JPH06157422A - Production of di-t-butyl dicarbonate - Google Patents

Abstract

PURPOSE:To provide an economical process for producing a dicarbonate in a short reaction time in high yield. CONSTITUTION:Di-t-butyl dicarbonate is produced by reacting an alkali metal (preferably Na) mono-t-butyl carbonate with an aromatic sulfonyl halide (e.g. p-toluenesulfonyl chloride) in the presence of a t-amine (e.g. triethylamine, N,N- dimethylaniline and pyridine) and dimethyl sulfoxide at -50 to +100 deg.C (preferably 0-50 deg.C). Preferably, the amount of the aromatic sulfonyl halide is 0.3-0.5 times mol, that of the t-amine is 0.001-20mol% (especially 0.05-10mol%) and that of dimethyl sulfoxide is 30-100mol% based on the t-butyl carbonate salt. The di-t-butyl dicarbonate is useful as an agent for introducing a protecting group to protect an amino group by tert-butoxycarbonylation.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to industrial use of di-tert-butyldicarbonate, which is a protective group-introducing agent useful when protecting an amino group by tert-butoxycarbonylation (hereinafter abbreviated as Boc). Regarding manufacturing method.

[0002]

As a Boc agent, the simplest structure is the corresponding chloroformate, but this compound is extremely unstable and difficult to handle. Therefore, di-tert-butyl dicarbonate (hereinafter sometimes simply referred to as dicarbonate) has been devised as a stable and highly reactive Boc agent. However, in the case of industrially producing dicarbonate, many problems such as raw materials and solvents and problems in reaction operation cannot be produced at low cost.

As a method for producing dicarbonate, various methods have been devised to obtain dicarbonate by condensing two molecules by reacting an alkali metal mono-tert-butyl carbonate with an appropriate reactant. As the type of the reactant, phosgene, methanesulfonyl halide, aromatic sulfonyl halide, etc. are known, but among them, the aromatic sulfonyl halide has an advantage that it can be reacted near room temperature with less restriction of temperature in the reaction. Have

As a method for obtaining a dicarbonate by reacting an alkali metal mono-tert-butyl carbonate with an aromatic sulfonyl halide, the following series of Czechoslovakian patents and JP-A-4-103562 are known. There is.

However, in the above-mentioned Czechoslovakian patent, CS247845 and CS24 are disclosed.
According to Japanese Patent No. 7846, the reaction is carried out in a DMF-toluene mixed solvent, but it takes 15 to 20 hours to complete the reaction, which is not satisfactory. After that, the reaction time was shortened in DMF-toluene by adding a quaternary ammonium salt, but the reaction time was still required to be 5 hours, which was not sufficient for industrial implementation (CS
No. 257157). Next, a further improvement was made in Czechoslovakian Patent No. CS260076, and dicarbonate was obtained in a high yield by adding pyridine in addition to a quaternary ammonium salt, and it was 90 minutes even though the solvent was only toluene. It has succeeded in shortening the reaction time. However, the amount of pyridine used here is as large as 110 mol% with respect to sodium tert-butyl carbonate, and it is not necessarily an economical method because pyridine is relatively expensive. It is also known that the presence of a large amount of pyridine induces the decomposition of dicarbonate (see JP-A-4-103562). Therefore, it is necessary to remove pyridine after completion of the reaction. Usually, acid washing is used to remove pyridine, but dicarbonate is a substance which is unstable to acid. That is, the use of a large amount of pyridine has a drawback that it causes a complicated operation in the post-treatment after the reaction.

Further, in the method described in JP-A-4-103562, a quaternary ammonium salt is not used, and a catalytic amount of an aliphatic tertiary amine is added in place of a large amount of pyridine to carry out the reaction in toluene. Although it does, it requires a reaction time of 22 hours. Similarly, the reaction is carried out in a toluene-DMF mixed solvent, but a reaction time of 7 hours is required.

That is, in a method for producing a dicarbonate by reacting an alkali metal mono-tert-butyl carbonate with an aromatic sulfonyl halide, when a large amount of amine is used as a catalyst, the reaction is fast, but after-treatment after the reaction and There is a problem in terms of economy, and conversely, if the amount of amine used is reduced, the reaction becomes slow, productivity becomes poor, and the cost of the apparatus increases, so this is not an economical method. Further, when the reaction time is shortened, unreacted aromatic sulfonyl halide remains, and it is difficult to separate it from dicarbonate, and a complicated operation for removing this is required.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide an economical method for producing dicarbonate in a high yield with a short reaction time.

[0009]

In view of the above-mentioned circumstances, the present inventors have found that dicarbonate can be obtained in high yield, and it is inexpensive and easy to remove and completes the reaction in a short time. The inventors conducted extensive studies on a reaction accelerator having the ability to cause the reaction. As a result, surprisingly, the reaction proceeds smoothly by reacting the mono-tert-butyl carbonate of an alkali metal with an aromatic sulfonyl halide in the presence of a reaction accelerator which is a combination of a tertiary amine and dimethyl sulfoxide. Then, it was found that dicarbonate was produced in a high yield in a short time, and the present invention was completed.

That is, the present invention relates to an alkali metal monolayer.
-tert-butyl carbonate and aromatic sulfonyl halide,
A method for producing a dicarbonate, which comprises reacting in the presence of a tertiary amine and dimethyl sulfoxide. The alkali metal mono-tert-butyl carbonate (hereinafter sometimes simply referred to as tert-butyl carbonate), which is the raw material of the present invention, is not particularly limited in production method, purity and shape. Normal,
It is prepared by carbonating carbon dioxide by bubbling carbon dioxide into alkali metal-tert-butoxide in an organic solvent.

Examples of the type of alkali metal in the alkali metal mono-tert-butyl carbonate include potassium and sodium, and sodium, which can be obtained at low cost, is preferably used.

The aromatic sulfonyl halide which is the raw material of the present invention can be used without particular limitation as long as it is a known aromatic compound having at least one halogenosulfone group. Specifically, benzenesulfonyl chloride,
Benzene disulfonyl dichloride, p-toluene sulfonyl chloride, p-ethylbenzene sulfonyl chloride, 2,4-dimethyl benzene sulfonyl chloride, p-fluorobenzene sulfonyl chloride, p-chlorobenzene sulfonyl chloride, p-bromobenzene sulfonyl chloride, p-nitrobenzene sulfonyl Chloride,
2,4-dichlorobenzenesulfonyl chloride, naphthalenesulfonyl chloride, benzenesulfonyl bromide, p-toluenesulfonyl bromide, p-chlorobenzenesulfonyl bromide and the like are preferably used.

The theoretically required amount of aromatic sulfonyl halide is 0.5 mole times that of tert-butyl carbonate, but if the amount of aromatic sulfonyl halide used is too large, the decomposition reaction will proceed due to the acid produced, which is preferable. On the contrary, if it is too small, the yield of dicarbonate decreases. Therefore,
The aromatic sulfonyl halide used in the present invention is preferably 0.3 to 0.5 mol times with respect to tert-butyl carbonate.

As the tertiary amine which is one of the reaction accelerators in the present invention, for example, triethylamine, N, N,
Aliphatic amines such as N ', N'-tetramethylethylenediamine, aromatic amines such as N, N-dimethylaniline, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4 , 0] Alicyclic amines such as undecene, pyridine,
Heterocyclic amines such as quinoline, N-methylmorpholine,
Examples include ether amines such as N-ethylmorpholine.

The amount of the amine used is tert-
0.001 to 20 mol% is preferable with respect to butyl carbonate, and 0.05 to 10 mol% is more preferable. When the amine is used alone, the reaction rate is slowed down so that it cannot be a practical method for producing a dicarbonate, and the reaction proceeds extremely efficiently only in the presence of dimethyl sulfoxide.

The amount of dimethyl sulfoxide used as another reaction accelerator in the present invention is preferably 30 to 100 mol% with respect to tert-butyl carbonate. If it is too small, a sufficient reaction rate cannot be obtained, and if it is too large, the effect remains unchanged, which is uneconomical.

The starting material, tert-butyl carbonate, is generally insoluble and forms a lump in an organic solvent. However, when dimethylsulfoxide is added to this state, surprisingly, the lumpy tert-butyl carbonate changes and swells. This phenomenon occurs only for dimethyl sulfoxide, suggesting that dimethyl sulfoxide forms a complex with tert-butyl carbonate. This increases the solubility of tert-butyl carbonate and / or
Alternatively, the solid surface area of tert-butyl carbonate increases. As a result, it is considered that the reaction with the aromatic sulfonyl halide is promoted in the presence of the tertiary amine. Dimethyl sulfoxide can be easily removed with neutral water after the reaction.

Examples of the reaction solvent used in the present invention include aromatic hydrocarbons such as benzene and toluene, aliphatic hydrocarbons such as hexane and heptane, halogenated aliphatic hydrocarbons such as methylene chloride and carbon tetrachloride, and tetrahydrofuran. , Cyclic ethers such as dioxane, aliphatic ethers such as diethyl ether, isopropyl ether, dibutyl ether, dimethoxyethane, and mixtures thereof. The amount of the reaction solvent used is not particularly limited, but it is usually 1 to 2 with respect to the starting alkali metal-tert-butoxide as the amount by which the reaction mixture is smoothly stirred.
0 weight times solvent is used.

The reaction temperature is preferably -50 to 100 ° C.
And more preferably 0 to 50 ° C. If the reaction temperature is too low, the reaction rate becomes very slow, and if it is too high, the product is decomposed and the yield is lowered. The reaction time is
The reaction time is usually 0.5 to 5 hours, though it is not always constant, depending on the amount of the reaction accelerator or the reaction temperature.

[0020]

EXAMPLES Next, the present invention will be described more specifically by way of examples, but the present invention is not limited to the following examples.

Example 1 20 equipped with a stirrer, gas inlet tube, cooler and thermometer
Purify 95.8 by replacing 0 ml 4 neck flask with nitrogen
% Sodium-tert-butoxide (11.42 g, 0.113 mol) and toluene (50 ml) were added, and carbon dioxide gas was adjusted to 12 while stirring and maintaining the temperature in the reaction vessel at 30 to 40 ° C.
A slurry solution of sodium-tert-butyl carbonate was prepared by introducing at a rate of 0 ml / min for 90 minutes. 3 in the sodium mono-tert-butyl carbonate slurry solution
N, N, N ', N'-tetramethylethylenediamine at 5-40 ° C
0.056 g (0.00048 mol), dimethylsulfoxide 4.15 g (0.0
531 mol), p-toluenesulfonyl chloride 10.00 g (0.0
525 mol) was added, and the mixture was reacted and stirred at 35 to 40 ° C. for 2 hours. After completion of the reaction, 50 ml of water was added to the reaction mixture, and the mixture was stirred and mixed, and then allowed to stand to separate an organic layer and an aqueous layer. Dicarbonate and unreacted p-toluenesulfonyl chloride in the organic layer were analyzed by gas chromatography to determine the yield of dicarbonate based on sodium-tert-butoxide, and the residual ratio of p-toluenesulfonyl chloride. It was The results are shown in Table 1.

Examples 2 to 5 The same reaction treatment was carried out except that the amine catalyst shown in Table 1 was used instead of the N, N, N ', N'-tetramethylethylenediamine used as the amine catalyst in Example 1. It was The yield of the obtained dicarbonate is shown in Table 1.

Comparative Examples 1 to 3 3.88 g (0.0531 mol) of dimethylformamide was used in place of dimethylsulfoxide in Example 1, and the reaction time was extended as in Example 1 or as shown in Table 1 to carry out the reaction. The reaction treatment was performed in the same manner as in Example 1 except for the above. The yield of the obtained dicarbonate and the residual ratio of p-toluenesulfonyl chloride are shown in Table 1.

[0024]

EFFECTS OF THE INVENTION According to the present invention, the reaction between a mono-tert-butyl carbonate and an aromatic sulfonyl halide is completed in a short time, and di-tert-butyl carbonate can be produced economically advantageously. . In addition, dimethyl sulfoxide constituting the reaction accelerator is inexpensive and can be easily removed with neutral water. Therefore, the present invention provides an economical and convenient industrial production method of dicarbonate.

[Table 1] Table 1

Claims (2)

[Claims] 1. A method for producing a dicarbonate, which comprises reacting an alkali metal mono-tert-butyl carbonate with an aromatic sulfonyl halide in the presence of a tertiary amine and dimethyl sulfoxide. 2. The method according to claim 1, wherein the type of alkali metal is sodium or potassium.