH0259146B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a novel method for synthesizing hydroxy acid derivatives.

The object compound of this invention can be produced by the method shown in the following reaction formula.

[In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a lower alkyl group, aralkyl group, benzoyl group, aryl group, cycloalkyl group, lower alkanoyl group, or N-benzyloxycarbonyl-D-phenylglycyl group, R ³ is a glycine residue, and CO—R ⁴ is an ester group , X is an oxygen atom or a sulfur atom, Z is a benzyloxycarbonyl group or a tertiary butoxycarbonyl group, n is 0 or 1
] In each of the above general formulas, the lower alkyl groups represented by R ¹ and R ² include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl,
Examples of the aralkyl group represented by R ² include tertiary butyl, pentyl, hexyl, etc., benzyl, phenethyl, benzhydryl, trityl, etc. as the aryl group, phenyl, naphthyl, tolyl, xylyl, etc. as the cycloalkyl group. Examples of lower alkanoyl groups include form, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl.

The glycine residue represented by R ³ means a residue obtained by removing an amino group and a carboxy group from glycine.

Examples of the ester group represented by the group CO--R ⁴ include alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, and pentyl ester, and aralkyl esters such as benzyl ester, benzhydryl ester, trityl ester, and phenethyl ester. Examples include esters.

In the method of this invention, the reaction between compound () and compound () is usually carried out in an organic solvent such as chloroform or methylene chloride at room temperature to heating. In addition, when using alcohol or thioalcohol as a raw material compound (), this reaction is usually carried out in the presence of a Lewis acid such as boron trifluoride. The resulting compound () is isolated and purified by conventional methods.

The compound () produced by this invention has the general formula [In the formula, R ¹ , R ² , R ³ , be.

This compound () is produced by the following method.

[In the formula, R ¹ , R ² , R ³ , R ⁴ , X, Z and n each have the same meaning as above] Compound () or its ester
It is produced by subjecting it to an elimination reaction of a butoxycarbonyl group.

For the elimination reaction of a benzyloxycarbonyl group or a tertiary butoxycarbonyl group, an optimal method may be adopted depending on the reaction. For example, a benzyloxycarbonyl group may be hydrogenated in the presence of a metal catalyst for catalytic reduction. is preferred.

In addition, a benzyloxycarbonyl group or a tertiary
Depending on the type of elimination reaction of the tertiary butoxycarbonyl group and the type of ester group represented by CO—R ⁴ in the compound (), an ester bond may also occur along with the elimination of the benzyloxycarbonyl group or the tertiary butoxycarbonyl group. A compound () having a free carboxyl group may be obtained by cleavage, and such cases are also included in this method.

The compound () produced by this reaction is isolated and purified by conventional methods.

Next, the method of the present invention will be explained using examples.

Example 1 [Synthesis of raw material compound] (1) Benzene sulfonate of serine benzyl ester (56 g) is dissolved in chloroform (100 ml), and triethylamine (42 ml) is added. A solution of trityl chloride (41.8 g) in chloroform (80 ml) was added to this under ice cooling, and the mixture was stirred at 0°C for 24 hours. The reaction solution was washed with 10% citric acid aqueous solution and water, dried over anhydrous sodium sulfate, and then
Upon concentration, oily N-tritylserine benzyl ester can be obtained quantitatively. [α] ²⁵ _D = +64.8° (c = 1.0, CH ₃ OH) Elemental analysis: C ₂₉ H ₂₇ NO ₃ Calculated value: C79.61, H6.22, N3.20 Experimental value: C79.43, H6 .32, N3.42 (2) Dissolve N-tritylserine benzyl ester (65.6 g) in dry pyridine (200 ml).
A solution of tosyl chloride (85.8 g) in dry pyridine (50 ml) was added to the mixture at -10°C for 1 hour, and the mixture was stirred at 0°C for 24 hours. Concentrate the reaction solution and dissolve the oily concentrate in ethyl acetate. This is washed successively with water, a 10% aqueous citric acid solution, and water, dried over anhydrous sodium sulfate, and then concentrated. The oily concentrate was dissolved in tetrahydrofuran (100 ml) and triethylamine (39.2
ml) and reflux at 75°C for 24 hours. This is concentrated, and the oily concentrate is dissolved in ethyl acetate (300 ml), washed successively with a 10% aqueous citric acid solution, a 1M aqueous sodium bicarbonate solution, and water, dried over anhydrous sodium sulfate, and then concentrated. The residue was crystallized from a mixture of ethyl acetate, ether and n-hexane to give 1-tritylaziridine-2-carboxylic acid benzyl ester (31.4g).
get. mp114-116℃.

[α] ²⁰ _D = -95.5° (c = 1.0, tetrahydrofuran) Elemental analysis: C ₂₉ H ₂₅ NO ₂ Calculated value: C83.03, H6.01, N3.34 Experimental value: C83.03, H5.84, N3.25 (3) 1-Tritylaziridine-2-carboxylic acid benzyl ester (5.04g) was dissolved in chloroform (10
ml) and to this anhydrous methanol (10 ml)
and then add trifluoroacetic acid (20ml).
Add under stirring at 5°C. The mixture is stirred for 2 hours and then concentrated. Add ether and water to the oily concentrate, and PH the aqueous layer with sodium bicarbonate.
Adjust to 8. The aqueous layer was extracted with ether, and the extract was dried over anhydrous sodium sulfate and concentrated to obtain oily benzyl aziridine-2-carboxylic acid ester (1.92 g).

[α] ²³ _D = -56.8° (c = 1.0, tetrahydrofuran) Elemental analysis: C ₁₀ H ₁₁ NO ₂ Calculated values: C67.78, H6.26, N7.91 Experimental values: C67.52, H6.31, N7.76 (4) Aziridine-2-carboxylic acid benzyl ester (10.6g) and triethylamine (8.4ml)
A solution of benzyl chlorocarbonate (8.6 ml) in chloroform (10 ml) was added dropwise to a solution of benzyl chlorocarbonate (8.6 ml) in chloroform (10 ml) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution is washed with water and 10% citric acid aqueous solution, dried over sodium sulfate, and then chloroform is distilled off under reduced pressure. The oily residue was purified by silica gel column chromatography to obtain oily 1-benzyloxycarbonylaziridine-2-carboxylic acid benzyl ester (14.9 g) [α] ²³ _D = -18.1° (c = 1.0, CH ₃ OH) [Synthesis of target compound] (5) 1-Benzyloxycarbonylaziridine-
2-Carboxylic acid benzyl ester (0.3g) was mixed with benzyl alcohol (5ml) and chloroform (3ml).
After adding a catalytic amount of boron trifluoride etherate to this mixture,
Leave it for a while. After washing the reaction solution with water and drying, the solvent was distilled off under reduced pressure, and the oily residue was purified by silica gel column chromatography to obtain oily N-benzyloxycarbonyl-O-benzyl-L-serine. Benzyl ester is obtained almost quantitatively.

When this product is treated with a 2N aqueous sodium hydroxide solution, N-benzyloxycarbonyl-O-benzyl-L-serine is obtained. mp97-98℃.

[α] ²³ _D = +9.4° (c = 1.3, CH ₃ OH) This completely matched the melting point and optical rotation of a standard product prepared from O-benzyl-L-serine by a different method.
This shows that the ring cleavage reaction of aziridine with alcohol occurs selectively between the N--C bond of the aziridine ring, and the conformation of L-serine is maintained.

Example 2 1-Benzyloxycarbonyl-L-aziridine-2-carboxylic acid benzyl ester (0.3 g) was dissolved in a mixture of chloroform (3 ml) and methanol (5 ml), and a catalytic amount of boron trifluoride etherate was added thereto. was added and treated in the same manner as in Example 1-(5), resulting in oily N-benzyloxycarbonyl-
O-methyl-L-serine benzyl ether is obtained.
Yield 64% [α] ²⁴ _D = -19.1° (c = 1.4, CH ₃ OH) Elemental analysis: C ₁₉ H ₂₁ NO ₅ Calculated values: C66.46, H6.16, N4.08 Experimental values: C66. 04, H6.32, N4.31 Example 3 (1) 1-Benzyloxycarbonyl-L-aziridine-2-carboxylic acid benzyl ester (0.3 g) was dissolved in a mixture of isopropyl alcohol (5 ml) and chloroform (3 ml). Then, a catalytic amount of boron trifluoride etherate is added thereto and treated in the same manner as in Example 1-(5) to obtain oily N-benzyloxycarbonyl-O-isopropyl-L-serine benzyl ester. Yield 95% [α] ²⁴ _D = -19.5° (c = 1.1, CH ₃ OH) Elemental analysis: C ₂₁ H ₂₅ NO ₅ Calculated values: C67.91, H6.78, N3.77 Experimental values: C67. 65, H6.90, N3.80 Reference Example 1 N-benzyloxycarbonyl-O-isopropyl-L-serine benzyl ester (218 mg) is catalytically hydrogenated in methanol using palladium black as a catalyst. The catalyst is removed from the reaction solution, and methanol is distilled off from the solution under reduced pressure. When the residue is recrystallized from water-acetone, O-isopropyl-L-serine is obtained almost quantitatively. mp221℃ (decomposition).

[α] ²³ _D = -11.8° (c = 1.0, CH ₃ OH) Elemental analysis: C ₆ H ₁₃ NO ₃ Calculated values: C48.97, H8.90, N9.52 Experimental values: C48.86, H8. 79,N9,49 Example 4 1-benzyloxycarbonyl-L-aziridine-2-carboxylic acid benzyl ester (0.3g)
Example 1-(5) was dissolved in a mixture of sec-butyl alcohol (5 ml) and chloroform (3 ml), and a catalytic amount of boron trifluoride etherate was added thereto.
When treated in the same manner as above, oily N-benzyloxycarbonyl-O-sec-butyl-L-serine benzyl ester is obtained. Yield 73%.

[α] ²⁴ _D = -17.4° (c = 0.9, CH ₃ OH) Elemental analysis: C ₂₂ H ₂₇ NO ₅ Calculated values: C68.55, H7.06, N3.63 Experimental values: C68.04, H7. 48, N3.85 Example 5 (1) 1-Benzyloxycarbonyl-L-aziridine-2-carboxylic acid benzyl ester (0.3 g) was dissolved in a mixture of tert-butyl alcohol (5 ml) and methylene chloride (3 ml). To this, a catalytic amount of boron trifluoride etherate is added and treated in the same manner as in Example 1-(5) to obtain oily N-benzyloxycarbonyl-O-tert-butyl-L-serine benzyl ester. . Yield 58%.

[α] ²⁴ _D = -20.0° (c = 1.0, CH ₃ OH) Elemental analysis: C ₂₂ H ₂₇ NO ₅ Calculated values: C68.55, H7.06, N3.63 Experimental values: C68.26, H7. 23, N4.17 Reference Example 2 N-benzyloxycarbonyl-O-tert-butyl-L-serine benzyl ester (100 mg) is catalytically hydrogenated in methanol (10 ml) using palladium black as a catalyst. Remove the catalyst from the reaction solution,
Methanol is distilled off from the liquid under reduced pressure. When the residue is recrystallized from water-acetone, O-tert-butyl-L
- Obtain serine almost quantitatively. mp209℃ (decomposition).

[α] ²³ _D = -14.8° (c = 1.0, H ₂ O) Elemental analysis: C ₇ H ₁₅ NO ₃ Calculated values: C52.16, H9.38, N8.69 Experimental values: C51.89, H9. 41, N8.57 Example 6 1-Benzyloxycarbonyl-L-aziridine-2-carboxylic acid benzyl ester (0.3 g) was mixed with cyclohexanol (5 ml) and methylene chloride (3
ml), added a catalytic amount of boron trifluoride etherate, and treated in the same manner as in Example 1-(5) to obtain an oily N-benzyloxycarbonyl-O-cyclohexyl-L- Obtain serine benzyl ester. Yield 57%.

[α] ²⁴ _D = -20.1° (c = 1.1, CH ₃ OH) Elemental analysis: C ₂₄ H ₂₉ NO ₅ Calculated values: C70.05, H7.10, N3.40 Experimental values: C69.51, H7. 23, N3.44 Example 7 [Synthesis of raw material compounds] (1) 3-Methyl-aziridine-2-carboxylic acid methyl ester (9 g) and triethylamine (10.9 ml) are dissolved in chloroform (200 ml). This is added to chlorobenzyl carbonate (11.1
ml) in chloroform (10 ml) was added dropwise under ice-cooling and treated in the same manner as in Example 1-(4), resulting in oily methyl 1-benzyloxycarbonyl-3-methyl-L-aziridine-2-carboxylate. Obtain ester (11.3g).

[α] ²³ _D = -66.2° (c = 1.1, CH ₃ OH) Elemental analysis: C ₁₃ H ₁₅ NO ₄ Calculated values: C62.64, H6.07, N5.62 Experimental values: C62.47, H6. 15, N5.35 [Synthesis of target compound] (2) 1-benzyloxycarbonyl-3-methyl-L-aziridine-2-carboxylic acid methyl ester (0.2 g) was dissolved in tert-butyl alcohol (5
ml) and chloroform (2 ml),
When a catalytic amount of boron trifluoride etherate was added to this and treated in the same manner as in Example 1-(5), oily N-benzyloxycarbonyl-O-tert
-Butyl-L-threonine methyl ester is obtained. Yield 94%.

[α] ²³ _D = +4.6° (c = 1.1, dimethylformamide) Elemental analysis: C ₁₇ H ₂₅ NO ₅ Calculated values: C63.14, H7.79, N4.33 Experimental values: C63.32, H8. 01, N4.21 Reference example 3 N-benzyloxycarbonyl-O-tert-butyl-L-threonine methyl ester (449 mg)
Dissolve in methanol, add 1N aqueous sodium hydroxide solution, and stir for 1 hour. The reaction solution was adjusted to pH 2 with citric acid, and N-benzyloxycarbonyl-O-tert-butyl-L-threonine was extracted with ethyl acetate. After drying the extract, the solvent is distilled off, and the residue is dissolved in methanol and catalytically hydrogenated using palladium black. The catalyst is removed from the reaction solution, and methanol is distilled off from the solution under reduced pressure. Crystallization of the residue from water-acetone yields O-tert-butyl-L-threonine almost quantitatively. mp207
°C (decomposition).

[α] ²³ _D = -41.6° (c = 1.1, H ₂ O) Elemental analysis: C ₈ H ₁₇ NO ₃ Calculated values: C54.83, H9.78, N7.99 Experimental values: C54.67, H9. 83, N8.03 Example 8 Using methanol (5 ml) instead of tert-butyl alcohol in Example 7-(2), Example 7
-Processing in the same manner as in (2) yields oily N-benzyloxycarbonyl-O-methyl-L-threonine methyl ester.

[α] ²⁴ _D = -6.4° (c = 1.1, CH ₃ OH) Elemental analysis: C ₁₄ H ₁₉ NO ₅ Calculated values: C59.77, H6.81, N4.98 Experimental values: C59.49, H6. 63, N4.81 Example 9 (1) When treated in the same manner as in Example 7-(2) using isopropyl alcohol (5 ml) instead of tert-butyl alcohol in Example 7-(2), an oily N-benzyloxycarbonyl-O-isopropyl-L-threonine methyl ester is obtained. Yield 98%.

[α] ²⁴ _D = -10.7° (c = 1.4, CH ₃ OH) Elemental analysis: C ₁₆ H ₂₃ NO ₅ Calculated values: C62.12, H7.49, N4.53 Experimental values: C61.93, H7. 46, N4.48 Reference example 4 N-benzyloxycarbonyl-O-isopropyl-L-threonine methyl ester (224mg)
was dissolved in methanol (3 ml), a 1N aqueous sodium hydroxide solution (2.5 ml) was added thereto, and the mixture was stirred for 1 hour. The reaction solution was adjusted to pH 2 with citric acid, and N-benzyloxycarbonyl-O-isopropyl-L-threonine was extracted with ethyl acetate. After drying the extract, the solvent was distilled off and the residue was dissolved in methanol (10ml).
and catalytically hydrogenate using palladium black. The catalyst is removed from the reaction solution, and methanol is distilled off from the solution under reduced pressure. Crystallization of the residue from water-acetone yields O-isopropyl-L-threonine almost quantitatively. mp212℃ (decomposition).

[α] ²³ _D = -45.8° (c = 1.0, H ₂ , O) Elemental analysis: C ₇ H ₁₂ NO ₃ Calculated values: C52.16, H9.38, N8.69 Experimental values: C51.96, H9 .26, N8.59 Example 10 When treated in the same manner as in Example 7-(2) using sec-butyl alcohol (5 ml) instead of tert-butyl alcohol in Example 7-(2), an oily N
-benzyloxycarbonyl-O-sec-butyl-L-threonine methyl ester is obtained. Yield 92
%.

[α] ²⁴ _D = -14.1° (c = 1.2, CH ₃ OH) Elemental analysis: C ₁₇ H ₂₅ NO ₅ Calculated values: C63.14, H7.79, N4.33 Experimental values: C62.89, H7. 61, N4.19 Example 11 Using cyclohexanol (5 ml) instead of tert-butyl alcohol in Example 7-(2),
When treated in the same manner as in Example 7-(2), oily N-benzyloxycarbonyl-O-cyclohexyl-
L-threonine methyl ester is obtained. Yield 92
%.

[α] ²⁴ _D = -9.1° (c = 1.1, CH ₃ OH) Elemental analysis: C ₁₉ H ₂₇ NO ₅ Calculated values: C65.31, H7.79, N4.01 Experimental values: C65.29, H7. 68, N3.97 Example 12 Using phenol (5 ml) instead of tert-butyl alcohol in Example 7-(2), Example 7-
When treated in the same manner as in (2), N-benzyloxycarbonyl-O-phenyl-L-threonine methyl ester is obtained. mp72~73℃. Yield 57%.

Elemental analysis: C ₁₉ H ₂₁ NO ₅ Calculated values: C66.46, H6.16, N4.08 Experimental values: C66.37, H5.96, N4.21 Example 13 Example 7 - tert in (2) - By using benzyl alcohol (5 ml) instead of butyl alcohol and treating in the same manner as in Example 7-(2), oily N-benzyloxycarbonyl-O-benzyl-L-threonine methyl ester was obtained. Yield 98%.

[α] ²⁴ _D = -6.9° (c = 1.1, CH ₃ OH) Elemental analysis: C ₂₀ H ₂₃ NO ₅ Calculated values: C67.21, H6.49, N6.92 Experimental values: C67.09, H6. 31, N4.06 Example 14 1-benzyloxycarbonyl-L-aziridine-2-carboxylic acid benzyl ester (200mg)
Benzylthiol (1.6 g) is added to a solution of 1.0 in methylene chloride (3 ml). Adding a catalytic amount of boron trifluoride etherate to this and treating in the same manner as in Example 1-(5), N-benzyloxycarbonyl-S
-Benzyl-L-cysteine benzyl ester (203 mg) was obtained. mp69~70.5℃.

[α] ²³ _D = -46.3° (c = 1.1, CH ³ OH) Example 15 [Synthesis of raw material compounds] (1) P-toluenesulfonate of glycine benzyl ester (32.1 g) in methylene chloride (200 ml)
Triethylamine (13.3ml) and N-
Add tert-butoxycarbonylserine (19.8g) at -20°C with stirring. A solution of dicyclohexylcarbodiimide (19.8 g) in methylene chloride (50 ml) was added to this, and the mixture was stirred at -20°C for 20 hours.
Acetic acid (1 ml) is added to this to remove dicyclohexyl urea and the liquid is concentrated. The resulting oil was dissolved in ethyl acetate (500 ml) and the precipitated dicyclohexyl urea was removed. After washing the solution successively with a saturated aqueous solution of sodium bicarbonate, water, and a 10% aqueous citric acid solution, trace amounts of dicyclohexylurea are removed again. The solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, treated with activated carbon, and then concentrated. The oily concentrate was crystallized from a mixture of ethyl acetate, ether and n-hexane, and recrystallized from the mixture to give N-(N-tert-butoxycarbonylseryl)glycine benzyl ester (20.5 g). mp81~83℃.

[α] ²³ _D = -12.5° (c = 0.92, CH ₃ OH) (2) Add anisole (1 ml) to a solution of N-(N-tert-butoxycarbonylseryl) glycine benzyl ester (20.5 g) in ethyl acetate (300 ml). )
After addition, dry hydrogen chloride gas is passed through at 0°C for 20 minutes with stirring. The reaction solution was left at room temperature for 2 hours and then concentrated. The precipitated crystals were collected and washed with anhydrous ether to obtain N-serylglycine benzyl ester hydrochloride (17.04 g). This product was used as it was in the next reaction.

(3) In a solution of N-serylglycine benzyl ester hydrochloride (17.04 g) in chloroform (100 ml),
Add triethylamine (16.4 ml) and trityl chloride (16.73 g) at -20°C with stirring,
Stir at room temperature for 20 hours. The reaction solution was concentrated and the resulting oil was dissolved in ethyl acetate (300 ml).
This dissolution was carried out 4 times with water and 2 times with 10% citric acid aqueous solution.
The mixture was washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain oily N-(N-tritylseryl)glycine benzyl ester (29.0 g).

[α] ²³ _D = −74.6° (c = 1.0, CH ₃ OH) (4) Tosyl chloride (34.3 g) and pyridine ( 100
ml) solution under stirring at −20° C. and stirred for an additional 40 hours at the same temperature. This is concentrated, and the resulting oil is washed twice with water and twice with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated again. The resulting oil was dissolved in tetrahydrofuran (300 ml), triethylamine (25.02 ml) was added thereto, and the mixture was refluxed for 40 hours. The reaction solution was concentrated and the resulting oil was dissolved in ethyl acetate (300 ml). Add this solution to 3
Wash twice with water, dry with anhydrous sodium sulfate, and then concentrate. The concentrate was subjected to silica gel column chromatography and eluted with a mixture of n-hexane and ethyl acetate (2:1). Concentration of the eluate yields oily N-(1-trityl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (24 g).

[α] ²³ _D = -82.2゜ (c = 1.0, CH ₃ OH) (5) N-(1-trityl-L-aziridine-2-
ylcarbonyl)glycine benzyl ester (7.15 g) was added to a mixture of trifluoroacetic acid (50 ml) and anhydrous methanol (5 ml) under stirring at 0°C, and the mixture was further stirred at 0°C for 2 hours. The reaction solution was concentrated, dry ether was added to the residue, and the resulting crystals were collected to obtain trifluoroacetate (4.17 g) of N-(L-aziridin-2-ylcarbonyl)glycine benzyl ester. mp101.5
-102℃.

[α] ²³ _D = −17.1° (c = 1.0, CH ₃ OH) (6) Trifluoroacetate (1.75 g) of N-(L-aziridin-2-ylcarbonyl) glycine benzyl ester in chloroform (10 ml) Benzyl chlorocarbonate (1.95 g) and triethylamine (1.94 ml) are added to the solution with stirring at 0° C., and the mixture is stirred at room temperature for 20 hours. The reaction solution was concentrated and the resulting oil was dissolved in ethyl acetate (60 ml). This solution was mixed once with water, three times with 10% citric acid solution, and once with saturated sodium chloride solution.
The mixture is washed three times with a saturated aqueous solution of sodium bicarbonate and three times with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated. The residue was treated with a mixture of ethyl acetate and petroleum ether, the precipitate was collected, and recrystallized from ethyl acetate to give N-(1-benzyloxycarbonyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (1.53 g). ).
mp109.0―110.0℃.

[α] ²⁵ _D = -50.6° (c = 1.0, CH ₃ OH) Elemental analysis: C ₂₀ H ₂₀ N ₂ O ₅ Calculated values: C65.21, H5.47, N7.60 Experimental values: C65.17, H5.50, N7.71 [Synthesis of target compound] (7) N-(1-benzyloxycarbonyl-L-
aziridin-2-ylcarbonyl)glycine benzyl ester (368 mg) in methylene chloride (5
ml) Add acetic acid (5 ml) to the solution and leave at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate ether to give N-
(benzyloxycarbonyl-O-acetyl-
L-seryl) glycine benzyl ester (388
mg).

mp123.0―123.5℃.

[α] ²³ _D = -6.2° (c = 1.0, CH ₃ OH) Elemental analysis: C ₂₂ H ₂₄ N ₂ O ₇ Calculated values: C61.63, H5.65, N6.54 Experimental values: C61.95, H5.64, N6.55 Example 16 Add N-benzyloxycarbonyl-D- to a solution of N-(1-benzyloxycarbonyl-L-aziridin-2-ylcarbonyl) glycine benzyl ester (368 mg) in methylene chloride (10 ml). Add phenylglycine (1.48g) and leave at room temperature for 4 days. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate. This is washed with a 1N aqueous sodium hydrogen carbonate solution and water, dried, and concentrated under reduced pressure. Crystallization of the residue from ether-hexane gives N-[N-benzyloxycarbonyl-O-(N-benzyloxycarbonyl-D-phenylglycyl)-L-seryl]glycine benzyl ester (622 mg). mp157―
159℃.

[α] ²³ _D = −16.1° (c = 1.0, dimethylformamide) Example 17 [Synthesis of raw material compounds] (1) N-(1-aziridin-2-ylcarbonyl) glycine benzyl ester (4.00 g) in chloroform (30 ml) solution were added 2-tert-butoxycarbonyloxyimino-2-phenylacetritrile (4.63 g) and triethylamine (2.38 ml) at -20°C with stirring, and at room temperature
Stir for an hour. The reaction solution was concentrated and the resulting oil was dissolved in ethyl acetate (100 ml). This solution was washed once with water, three times with a 10% citric acid aqueous solution, three times with a saturated aqueous sodium chloride solution, three times with a saturated aqueous sodium bicarbonate solution, and three times with a saturated aqueous sodium chloride solution, and then washed with anhydrous sodium sulfate. After drying, concentrate. The resulting oil was subjected to silica gel column chromatography using a mixture of chloroform and ethyl acetate (3:
Elute with 1). The eluate was concentrated and the oily residue was crystallized from a mixture of ethyl acetate and n-hexane to yield N-(1-tert-butoxycarbonyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (3.51 g). obtain.

mp71.0―72.5℃.

[α] ²⁵ _D = -80.4° (c = 1.0, CH ₃ OH) Elemental analysis: C ₁₇ H ₂₂ N ₂ O ₅ Calculated values: C61.07, H6.63, N8.34 Experimental values: C61.22, H6.85, N8.35 [Synthesis of target compound] (2) N-(1-tert-butoxycarbonyl-L-
aziridin-2-ylcarbonyl) glycine benzyl ester (334 mg) in methylene chloride (10
ml) solution, N-benzyloxycarbonyl-
D-phenylglycine (1.48g) was added and treated in the same manner as in Example 16, resulting in N-[N-tert-butoxycarbonyl-O-(N-benzyloxycarbonyl-D-phenylglycyl)-L-seryl]glycine. Obtain benzyl ester (485 mg). mp100.5―102.5℃.

[α] ²³ _D = -20.3° (c = 1.0, dimethylformamide) Example 18 [Synthesis of raw material compound] (1) N-(3-methylaziridin-2-ylcarbonyl) glycine benzyl ester (1.87g)
chloroform benzyl ester (1.19 ml) was added to a solution of triethylamine (1.05 ml) in chloroform (15 ml) under ice cooling, and the mixture was stirred at room temperature for 20 hours. The reaction solution is washed with water and a 10% aqueous citric acid solution, dried, and then the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from ethyl acetate/hexane to give N-(1-benzyloxycarbonyl-3-methyl-L-aziridine-2
-Ircarbonyl)glycine benzyl ester (2.10g) is obtained. mp62-64℃.

[α] ²³ _D = -63.2° (c = 1.0, CH ³ OH) Elemental analysis: C ₂₁ H ₂₂ N ₂ O ₅ Calculated values: C65.96, H5.80, N7.33 Experimental values: C65.95, H5.83.N7.42 [Synthesis of target compound] (2) N-(1-benzyloxycarbonyl-3-
Acetic acid (5 ml) was added to a solution of methyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (382 mg) in methylene chloride (5 ml), and the mixture was allowed to stand at room temperature for 6 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was crystallized from ethyl acetate/ether to obtain N-(N-benzyloxycarbonyl-O-acetyl-L-threonyl)glycine benzyl ester (395 mg). mp122-123℃.

[α] ²³ _D = +6.4゜ (c = 1.0, CH ₃ OH) Elemental analysis: C ₂₃ H ₂₆ N ₂ O ₇ Calculated values: C62.43, H5.92, N6.33 Experimental values: C62.59 , H6.22, N6.70 Example 19 [Synthesis of raw material compounds] (1) N-(3-methyl-L-aziridin-2-ylcarbonyl) glycine benzyl ester (1.25 g) and triethylamine (0.7 ml) 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1.4 g) was added to a chloroform (12 ml) solution under ice cooling, and the mixture was stirred at room temperature for 3 days. The reaction solution is washed with water, a 10% aqueous citric acid solution and a 1N aqueous sodium bicarbonate solution, dried, and the solvent is distilled off under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give N-(1-tert-butoxycarbonyl-3-methyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (2.03 g).
get. mp89.5―90℃.

[α] ²³ _D = -70.0° (c = 1.1, CH ₃ OH) Elemental analysis: C ₁₈ H ₂₄ N ₂ O ₅ Calculated values: C62.06, H6.94, N8.04 Experimental values: C62.21, H7.24, N8.01 [Synthesis of target compound] (2) N-(1-tert-butoxycarbonyl-3-
N-benzyloxycarbonyl-D-phenylglycine (1.48 g) was added to a solution of methyl-L-aziridin-2-ylcarbonyl) glycine benzyl ester (334 mg) in methylene chloride (10 ml).
Add and leave at room temperature for 3 days. When the reaction solution was treated in the same manner as in Example 16, N-[N-tert-butoxycarbonyl-O-(N-benzyloxycarbonyl-D-phenylglycyl)-L-threonyl]glycine benzyl ester (588 mg)
get. mp101-103℃.

[α] ²³ _D = -3.0° (c = 1.0, dimethylformamide) Example 20 Chlorination of N-(1-benzyloxycarbonyl-3-methyl-L-aziridin-2-ylcarbonyl) glycine benzyl ester (382 mg) Add N-benzyloxycarbonyl-D-phenylglycine (1.48 g) to a methylene (10 ml) solution and leave at room temperature for 3 days. The reaction solution was treated in the same manner as in Example 16 to obtain N-[N-benzyloxycarbonyl-O-(N-benzyloxycarbonyl-D-phenylglycyl)-L-threonyl]glycine benzyl ester (510 mg). mp168.5―
169.5℃.

[α] ²³ _D = -2.6° (c = 1.0, dimethylformamide) Example 21 1-benzyloxycarbonylaziridine-2
-Dissolve benzyl carboxylic acid ester (200 mg) in thioacetic acid (3 ml), add a catalytic amount of boron trifluoride etherate, and let stand for 24 hours. Thioacetic acid is distilled off from the reaction solution under reduced pressure, and the acid residue is dissolved in ether. This solution is washed with a 1N aqueous sodium hydrogen carbonate solution, dried, and then the ether is distilled off under reduced pressure. When the residue was purified by silica gel column chromatography, an oily N-
Benzyloxycarbonyl-S-acetylcysteine benzyl ester is obtained quantitatively.

NMR (CDCl ₃ ): δ1.42 (3H, s), 3.2-3.5 (2H,
m), 4.45-4.80 (1H, m), 5.05, 5.10 (4H, 2s),
5.60 (1H, d) 7.25, 7.27 (10H, 2s) Example 22 N-(1-benzyloxycarbonyl-3-methylaziridin-2-ylcarbonyl) glycine benzyl ester (200 mg) in thioacetic acid (3 ml)
Dissolve in and leave at room temperature for 24 hours. Thioacetic acid is distilled off from the reaction solution under reduced pressure, and the residue is recrystallized from chloroform ether to quantitatively obtain N-(2-benzyloxycarbonylamino-3-acetylthiobutyryl)glycine benzyl ester.

mp149-150℃.

NMR (CDCl ₃ ): δ1.33 (3H, d), 2.24 (3H,
s), 4..02 (2H, d), 3.85-4.6 (2H, m), 5.06,
5.13 (4H, 2s), 5.76 (1H, d), 6.8 (1H, m),
7.28 (10H, s) Example 23 Thiobenzoic acid (1.88%
ml) and boron trifluoride etherate (0.1
ml) under ice-cooling and reacted at room temperature for 7 hours to obtain N-benzyloxycarbonyl-S-benzoyl-L-cysteine methyl ester (4.04 g).
get. mp85-86℃.

Example 24 Using 1-benzyloxycarbonyl-D-aziridine-2-carboxylic acid methyl ester (21.0 g), methylene chloride (50 ml), thiobenzoic acid (15.7 ml) and boron trifluoride etherate (0.6 ml) The mixture was treated in the same manner as in Example 23 to obtain N-benzyloxycarbonyl-S-benzoyl-D-cysteine methyl ester (19.5 g).

mp86-87℃.

Example 25 1-benzyloxycarbonyl-3-methyl-
Treated as in Example 23 using L-aziridine-2-carboxylic acid methyl ester (3.05 g), methylene chloride (20 ml), thiobenzoic acid (1.57 ml) and boron trifluoride etherate (0.1 ml). Then, oily L-2-benzyloxycarbonylamino-3-benzoylthiobutyric acid methyl ester (3.46 g) was obtained.

Example 26 1-benzyloxycarbonyl-3-methyl-
Same as Example 23 using D-aziridine-2-carboxylic acid memethyl ester (5.45 g), methylene chloride (30 ml), thiobenzoic acid (2.82 ml) and boron trifluoride etherate (0.15 ml). Upon treatment, oily D-benzyloxycarbonylamino-3-benzoylthiobutyric acid methyl ester (4.77 g) is obtained.

Example 27 N-(1-tert-butoxycarbonyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (91 mg) was dissolved in methylene chloride (2 ml), and 2 equivalents of thiobenzoic acid was added thereto at room temperature. Stir for 24 hours. Add ethyl acetate to the reaction solution,
The mixture is washed three times with a saturated aqueous sodium bicarbonate solution and then three times with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. When the residue is treated with n-hexane and the resulting crystals are recrystallized from ethyl acetate/n-hexane, N-
(N-tert-butoxycarbonyl-S-benzoyl-L-cysteinyl)glycine benzyl ester (113 mg) was obtained. mp101~103℃.

Example 28 Treated as in Example 27 using N-(1-tert-butoxycarbonyl-3-methyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (94 mg) and 2 equivalents of thiobenzoic acid. Then, N-(L-2-tert-butoxycarbonylamino-3-benzoylthiobutyryl)glycine benzyl ester (101 mg) was obtained.

mp125-127℃.

Example 29 When treated as in Example 27 using N-(1-benzyloxycarbonyl-3-methyl-L-aziridin-2-ylcarbonyl)glycine benzyl ester (86 mg) and 2 equivalents of thiobenzoic acid, , N-(L-2-benzyloxycarbonylamino-3-benzoylthiobutyryl)glycine benzyl ester (97 mg) was obtained.

mp130.5―133℃.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom or a lower alkyl group,
R ³ is a glycine residue, CO-R ⁴ is an ester group, Z
is a ^{benzyloxycarbonyl} group or a tertiary butoxycarbonyl group, and n means 0 or ¹ , respectively).
benzoyl group, aryl group, cycloalkyl group,
A compound represented by a lower alkanoyl group or a N-benzyloxycarbonyl-D-phenylglycyl group (X means an oxygen atom or a sulfur atom, respectively) is reacted with the compound represented by the general formula (In the formula, R ¹ , R ² , R ³ , R ⁴ , X, Z and n each have the same meanings as before.) A method for synthesizing an amino acid derivative, which is characterized by obtaining a compound represented by the following.