JPH09328454A - Production of ditertiary butyl dicarbonate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound in a short time in high yield by reacting a carbonic acid monotertiary butyl monoalkali metal salt with an aromatic sulfonyl halide under a specific condition. SOLUTION: A carbonic acid monotertiary butyl monoalkali metal salt is reacted with an aromatic sulfonyl halide in a mixed solvent of a water-insoluble solvent and an aprotic polar solvent (e.g. toluene/N,N-dimethylformamide) in the presence of a heterocyclic compound (e.g. pyridine) having aromatic properties, containing no hydrogen atom except a hydrogen atom on a cyclic nucleus and a phase transfer catalyst (e.g. tetra-n-butylammonium bromide) at -50 to 100 deg.C. The mixed solvent comprises 1 pt.wt. of the water-insoluble solvent and 0.01-2 pts. wt. of the aprotic polar solvent. The isolation and purification of the prepared tertiary butyl carbonate can be extremely simplified.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the addition of a monotertiary-butyl monocarbonate carbonate and an aromatic sulfonyl halide in a mixed solvent of a water-insoluble solvent and an aprotic polar solvent except for the ring nucleus. The present invention relates to a method for producing ditertiary-butyl dicarbonate, which is commonly referred to as BOC-D, by reacting in the presence of a nitrogen atom-free aromatic heterocyclic compound and a phase transfer catalyst.

[0002]

BOC-D is known as an amino group-protecting agent for protecting various amino groups by BOC conversion (tertiary-butoxycarbonylation), and has good reactivity during BOC conversion. Most of the by-products are tertiary
Since it is butanol and carbon dioxide, post-treatment after the reaction is easy and it is an ideal amino group protecting agent. BOC-D
As a method for producing the above, a method using phosgene and a method using sulfonyl halide are known. In the former method, monotertiary butyl carbonate monoalkali metal salt and phosgene are reacted in the presence of a tertiary amine (Japanese Patent Publication No. 6-29225). On the other hand, the method using a sulfonyl halide is, for example, a method in which methanesulfonyl chloride is reacted with a monotertiary butyl carbonate monoalkali metal salt in the presence of an aromatic amine and / or a phase transfer catalyst (JP-A-4-217643, JP Kaihei 4-211643
No.) or an aromatic sulfonyl halide in the presence of a quaternary ammonium salt as a catalyst in a N, N-dimethylformamide solvent (Czech Patent No. 257157).
No.), aromatic sulfonyl halides with pyridine as catalyst 4
A method of reacting in a toluene solvent in the presence of a primary ammonium salt (Czech Patent No. 260076), an aromatic tertiary in which an aromatic ring is bound to a nitrogen atom of an aromatic sulfonyl chloride via an aliphatic tertiary amine or an alkylene group A method of reacting with mono-tertiary-butyl carbonate monoalkali metal salt in the presence of amine (Japanese Patent Publication No. 7-10809) is known.

[0003]

However, although the method using phosgene can surely produce BOC-D in a high yield, handling highly toxic phosgene requires a high degree of skill, and its handling place is high. Has the drawback that it is limited. Further, in the method using sulfonyl halide, the yield based on monotertiary-butyl monoalkali metal carbonate is at most 80%, and in particular, the method of the Czechoslovak patent has a yield of at most about 50%, Further, a production method with a good yield has been desired.

[0004]

SUMMARY OF THE INVENTION In view of the above situation, the present inventors have made BOC-reactive by reacting an aromatic sulfonyl halide with a monotertiary-butyl monocarbonate carbonate.
In producing D, the present invention aims to provide a method for producing BOC-D in a higher yield. That is, a mixed solvent of a water-insoluble solvent and an aprotic polar solvent is used at the time of reaction of a monotertiary butyl carbonate monoalkali metal salt and an aromatic sulfonyl halide, and a nitrogen atom is present in addition to the ring nucleus. When the reaction is carried out in the presence of a heterocyclic compound having aromaticity and a phase transfer catalyst, BOC-D is surprisingly obtained in a high yield within a short time, and as a result, BOC after the reaction is obtained. The present inventors have completed the present invention by finding that the method for isolating and purifying -D is significantly simplified.

That is, according to the present invention, a monotertiary butyl carbonate monoalkali metal salt and an aromatic sulfonyl halide are used in a mixed solvent of a water-insoluble solvent and an aprotic polar solvent, in addition to the ring nucleus, a nitrogen atom. The present invention provides a method for producing ditertiary-butyl dicarbonate, which comprises reacting in the presence of a heterocyclic compound having no aromatic group and a phase transfer catalyst.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Monotertiary butyl carbonate monoalkali metal salt: The starting material of the present invention is monotertiary butyl carbonate monoalkali metal salt, which is obtained by adding carbon dioxide gas to alkali metal tertiary butoxide in an organic solvent. It can be easily manufactured by making it act. As the alkali metal, sodium or potassium is generally used, and among them, inexpensive and easily available sodium is preferably used. If water is present in the solvent used for the reaction with the carbon dioxide gas, the alkali metal tertiary-butoxide, which is the raw material, is decomposed. Therefore, it is desirable to use a solvent having a minimum water content.

Aromatic Sulfonyl Halide: As the aromatic sulfonyl halide used in the present invention, known compounds having a halogenosulfone group bonded to an aromatic ring can be used without any limitation. Specifically, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,4-dimethylbenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, 2,4-dichlorobenzenesulfonyl chloride, benzenesulfonyl bromide, p-toluenesulfonyl bromide, p-chlorobenzene sulfonyl bromide etc. are mentioned. Among them, p-toluenesulfonyl chloride, which is easily available and inexpensive, is preferably used.

The amount of the aromatic sulfonyl halide relative to the raw material monotertiary butyl carbonate monoalkali metal salt is 2%.
Since one molecule of BOC-D is produced from the molecule, it is usually selected in the range of 0.4 to 0.6 mol with respect to 1 mol of the monotert-butyl monoalkali metal carbonate. If less than this range, a large amount of unreacted raw material remains,
It is not preferable because the consistent yield decreases. On the other hand, if the amount exceeds this range, excess aromatic sulfonyl halide, which is difficult to separate from the product, remains, which makes purification difficult and is not preferable.

Catalyst: In the present invention, it is essential to use a heterocyclic compound having aromaticity and having no nitrogen atom other than the ring nucleus. As the heterocyclic compound having an aromaticity and having no nitrogen atom other than the ring nucleus, known compounds can be adopted without any limitation. Among them, 5 member ring, 6
A heterocyclic compound having a member ring is preferably used. In this reaction, not the nitrogen of the amino group but the ring nucleus nitrogen of these heterocyclic compounds effectively acts. As a result, surprisingly, BOC-D was produced in a high yield in a shorter time than ever before. Can be manufactured. These heterocycles may have a substituent other than the amino group, which is inert to the reaction. Specific examples of such a heterocyclic compound include 2H-pyrrole, isoxazole, thiazole, inchiazole, 2H-imidazole, furazan, pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 3H-indole, benzoxazole, benzothiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, acridine, phenanthridine, 1,10-phenanthroline, phenazine, indolizine, 4H-quinolidine, 1,8-naphthyridine, pteridine. Etc. Among them, inexpensive pyridine, picoline, quinoline and the like are preferably used, and more preferably, pyridine which is easily available is used.

No nitrogen atom other than these ring nuclei,
The amount of the heterocyclic compound having aromaticity is not particularly limited, but in order to obtain a sufficient reaction rate, it is 50 mol% with respect to the starting material monotertiary-butyl monoalkali metal carbonate. It is desirable that the amount is below, more preferably 20 mol% or less. When the amount is more than this range, the BOC-D produced may be decomposed and the yield may be lowered, which is not preferable.

Phase transfer catalyst: In the present invention, it is essential to further use a phase transfer catalyst. As the phase transfer catalyst, known substances can be used without any limitation, and examples thereof include general phase transfer catalysts such as quaternary ammonium salts and pyridinium salts. Specific examples of the phase transfer catalyst, tetramethyl ammonium fluoride, tetramethyl ammonium chloride, tetramethyl ammonium bromide, tetramethyl ammonium iodide, tetramethyl ammonium perchlorate,
Tetramethylammonium tetrafluoroborate, tetramethylammonium hexafluorophosphate, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetraethylammonium perchlorate,
Tetraethylammonium tetrafluoroborate, tetraethylammonium acetate, tetraethylammonium p-toluenesulfonate, tetra-n-propylammonium chloride, tetra-n-propylammonium bromide,
Tetra-n-propylammonium iodide, tetra-n-propylammonium perchlorate, tetra-n-fluoride
Butyl ammonium, tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium bromide, tetra-n-butyl ammonium iodide, tetra-n-perchloric acid
Butyl ammonium, tetra-n-butyl ammonium hydrogen sulfate, tetra-n-pentyl ammonium bromide, tetra-n-hexyl ammonium bromide, tetra-n tetra-n
-Heptyl ammonium, tetra-n-octyl ammonium bromide, phenyl trimethyl ammonium chloride, phenyl trimethyl ammonium bromide, phenyl trimethyl ammonium iodide, phenyl triethyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl trimethyl ammonium bromide, benzyl trimethyl iodide Ammonium, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltri-n-butylammonium chloride, benzylcetyldimethylammonium chloride, benzyldimethylstearylammonium chloride, cetyltrimethylammonium chloride,
Quaternary ammonium salts such as cetyltrimethylammonium bromide, lauryltrimethylammonium chloride, lauryltrimethylammonium bromide, methyltri-n-octylammonium chloride, N-n-butylpyridinium chloride, N-n-butylpyridinium bromide, and chloride N-n-pentylpyridinium, N-n-pentylpyridinium bromide, N-n-octylpyridinium chloride, N-n-bromide
Octylpyridinium, N-cetylpyridinium chloride,
N-cetylpyridinium bromide, N-laurylpyridinium chloride, N-laurylpyridinium bromide, N-n-chloride
Butyl-2-picolinium, Nn-butyl-2-bromide
Picolinium, N-n-pentyl-2-picolinium chloride, N-n-pentyl-2-picolinium bromide, N
-N-octyl-2-picolinium, N-n-octyl-2-picolinium bromide, N-cetyl-2-picolinium chloride, N-cetyl-2-picolinium bromide, N-
Lauryl-2-picolinium, N-lauryl-2-bromide
Picolinium, N-n-butyl-3-picolinium chloride, Nn-butyl-3-picolinium bromide, N-
n-Pentyl-3-picolinium, N-n-pentyl-3-picolinium bromide, N-n-octyl-3-picolinium chloride, N-n-octyl-3-picolinium bromide, N-cetyl-3-chloride Picolinium, N-cetyl-3-picolinium bromide, N-lauryl-3-picolinium chloride, N-lauryl-3-picolinium bromide, N-chloride
-N-butyl-4-picolinium, N-n-butyl-4-picolinium bromide, N-n-pentyl-4-picolinium chloride, N-n-pentyl-4-picolinium bromide,
Nn-octyl-4-picolinium chloride, Nn bromide
-Octyl-4-picolinium, N-cetyl-4-chloride
Picolinium, N-cetyl-4-picolinium bromide, N-cetyl-4-picolinium bromide, N-lauryl chloride-
Examples thereof include pyridinium salts such as 4-picolinium and N-lauryl-4-picolinium bromide.

In the present invention, it is preferable to use the quaternary ammonium salt and the pyridinium salt as described above, singly or as a mixture, and among them, a tetraalkylammonium halide, a benzyltrialkylammonium halide and an N-alkylpyridinium halide are used. Single or a mixture of the above is particularly preferably used. Specifically, easily available tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, and benzyltrimethylammonium chloride are preferred, and more preferably, inexpensive tetra-n-butylammonium chloride or tetra-n-butyl. Ammonium bromide is used. The amount of the phase transfer catalyst used is usually 0.001 to 100 mol% or less, and more preferably, with respect to the raw material monotertiary-butyl monoalkali metal carbonate.
It is in the range of 0.005 to 10 mol%. If the amount used is too small, the yield of the desired BOC-D will be reduced, and if it is more than this, the effect of the phase transfer catalyst will reach a ceiling and it is uneconomical.

Mixed solvent: In the present invention, the reaction is carried out in a mixed solvent of a water-insoluble solvent and an aprotic polar solvent. Since the non-water-soluble solvent dissolves the non-water-soluble BOC-D, which is the product, well, it is possible to sufficiently purify the BOC-D by washing with water after the reaction.
It is possible to obtain OC-D. Further, the aprotic polar solvent has almost no solubility in a non-water-soluble solvent,
As a result, the solubility of the starting material monotertiary-butyl monoalkali metal carbonate, or the reaction intermediate is increased, and as a result,
It has the effect of increasing the reactivity with aromatic sulfonyl halides.

Non-water-soluble solvent: As the non-water-soluble solvent, known substances can be used without any limitation as long as they are non-water-soluble solvents which are inert to the reaction. Specific examples include aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, heptane and octane, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane. It is preferable to use toluene, xylene, heptane or the like, which is easy to handle and can be easily dehydrated by azeotropic dehydration. In the present invention, high-purity BOC-D is obtained by removing the by-product and aprotic polar solvent by washing with water after completion of the reaction. Thereafter, in order to recover and reuse the non-water-soluble solvent, the recovered solvent is used. It is necessary to dehydrate. Therefore, whether or not dehydration is easy is an important factor. More preferably, toluene, which is easily available and inexpensive, is used.
These non-water-soluble solvents may be used alone or as a mixed solvent of two or more kinds.

Aprotic polar solvent: As the aprotic polar solvent, any known aprotic polar solvent can be used without any limitation as long as it is an aprotic polar solvent which is soluble in the above-mentioned non-water-soluble solvent and is inert to the reaction. To be As a specific example, N, N-
Common aprotic polar solvents such as dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone are mentioned, and N, N-dimethylformamide which is easily available and inexpensive is preferable. Used. These aprotic polar solvents may be used alone or as a mixed solvent of two or more kinds.

In the present invention, the reaction is carried out in a non-water-soluble solvent, but since the raw materials and reaction intermediates are hardly dissolved in the non-water-soluble solvent, they are dissolved by an aprotic polar solvent and a phase transfer catalyst. This is done by improving the character. Therefore, when a large amount of the phase transfer catalyst is used, the amount of the aprotic polar solvent may be small, and conversely, when the amount of the phase transfer catalyst is small, it is better to increase the amount of the aprotic polar solvent. There are good cases. Since the amount of the phase transfer catalyst and the amount of the aprotic polar solvent vary depending on the type of the non-water-soluble solvent used, the amount may be appropriately selected and the amount used may be determined. The amount used is 0.01 to 40 parts by weight, preferably 0.01 to 2 parts by weight, based on 1 part by weight of the non-water-soluble solvent. When the amount of the aprotic polar solvent is less than this, the solubility of the raw material and the reaction intermediate in the water-insoluble solvent decreases, so it takes a long time to complete the reaction,
Moreover, even if it is used in a larger amount than this range, the effect reaches the ceiling and it is not economical. The mixed solvent is 0.1 to 2 per 1 part by weight of monotert-butyl carbonate alkali metal salt.
00 parts by weight, preferably 1 to 50 parts by weight, and most preferably 3 to 30 parts by weight.

Reaction: To carry out the reaction of the present invention, a heterocyclic ring having aromaticity and having no nitrogen atom other than the ring nucleus in a solvent containing monotertiary-butyl monocarbonate carbonate is usually used. After the addition of the formula compound, the reaction is carried out by gradually supplying the aromatic sulfonyl halide with stirring while cooling from the outside so that the temperature in the system is kept within a predetermined range. Since the reaction is an exothermic reaction, the supply rate of the aromatic sulfonyl halide is determined according to the degree of heat removal in the system. The aromatic sulfonyl halide may be dissolved in an aprotic polar solvent and supplied. Further, when the reaction mixture of alkali metal tertiary-butoxide and carbon dioxide gas is continuously used as the reaction raw material, the heterocyclic compound having aromaticity and / or the phase transfer catalyst having no nitrogen atom other than the ring nucleus is used. It may be added from the time of the reaction in the first stage.

The reaction temperature is usually -50 ° C to 100 ° C,
More preferably, it is in the range of -20 ° C to 60 ° C. If the reaction temperature is too low, the reaction rate decreases and the cost for cooling increases, which is not preferable. On the contrary, if it is too high, the raw materials, reaction intermediates, or products are decomposed, resulting in a decrease in yield. The reaction time is affected by the reaction temperature and cannot be specified, but it is usually in the range of 0.5 to 100 hours. After the reaction, the mixture is washed with water to remove the by-product and the aprotic polar solvent and to obtain a highly pure BO.
C-D can be obtained. When it is desired to obtain BOC-D of higher purity, it can be obtained by distilling a non-water-soluble solvent that dissolves BOC-D under reduced pressure by a method such as a thin film evaporator that does not apply heat as much as possible.

The reaction of the present invention can be carried out under any of pressure, normal pressure and reduced pressure. Further, this reaction can be carried out by any of batch, continuous and semi-continuous methods. Furthermore, in the present invention, it is possible to carry out the reaction by flowing or sealing a gas inert to the reaction in the gas phase part of the reactor. Such a gas can be used without any limitation as long as it is inert to the reaction. Specific examples include nitrogen, helium, argon, carbon dioxide gas, etc.
Inexpensive nitrogen gas is preferably used.

[0020]

EXAMPLES Next, the present invention will be specifically described by way of examples. Example 1 20 equipped with stirrer, gas inlet tube, thermometer and cooler
The inside of the 0 ml four-necked flask was replaced with nitrogen, and sodium-
Tertiary-butoxide 9.61 g (0.100 mol), toluene 72.08 g, pyridine 0.40 g
(0.005 mol, 0.05 mol ratio of substrate) and 0.32 g of tetra-n-butylammonium bromide (0.
(001 mol, 0.01 mol ratio to the substrate) was charged, and carbon dioxide gas was introduced at a rate of 56 ml / min for 60 minutes while stirring and maintaining the temperature of this mixture at 30 ° C. or lower, and mono-tert-butyl sodium carbonate was added. A salt slurry was prepared.

The above reaction mixture was then cooled to 20 ° C. and 9.15 g of p-toluenesulfonyl chloride (0.
(048 mol, 0.48 mol ratio to the substrate) and 18.27 g of N, N-dimethylformamide were added, and the mixture was stirred at 20 ° C to 30 ° C for 45 min, and then at 40 ° C for 3 hr 30 min. When the reaction mixture was analyzed by gas chromatography, the yield of di-tert-butyl dicarbonate based on mono-tert-butyl sodium carbonate was 93.3% and the yield based on p-toluenesulfonyl chloride was 93.3%. The rate was 95.2%, and no p-toluenesulfonyl chloride remained.

Example 2 20 equipped with a stirrer, gas inlet tube, thermometer and cooler
The inside of the 0 ml four-necked flask was replaced with nitrogen, and sodium-
9.61 g (0.100 mol) of tertiary-butoxide, 96.10 g of toluene, 0.40 g of pyridine.
(0.005 mol, 0.05 mol ratio to substrate) and 1.61 g (.0.) Of tetra-n-butylammonium bromide.
(005 mol, 0.05 mol ratio to the substrate) was charged, and carbon dioxide gas was introduced at a rate of 56 ml / min for 60 minutes while maintaining the temperature of this mixture at 30 ° C. or lower with stirring to mono-tertiary-butyl sodium carbonate. A salt slurry was prepared.

The above reaction mixture was then cooled to 20 ° C. and 9.01 g of p-toluenesulphonyl chloride (0.
(047 mol, 0.47 mol ratio to the substrate) and 18.27 g of N, N-dimethylformamide were added, and the mixture was stirred at 20 ° C to 30 ° C for 30 min, and further stirred at 40 ° C for 2 hr. The reaction mixture was analyzed by gas chromatography to find that the yield of di-tert-butyl dicarbonate based on mono-tert-butyl sodium carbonate was 91.1% and the yield based on p-toluenesulfonyl chloride was 91.1%. The rate was 93.0%, and no p-toluenesulfonyl chloride remained.

Example 3 20 equipped with a stirrer, gas inlet tube, thermometer and cooler
The inside of the 0 ml four-necked flask was replaced with nitrogen, and sodium-
Tertiary-butoxide 7.69 g (0.080 mol), toluene 76.90 g, pyridine 0.32 g
(0.004 mol, 0.05 mol ratio of substrate), N, N-
Dimethylformamide (14.62 g) and benzyltrimethylammonium chloride (0.15 g, 0.008 mol, 0.01 mol ratio to substrate) were charged, and while stirring, the temperature of the mixture was kept at 30 ° C. or lower and carbon dioxide gas was adjusted to 45 ° C.
It was introduced at a rate of ml / min for 60 minutes to prepare a slurry of mono-tert-butyl sodium carbonate salt.

Then, the above reaction mixture was kept at 40 ° C., and 7.36 g of p-toluenesulfonyl chloride (0.
(0386 mol, 0.4825 mol ratio of substrate) was added and 3
Stirring was performed for hours. When the reaction mixture was analyzed by gas chromatography, the yield of carbonic acid mono-tert-butyl sodium salt or di-tert-butyl dicarbonate based on p-toluenesulfonyl chloride was 90.0%.

Comparative Example 1 20 equipped with a stirrer, a gas inlet tube, a thermometer and a cooler
The inside of the 0 ml four-necked flask was replaced with nitrogen, and sodium-
Tertiary-butoxide 7.69 g (0.080 mol), toluene 76.90 g, pyridine 0.32 g
(0.004 mol, 0.05 mol ratio of substrate), N, N-
Charge 14.62 g of dimethylformamide, and stir,
While maintaining the temperature of this mixture at 30 ° C. or lower, carbon dioxide gas was introduced at a rate of 45 ml / min for 60 minutes to prepare a slurry liquid of mono-tert-butyl carbonate sodium salt. No phase transfer catalyst was added.

Then, the above reaction mixture was kept at 40 ° C., and 7.34 g of p-toluenesulfonyl chloride (0.3.
(0385 mol, 0.48125 mol ratio of substrate)),
It was stirred for 4 hours. When the reaction mixture was analyzed by gas chromatography, the yield of carbonic acid mono-tertiary-butyl sodium salt or di-tert-butyl dicarbonate based on p-toluenesulfonyl chloride was 72.0%. The residual rate of p-toluenesulfonyl chloride was 18.7%.

[0028]

According to the present invention, carbonic acid mono-tertiary
By reacting a butyl monoalkali metal salt with an aromatic sulfonyl halide, ditertiary-butyl dicarbonate can be produced in a short time and in a very high yield of 90% or more. Furthermore, the isolation and purification methods of the produced ditertiary-butyl dicarbonate can be significantly simplified.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ryoichi Morito 8-3-11 Morofuku, Daito City, Osaka Prefecture Daito Chemix Co., Ltd. New Development Department (72) Inventor Yutaka Sumi 8-3-11 Morofuku, Daito City, Osaka Prefecture No. Daito Chemix Co., Ltd. New Development Department (72) Inventor Yoshinori Nakayama 8-3-11 Morofuku, Daito City, Osaka Prefecture Daito Chemix Co., Ltd. New Development Department

Claims (3)

[Claims] 1. A fragrance containing a monotertiary butyl carbonate monoalkali metal salt and an aromatic sulfonyl halide in a mixed solvent of a water-insoluble solvent and an aprotic polar solvent and having no nitrogen atom other than the ring nucleus. A method for producing ditertiary-butyl dicarbonate, which comprises reacting in the presence of a heterocyclic compound having a group property and a phase transfer catalyst. 2. The method according to claim 1, wherein the mixed solvent is used in a proportion of 0.01 to 2 parts by weight of the aprotic polar solvent with respect to 1 part by weight of the water-insoluble solvent. 3. The non-water-soluble solvent is toluene, the aprotic polar solvent is N, N-dimethylformamide, and the heterocyclic compound having aromaticity and having no nitrogen atom other than the ring nucleus is pyridine. And the phase transfer catalyst is tetra-n-butylammonium chloride or tetra-n-butylammonium bromide.