JPH0737440B2 - Method for producing sulfonium compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to an acylation reaction of peptides, amino acids and the like, and particularly to a method for producing a sulfonium compound useful as an excellent acylating reagent that enables acylation in an aqueous solution. .

(Prior Art) Conventionally, as a method for producing a sulfonium compound represented by the following general formula (II), p-dimethylsulfoniophenol methylsulfate in the presence of triethylamine,
Patent publication Sho 63-8365
No. However, in this method, the above-produced compound has similar solubility to triethylamine hydrochloride as a by-product and various solvents, and therefore it is difficult to separate it from this triethylamine hydrochloride, and a complicated purification step is required, There were problems such as not being economical.

Further, as a method of directly reacting a thioanisole derivative and dimethyl sulfate to obtain a sulfonium compound, the method of the Journal of American Chemical Society (J. Am
er.Chem.Soc.) Vol. 78, 87-91 (1956), there is a description that a p-hydroxyphenylmethyl sulfide and dimethyl sulfate are allowed to directly act without a solvent to obtain a sulfonium compound.
However, when the method described in this Journal of American Chemical Society is adopted for the reaction of p-acyloxyphenyl methyl sulfide and dimethyl sulfate, the acyl group part is thermally decomposed or the acidity of methyl sulfate ion is strong. , The desired sulfonium compound cannot be obtained.

(Object of the Invention) An object of the invention is to provide a method for producing a sulfonium compound represented by the following general formula (II), which is simple and does not require a purification step.

(Structure of the Invention) The present invention relates to a method for producing a sulfonium compound represented by the general formula (II), which comprises reacting a thioanisole derivative represented by the general formula (I) with dimethyl sulfate in a solvent at a specific temperature. Is. In this reaction, dimethyl sulphate was added to the thioanisole derivative in an organic solvent with a boiling point of 70 to 120 ° C
Temperature range of 0 ℃ ~ 90 ℃ (However, the boiling point of the organic solvent is 9
If the temperature is 0 ° C. or lower, the boiling point is the upper limit, and the reaction is performed to obtain a sulfonium compound represented by the following general formula.

[In the formula, R is any of a benzyloxy group, a p-methoxybenzyloxy group and a phenyl group] [Wherein R has the same meaning as described above] Specific examples of the organic solvent include benzene, toluene,
Examples are ethanol and acetonitrile. The reaction temperature is in the range of 70 ° C to 90 ° C (however, if the boiling point of the organic solvent is 90 ° C or less, the boiling point is the upper limit). If it is below this range, the reaction is slow and it is not practical in the production of compounds. If the temperature exceeds this range, the above-mentioned compound (II) is thermally decomposed to give an unfavorable result.

Compared with the conventional method, the present invention does not require the use of amines such as triethylamine, which was required for the purpose of neutralization, can obtain a high-purity product that does not require purification in one step, production The process is simplified,
This is an industrially advantageous manufacturing method.

(Examples) Hereinafter, the present invention will be described in detail with reference to synthesis examples, but the advantages of the present invention are not limited to the following.

Synthesis Example 1 Synthesis of p-methylthiophenylbenzyl carbonate methyl sulfate 40 g of p-methylthiophenylbenzyl carbonate (0.1
40 ml of toluene was added to (46 mol), 18.4 g (0.146 mode) of dimethyl sulfate was added dropwise at 70 to 80 ° C., and the reaction was further performed in this temperature range for 2 hours. After the reaction is complete, cool and filter,
Dried.

Yield 45.7g (78.3%) mp121-124 ℃ Elemental analysis value (theoretical value) C, 51.25% (51.01%) H, 5.12% (4.99%) S, 15.92% (15.99%) Synthesis example 2 p-Dimethylsulfonio Synthesis of Phenylbenzoate Methyl Sulfate 40 g (0.164 mol) p-methylthiophenylbenzoate
Toluene (40 ml) is added, and dimethyl sulfate (20 g) is added at 80-90 ℃.
(0.159 mol) was added dropwise, and the reaction was continued for 2 hours in this temperature range. After the reaction was completed, it was cooled, filtered, and dried.
Yield 47.6g (78.4%) mp172-175.9 ° C Elemental analysis value (theoretical value) C, 51.91% (51.88%) H, 4.98% (4.90%) S, 17.29% (17.31%) Comparative Example 1 p-Dimethylsulfonio Synthesis of Phenylbenzyl Carbonate Methyl Sulfate p-Dimethylsulfoniophenol Methyl Sulfate 26g
Was dissolved in 200 ml of acetonitrile, and 16 ml of benzyloxycarbonyl chloride and 14 ml of triethylamine were added dropwise while stirring at room temperature. After completion of the reaction, the mixture is filtered to remove most of triethylamine hydrochloride, the filtrate is concentrated under reduced pressure, DMF-ether mixed solution is added to the residue, and the precipitated triethylamine hydrochloride is removed by filtration. Further, the filtrate is concentrated under reduced pressure, a mixed solution of n-hexane-DMF is added, and the precipitated triethylamine hydrochloride is removed by filtration. Next, the filtrate was concentrated under reduced pressure, and ether was added to the residue for crystallization. Yield 30 g (75%) Elemental analysis value (theoretical value) C, 51.31% (51.01%) H, 5.13% (4.99%) S, 15.95% (15.99%) Comparative Example 2 The reaction of Synthesis Example 1 was carried out at 95-105 ° C. I went there. When the reaction was carried out for 2 hours in this temperature range, the product was p-dimethylsulfoniophenol methylsulfate in which the benzyloxycarbonyl group was eliminated by thermal decomposition.

Comparative Example 3 The reaction of Synthesis Example 1 was changed to an ethanol solvent and carried out at 60 ° C. The reaction was carried out in this temperature range for 2 hours. After the reaction was completed, it was cooled, filtered, and dried, and the yield was 19.2 g (32.9
%)Met.

Reference Example Synthesis of benzyloxycarbonylglycine 40 g of p-dimethylsulfoniophenylbenzyl carbonate methylsulfate prepared in Synthesis Example 1 was dissolved in water, and an aqueous solution of 7.5 g of glycine and 14 ml of triethylamine was added dropwise with stirring. The mixture was stirred at room temperature, HCl was added to the reaction solution to pH 2, and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated under reduced pressure, and ether was added to the obtained residue to give white crystals. Yield 20.6g (95.8%) mp119-120 ℃
(Reference value: 120 ° C.) (Effect of the invention) According to the method of the present invention, a sulfonium compound is obtained by reacting a thioanisole derivative with only dimethyl sulfate in a solvent, so that purification for removal of triethylamine hydrochloride can be performed. Since it is not necessary, the process is simplified and the solvent cost is reduced. As described above, it was found that the method for producing a sulfonium compound according to the present invention contributes as a useful method for producing an acylating reagent.

Claims (1)

[Claims] 1. A thioanisole derivative represented by the general formula (I) and dimethyl sulfate in an organic solvent having a boiling point of 70 ° C. to 120 ° C. in a temperature range of 70 ° C. to 90 ° C. (provided that the boiling point of the organic solvent is A method of producing a sulfonium compound represented by the general formula (II), which comprises reacting at a boiling point of up to 90 ° C.). [In the formula, R is any of a benzyloxy group, a p-methoxybenzyloxy group, and a phenyl group] [Wherein R has the same meaning as described above]