JP2010248137A - Method for producing gamma-thujaplicin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for readily obtaining γ-thujaplicin useful as a pharmaceutical drug intermediate at a low cost in a high yield. <P>SOLUTION: The method for producing γ-thujaplicin comprises: (1) a first step of reacting cyclopentadiene with sodium amide in an N, N-dimethylformamide solvent so as to prepare sodium cyclopentadienylide and reacting the same with an isopropylating agent so as to obtain an isopropyl cyclopentadiene mixture; (2) a second step of reacting the isopropyl cyclopentadiene mixture with dichloroketene so as to obtain a 7,7-dichlorobicyclo[3.2.0]-hepto-2-en-6-one derivative mixture; and (3) a third step of subjecting the 7,7-dichlorobicyclo[3.2.0]-hepto-2-en-6-one derivative mixture to solvolysis under a basic condition so as to obtain a crude product and isolating γ-thujaplicin from the same by crystallization. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a method for producing γ-tjapricin useful as a pharmaceutical intermediate.

γ-Tyaprisin [5-isopropyltropolone] is a natural product contained in essential oils of Aomori Hiba and Taiwan Hinoki, and is an tropolone analog having antibacterial and antifungal activities. In addition, it is an intermediate for producing eguarene sodium, an anti-ulcer agent. Regarding the method for producing γ-tyaprisin, the following production method has been reported. That is, (1) a method in which 2-chloro-5-isopropyltropone is refluxed with phosphoric acid in glacial acetic acid to synthesize γ-tyaprisin (Non-patent Document 1), and this 2-chloro-5 is also reported. A method for synthesizing isopropyl tropone using 4-isopropylanisole as a starting material has been proposed (Patent Document 1). This method is multi-stage (5 steps) and involves ultra-low temperature reactions. Furthermore, the use of dangerous reagents is dangerous in terms of operation. In addition, 4-isopropylanisole is expensive.

Furthermore, (2) cyclopentadiene and Grignard reagent (ethylmagnesium bromide) were reacted in tetrahydrofuran solvent at the solvent reflux temperature, and then isopropyl tosylate was reacted to obtain isopropylcyclopentadiene, which was subjected to addition reaction of dichloroketene. Then, it is solvolyzed under basic conditions, the crude solvolysis product is acidified to precipitate the tropolone compound, and γ-Tyapricin and its isomer β-Tyapricin are separated by column chromatography. A method for obtaining γ-tyaprisin has been reported (Non-patent Document 2). When performing column chromatography industrially, problems arise in productivity and production cost. For example, the purification cost is high, such as using a large amount of solvent or requiring complicated operations such as regeneration and treatment of the adsorbent, which is not industrially preferable.

(3) As a method for producing hinokitiol (β-tyaprisin), a step of preparing cyclopentadienyl metal from cyclopentadiene and an alkali metal, reacting the cyclopentadienyl metal with an isopropylating agent, Obtaining cyclopentadiene, selectively isomerizing 5-isopropylcyclopentadiene into 1-isopropylcyclopentadiene in isopropylcyclopentadiene, reacting 1-isopropylcyclopentadiene with dihaloketene to produce a ketene adduct. A method for producing hinokitiol comprising a step of obtaining and a step of decomposing the ketene adduct has been proposed (Patent Document 2).

(4) As a method for producing a tropolone compound, particularly β-tyaprisin, a substituted or unsubstituted cyclopentadiene and dichloroketene are subjected to an addition reaction to produce 7,7-dichlorobicyclo [3.2.0] -hept-2-ene. -6-one compound was obtained and decomposed in the presence of a base to produce a tropolone compound. The above-mentioned compound was obtained by distillation under reduced pressure before decomposition in the presence of a base, and decomposition in the presence of a base. A method for producing a tropolone compound by performing a process of purifying a crude tropolone compound by distillation and crystallization has been proposed (Patent Document 3). Furthermore, purification of a crude tropolone compound that crystallizes a crude tropolone compound obtained by solvolysis of a dichloroketene adduct obtained by reacting cyclopentadiene with dichloroketene using a solvent having a specific solubility parameter. A method has been proposed (Patent Document 4).

As seen in the production methods (2) to (4) above, in the production of a tropolone compound to which γ-tyaprisin belongs, conventionally, cyclopentadiene is used as a starting material, and this is reacted with an isopropylating agent to produce isopropylcyclopentadiene. Further, the ketene adduct is obtained by further reacting with dichloroketene, and the mixture of the crude tropolone compound obtained by solvolysis is purified into a tropolone compound mixture, from which the desired tropolone compound is separated. When obtaining the isopropylcyclopentadiene described above, cyclopentadiene and sodium amide are reacted in N, N-dimethylformamide to obtain sodium cyclopentadienylide, which is reacted with an isopropylating agent. It is not known that an equilibrium mixture of pentadiene can be obtained with good yield and reproducibility. In addition, it is known to purify a crude tropolone compound by distillation or crystallization, but it is not known to separate γ-tjapricin from this mixture of crude tropolone compounds by crystallization.

In addition, sodium cyclopentadienylide can be prepared by (i) reaction of sodium metal with cyclopentadiene in liquid ammonia (Non-patent Document 3), (ii) in an organic solvent such as dimethoxyethane or diglyme. The reaction of sodium metal with cyclopentadiene (Non-patent Document 4), (iii) the reaction of sodium hydride with cyclopentadiene in a tetrahydrofuran solvent (Patent Document 5), and the like are known. Thus, it is not known that cyclopentadiene and sodium amide are reacted to obtain sodium cyclopentadienylide, and this reaction is not known to be performed in an N, N-dimethylformamide solvent.

Japanese Patent Laid-Open No. 3-193743 U.S. Patent No. 6310255 Japanese Patent Laid-Open No. 2001-97915 Japanese Patent Laid-Open No. 2002-255887 JP 54-63063 A

Journal of Organic Chemistry, 1978, 43, 3621 Tetrahedron, 1971, 27, 4889 Izv. Vyssh. Vchebn. Zaved., Khim. Khim. Technol., 1970, 19, 1511 Tetrahedron, 1965, 21, 21313

In view of the above circumstances, an object of the present invention is to provide a method for producing γ-tjapricin inexpensively and easily with high yield.

As a result of intensive studies, the present inventor has found that sodium cyclopentadienyl can be smoothly prepared from cyclopentadiene in an N, N-dimethylformamide solvent by using sodium amide. An isopropylating agent can be reacted with sodium cyclopentadienylide prepared in step 1 to obtain an isopropylcyclopentadiene mixture with good yield and reproducibility, and further, crystals from a crude product produced using the mixture can be obtained. It was found that high-purity γ-tyaprisin can be separated by an analysis operation, and the present invention has been completed.

That is, the present invention includes the following steps (1) to (3):
(1) In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienylide, and this sodium cyclopentadienylide is reacted with an isopropylating agent to produce isopropylcyclohexane. A first step of obtaining a mixture of pentadienes;
(2) a second step of reacting the isopropylcyclopentadiene mixture with dichloroketene to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives;
(3) The above mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative is solvolyzed under basic conditions, and γ- A third step of separating tsuyaprisin,
Is a method for producing γ-tsuyaprisin.

INDUSTRIAL APPLICABILITY According to the present invention, γ-tjapricin useful as a pharmaceutical or the like or an intermediate thereof can be produced inexpensively and easily with a high yield. That is, sodium cyclopentadienyl can be prepared by the reaction of sodium amide and cyclopentadiene in an N, N-dimethylformamide solvent, and by reacting this with an isopropylating agent, a mixture of isopropylcyclopentadiene is obtained in a yield. In addition, it can be produced with good reproducibility, and γ-Tyapricin is separated by crystallization from the solvolysis crude product of a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives. Therefore, there is an advantage that γ-tyapricin can be produced inexpensively and easily with a high yield.

The method for producing γ-tyaprisin of the present invention is shown in a scheme, and each step is described.

(式中、Ｒはハロゲン原子、メタンスルホニル基、アリールスルホニル基、トリフルオロメタンスルホニル基を示す。)

(In the formula, R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, or a trifluoromethanesulfonyl group.)

First step: Sodium cyclopentadienyl is prepared by reacting cyclopentadiene with sodium amide in a N, N-dimethylformamide solvent, and this sodium cyclopentadienyl is converted to an isopropylating agent (structure formula I). Is a step of obtaining a mixture (mixture of isomers) of isopropylcyclopentadiene (structure II). At that time, an isopropylating agent (Structural Formula I) can be added to the prepared reaction solution of sodium cyclopentadienylide for reaction.
The isopropylating agent used here has the following general formula:

（式中、Ｒはハロゲン原子、メタンスルホニル基、アリールスルホニル基、トリフルオロメタンスルホニル基を示す。）

(In the formula, R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, or a trifluoromethanesulfonyl group.)

It is a compound shown by these. Examples thereof include 2-chloropropane, 2-bromopropane, 2-iodopropane, isopropyl methanesulfonate, isopropylbenzene sulfonate, isopropyl tosylate, isopropyl trifluoromethanesulfonate, and the like, and 2-bromopropane is preferable.

Patent Document 2 described above describes a method for producing isopropylcyclopentadiene using potassium hydroxide as a base and 2-bromopropane as an isopropylating agent. Potassium cyclopentadienylide using dimethyl sulfoxide as a reaction solvent. And 2-bromopropane are reacted to selectively produce 5-isopropylcyclopentadiene, which is selectively isomerized to 1-isopropylcyclopentadiene, and this reaction is further described as N, N-dimethyl. It has been described that 2-isopropylcyclopentadiene is formed slightly more favorably in a formamide solvent (1-isopropylcyclopentadiene / 2-isopropylcyclopentadiene = 41/58).

Then, potassium hydroxide was added to and reacted with N, N-dimethylformamide solution of cyclopentadiene, and this reaction solution was dropped into 2-bromopropane to produce a mixture of isopropylcyclopentadiene. Due to the influence of dissolution in N-dimethylformamide, the reaction time required for the preparation of potassium cyclopentadienylide varied, and as a result, variation in yield was observed. However, according to the present invention, by using sodium amide as a base, the preparation of sodium cyclopentadienide proceeds smoothly, and the subsequent reaction with the isopropylating agent (I) results in isopropylcyclopentadiene (II). Can be obtained with good yield and reproducibility. In addition, in order to perform the reaction between the sodium cyclopentadienylide and the isopropylating agent in N, N-dimethylformamide, the above-mentioned sodium cyclopentadienide preparation methods (i) to (iii) Since it is necessary to replace each solvent with N, N-dimethylformamide, the production process becomes complicated.

In the first step of the present invention, the molar ratio of cyclopentadiene to sodium amide is in the range of 1-2. The molar ratio of isopropylating agent to sodium amide is 1-5, preferably in the range of 1-2. The molar ratio of N, N-dimethylformamide to sodium amide is 1-10, preferably 5-7. The reaction is carried out at -78 ° C to the solvent reflux temperature, and the preferred reaction temperature is in the range of -5 ° C to 40 ° C. Isopropylcyclopentadiene (II) may be purified by distillation, but after quenching the reaction with an acidic aqueous solution, it is extracted with a hydrocarbon solvent such as hexane, heptane, toluene, etc., and the extract is used as it is in the next step. Is preferred.

Second step: The mixture of isopropylcyclopentadiene (II) obtained above is reacted with dichloroketene to produce a 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (structure III ). Dichloroketene can be generated from dichloroacetic acid chloride and triethylamine. The molar ratio of dichloroacetic acid chloride and triethylamine to sodium amide used in the first step is 0.5-2, preferably 0.9-1.2. The reaction is carried out using the extract of the first step as it is, and is carried out at -78 ° C to the solvent reflux temperature, and the preferred reaction temperature is in the range of -5 ° C to 20 ° C. The obtained crude 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) is preferably purified by distillation.

Third step: The crude product obtained by solvolysis of the mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) obtained above under basic conditions In this step, γ-tyapricin (Structural Formula IV) is separated from the product by crystallization. This decomposition reaction is carried out in an acetone-acetic acid-water mixed solvent, and the molar ratio to the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) at the reaction solution reflux temperature. Triethylamine in the range of 1-5 is added dropwise. After the dropwise addition, the mixture is stirred at a solvent reflux temperature for 1 to 10 hours. After completion of the reaction, normal post-treatment is performed, and a solvent such as hexane, heptane, water-containing methanol, water-containing ethanol and the like is added to the obtained crude product and dissolved, and seed crystals (γ-tyaprisin) are added to this solution, After stirring at 0 ° C. to room temperature, the precipitated γ-tjapricin is collected by filtration. The amount of the solvent used for crystallization is 3 to 10 times the amount of the mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III). When insoluble matter is observed when the solvent is added, the supernatant may be removed by decantation.

(1) Preparation of a mixture of isopropylcyclopentadiene (II) Sodium amide (7.3 g, 92.7% purity) in a solution of cyclopentadiene (14.0 g) in N, N-dimethylformamide (76.3 g) at 15 ° C. or lower. ) And then stirred at room temperature for 1 hour. 2-Bromopropane (41.7 g) was added dropwise to the reaction solution at 10 ° C. or lower, followed by stirring for 1 hour. A 10% aqueous hydrochloric acid solution (30 mL) and water (30 mL) were added to the reaction solution, and the mixture was extracted with n-hexane (250 mL). The n-hexane extract was washed with water (2 × 100 mL) and then dried over anhydrous sodium sulfate. Filtration gave an n-hexane solution of a mixture of isopropylcyclopentadiene (II).

(2) Preparation of a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) Into an n-hexane solution of the above isopropylcyclopentadiene (II) mixture, Acetic acid chloride (17.3 mL) was added. Triethylamine (26.5 mL) was added dropwise at 5 ° C. or less over 1 hour and 20 minutes, followed by stirring for 1 hour and 30 minutes. A 10% aqueous hydrochloric acid solution (50 mL) and water (50 mL) were added to the reaction solution, and then the organic layer was separated. The organic layer was washed successively with water (2 × 50 mL), saturated aqueous sodium hydrogen carbonate solution (1 × 50 mL) and saturated brine (1 × 50 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, and the resulting residue was distilled to obtain a mixture of the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) (23. 8 g: a fraction having a boiling point of 105 to 107 ° C./5 mmHg).

(3) Production of γ-Tyapricin (IV) Acetone (139 g) of a mixture (42.0 g) of the above 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) Acetic acid (11.3 g) and water (22.6 g) were added to the solution, and then triethylamine (66.8 mL) was added dropwise at reflux temperature for 1 hour and 16 minutes, followed by stirring at the same temperature for 5 hours. The reaction mixture was allowed to cool, and water (140 mL) and 10% aqueous hydrochloric acid (14 mL) were added. Toluene (twice with 140 mL) was extracted, and the combined extracts were washed with water (twice with 70 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, n-hexane (160 mL) was added to the resulting residue, and the mixture was stirred at about 50 ° C. and then allowed to cool. After the solution part was fractionated by decantation, seed crystals (γ-tyaprisin) were added and stirred at room temperature. Precipitated crystals were collected by filtration and dried to obtain γ-tjapricin (IV) (8.2 g, GC purity 99% or more).

Claims (1)

The following steps (1) to (3):
(1) In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienylide. A first step of obtaining a mixture of pentadienes;
(2) a second step of reacting the isopropylcyclopentadiene mixture with dichloroketene to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives;
(3) The above mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative is solvolyzed under basic conditions, and γ- A third step of separating tsuyaprisin,
A method for producing γ-tyaprisin comprising: