JP2018127405A - Process for producing blonanserin - Google Patents

Abstract

[PROBLEMS] To produce blonanserin with a high yield under mild reaction conditions. 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1-ethylpiperazine are mixed with an organic solvent in the presence of a base. A process for producing blonanserin by reacting with a palladium complex as a catalyst. [Selection figure] None

Description

  The present invention relates to a method for producing blonanserin. More specifically, the present invention relates to 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1-ethylpiperazine. The present invention relates to a production method for obtaining blonanserin by reacting with a palladium complex as a catalyst in an organic solvent in the presence of a base.

Blonanserin (formula III) which is a D ₂ receptor · 5-HT ₂ receptor blocker (SDA) is a psychotropic agent useful as a therapeutic agent for schizophrenia (Patent Document 1).
Blonanserin is, for example, 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (formula IV) and 1-ethylpiperazine (formula II). Is known to be obtained by heating at 170 ° C. in the presence of potassium iodide. However, this method requires a high temperature of 170 ° C., and requires a long time to complete the reaction (Comparative Examples 1 to 3). It has been found that blonanserin undergoes deethylation when heated at a high temperature, and the deethylated form remains as an impurity. This phenomenon has been confirmed in the same way even when heated for a long time at a low temperature (Table I). Therefore, in the method of Patent Document 1, the yield is not so high and it is difficult to obtain blonanserin of good quality. In addition, industrial production requires equipment capable of high-temperature reaction, and it is a neat reaction and handling is very difficult in large-scale synthesis. Therefore, in order to use blonanserin as a medicine, a technique for industrially efficient production under mild conditions has been demanded.

Therefore, a method for producing blonanserin by a method such as using an organic solvent and performing a reaction at a temperature lower than 170 ° C. has been reported.
For example, in Patent Document 2, 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1-ethylpiperazine are substituted with N-methylpyrrolidone. And heated at 170 ° C. in the presence of an organic solvent such as dimethyl sulfoxide. After completion of the reaction, the mixture is cooled, water and ethyl acetate are added, the aqueous layer is extracted with ethyl acetate, extracted with hydrochloric acid, aqueous ammonia And extraction with ethyl acetate, the organic layer was extracted with ethyl acetate and concentrated, and the residue was recrystallized with ethanol to obtain blonanserin. This method requires a reaction at a high temperature similar to that of Patent Document 1 in addition to a decrease in reactivity due to the use of a solvent and a long heating time.

In Patent Document 3, 2-chloro-4- (4-fluorophenyl) -5,6,7,8,
An example is described in which 9,10-hexahydrocycloocta [b] pyridine and 1-methylpiperazine are refluxed for 12 hours in a toluene solvent to which sodium iodide is added. However, although this method was carried out using 1-ethylpiperazine, the formation of blonanserin was hardly confirmed, resulting in a large amount of raw materials remaining (see Comparative Example 4 below).

  In other Patent Document 4, 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1-ethylpiperazine are mixed with dimethyl sulfoxide, N , N-dimethylformamide in a solvent, potassium carbonate or sodium carbonate is used as a basic catalyst, potassium iodide or sodium iodide is added as an activator, and the mixture is heated to 80 ° C. for reaction. Bronanserin is obtained by filtering, extracting by adding water, concentrating and recrystallizing. In this method, the reaction temperature is lowered. However, as in Patent Document 2, heating for a long time is required.

  Next, in Patent Document 5, the chloro group of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine is converted to a tosyl group, a mesyl group, Using a compound converted to a sulfonate derivative having a good leaving property such as a benzenesulfonyl group, the compound and 1-ethylpiperazine are mixed with a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc. The reaction was conducted by adding an organic or inorganic base under the conditions described above, followed by heating. After completion of the reaction, cooling and adding water and ethyl acetate, the aqueous layer was extracted with ethyl acetate, extracted with hydrochloric acid, with potassium bicarbonate solution Bronanserin is obtained by collecting the residue deposited by freezing and recrystallizing the residue with ethanol. Even in this method, although not as high as the temperature described in Patent Document 1, a high-temperature reaction of 140 ° C. or higher is required, and a long-time heating is required as in Patent Document 2.

  As described above, in the prior art approach, if the reaction temperature is lowered, the reaction (heating) time becomes longer, etc., so that the mild reaction conditions as a whole are not achieved or the yield is deteriorated. It is hard to say that the above problems have been solved. Accordingly, there remains a need for a method for producing blonanserin in high yield under mild reaction conditions suitable for industrial production.

Japanese Patent Publication No. 7-47574 JP 2013-216655 A Chinese Patent Application No. 101531634 Chinese Patent Application Publication No. 101955459 Chinese Patent Application No. 102887856

  An object of the present invention is to solve the above-mentioned problems of the prior art and to provide a method capable of producing blonanserin industrially efficiently and under mild conditions.

As a result of intensive studies on a process that can produce blonanserin industrially efficiently and under mild conditions, the present inventors have determined that reaction conditions include an organic solvent such as an aromatic hydrocarbon solvent, a palladium complex such as Using a complex composed of a palladium compound and a phosphine-based ligand as a catalyst, a base such as a metal alkoxide is added, and the reaction system is placed in a nitrogen or argon atmosphere as necessary, the reaction temperature is set to 50 to 120 ° C., and 2- It was found that the above problem can be solved by reacting halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine with 1-ethylpiperazine, The present invention has been completed.

（２）反応系中を不活性ガス雰囲気下にする（１）に記載の製造方法。
（３）反応温度が５０〜１２０℃の範囲内である（１）または（２）に記載の製造方法。（４）有機溶媒が芳香族炭化水素である（１）〜（３）のいずれか記載の製造方法。
（５）塩基が金属アルコキシドである（１）〜（４）のいずれか記載の製造方法。 That is, the present invention relates to the following method:
(1) 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (formula I) and 1-ethylpiperazine (formula II) A process for producing blonanserin (formula III) by reacting with a palladium complex as a catalyst in an organic solvent in the presence of a base.

(2) The production method according to (1), wherein the reaction system is placed in an inert gas atmosphere.
(3) The manufacturing method as described in (1) or (2) whose reaction temperature exists in the range of 50-120 degreeC. (4) The production method according to any one of (1) to (3), wherein the organic solvent is an aromatic hydrocarbon.
(5) The production method according to any one of (1) to (4), wherein the base is a metal alkoxide.

  According to the present invention, blonanserin has the advantage that it can be produced industrially efficiently and under mild conditions.

  The present invention relates to a method for producing blonanserin. More specifically, the present invention relates to 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (formula I) and 1-ethyl. The present invention relates to a production method for obtaining blonanserin (formula III) by reacting piperazine (formula II) in an organic solvent in the presence of a base using a palladium complex as a catalyst.

The 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine used in the present invention is not particularly limited. -Chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine, 2-bromo-4- (4-fluorophenyl) -5,6 7,8,9,10-hexahydrocycloocta [b] pyridine, among which 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexa Hydrocycloocta [b] pyridine is preferred. These compounds can be prepared according to the prior art.
The amount of 1-ethylpiperazine used is not particularly limited, but 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta used. [B] About 1 to 3 mol times (mol / mol) of pyridine is preferable.

In the method of the present invention, an organic solvent is used as a solvent. In the present application, “solvent” means a compound that can dissolve the compound used in the reaction, and “organic solvent” means a compound containing carbon (organic compound) that can be used as a solvent. Although there is no restriction | limiting in particular as an organic solvent, Aromatic hydrocarbon is preferable. Examples of the aromatic hydrocarbon include toluene, xylene, mesitylene and the like, and toluene is more preferable.
The amount of the solvent to be used is not particularly limited, but 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] to be used is used.
About 3-9 times amount (v / w) is preferable with respect to pyridine, and about 6-7 times amount (v / w) is especially preferable.

  In the method of the present invention, a palladium complex is used as a catalyst. In the present application, “palladium complex” represents a complex composed of palladium, which is a central metal, and an organic molecule (ligand) coordinated thereto. The palladium complex is not particularly limited, but preferably contains a phosphine-based ligand. Examples of such phosphine-based ligands are triphenylphosphine, tris (4-methoxyphenyl) phosphine, dicyclohexyl (1,1-diphenyl-1-propen-2-yl) phosphine, and the like. Alternatively, a carbene ligand may be selected.

  The amount of the catalyst to be used is not particularly limited. For example, when palladium (II) acetate and triphenylphosphine are used, 2-halogeno-4- (4-fluorophenyl) -5,6,7 , 8,9,10-Hexahydrocycloocta [b] pyridine is about 0.01 to 0.1 mol times (mol / mol) of palladium (II) acetate and palladium (II) about It is preferable to use 2 to 5 mol times (mol / mol) of triphenylphosphine.

  A method for forming a palladium complex in the reaction system as described above, or 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine On the other hand, it is preferable to use about 0.01 to 0.1 mole times (mol / mol) of a palladium complex compound (for example, tetrakis (triphenylphosphine) palladium (0)).

The base used in the present invention is not particularly limited, but a metal alkoxide is preferable. In the present application, “metal alkoxide” represents a compound in which the hydrogen of the hydroxyl group (—OH) of an alcohol is replaced with a metal element. As the metal alkoxide, sodium-tert-butoxide and potassium-tert-butoxide are particularly preferable.
The amount of the base used is not particularly limited, but 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9 to be used in consideration of the balance with the production cost.
, 10-hexahydrocycloocta [b] pyridine is preferably about 1 to 2 mol times (mol / mol).

  In the method of the present invention, optional components can be added as necessary as long as the yield of blonanserin is not adversely affected. Such components are well known in the art.

  The reaction of the present invention is not particularly limited, but is preferably performed in an inert gas atmosphere, for example, in a nitrogen or argon atmosphere. This is aimed at degassing and expelling oxygen present in the reaction system. The method for degassing the reaction system is not particularly limited, but nitrogen or argon is allowed to flow into the reaction vessel (flow degassing method), and nitrogen or argon is allowed to flow directly into the reaction system (bubble degassing). Gas method), a method of refluxing in a nitrogen or argon atmosphere, a method of reducing the pressure in the reaction vessel and then introducing nitrogen or argon (vacuum degassing method), and the vacuum degassing method is preferred.

  The process of the present invention can be carried out at a lower reaction temperature than before. The reaction temperature is not particularly limited, but is usually in the range of about 25 ° C. to the boiling point of the solvent, and is preferably about 50 to 120 ° C., more preferably about 60 to 90 ° C. in consideration of production in general equipment. . The reaction temperature is, for example, about 50 to 120 ° C, about 50 to 110 ° C, about 50 to 100 ° C, about 50 to 90 ° C, about 50 to 80 ° C, about 50 to 70 ° C, about 50 to 60 ° C, about 60 -120 ° C, about 60-110 ° C, about 60-100 ° C, about 60-90 ° C, about 60-80 ° C, about 60-70 ° C, about 70-120 ° C, about 70-110 ° C, about 70-100 C, about 70-90 ° C, about 70-80 ° C, about 80-120 ° C, about 80-110 ° C, about 80-100 ° C, about 80-90 ° C, about 90-120 ° C, about 90-110 ° C, It is in the range of about 90-100 ° C, about 100-120 ° C, about 100-110 ° C, or about 110-120 ° C. In the present application, “reaction temperature” refers to 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (formula I) and 1-ethyl. It means the temperature at which the reaction for obtaining blonanserin (formula III) from piperazine (formula II) is carried out.

  The process of the present invention is characterized by the fact that it does not require a long reaction time, even though it is carried out at a low reaction temperature. The reaction time varies depending on the reaction conditions such as the reactants, the amount of solvent, the amount of catalyst, the amount of base, the reaction temperature, etc., but usually about 1 to 20 hours is preferable. The reaction time is, for example, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, or between these Any time, such as about 1-9 hours, about 1-7 hours, about 1-3 hours, about 3-9 hours, about 3-7 hours, about 7-9 hours as shown in the Examples below. Etc. In the present application, “reaction time” refers to 2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (formula I) and 1-ethyl. It means the time required for the reaction for obtaining blonanserin (formula III) from piperazine (formula II), and does not include the time for extracting and purifying the obtained blonanserin (formula III) from the reaction system.

The process of the present invention is further characterized by providing a high yield, ie high blonanserin conversion, despite the reaction under low reaction temperature and short reaction time. The conversion of blonanserin in the method of the present invention is 75% or more, such as 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 100%. Even there.
The following examples are intended to explain the present invention more specifically, and the scope of the present invention is not limited by these examples.

Example 1 Production of Blonanserin A 200 mL flask was placed in a nitrogen atmosphere, and 33.5 mL of toluene and 5.91 g (51.77 mmol) of 1-ethylpiperazine were added and stirred. After cooling to 10 ° C. or less, 5.00 g (17.26 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1.99 g (20.71 mmol) of sodium-tert-butoxide was added. The operation of reducing the pressure to 100 hPa or less and stirring for 2 minutes and then returning to pressure with nitrogen was repeated three times. After adding 0.0775 g (0.345 mmol) of palladium (II) acetate and 0.2715 g (1.035 mmol) of triphenylphosphine, the pressure was reduced to 100 hPa or less, the mixture was stirred for 2 minutes, and then the pressure was restored by nitrogen five times. And stirred at 70 ° C. for 7 hours. The reaction solution was cooled to room temperature, 50 mL of water was added little by little, and the mixture was stirred for 30 minutes. The precipitate was removed by filtration using a φ40 mm Kiriyama funnel mounted with 2.50 g of Celite, and washed twice with 10 mL of toluene. . The obtained filtrate was transferred to a 300 mL separatory funnel, and the aqueous layer was removed (pH 13.0). 50 mL of water was added to the organic layer, vigorously shaken for 2 minutes, and allowed to stand for 10 minutes to remove the aqueous layer. This water washing operation was repeated until the aqueous layer had a pH of 9 or less to obtain 49.86 g of a toluene solution of blonanserin. Blonanserin content: 5.67 g, reaction yield: 89.12%, HPLC purity: 87.70%.

Example 2 Production of Blonanserin A 200 mL flask was placed in a nitrogen atmosphere, and 13.4 mL of toluene and 2.36 g (20.71 mmol) of 1-ethylpiperazine were added and stirred. After cooling to 10 ° C. or lower, 2.00 g (6.90 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and Sodium-tert-butoxide 0.80 g (8.28 mmol) was added. The operation of reducing the pressure to 100 hPa or less and stirring for 2 minutes and then restoring the pressure with nitrogen was repeated 5 times. After adding 0.0310 g (0.138 mmol) of palladium (II) acetate and 0.1086 g (0.414 mmol) of triphenylphosphine, the pressure was reduced to 100 hPa or less, the mixture was stirred for 2 minutes, and then the pressure was restored by nitrogen twice. And stirred at 80 ° C. for 3 hours. The reaction solution was cooled to room temperature, 16 mL of water was added little by little, and the mixture was stirred for 30 minutes. The precipitate was removed by filtration using a φ21 mm Kiriyama funnel mounted with 1.0 g of Celite, and washed twice with 4 mL of toluene. . The obtained filtrate was transferred to a 100 mL separatory funnel, and the aqueous layer was removed (pH 13.0). 20 mL of water was added to the organic layer, vigorously shaken for 2 minutes, allowed to stand for 10 minutes, and the aqueous layer was removed. This water washing operation was repeated until the aqueous layer had a pH of 9 or less to obtain 20.09 g of a toluene solution of blonanserin. Blonanserin content: 2.25 g, reaction yield: 87.71%, HPLC purity: 87.52%

Example 3 Production of blonanserin
The results obtained by changing the reaction temperature under the conditions of Example 2 are shown in Table II.

Example 4 Production of blonanserin
The results obtained by changing the amount of the metal catalyst under the conditions of Example 2 are shown in Table III.

Example 5 Production of Blonanserin Table IV shows the results obtained by changing the amount of ligand under the conditions of Example 2.

Example 6 Preparation of blonanserin A 200 mL flask was placed under a nitrogen atmosphere, and 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine 12. 00 g (41.41 mmol), palladium (II) acetate 0.1859 g (0.828 mmol), and dicyclohexyl (1,1-diphenyl-1-propen-2-yl) phosphine 0.6469 g (1.656 mmol), sodium 4.78 g (49.70 mmol) of tert-butoxide was added. Toluene bubbled 80.4 mL and 1-ethylpiperazine 5.20 g (45.55 mmol) were added for 30 minutes, and the mixture was stirred at 93 ° C. for 2 hours. The reaction liquid was cooled to room temperature, 60 mL of water was added little by little, and after stirring for 30 minutes, the aqueous layer was removed (pH 13.0). The precipitate was removed by filtration using a φ40 mm Kiriyama funnel mounted with 5.98 g of silica gel and 5.98 g of Celite, and washed twice with 24 mL of toluene to obtain 107.59 g of a toluene solution of blonanserin. Blonanserin content: 12.82 g, reaction yield: 84.31%, HPLC purity: 91.78%

Example 7 Production of blonanserin A 200 mL flask was placed in a nitrogen atmosphere, and 20.0 mL of toluene and 3.52 g (30.83 mmol) of 1-ethylpiperazine were added and stirred. After cooling to below 10 ° C., 2.99 g (10.32 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and Sodium-tert-butoxide 1.20 g (20.49 mmol) was added. The operation of reducing the pressure to 100 hPa or less and stirring for 2 minutes and then restoring the pressure with nitrogen was repeated 5 times. After adding tetrakis (triphenylphosphine) palladium (0) 0.2426 g (0.299 mmol), 100 h
The pressure was reduced to Pa or lower and the mixture was stirred for 2 minutes, and then the operation of restoring the pressure with nitrogen was carried out three times. The reaction solution was cooled to room temperature, 30 mL of water was added little by little, and the mixture was stirred for 30 minutes. The precipitate was removed by filtration using a φ21 mm Kiriyama funnel mounted with 1.50 g of Celite, and washed twice with 6 mL of toluene. . The obtained filtrate was transferred to a 250 mL separatory funnel, and the aqueous layer was removed (pH 13.0). 30 mL of water was added to the organic layer, vigorously shaken for 2 minutes, allowed to stand for 10 minutes, and the aqueous layer was removed. This water washing operation was repeated until the aqueous layer had a pH of 9 or less to obtain 33.96 g of a blonanserin toluene solution. Conversion to blonanserin: 98.97%, HPLC purity: 90.92%.

Comparative Example 1 Production of blonanserin (Trace of Patent Document 1)
In a 200 mL flask, 2.92 g (10.08 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1-ethyl Piperazine 3.52 g (30.82 mmol) and potassium iodide 1.60 (7.48 mmol) were added, and the mixture was stirred at 170 ° C. for 5 hours. However, the raw material remained at 40% or more, and the reaction end point was not reached. HPLC purity: 51.64%.

Comparative Example 2 Production of blonanserin (implemented at a lower temperature than Comparative Example 1)
In a 50 mL flask, 1.00 g (3.45 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and 1-ethyl Piperazine 1.31 g (11.47 mmol) and potassium iodide 0.55 (2.57 mmol) were added, and the mixture was stirred at 140 ° C. for 5 hours. However, 90% or more of the raw material remained, and the reaction end point was not reached. HPLC purity: 7.55%.

Comparative Example 3 Production of blonanserin (Trace of Patent Document 3)
In a 100 mL test tube, 0.5967 g (2.06 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine and sodium iodide ( 1.49 mmol), 8.6 mL of toluene, and 0.67 g (5.87 mmol) of 1-ethylpiperazine were added and stirred for 5 hours under reflux, but blonanserin was hardly produced. Heating was continued for 5 hours, but formation was not confirmed.

Comparative Example 4 Production of blonanserin (using nickel catalyst)
A 50 mL flask was placed under a nitrogen atmosphere, and 0.50 g (1.73 mmol) of 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine was obtained. , Nickel chloride (II) 0.0226 g (0.174 mmol), triphenylphosphine 0.1352 g (0.516 mmol) and potassium carbonate 0.72 g (5.17 mmol) were added and stirred, and the system was flushed with nitrogen for 30 minutes. did. 7.5 mL of xylene and 0.0227 g (0.195 mmol) of tetramethylethylenediamine were added and stirred, and 0.23 g (2.05 mmol) of 1-ethylpiperazine was added and heated at 100 ° C. for 2.5 hours, but blonanserin was produced. I did not.

Comparative Example 5 Production of blonanserin (using copper catalyst)
The inside of the 50 mL flask was put under a nitrogen atmosphere, and 0.33 g (1.73 mmol) of copper (II) iodide and 5.0 mL of xylene were added and stirred. Further, 0.42 g (3.61 mmol) of tetramethylethylenediamine was added and stirred, and 2-chloro-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine. 0.50 g (1.73 mmol), 1-ethylpiperazine 0.27 g (2.36 mmol) and sodium-tert-butoxide 0.20 g (2.07 mmol) were added and stirred. After heating at 100 ° C. for 2 hours, Although heated at 140 ° C. for 2 hours, blonanserin hardly formed.

Claims (5)

2-halogeno-4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine (formula I) and 1-ethylpiperazine (formula II) in the presence of a base A process for producing blonanserin (formula III) by reacting in a lower organic solvent using a palladium complex as a catalyst.

  The production method according to claim 1, wherein the reaction system is placed in an inert gas atmosphere.   The process according to claim 1 or 2, wherein the reaction temperature is in the range of 50 to 120 ° C.   The method according to any one of claims 1 to 3, wherein the organic solvent is an aromatic hydrocarbon.   The production method according to any one of claims 1 to 4, wherein the base is a metal alkoxide.