JP4803395B2 - Method for silylation of hydroxyl group - Google Patents

Description

  The present invention relates to a method for silylating a hydroxyl group. The hydroxyl group silylation method of the present invention is efficiently silylated and protected by reacting a hydroxyl group-containing compound and a chlorosilane compound in the presence of a base, preferably using a sulfonic acid compound or a derivative thereof or a copper compound as a catalyst. Therefore, it is useful for the synthesis of pharmaceuticals and agricultural chemicals.

  The reaction for silylating a hydroxyl group is an important reaction in organic synthesis, and is one of the reactions indispensable for the production of pharmaceuticals such as carbapenem antibiotics, various agricultural chemicals, and other fine chemical products. Among them, the t-butyldimethylsilyl group is useful as a protecting group for a hydroxyl group because it is stable under various reaction conditions and can be easily deprotected by an acid catalyst, a fluorine anion or the like.

  When the hydroxyl group is silylated, chlorosilane, silyl trifluoromethanesulfonate, or the like is used. When silylating a hydroxyl group with chlorosilane, for example, when performing silylation reaction using t-butyldimethylchlorosilane, a method of reacting with an anhydrous DMF solvent using 2 equivalents or more of imidazole is known. (Non-Patent Document 1: Guide to Organic Chemistry Experiments, page 6, Chemistry Doujin). However, in this method, it is necessary to use a large amount of expensive imidazole, and since the solvent DMF is water-soluble, water is added to remove imidazole hydrochloride that is by-produced in post-treatment after the reaction. In addition, a solvent for extraction is required, and DMF is dissolved in the aqueous layer together with the hydrochloride, which makes it difficult to treat the aqueous layer.

  In addition, a method is known in which t-butyldimethylsilyl trifluoromethanesulfonate is reacted in methylene chloride using 2,6-lutidine as a base when the hydroxyl group is bulky and the reactivity with chlorosilane is low (non-patent document). Reference 1: Guide to Organic Chemistry Experiments, page 6, chemistry coterie). However, t-butyldimethylsilyl trifluoromethanesulfonate is expensive and not suitable for industrial use.

In the reaction between a hydroxyl group and chlorosilane, as a method of performing a reaction using a catalyst, dimethylaminopyridine is used as a catalyst, and t-butyldimethylchlorosilane is reacted in methylene chloride in the presence of triethylamine to form a primary hydroxyl group. A method of selectively silylating a group is known (Non-Patent Document 2: Hernandez, O .; Chaudhary, S. K. Tetrahedron Lett. 1979, 99.). However, this method cannot be applied in the case of a secondary hydroxyl group or the like. Further, it has been shown that in order to t-butyldimethylsilylate a secondary amine, it is necessary to use a polar solvent such as DMF even when a dimethylaminopyridine catalyst is used (Non-patent Document 2: Hernandez, O .; Chaudhary, SK Tetrahedron Lett. 1979, 99.).
As described above, the activity of the catalyst has not been satisfactory in the method of silylating a hydroxyl group with chlorosilane using a catalyst.

  On the other hand, t-butyldimethylchlorosilane, which is often used for protecting hydroxyl groups, is crystalline at room temperature, and may be problematic in handling at an industrial level. In order to facilitate handling, a solution in which t-butyldimethylchlorosilane is dissolved in a solvent such as toluene or ethyl acetate is industrially used. In addition, when a hydrocarbon solvent is used in the silylation reaction of the hydroxyl group with chlorosilane, when the by-product hydrochloride is dissolved by adding water, the solvent does not migrate to the aqueous layer, There is also an advantage that free base recovery from the hydrochloride of the base used in the reaction is facilitated. However, when a hydroxyl group is silylated using chlorosilane in a hydrocarbon solvent such as toluene, the reactivity may be lower than when a polar solvent such as DMF is used. there were.

  From the above, it has been desired to develop a method for improving reactivity using a catalyst when silylating a hydroxyl group with chlorosilane, particularly a method for silylation in a nonpolar solvent.

Guide to Organic Chemistry Experiments, page 6, Chemistry hernandez, O .; Chaudhary, S .; K. Tetrahedron Lett. 1979, 99.

  The present invention has been made in response to the above-mentioned demand, and can promote the reaction of silylating a hydroxyl group with chlorosilane using a nonpolar solvent. The object is to provide a method for the silylation of radicals.

  As a result of intensive studies to achieve the above object, the present inventors have promoted the silylation reaction of a hydroxyl group with a chlorosilane compound by adding a sulfonic acid compound or a derivative thereof or a copper compound to the reaction system. This has been found and the present invention has been achieved.

That is, the present invention provides a method for silylating a hydroxyl group, wherein the hydroxyl group of a hydroxyl group-containing compound is silylated with chlorosilane in the presence of a copper compound. In this case, the reaction is preferably performed using a nonpolar solvent.

  According to the method for silylating a hydroxyl group-containing compound of the present invention, the reaction of silylating a hydroxyl group with chlorosilane can be promoted, and in particular, it can be effectively silylated in a nonpolar solvent.

  The method for silylating a hydroxyl group-containing compound of the present invention is to silylate a hydroxyl group of a hydroxyl group-containing compound with chlorosilane in the presence of a sulfonic acid compound or a derivative thereof or a copper compound.

  In this case, in the sulfonic acid compound and the derivative catalyst thereof of the present invention, the sulfonic acid compound is not particularly limited as long as it is a compound having a sulfonic acid group, and even anhydrous sulfonic acid is p-toluenesulfonic acid / 1 water. It may be a hydrate such as a hydrate. Specifically, as the sulfonic acid compound, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, butanesulfonic acid, hexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid monohydrate, dodecylbenzenesulfonic acid And trifluoromethanesulfonic acid. In particular, methanesulfonic acid, p-toluenesulfonic acid monohydrate, and dodecylbenzenesulfonic acid are preferably used. Examples of the derivative of the sulfonic acid compound include amine salts and metal salts of sulfonic acid, silyl esters of sulfonic acid, and the like. Examples of the amine salt of sulfonic acid include ammonium salt, methylamine salt, ethylamine salt, dimethylamine salt, diethylamine salt, triethylamine salt, diisopropylethylamine salt, dimethylaniline salt, aniline salt, 2-picoline salt, 3- Examples include picoline salt, 4-picoline salt, quinoline salt, and tetramethylethylenediamine salt. Examples of the metal salt of sulfonic acid include lithium salt, sodium salt, potassium salt and the like of the above sulfonic acid. Examples of the silyl ester of sulfonic acid include trimethylsilyl ester, ethyldimethylsilyl ester, diethylmethylsilyl ester, triethylsilyl ester, tert-butyldimethylsilyl ester, tert-butyldiphenylsilyl ester, triisopropylsilyl ester, tri- Examples thereof include n-butylsilyl ester and silyl ester.

  Specific examples of the copper compound of the present invention include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (I) cyanide, and thiocyanic acid. Examples include copper (I), copper (II) chloride, copper (II) bromide, copper (II) iodide and the like. In particular, it is preferable to use copper (I) chloride, copper (I) bromide, or copper (I) iodide.

  The amount of the sulfonic acid compound of the present invention and its derivative catalyst used is preferably 0.001 to 0.1 mol, particularly preferably 0.002 to 0.05 mol, based on 1 mol of the hydroxyl group-containing compound. Preferably, 0.005 to 0.03 mol is used. If the amount is less than this, the reaction rate may be slow, which is not practical, and if it is used more than this, the reaction rate may not be further improved, which is not economical.

  The use amount of the copper compound of the present invention is preferably 0.001 to 0.2 mol, particularly preferably 0.005 to 0.1 mol, and more preferably 0.01 to 1 mol of the hydroxyl group-containing compound. It is preferable to use ~ 0.05 mol. If the amount is less than this, the reaction rate may be slow, which is not practical, and if it is used more than this, the reaction rate may not be further improved, which is not economical.

  The compound containing a hydroxyl group of the present invention is not particularly limited as long as it is a compound having an alcoholic or phenolic hydroxyl group. For example, primary, secondary and tertiary alcohols, alcohols having a substituent such as halogen, diorganoamino group, ester group, cyano group as a substituent, substituted or unsubstituted phenols, plural in the same molecule And polyhydric alcohols having a hydroxyl group.

  As primary alcohol, methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-octanol, 2-ethylhexanol, n-decanol, allyl alcohol, 3-buten-1-ol 5-hexen-1-ol, 10-undecen-1-ol, 2-chloroethanol, 2-bromoethanol, 3-chloropropanol, 3-bromopropanol, 4-chlorobutanol, 4-bromoethanol, 2-dimethyl Examples include aminoethanol, 2-diethylaminoethanol, 3-dimethylaminopropanol, and 3-diethylaminopropanol.

  Examples of the secondary alcohol include 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, cyclopentanol, 2-hexanol, 3-hexanol, cyclohexanol, cyclooctanol and the like.

  Examples of the tertiary alcohol include t-butanol, t-amyl alcohol, 2-methyl-3-buten-2-ol, 3-methyl-1-penten-3-ol and the like.

  The phenols include phenol, o-cresol, m-cresol, p-cresol, 2-ethylphenol, 3-ethylphenol, 4-ethylphenol, 2-t-butylphenol, 3-t-butylphenol, 4-t- Butylphenol, 2,6-di-t-butylphenol, 2,6-di-t-butyl-4-methylphenol, o-chlorophenol, m-chlorophenol, p-chlorophenol, o-bromophenol, m-bromo Phenol, p-bromophenol, etc. are mentioned.

  Examples of the polyol having two or more hydroxyl groups include ethylene glycol, propylene glycol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2,3-butanediol, 2-butene-1, 4-diol etc. are mentioned.

  There is no restriction | limiting in particular as chlorosilane of this invention. As chlorosilanes, monochlorosilanes such as trimethylchlorosilane, ethyldimethylchlorosilane, diethylmethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, triisopropylchlorosilane, tri-n-butylchlorosilane, triisobutylchlorosilane, And dichlorosilanes such as di-tert-butyldichlorosilane and 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane. As these chlorosilanes, liquid chlorosilanes can be used as they are, and chlorosilanes which are solid at room temperature such as tert-butyldimethylchlorosilane may be used as they are, and can be used in a solvent such as toluene or ethyl acetate. It can also be dissolved and used as a solution.

  The amount of the chlorosilane used in the present invention is preferably 0.5 to 2.0 mol, more preferably 0.8 to 1.8 mol, particularly 0.9 to 1.5 mol, relative to 1 mol of hydroxyl group. It is preferable to use it. If it is less than this, the silylation reaction may not proceed sufficiently, and if it is more than this, the reaction rate does not improve and it is not economical.

  The hydroxyl group silylation reaction of the present invention can be carried out under reflux conditions or the like while removing the by-produced hydrogen halide outside the reaction system. It is preferable to trap hydrogen chloride. The base to be used is not particularly limited, but amines are preferably used. Specific examples of amines include ammonia, primary amines such as methylamine and ethylamine, secondary amines such as dimethylamine and diethylamine, tertiary amines such as triethylamine, diisopropylethylamine and dimethylaniline, aniline and 2-picoline. Aromatic amines such as 3-picoline, 4-picoline and quinoline, and diamines such as tetramethylethylenediamine and 1,8-diazabicyclo [5.4.0] undec-7-ene. Of these, tertiary amines such as triethylamine and diisopropylethylamine are preferably used.

  In this case, the amount of amine used is 0.5 to 2.5 mol, preferably 0.8 to 2.0 mol, more preferably 1.1 to 1.7 mol, relative to 1 mol of hydroxyl groups. If the amount of amine used is less than 0.5 mol, the silylation reaction may not proceed sufficiently, and if it is more than 2.5 mol, the reaction rate does not improve and may not be economical.

  In the present invention, the reaction can be carried out using a solvent, and a nonpolar solvent is preferred as the solvent. Nonpolar solvents include n-pentane, n-hexane, n-heptane, n-octane, n-decane, isooctane, cyclopentane, cyclohexane, cyclooctane, toluene, o-xylene, m-xylene, p-xylene, Examples thereof include ethylbenzene, mesitylene, diethylbenzene and the like. These nonpolar solvents may be used alone or in combination of two or more. The amount used is 20 to 1,000 ml, preferably 50 to 500 ml, more preferably 100 to 300 ml, per 1 mol of hydroxyl groups. If the amount of nonpolar solvent used is less than 20 ml, stirring may not be possible, and if it exceeds 1,000 ml, the pot yield may decrease.

  The silylation reaction of the hydrosilyl group is preferably performed at a reaction temperature of 0 to 200 ° C, more preferably 10 to 180 ° C. Especially preferably, it is 20-150 degreeC. If it is lower than this temperature, the reaction rate becomes slow and may become impractical, and if it is higher than this temperature, side reactions may occur and the yield may decrease.

  The hydroxyl group silylation reaction can be performed by adding chlorosilane, a base, a catalyst, and a solvent, and adding a hydroxyl group-containing compound. Alternatively, a hydroxyl group-containing compound, a base, a catalyst, and a solvent are charged and chlorosilane is added. In this case, when the chlorosilane compound is a solid such as tert-butyldimethylchlorosilane, it is preferably used as a solution dissolved in a solvent. Alternatively, chlorosilane, a hydroxyl group-containing compound, a base, a catalyst, and a solvent can be charged all at once and heated. In these, it is preferable to carry out by adding chlorosilane, a base, a catalyst, a solvent, and adding a hydroxyl group-containing compound. Here, when an amine salt of sulfonic acid is used as a catalyst, it may be added as an amine salt of sulfonic acid, or a mixture of sulfonic acid and amine may be used as a sulfonic acid amine salt in the reaction system. Good. Similarly, the silyl ester of sulfonic acid may be added using sulfonic acid silyl ester as a catalyst, or chlorosilane and sulfonic acid may be mixed in the reaction system and used as sulfonic acid silyl ester.

  In the hydroxyl group silylation reaction, hydrochloric acid produced as a by-product reacts with a base to form a hydrochloride of the base. The produced hydrochloride may be removed by filtration, or water may be added to the reaction solution to dissolve the hydrochloride and remove it by liquid separation. The hydrochloride may be discarded as it is, but it is preferable to purify and reuse it after neutralizing with a strong base such as an aqueous sodium hydroxide solution to give a free base.

  The silylated product obtained by the hydrosilylation reaction of the hydroxyl group can be purified by distillation or column chromatography after removing the by-product hydrochloride by the above method. Moreover, it can also be purified by column chromatography or the like without removing the by-product hydrochloride. Moreover, it can also use as it is, without refine | purifying, after removing hydrochloride by the said method.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not limited to the following Example. The reaction rate in an Example was calculated | required from the area percent of the gas chromatography.

[ Reference Example 1]
A 300 ml four-necked glass flask was equipped with a reflux condenser, a thermometer and a stirrer, and the interior was purged with nitrogen. To this flask, 31.6 g (0.21 mol) of t-butyldimethylchlorosilane, 14.8 g (0.2 mol) of 2-butanol, 22.3 g (0.22 mol) of triethylamine, 0.38 g (0.004 mol) of methanesulfonic acid ) And dissolved by adding 50 ml of toluene. Aging was performed under reflux, and the progress of the reaction was followed by gas chromatography. The reaction rate reached 100% after 3 hours of aging. Table 1 shows the relationship between the aging time and the reaction rate.

[ Reference Example 2]
The reaction was conducted in the same manner as in Reference Example 1 except that methanesulfonic acid was changed to 0.19 g (0.002 mol), and the reaction rate was monitored by gas chromatography. The results are shown in Table 1.

[Comparative Example 1]
The reaction was carried out in the same manner as in Reference Example 1 except that methanesulfonic acid was not added, and the reaction rate was monitored by gas chromatography. The results are shown in Table 1.

[ Reference Example 3]
The reaction was conducted in the same manner as in Reference Example 1 except that methanesulfonic acid was changed to 0.38 g (0.002 mol) of p-toluenesulfonic acid monohydrate, and the reaction rate was monitored by gas chromatography. The results are shown in Table 1.

[Example 1 ]
The reaction was carried out in the same manner as in Reference Example 1 except that methanesulfonic acid was changed to 0.40 g (0.004 mol) of CuCl, and the reaction rate was monitored by gas chromatography. The results are shown in Table 1.

[Example 2 ]
The reaction was conducted in the same manner as in Reference Example 1 except that methanesulfonic acid was changed to CuBr 0.57 g (0.004 mol), and the reaction rate was monitored by gas chromatography. The results are shown in Table 1.

[Example 3 ]
The reaction was conducted in the same manner as in Reference Example 1 except that methanesulfonic acid was changed to 0.76 g (0.004 mol) of CuI, and the reaction rate was monitored by gas chromatography. The results are shown in Table 1.

[ Reference Example 4 ]
A 300 ml four-necked glass flask was equipped with a reflux condenser, a thermometer and a stirrer, and the interior was purged with nitrogen. To this flask, 31.6 g (0.21 mol) of t-butyldimethylchlorosilane, 20.4 g (0.2 mol) of 1-hexanol, 22.3 g (0.22 mol) of triethylamine, 0.19 g (0.002 mol) of methanesulfonic acid. ) And dissolved by adding 50 ml of toluene. Aging was performed under reflux, and the progress of the reaction was followed by gas chromatography. The reaction rate reached 100% after 1 hour of aging.

[Comparative Example 2]
The reaction was performed in the same manner as in Reference Example 4 except that methanesulfonic acid was not added, and the reaction rate was monitored by gas chromatography. The results are shown in Table 2.

[Example 4 ]
The reaction was conducted in the same manner as in Reference Example 4 except that the methanesulfonic acid was changed to CuCl 0.40 g (0.004 mol), and the reaction rate was monitored by gas chromatography. The results are shown in Table 2.

[ Reference Example 5 ]
A 300 ml four-necked glass flask was equipped with a reflux condenser, a thermometer and a stirrer, and the interior was purged with nitrogen. To this flask, 40.5 g (0.21 mol) of triisopropylchlorosilane, 20.4 g (0.2 mol) of 1-hexanol, 22.3 g (0.22 mol) of triethylamine, and 0.38 g (0.004 mol) of methanesulfonic acid were added. Charge and dissolve 50 ml of toluene. Aging was performed under reflux, and the progress of the reaction was followed by gas chromatography. After 4 hours of aging, the reaction rate was 99%.

[Comparative Example 3]
The reaction was carried out in the same manner as in Reference Example 5 except that methanesulfonic acid was not added, and the reaction rate was monitored by gas chromatography. The results are shown in Table 3.

[ Reference Example 6 ]
The reaction was conducted in the same manner as in Reference Example 5 except that methanesulfonic acid was changed to 0.76 g (0.004 mol) of p-toluenesulfonic acid monohydrate, and the reaction rate was monitored by gas chromatography. The results are shown in Table 3.
[Example 5 ]
The reaction was conducted in the same manner as in Reference Example 5 except that methanesulfonic acid was changed to CuCl 0.59 g (0.006 mol), and the reaction rate was monitored by gas chromatography. The results are shown in Table 3.

[ Reference Example 7 ]
A 300 ml four-necked glass flask was equipped with a reflux condenser, a thermometer and a stirrer, and the interior was purged with nitrogen. This flask was charged with 63.3 g (0.42 mol) of t-butyldimethylchlorosilane, 44.5 g (0.44 mol) of triethylamine, and 0.77 g (0.002 mol) of methanesulfonic acid, and dissolved by adding 120 ml of toluene. . 2-Bromoethanol 50.0g (0.4mol) was dripped over 50 minutes at room temperature, and it stirred as it was for 2 hours. The salt formed by adding 80.0 g of water was dissolved, and the aqueous layer was removed by liquid separation. The obtained organic layer was distilled under reduced pressure to obtain 79.0 g (0.33 mol, boiling point: 70 ° C./0.8 kPa) of (2-bromoethoxy) -t-butyldimethylsilane. The yield was 83%.

[Comparative Example 4]
A 300 ml four-necked glass flask was equipped with a reflux condenser, a thermometer and a stirrer, and the interior was purged with nitrogen. This flask was charged with 63.3 g (0.42 mol) of t-butyldimethylchlorosilane and 44.5 g (0.44 mol) of triethylamine, and dissolved by adding 120 ml of toluene. Although 2-bromoethanol 50.0g (0.4mol) was dripped over 50 minutes at room temperature, reaction did not advance. When heated to 70 ° C. with an oil bath, the reaction proceeded exothermically and the internal temperature rose to 105 ° C. When analyzed by gas chromatography, (2-bromoethoxy) -t-butyldimethylsilane and (2-chloroethoxy) -t-butyldimethylsilane were produced at a ratio of 2: 1. This indicates that the reaction without using a catalyst does not proceed at room temperature and a side reaction occurs when heated.

Claims (3)

A method for silylating a hydroxyl group, comprising silylating a hydroxyl group of a hydroxyl group-containing compound with chlorosilane in the presence of a copper compound.   The method for silylating a hydroxyl group according to claim 1, wherein the reaction is carried out using a nonpolar solvent. The method for silylating a hydroxyl group according to claim 1 or 2, wherein the reaction is carried out in the presence of a base.