KR101659624B1 - Method for preparation of -thujaplicin - Google Patents

Abstract

The present invention relates to (1) a process for preparing a cyclopentadienyl derivative of sodium by reacting a cyclopentadiene and sodium amide in a N, N-dimethylformamide solvent, reacting the sodium cyclopentadienylide with an isopropylating agent, (2) subjecting the mixture of isopropylcyclopentadiene to reaction with dichloro ketene to obtain 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6 2-ene-6-one derivative obtained in the step (1) is subjected to solvolysis in the presence of a basic condition to obtain a mixture of the 7,7-dichlorobicyclo [3.2.0] And a third step of separating? -Toyoplysine from the crude product by crystallization. According to this method,? -Toyoplycine, which is useful as an intermediate of medicine, can be obtained inexpensively and easily and in a good yield.

Description

[0001] The present invention relates to a method for preparing gamma-thujaplicin,

The present invention relates to a process for the preparation of < RTI ID = 0.0 > y-thyaplycine < / RTI > useful as a medicament intermediate.

γ-touyaprysin [5-isopropyltroporon] is a natural product contained in the leaves of Aomori cypress trees and essential oils of Japanese cypress trees. It is a natural product containing antibacterial and anti-moldy troponin eosin )to be. It is also an intermediate for the production of antiallergic agent, allalan sodium. As to the production method of this? -Toyoplysine, the following production method has been reported. In other words,

(1) A method of synthesizing? -Toyoplysine by refluxing 2-chloro-5-isopropyltropone with phosphoric acid in glacial acetic acid has been reported (Non-Patent Document 1). Further, a method of synthesizing this 2-chloro-5-isopropyltropone with 4-isopropyl anisole as a starting material has been proposed (Patent Document 1). This method is multistage (5 steps) and involves a cryogenic reaction. In addition, since dangerous reagents are used, they involve operational risks. Also, 4-isopropyl anisole is expensive.

(2) Cyclopentadiene and Grignard reagent (ethyl magnesium bromide) are reacted in a tetrahydrofuran solvent at a solvent reflux temperature, and then isopropyltosylate is reacted to obtain isopropylcyclopentadiene. This isopropylcyclopentadiene is subjected to an addition reaction with dichloro ketene, followed by solvolysis under basic conditions, and the crude soluble disintegration product is made acidic to precipitate the tropolone compound. There has been reported a method of separating γ-thyaflocin and its isomer β-touyaplycine from the precipitated trolofone compound by column chromatography to obtain γ-thyaflocin (Non-Patent Document 2). When performing column chromatography industrially, problems arise in productivity and production cost. For example, a large amount of solvent is used, or a troublesome operation such as regeneration and treatment of an adsorbent becomes necessary, and the purification cost becomes high, which is industrially undesirable.

(3) A process for producing hinokitiol (beta -touyaplicin), comprising the steps of preparing a cyclopentadienyl metal from cyclopentadiene and an alkali metal, reacting the cyclopentadienyl metal with an isopropylating agent, (Isomerization) of 5-isopropylcyclopentadiene in isopropylcyclopentadiene with 1-isopropylcyclopentadiene, a step of reacting the 1-isopropylcyclopentadiene and the 1-isopropylcyclopentadiene, A step of reacting dihaloketene to obtain a ketene adduct and a step of decomposing the ketene adduct have been proposed (Patent Document 2).

(4) an addition reaction of a substituted or unsubstituted cyclopentadiene and dichloro ketene to obtain a 7,7-dichlorobiscyclo [3.2.0] -hept-2-enone compound which is decomposed in the presence of a base to give A step of subjecting the compound to distillation purification under reduced pressure before decomposition in the presence of a base and a step of purifying the crude tropolone compound obtained by the decomposition in the presence of a base by distillation and crystallization (Patent Document 3) discloses a method for producing a tropolone compound, particularly? -Toyoplysine. There has also been proposed a process for purifying a chitroporon compound which comprises crystallizing a chitroporone compound obtained by solvolysis of a dichloro ketene adduct obtained by reacting cyclopentadiene and dichloro ketene with a solvent having a specific solubility parameter (Patent Document 4).

As shown in the production methods of (2) to (4) above, in the production of the tropolone compound belonging to? -Toyoplysine, cyclopentadiene is used as a starting material and an isopropylating agent is reacted with isopropyl Cyclopentadiene is synthesized, dichloro ketene is further reacted to synthesize a ketene adduct, and the mixture of the zetropholone compound obtained by solvolysis of the ketene adduct is purified to form a troponone compound mixture. From this mixture, Of the tropolone compound. However, when the isopropylcyclopentadiene is obtained, sodium cyclopentadienylide is synthesized by reacting cyclopentadiene and sodium amide in N, N-dimethylformamide, and an isopropylating agent is reacted with the cyclopentadiene to obtain isopropyl A method of obtaining an equilibrium mixture of propylcyclopentadiene with good yield and good reproducibility is not known. It is also known to purify the zottroplone compound by distillation or crystallization, but it is not known to separate y-thyaflocin from the mixture of zottroplone compounds by crystallization.

Examples of the method for preparing sodium cyclopentadienylide include (i) a method of reacting sodium metal with cyclopentadiene in liquid ammonia (Non-Patent Document 3), (ii) a method of reacting sodium metal with an organic solvent such as dimethoxyethane or diglyme , A method of reacting sodium metal with cyclopentadiene (Non-Patent Document 4), (iii) a method of reacting sodium hydride with cyclopentadiene in a tetrahydrofuran solvent (Patent Document 5), and the like. However, it is not known that sodium cyclopentadienylide is obtained by reacting cyclopentadiene with sodium amide, and it is not known that this reaction is carried out in a N, N-dimethylformamide solvent.

Japanese Unexamined Patent Application Publication No. 3-193743 U.S. Patent No. 6310255 Japanese Patent Laid-Open No. 2001-97915 Japanese Patent Application Laid-Open No. 2002-255887 Japanese Patent Application Laid-Open No. 54-63063

Journal of Organic Chemistry, 1978, volume 43, page 3621 Tetrahedron, 1971, 27, 4889 Izv. Vyssh. Vchebn. Zaved., Khim. Khim. Technol., 1970, vol. 19, p. 1511 Tetrahedron, 1965, vol. 21, p. 2313

SUMMARY OF THE INVENTION In view of the above circumstances, it is an object of the present invention to provide a process for producing γ-butyropycin inexpensively and easily and in a good yield.

The inventors of the present invention have conducted intensive studies and found that sodium cyclopentadienylide can be prepared from cyclopentadiene in an N, N-dimethylformamide solvent by using sodium amide, The isopropylcyclopentadienyl compound can be obtained in good yield and reproducibility by reacting the prepared sodium cyclopentadienylide with an isopropylating agent. From the crude product prepared using this mixture, a high purity γ- The present inventors have found that tauaplycine can be separated and completed the present invention.

That is, the present invention relates to the following steps (1) to (3):

(1) Synthesis of sodium cyclopentadienylide by reacting cyclopentadiene with sodium amide in a N, N-dimethylformamide solvent, reacting the sodium cyclopentadienylide with an isopropylating agent to obtain isopropylcyclopentane A first step of obtaining a mixture of dienes,

(2) a second step of reacting the mixture of isopropylcyclopentadiene with dichloro ketene to obtain a mixture of 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivatives,

(3) The above 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative is solvolyzed under basic conditions, and from the obtained crude product, γ- A third step of separating,

Of the present invention.

According to the present invention,? -Toyoplycine, which is useful as a medicine or the like or an intermediate thereof, can be produced inexpensively and easily and at a high yield. Namely, sodium cyclopentadienylide can be prepared by the reaction of sodium amide and cyclopentadiene in a N, N-dimethylformamide solvent. In addition, by reacting the isopropylating agent with the isopropylating agent, a mixture of isopropylcyclopentadiene can be produced with good yield and reproducibility. In addition, γ-butyropicin was inexpensive because it was separated from the soluble miniscule crude product of the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative mixture by crystallization There is an advantage that it can be produced easily and in a good yield.

The method for producing [gamma] -toyoplysin of the present invention will be schematically shown, and each step will be described.

(Wherein R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, or a trifluoromethanesulfonyl group.)

Step 1: Cyclopentadiene is reacted with sodium amide in an N, N-dimethylformamide solvent to prepare sodium cyclopentadienylide, and an isopropylating agent (structural formula I) is reacted with the sodium cyclopentadienylide To obtain a mixture (isomer mixture) of isopropylcyclopentadiene (structural formula II). At this time, an isopropylating agent (structural formula I) may be added to the reaction solution of the prepared sodium cyclopentadienylide and reacted.

The isopropylating agent used herein is represented by the following general formula:

(Wherein R represents a halogen atom, a methanesulfonyl group, an arylsulfonyl group, or a trifluoromethanesulfonyl group.)

≪ / RTI > Examples thereof include 2-chloropropane, 2-bromopropane, 2-iodopropane, isopropylmethane sulfonate, isopropylbenzene sulfonate, isopropyltosylate, isopropyltrifluoromethane sulfonate and the like But is preferably 2-bromopropane.

Patent Document 2 described above discloses a process for producing isopropylcyclopentadiene using potassium hydroxide as a base and 2-bromopropane as an isopropylating agent. Further, when potassium cyclopentadienylide and 2-bromopropane are reacted with dimethylsulfoxide in the reaction solvent, 5-isopropylcyclopentadienyl is selectively generated, and this is selectively reacted with 1-isopropylcyclopentadiene . ≪ / RTI > In addition, it is described that when this reaction is carried out in a N, N-dimethylformamide solvent, 2-isopropylcyclopentadiene is slightly predominantly produced (1-isopropylcyclopentadiene / 2-isopropylcyclopentadiene = 41/58).

Thus, with reference to Patent Document 2, potassium hydroxide is added to a N, N-dimethylformamide solution of cyclopentadiene and reacted, and the reaction solution is added dropwise to 2-bromopropane to prepare a mixture of isopropylcyclopentadiene , The dissolution of potassium hydroxide into N, N-dimethylformamide affected the reaction time required for the preparation of potassium cyclopentadienylide, resulting in a variation in the yield . However, according to the present invention, by using sodium amide as a base, the preparation of sodium cyclopentadienylide proceeds smoothly, and the reaction with isopropylating agent (I) is carried out to obtain isopropylcyclopentadiene (II) Can be obtained with good yield and good reproducibility.

Further, in order to carry out the reaction between the sodium cyclopentadienylide and the isopropylating agent in N, N-dimethylformamide, in the case of the sodium cyclopentadienylide preparation method described in the above (i) to (iii) Of N, N-dimethylformamide is required to be replaced with N, N-dimethylformamide. Thus, the production process becomes troublesome. In the present invention, however, there is no need to replace the solvent with N, N-dimethylformamide.

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

Second Step: A mixture of isopropylcyclopentadiene (II) obtained above was reacted with dichloro ketene to obtain 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative ) Is obtained. Dichloro ketene can be generated from dichloroacetic acid chloride and triethylamine. The molar ratio of dichloroacetic acid chloride to triethylamine to sodium amide used in the first step is 0.5 to 2, preferably 0.9 to 1.2. The reaction is carried out at -78 ° C to the reflux temperature of the solvent using the extract of the first step as it is, and the preferred reaction temperature is in the range of -5 ° C to 20 ° C. The obtained crude 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative (III) is preferably distilled and purified.

Step 3: A mixture of the 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative (III) obtained above is subjected to solvolysis under basic conditions, To isolate? -Toyoplysine (formula IV). This decomposition reaction is carried out in an acetone-acetic acid-water mixed solvent. Dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative (III) in a molar ratio of 1 to 5 with respect to the derivative (III) Amines are added. After dropwise addition, the mixture is stirred at a solvent reflux temperature for 1 to 10 hours. After completion of the reaction, the reaction mixture is subjected to usual post-treatment, and a solvent such as hexane, heptane, hydrous methanol or water ethanol is added to the obtained crude product to dissolve the solution, seed crystals (gamma -touyaplicin) After stirring at 0 ° C to room temperature, the precipitated γ-thyaflycine is collected by filtration. The amount of the solvent used in the crystallization is 3 to 10 times the amount of the mixture of 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative (III). When insoluble matter is observed when the solvent is added, the supernatant may be taken by decantation.

Example 1

(1) Preparation of a mixture of isopropylcyclopentadiene (II)

Sodium amide (7.3 g, 92.7% purity) was added to a solution of cyclopentadiene (14.0 g) in N, N-dimethylformamide (76.3 g) at 15 占 폚 or lower and the mixture was stirred at room temperature for 1 hour. 2-Bromopropane (41.7 g) was added dropwise at 10 占 폚 or lower to the reaction solution, and the mixture was stirred for 1 hour. To the reaction mixture was added a 10% aqueous hydrochloric acid solution (30 mL) and water (30 mL), followed by extraction with n-hexane (250 mL). The n-hexane extract was washed with water (100 mL twice) and dried over anhydrous sodium sulfate. Filtered to obtain a n-hexane solution of a mixture of isopropylcyclopentadiene (II).

(2) Preparation of a mixture of 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivative (III)

To the n-hexane solution of the isopropylcyclopentadiene (II) mixture was added dichloroacetic acid chloride (17.3 mL). Triethylamine (26.5 mL) was added dropwise at 5 DEG C or lower over 1 hour and 20 minutes, and the mixture was stirred for 1 hour and 30 minutes. To the reaction mixture was added a 10% hydrochloric acid aqueous solution (50 mL) and water (50 mL), and the organic layer was separated. The organic layer was washed sequentially with water (2 x 50 mL), saturated aqueous sodium bicarbonate solution (1 x 50 mL), saturated brine (1 x 50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, and the resulting residue was distilled to obtain 23.8 g of a mixture of 7,7-dichlorobicyclo [3.2.0] hept-2-en-6-one derivative (III) ~ 107 ° C / 5 mmHg of oil).

(3) Preparation of γ-thuyaplicin (IV)

Acetic acid (11.3 g) and water (22.6 g) were added to a solution of the above 7,7-dichlorobicyclo [3.2.0] hept-2-en-6-one derivative (III) ), Triethylamine (66.8 mL) was added dropwise at reflux temperature over 1 hour and 16 minutes, and then stirred at the same temperature for 5 hours. The reaction solution was allowed to cool, and water (140 mL) and a 10% hydrochloric acid aqueous solution (14 mL) were added. Toluene was extracted twice (140 mL), and the combined extracts were washed with water (2 x 70 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, n-hexane (160 mL) was added to the obtained residue, stirred at about 50 캜, and then allowed to cool. The solution portion was collected by decantation, followed by addition of a seed crystal (? -Toyoplysine) and stirring at room temperature. Precipitated crystals were collected by filtration and dried to obtain? -Toyaplycine (IV) (8.2 g, GC purity of 99% or more).

Claims (2)

The following steps (1) to (3)
(1) Synthesis of sodium cyclopentadienylide by reacting cyclopentadiene and sodium amide in a N, N-dimethylformamide solvent, reacting the sodium cyclopentadienylide with an isopropylating agent to obtain isopropylcyclopentane A first step of obtaining a mixture of dienes,
(2) a second step of reacting the mixture of isopropylcyclopentadiene with dichloro ketene to obtain a mixture of 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivatives,
(3) Solubilization of the mixture of the 7,7-dichlorobiscyclo [3.2.0] -hept-2-en-6-one derivatives under basic conditions, and from the resulting crude product, A third step of separating gamma -uyapylysincene by crystallization using an amorphous crystal,
≪ / RTI > The method according to claim 1,
Wherein the isopropylating agent has the general formula:

(Wherein R represents a halogen atom, a methanesulfonyloxy group, an arylsulfonyloxy group, or a trifluoromethanesulfonyloxy group).
≪ / RTI >