JPH02124870A - Production of sulfonium compound - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a reagent for introducing acyl group as a protecting group in the field of organic synthetic chemistry in high yield by reacting a p-dialkylsulfoniophenol with a carbonyl halogenide compound in the presence of a specific secondary amine. CONSTITUTION:The objective compound of formula III (Y<-> is halogen anion, perchlorate radical, etc.) can be produced by reacting a p-dialkylsulfoniophenol of formula I (R<1> and R<2> are alkyl; X<1> is H, halogen or alkyl) with preferably 0.8-1.5mol (based on 1mol of the compound of formula I) of a carbonyl halogenide compound of formula II (R is alkyl, t-butoxy, benzyloxy, p- methoxybenzyloxy or phenyl) in the presence of a base consisting of a secondary amine having two secondary alkyl groups bonded to a nitrogen atom at -80-+25 deg.C. The secondary amine is e.g., dicyclohexylamine and its amount is 0.8-1.5mol per 1mol of the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing a sulfonium compound. More specifically, the present invention provides p represented by the following general formula (1).
-A method for producing a sulfonium compound represented by formula (II[) by acylating a phenolic hydroxyl group of a dialkylsulfoniophenol. Here, acyl means a group obtained by removing a hydroxyl group from a carboxylic acid or carbonic acid monoester.

y+ The sulfonium compound represented by the above general formula (II[) exhibits an acylation effect in an aqueous solution, so it is useful as a reagent for introducing an acyl group as a protective group in the field of organic synthetic chemistry such as peptide synthesis. It is a compound.

[Prior art and its problems] Conventionally, as a method for acylating the phenolic hydroxyl group of p-dialkylsulfoniophenol represented by the above general formula (1), an acid halide, that is, a carbonyl halide compound, is acylated with a base. Generally, the reaction is carried out in the presence of. For example, JP-A-63-8365 describes an example in which an acid chloride is used as the acid halide and a tertiary amine such as triethylamine is used as the base. The reason why tertiary amines are usually used as bases rather than primary or secondary amines is to avoid side reactions.

However, when acylating the phenolic hydroxyl group of p-dialkylsulfoniophenol represented by general formula (1), when reacting a carbonyl halide compound with the phenol represented by general formula (1), triethylamine is used as a base. When a tertiary amine such as a tertiary amine is used, the yield of the target compound represented by the above general formula (II[) is low, and the method is not necessarily industrially sufficient.

Incidentally, when p-dimethylsulfoniophenol methyl sulfate and p-methoxybenzyloxycarbonyl chloride are reacted in the presence of triethylamine as a tertiary amine, the target product p-methoxybenzyl (p
-dimethylsulfoniophenyl) carbonate methyl sulfate yield was less than 30%. Also, N as a tertiary amine.

When N-dimethylaniline was used, the target compound was not obtained at all.

[Means for Solving the Problems] In view of the above circumstances, the present inventors have developed a carbonyl halide compound (II) when acylating the phenolic hydroxyl group of p-dialkylsulfoniophenols.
We have conducted intensive research on the reaction between phenol compound (1) and the above phenol compound (1). As a result, it was surprisingly discovered that the desired sulfonium compound could be efficiently obtained by using a secondary amine having a specific structure as a base, and the present invention was completed.

That is, the present invention combines a p-dialkylsulfoniophenol represented by the general formula (I) and a carbonyl halide represented by the -a formula (U), in which two secondary alkyl groups are bonded to the nitrogen atom. The present invention relates to a method for producing a sulfonium compound represented by general formula (IIl), which is characterized by carrying out the reaction in the presence of a secondary amine having the following structure.

General formula (II): R-COX"I [R1 and R in general formulas (1) and (lI[)
2 represents an alkyl group, and may be the same or different from each other. x1 is either a hydrogen atom, a halogen atom, or an alkyl group. Y- is either a halogen anion, a perchlorate group, an alkyl sulfate group, a hydrogen sulfate group, or a p-)luenesulfonate group. Also, general formula (II)
and (II [), R is an alkyl group, t-butoxy group, benzyloxy group, p-methoxybenzyloxy group, phenyl group, and X2 is a halogen atom such as chlorine or bromine] In the present invention, the above general Examples of the carbonyl halide compound which is an acid halide represented by formula (II) include acetyl fluoride, acetyl chloride, propionyl chloride, propionyl bromide, butyryl chloride, valeryl chloride, hexanoyl chloride, octanoyl chloride, decanoyl chloride, and lauroyl chloride. , myristoyl chloride, balmitoyl chloride, stearoyl chloride, [-butoxycarbonyl chloride, benzyloxycarbonyl chloride, p-
Examples include methoxybenzyloxycarbonyl chloride, benzoyl chloride, and benzoyl bromide. Among these halides, chlorides are preferred in terms of stability and reactivity.

The method of the present invention uses t-butoxycarbonyl chloride and p-
The use of relatively unstable acid halides such as -methoxybenzyloxycarbonyl chloride is particularly preferred since the yield of the target product is greatly improved.

Moreover, in the p-dialkylsulfoniophenol represented by the formula (T), ill, )l! The alkyl group is preferably a lower alkyl group having 1 to 4 carbon atoms, particularly preferably a methyl group or an ethyl group.

In addition, the anion Y- is a halogen anion, a perchlorate group,
Either an alkyl sulfate group, a hydrogen sulfate group or a p-toluenesulfonic acid group, but from the viewpoint of water solubility of the target product, alkyl sulfate groups and hydrogen sulfate groups are preferable, and among alkyl sulfate groups, methyl sulfate groups are particularly preferred. preferable.

Xl is appropriately selected depending on the solubility and acylation reactivity of the compound represented by the general formula (■), but when XI is an alkyl group, it is preferably a lower alkyl group having 1 to 4 carbon atoms.

One of the characteristics of the method of the present invention is that the above-mentioned birch has the general formula (1
) and the carponyl halide compound represented by the general formula <II),
The purpose is to use a secondary amine (hereinafter sometimes simply referred to as secondary amine) having a specific structure.

The secondary amine having a specific structure in the present invention is a secondary amine having a structure in which two secondary alkyl groups are bonded to a nitrogen atom. Here, the "secondary alkyl group" includes a cyclic alkyl group, and the "two secondary alkyl groups" include an alkylene group with branched carbon chains at both ends. Examples of the secondary amines used in the present invention include dicyclohexylamine, diisopropylamine, di-sec-butylamine, and 2,6-dimethylpiveridine.

In the method of the present invention, a secondary amine and 0.5 to 2.0 times the mole, preferably 0.8 to 1.5
Double the molar amount of the carbonyl halide compound represented by the general formula (n) is used.

In addition, in the method of the present invention, the carbonyl halide compound used varies depending on the type, but generally -
It is added while maintaining the temperature at 80-25°C, preferably -30-10°C. At temperatures higher than this, the carponyl halide compound may decompose. Moreover, it is uneconomical and undesirable to maintain the temperature at a temperature lower than this. For the same reason, the reaction temperature is -80 to 25°C, preferably -3
It is maintained at 0 to 10°C and allowed to react for about 30 minutes to 10 hours.

The reaction of the present invention is usually carried out in a solvent, and examples of the solvent used include aprotic polar solvents such as acetonitrile, ethers such as ether and tetrahydrofuran, and halogenated hydrocarbons such as dichloromethane. Among them, acetonitrile is preferable. After completion of the reaction,
After the produced solid is filtered and the solvent is distilled off from the filtrate, crystals are precipitated from the concentrated solution and recrystallized to isolate and purify the target compound, the sulfonium compound.

[Example] Next, the method of the present invention will be explained in more detail with reference to Examples.

Example 1 (Synthesis example using t-butoxycarbonyl chloride and dicyclohexylamine) As a reaction vessel, a separable flask with a glass filter and a stopcock attached to the bottom to enable suction filtration and a jacket to enable cooling was used. Using. 7.41 g (0.1 mol) of t-butyl alcohol in this flask.
After adding 150 ml of dry ether and cooling to -40°C, 13.2 ml of phosgene (0.2 mol) was introduced. Then pyridine 9.7m I2. (0.12m
A solution prepared by diluting the solution with 40 ml of ether was added dropwise over 30 minutes at -40°C while stirring. After the dropwise addition was completed, the reaction temperature was raised to -20°C, stirred for 2 hours, and further left at -20°C for 15 hours. (This will be referred to as "A") Apart from this, p-dimethylsulfoniophenol
Dissolve 10.64 g (0.04 mo+) of methyl sulfate in dry acetonitrile 200+nff1 at 40°C,
To this, dicyclohexylamine 8.0 mj2 (0
,04 mol) to make a mixture in which the salt was precipitated,
Ice cold. (This will be referred to as "B") Excess phosgene and ether are distilled off as a mixture under reduced pressure to a total of 100 mff1 at -20°C or lower to obtain a solution containing t-butoxycarbonyl chloride, and at this temperature The mixture was added dropwise to the mixture B while being filtered through a glass filter. The solids remaining on the glass filter are mixed with ether 100, which has been cooled to below -20°C.
+/2 and dripped in the same manner through a glass filter. The time required for dropping was 30 minutes.

After stirring the reaction solution at 0°C for 2 hours, the white solid, which was amine hydrochloride, was filtered off. Add this solid to 200+n
I! , and washed with acetonitrile. 'A solution and the washing solution were mixed, and then the solution was concentrated using an evaporator. Ethyl acetate was added to this to crystallize a white solid product, which was then filtered off.

The solid was recrystallized from acetonitrile to obtain the desired sulfonio compound, t-butyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate.

Yield 4.62g (12,6n+mol Yield 31.5
χ) m, p, 118-121°C'H-NMRδ=1.54,9tl(s): δ=
3.43,6H(s); δ=3.66,38(s);
δ=7.39.20 (d, J=10Hz); δ=8
．． 17.2B, (d, J=10Hz) Comparative Example 1 The same operation as in Example 1 was performed except that triethylamine was used instead of dicyclohexylamine in Example 1. Since the product contained a considerable amount of impurities, the resulting solid was purified through a silica gel column (CHCffix: Meo
) I = 9:l) and then reprecipitated from acetonitrile/ether to obtain the desired sulfonium compound,
t-Butyl (p-dimethylsulfonium phenyl) carbonate methyl sulfate 0.36g (0.98mmo
1, yield 2.5χ).

Example 2 p-dimethylsulfoniophenol methyl sulfate8.
Dry 0g (30fflIwol) with acetonitrile 2
00a+N and stirred at room temperature for 30 minutes. 6.0 g (33 mmol) of dicyclohexylamine was added dropwise thereto, and the mixture was further stirred at room temperature for 1 hour and then cooled to 0°C.

Ether solution 2 containing 6°6 g (33111 mol) of p-methoxybenzyloxycarbonyl chloride
Add 0 ml while keeping the temperature at 0°C, then add 4 ml at 0°C.
Stir for hours.

The generated dicyclohexylamine hydrochloride was filtered, the solvent was distilled off and concentrated, and ethyl acetate was added to the concentrated solution to crystallize it to obtain p-methoxybenzyl (p dimethylsulfoniophenyl) carbonate methyl sulfate 9 .1 g was obtained (yield 70.7χ).

Melting point; 106-108'C [R: 1750 cm-'(C=O)'H
-NMR(DMso-a6)δ=3.27.6
H(s) 3.37,3H(s) 3.76.3H(s) 5.22.2H(s) 6.95.7.40,4H(each d, J=9.0
)Iz,)? , 61.8.13, 411 (each d
, J=9.0IIz,) Elemental analysis theoretical value C: 50.22χ, H: 5.15χ calculated value
C: 49.73χ, H: 5.24χ Comparative Example 2 Triethylamine 3 instead of dicyclohexylamine
．． Example 2 except that 0g (30mm+ol) was used.
The reaction was carried out in the same manner.

The target p-methoxyhensyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate is 3.7 g.
(yield 28.7x) was obtained, and a large amount of by-products were produced.

Comparative Example 3 A reaction was carried out in the same manner as in Example 2 except that 3.6 g (30 mmol) of N,N-dimethylaniline was used instead of dicyclohexylamine.

The desired p-methoxybenzyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate was not obtained at all.

Example 3 p-dimethylsulfoniophenol methyl sulfate 28
．． 76 g (108 mmol) in acetonitrile 750
mff1 and stirred at room temperature for 30 minutes. 27.20 g (150 mmol) of dicyclohexylamine was added dropwise to the mixture, and the mixture was further stirred at room temperature for 1 hour and then cooled to 0°C. 24.07g (120v++ol) of ρ-methoxybenzyloxycarbonyl chloride was added to this while maintaining the temperature at 0°C, and the mixture was further stirred at O''C for 3 hours. The generated dicyclohexylamine hydrochloride was filtered off, and the solvent was distilled off. The concentrated solution was crystallized by adding ethyl acetate to obtain 33.10 g (yield: 71.2x) of p-methoxyhensyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate.

Example 4 Using 16.98 g (150 mmol) of 2,6-dimethylpiveridine instead of dicyclohexylamine,
Example 3 except that 700 mj2 of acetonitrile was used
The reaction was carried out in the same manner. 23.87 g (yield: 51.3χ) of the desired ρ-methoxybenzyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate was obtained.

Comparative example 4 2,6-lutidine 1 instead of dicyclohexylamine
The reaction was carried out in the same manner as in Example 3, except that 6.07 g (150 mmol) and 300 ml of acetonitrile were used.

The target p-methoxybenzyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate is 12.5
7g (yield: 27.0x), and a large amount of by-products were produced.

Comparative Example 5 Dicyclohexylethylamine instead of dicyclohexylamine 25. Example 3 except that OOg (119 mmol) and acetonitrile 700n+42 were used.
The target p-methoxybenzyl (p-dimethylsulfoniophenyl) carbonate methyl sulfate was 6.87.
g (yield: 14.8χ), and a large amount of by-products were produced.

Example 5 15.18 g (150 mmol) of diisopropylamine was used instead of dicyclohexylamine, and 400 nI of acetonitrile! The reaction was carried out in the same manner as in Example 3 except that , was used. 19.15 g (yield: 41°2χ) of the desired p-methoxybenzyl (p-dimethylsulfoniophenol) carbonate methyl sulfate was obtained.

Example 6 A reaction was carried out in the same manner as in Example 3 except that 19.39 g (150 mmol) of %C-butylamine was used instead of dicyclohexylamine and 700 mN of acetonitrile was used. The target p-methoxybenzyl (p-
17.04g (yield 36.8χ) of dimethylsulfoniophenyl) carbonate methyl sulfate was obtained.

Example 7 (Acylation in aqueous solution) Phenylalanine 0.83g (5.03mmol) was mixed with water at 10+F! After adding 1.05 m of triethylamine
1 (7.53 mmol) was added and stirred at room temperature to dissolve.

This was added to p-methoxybenzyl (p-
Dimethylsulfoniophenyl) carbonate methyl sulfate (PMZ-DSP) 2.60g (6.04mmo+
) and stirred at room temperature for 15 hours. Add to this 2χH(12
After adding an aqueous solution to make p)I 3 to 4, the mixture was extracted twice with 10 mQ of ethyl acetate. The extract is diluted with 20 ml of water.
After washing twice and drying over anhydrous sodium sulfate, the solvent was distilled off and concentrated, 30 ml of ether was added to the concentrated solution, and 0.9 g of dicyclohexylamine (DCH8) (
4.5 mmol) was added to crystallize.

1.94 g of the desired product was obtained as PMZ-Phc-Oll.DCliA (yield: 75.5x).

[Effects of the Invention] According to the method of the present invention, the secondary amine used as a base causes almost no undesirable side reactions, and the target sulfonium compound can be obtained in high yield. Moreover, the amine salt produced can be easily removed, and the target sulfonium compound can be easily isolated and purified.

Therefore, the method of the present invention is extremely useful as a method for producing a sulfonium compound represented by general formula (III).

Patent applicant: Mitsubishi Gas Chemical Co., Ltd. Agent Patent Attorney Sadafumi Kohori

Claims (2)

[Claims] (1) A structure in which p-dialkylsulfoniophenols represented by general formula (I) and a carbonyl halide compound represented by general formula (II) are combined with two secondary alkyl groups bonded to the nitrogen atom. A method for producing a sulfonium compound represented by general formula (III), which comprises reacting in the presence of a secondary amine having the following. General formula (I): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ General formula (II): R-COX^2 General formula (III): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [General formula (I) and In (III) R^1 and R
^2 is an alkyl group, and may be the same or different from each other. X^1 is either a hydrogen atom, a halogen atom, or an alkyl group. Y^- is a halogen anion, perchlorate group, alkyl sulfate group, hydrogen sulfate group, or p-
Either toluenesulfonic acid radical. Also, the general formula (
In II) and (III), R is an alkyl group, t-butoxy group, benzyloxy group, p-methoxybenzyloxy group, or phenyl group, and X^2 is a halogen atom such as chlorine or bromine. ] (2) At least one secondary amine having a structure in which two secondary alkyl groups are bonded to a nitrogen atom is selected from dicyclohexylamine, diisopropylamine, di-sec-butylamine, and 2,6-dimethylpiveridine. The method according to claim 1, which is one type.