JPS5953901B2 - New method for producing α-mercaptoamino acid derivatives - Google Patents

Description

Detailed Description of the Invention The present invention is based on the general formula R1 -C-C00R3[1]' (wherein R1 is a hydrogen atom, an alkyl group or an aralkyl group, R2 is an acyl group, R3 is an ester residue, and R4 is an alkyl group) , represents an aryl group or an aralkyl group.

) Novel compounds of α-mercaptoamino acid derivatives
Regarding the manufacturing method.

Many sulfur-containing amino acids have biological activity, and among them, sporidesmin [tetrahedron letters, 12
65-1260 (1962)], Alatinone [Journal of the American Chemical Society, Vol. 90, pp. 6517-6519 (1968)]
etc. Antibiotics are known.

Several methods have been known to synthesize α-mercaptoamino acids.

For example, a method via oxazolinone [Tetrahedron Letters, pp. 3077-3079 (1971)] a method via dehydroamino acids [Journal of Organic Chemists, Vol. 38, 126-128.
(1973)], but all of these methods have the disadvantage that the synthesis of the starting compounds is complicated and only a limited number of target compounds can be obtained. The present invention etc. is based on α represented by the following general formula]
- We established a simple method for producing an acetoxyamino acid derivative (Japanese Patent Application Laid-Open No. 105120/1989), but after careful investigation of the chemical properties of this α-acetoxyamino acid derivative, we found that this compound [0 reacts with a mercaptan compound in high yield]. death,
The present inventors have discovered that an α-mercabutamino acid derivative represented by the general formula [1] can be obtained, and have completed the present invention. That is, according to the present invention, the target compound [] can be produced by reacting an α-acetoxyamino acid derivative [] and a mercaptan compound [] as shown in the reaction formula below.

(However, Rl, R2, R3 and R4 have the same meanings as above.) In the present invention, the group or atom represented by the symbol R1 is, for example, a methyl group, an ethyl group, a propyl group, Isopropyl group, butyl group,
Alkyl groups such as isobutyl group, 1-methylpropyl group, aralkyl groups such as benzyl group, p-hydroxybenzyl group, 3,4-dihydroxybenzyl group, hydrogen atom, etc., and the acyl group represented by the symbol R2 is, for example, acetyl group. aliphatic acyl groups such as propionyl groups, butyl groups,
An aromatic acyl group such as a benzoyl group, and the ester residue represented by the symbol R3 is an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an aralkyl group such as a benzyl group, etc. Examples include compounds that are .

Examples of the other raw material compound ['' include the group represented by the symbol R4, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, amyl group,
Examples include compounds having an alkyl group such as an isoamyl group, an aryl group such as a phenyl group, an aralkyl group such as a benzyl group, and the like. The reaction of the present invention may be carried out, for example, by dissolving the above-mentioned raw material compound [l] in a suitable solvent and adding the raw material mercaptan compound [] to this. In this case, the reaction is carried out with O
It progresses suitably at around ~60°C.

As the reaction solvent, for example, tetrahydrofuran, acetonitrile, acetic acid, etc. can be used as appropriate.

The target compound [1] thus produced can be purified by known isolation and purification methods such as extraction, concentration, silica gel chromatography,
It can be easily obtained by appropriately combining recrystallization and the like. The object compound [1] of the present invention is, for example, 3,6
- Dimercaptopiperazine is useful as a synthetic intermediate for antibacterial agents such as 2,5-dione;
1] is a compound that is also useful as an intermediate for the synthesis of α-keto acids.

Example 1 0.99 (5 mmol) of N-acetyl-α-acetoxyglycine ethyl ester was dissolved in 3d of acetonitrile, and 0.52f of isoamylmercaptotan was added to the solution. (5 mmol) and triethylamine 0.59 (5 mmol) and stirred for 15 hours.

After the reaction, the solvent is distilled off and the resulting residue is dissolved in ethyl acetate. This liquid was washed with water, dried, and then the solvent was distilled off. The resulting oil was passed through a column filled with 20 g of silica gel (trade name: Kieselgel, manufactured by Talc), and eluted with chloroform. Acetyl-
α-isoamylthioglycine ethyl ester 0.75
f! get.

Yield 68%. Film. IRν ・Max 332O (NH), 1750 (C=0) 1670 (C=0), 1530 (C=0) (CIIL-
1) NMR (CDCl, δ) v crystalline (T, 3H, CH3), 1.4-1.7 (M, 3H,]
CH2CH, 1), 2.07 (S, 3H, CH3), 2
．． 71 (T, 2H, -CHi-S-), 54.24 (Q
, 2H, CH2), 5.52 (D, lH, CH), 6.
55 (Br, d, lH, NH), Example 2N-acetyl-α-acetoxyphenylalanine ethyl ester 1
．． 5.9 (5 mmol) was dissolved in 1 acetate and 3 d of nitrile, and 0.6 f of benzyl mercaptan! (5 mmol)
and triethylamine 0.59 (5 mmol),
Stir at room temperature for 3 hours.

After the reaction, the solvent is distilled off and the resulting residue is extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off.

The resulting residue is recrystallized from diisopropyl ether to obtain 1.8 g of N-acetyl-α-benzylthiophenylalanine ethyl ester. Yield 100
%. Mp. 9O~92℃ NujOl. IRν: Max 322O(NH), 1730(C=0), 1640(C
=0), 1540 (C=0) (C!FL-1) NMR (CDCl,.δ): 1.31 (T, 3H, CH,), 1.78 (S, 3H
, CH3), 3.72 (ABq, 2H, CH2-, h)
, 3.76 (S, 2H, S-CH2), 4.15 (Q,
2H, CH, ), 6.28 (Br, s, lH, NH),
7.1-7.3 (M, 1OH, phenyl) Examples
3 N-acetyl-α-acetoxyalanine ethyl ester 1.1f1 (5 mmol) was dissolved in acetonitrile 3d, benzyl mercaptan 0.69 (5 mmol) and triethylamine 0551 (5 mmol) were added thereto, and 3 Stir for a while.

Hereinafter, by treating in the same manner as in Example 2, N-acetyl-α-benzylthioalanine ethyl ester 1.4
Get 9. Yield 100%. Mp. 68~70℃NujO
l IRν: Max 325O(NH), 1740(C=0),) 1640(C:O), 1550(C=0)(Cm-1) NMR(CDCl3,δ): 1.30(T, 3H, CH3), 1.76(S,3H
, CH3), 1.89 (S, 3H, CH3), 3.72
(S, 2H, S-CH2), 4.21 (Q, 2H, CH
2), 6.28 (Br, lH, NH), 7.30 (D,
5H, phenyl) Example 4 0.9 (5 mmol) of N-acetyl-α-acetoxy-glycine ethyl ester was dissolved in tetrahydrofuran, and 0.559 (5 mmol) of thiophenol and 0.59 (5 mmol) of triethylamine were dissolved in tetrahydrofuran. ) and stir at room temperature for 5 hours.

By treating in the same manner as in Example 2, N-acetyl-α-phenylthioglycine ethyl ester 1.1
Get 69. Yield 95Cf1). Mp. 58~60℃
. NujOl IRν: Max 337O(NH), 1730(C=0) 1680(C=0), 1500(C=0)(CflL-
1) NMR (CDCl3, δ): 1.26 (T, 3H, CH3), 2.00 (S, 3H
, CH3), 4.19 (Q, 2H, CH3), 5.75
(D, lH, CH), 6.60 (Br, d, lH, NH
), 7.2-7,7 (M, 5H2phenyl) Example 1.19 (5 mmol) of 5N-acetyl-α-acetoxy-alanine ethyl ester was dissolved in tetrahydrofuran, and 0.559 (5 mmol) of thiophenol was dissolved in this. ) and 0.59 (5 mmol) of triethylamine are added.

By processing in a shell-like manner as in Example 4 below, N-acetyl-α-phenylthioalanine ethyl ester 1.2
Obtain 5g. Yield 95%. Mp. l2l~123°C NuJOi. IRν: Max 33OO(NH), 1740(C=O), 1670(C
= 0), 1555 (C = 0) (CIIL-1) NMR (CDCl,, δ): 1.29 (T, 3H, CH3), 1.92 (S, 3H
, CH3), 1,99 (S, 3H, CH3), 4.19
(Q, 2H, CH,), 6.55 (bτ, S, lH, N
H), 7.38 (S5H, phenyl').

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is a hydrogen atom, an alkyl group or an aralkyl group, R^2 is an acyl group, and R^3 is an ester residue. ) and the α-acetoxyamino acid derivative represented by the general formula R
^4-SH (However, R^4 represents an alkyl group, an aryl group, or an aralkyl group.) A general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( However, R^1, R^2, R^3 and R^4 represent the same meanings as above.) A method for producing an α-mercaptoamino acid derivative. 2 An α-acetoxyamic acid derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the same general formula, the symbol R^1 is a hydrogen atom, a lower alkyl group or a benzyl group, and the symbol R^2 is a lower aliphatic group. Group acyl group, symbol R
^3 represents a lower alkyl group, and the general formula R^4-S
2. The method according to claim 1, wherein the mercaptan compound represented by H 2 has the same general formula, and the symbol R^4 represents a lower alkyl group, a phenyl group, or a benzyl group.