JP6733449B2 - Method for producing berberine alkaloid - Google Patents

Description

The present invention relates to a method for producing berberine-type alkaloids, and more particularly to a method for producing berberine-type alkaloids that can efficiently produce berberine-type alkaloids.

Berberine-type alkaloids (mainly berberine, palmatin, thalifendine, jateorrhizine, berberrubine, coptisine, and methylene berberine). It is known as a contained component and has interesting pharmacological actions such as strong antibacterial action and anti-inflammatory action.

Berberine-type alkaloids are important components in quality control. In particular, berberine, palmatine, and coptisine chlorides are used for confirmation tests and quantitative tests for crude drugs such as "Ohren" and "Ohaku" and prescription extracts such as Orengedokuto (including also as a resolution marker). ) Is widely used as a standard product.

On the other hand, focusing on the method for preparing berberine-type alkaloids, berberine can be easily purchased as a commercial reagent, but other berberine-type alkaloids containing coptisine chloride, which is one of the important components for quality control, However, an efficient manufacturing method has not been found yet. For example, coptisine chloride has hitherto been extracted from Orion, and isolated and purified to produce it, but it requires a long time operation, is difficult to purify, and can be efficiently and inexpensively secured. could not. Further, Non-Patent Document 1 describes a method for synthesizing coptisine chloride using 2,3-dimethoxybenzaldehyde as a starting material, but the total yield is low because the yield of the final step is as low as 23.4%. The ratio remains at about 10%, and a large number of similar compounds are produced in the final step, so it is considered difficult to separate and purify the target coptisine chloride. Non-Patent Document 2 also describes a method for synthesizing a berberine-type alkaloid, but as described later, it was an inefficient method from the viewpoint of the number of steps and the yield. Attempts have also been made to convert coptisine chloride from berberine, which is obtained in large amounts from yellow oak, but an efficient synthetic method has not been established.

S. Chen, et al. , Chinese Journal of Synthetic Chemistry 17, 4, 512-513 (2009). R. RAJARAMAN et al. , Indian Journal of Chemistry, vol. 15B, pp. 876-879 (1977)

Then, the objective of this invention is providing the manufacturing method of the berberine type alkaloid which can manufacture a berberine type alkaloid efficiently.

As a result of earnest studies on the above problems, the present inventor has selected a specific compound by using trifluoromethanesulfonic anhydride and 2,6-di-tert-butyl-4-methylpyridine in the intramolecular cyclization. It is possible to achieve highly efficient intramolecular cyclization, and when the specific compound is aromatically cyclized, a quinone-based oxidant is used to enable highly efficient aromatic cyclization, thereby solving the above problems. The present invention has been completed and the present invention has been completed.

The method for producing the berberine-type alkaloid of the present invention is the following [1] to [12].

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。）
トリフルオロメタンスルホン酸無水物と２，６−ジ−ｔｅｒｔ−ブチル−４−メチルピリジンを用いて下記一般式（Ｉａ）で表される化合物を分子内環化反応させて得られる下記一般式（Ｉａ’）で表される化合物を還元剤を用いて還元し、下記一般式（Ｉｂ）で表される化合物を合成する工程、

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。）

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。）

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。）
前記一般式（Ｉｂ）で表される化合物を脱ブロモ化して、下記一般式（Ｉｃ）で表される化合物を合成する工程、

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。）
前記一般式（Ｉｃ）で表される化合物を、キノン系酸化剤を用いて芳香環化する工程を含むことを特徴とする製造方法。 [1] A method for producing a berberine-type alkaloid represented by the following general formula (I):

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)
A compound represented by the following general formula (Ia) obtained by an intramolecular cyclization reaction of a compound represented by the following general formula (Ia) using trifluoromethanesulfonic anhydride and 2,6-di-tert-butyl-4-methylpyridine. A compound represented by the following general formula (Ib) is reduced by using a reducing agent to reduce the compound represented by

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)
Debrominating the compound represented by the general formula (Ib) to synthesize a compound represented by the following general formula (Ic),

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)
A production method comprising a step of subjecting the compound represented by the general formula (Ic) to an aromatic cyclization using a quinone-based oxidizing agent.

[2] The production method according to [1], wherein the intramolecular cyclization reaction of the compound represented by the general formula (Ia) is performed at 15°C to 50°C.

[3] The production method according to [1] or [2], wherein dichloromethane is used as a reaction solvent for the intramolecular cyclization reaction of the compound represented by the general formula (Ia).

[4] The production method according to any one of [1] to [3], wherein the reducing agent used for reducing the compound represented by the general formula (Ia′) is a reducing agent used for hydride reduction.

[5] The quinone-based oxidizing agent used for the aromatic cyclization of the compound represented by the general formula (Ic) is 2,3-dichloro-5,6-dicyano-p-benzoquinone [1] to [4]. The manufacturing method according to any one of 1.

[6] The production method according to any one of [1] to [5], wherein the aromatic cyclized compound is treated with hydrochloric acid after the step of aromatic cyclization.

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。） [7] A step of synthesizing the compound represented by the general formula (Ia) by formylating the compound represented by the following general formula (II) with N-formylsaccharin [1] to []. [6] The method according to any one of [6].

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成し、Ｂｏｃは、二炭酸ジ−ｔｅｒｔ−ブチル由来の保護基を示す。）

（式中、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。） [8] A compound represented by the general formula (II) is synthesized by reacting a compound represented by the following general formula (III-1) with a compound represented by the following general formula (IV-1). The production method according to [7], which includes the step of:

(In the formula, R ¹ and R ² are each a methoxy group, or R ¹ and R ² are bonded to each other to form a methylenedioxy group, and Boc is a protective group derived from di-tert-butyl dicarbonate. Indicates a group.)

(In the formula, R ³ and R ⁴ are each a methoxy group, or R ³ and R ⁴ are combined to form a methylenedioxy group.)

（式中、Ｒ^１およびＲ^２は、それぞれメトキシ基であるか、又は、Ｒ^１とＲ^２が結合してメチレンジオキシ基を形成する。） [9] A step of synthesizing the compound represented by the general formula (III-1) by reacting the compound represented by the following general formula (III-2) with di-tert-butyl dicarbonate. The manufacturing method according to [8].

(In the formula, R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group.)

（式中、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。） [10] In [8] including a step of synthesizing the compound represented by the general formula (IV-1) using a compound represented by the following general formula (IV-2), trimethylsilyl chloride and sodium iodide. The manufacturing method described.

(In the formula, R ³ and R ⁴ are each a methoxy group, or R ³ and R ⁴ are combined to form a methylenedioxy group.)

（式中、Ｒ^３およびＲ^４は、それぞれメトキシ基であるか、又は、Ｒ^３とＲ^４が結合してメチレンジオキシ基を形成する。） [11] A step of synthesizing the compound represented by the general formula (IV-2) by reacting a compound represented by the following general formula (IV-3) with triphenylphosphine methoxymethyl chloride The manufacturing method according to [10].

(In the formula, R ³ and R ⁴ are each a methoxy group, or R ³ and R ⁴ are combined to form a methylenedioxy group.)

[12] The production method according to any one of [1] to [11], wherein the compound represented by the general formula (I) is a berberine-type alkaloid selected from the group consisting of berberine, palmatin and coptisine.

ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of the berberine type alkaloid which can manufacture a berberine type alkaloid efficiently can be provided.

It is a chart figure which shows the specific example of the synthetic|combination method of coptisine chloride using the manufacturing method of the berberine type alkaloid of this invention.

In the present invention, by using the compound represented by the above general formula (Ia) with trifluoromethanesulfonic anhydride and 2,6-di-tert-butyl-4-methylpyridine, an intramolecular ring having high selectivity can be obtained. Since the compound represented by the general formula (Ib) can be synthesized in a high yield, it becomes possible to efficiently produce a berberine-type alkaloid. In Non-Patent Document 2, the compound represented by the general formula (Ia) is intramolecularly cyclized with phosphorus oxybromide (POBr ₃ ) to give the compound represented by the general formula (Ib). However, the yield of the target product in this step was about 20% and the selectivity was extremely low, which was not suitable for the synthesis of berberine-type alkaloids.

Further, in the present invention, by using a quinone-based oxidant, preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone, for the compound represented by the general formula (Ic), high efficiency can be obtained. By enabling the aromatic cyclization, it became possible to efficiently produce a berberine-type alkaloid.

The compound represented by the above general formula (Ia) could be produced in high yield by the synthetic method described below. Incidentally, the above-mentioned Non-Patent Document 2 also describes a method for synthesizing the compound represented by the general formula (Ia), but it is an inefficient method of synthesizing 4 steps from 2 compounds, Was scarce. With the synthetic method as described below, it is possible to synthesize the compound represented by the general formula (Ia) from two kinds of compounds in two steps. In particular, N-formylsaccharin is used for the formylation to quantify the compound. Thus, the compound represented by the above general formula (Ia) could be obtained.

As a specific example of the total synthesis of berberine-type alkaloids using the production method of the present invention, the total synthesis of coptisine chloride shown in FIG. 1 is mentioned, but the present invention is not limited thereto. According to the total synthesis of coptisine chloride shown in FIG. 1, the overall yield is high, and the reaction conditions are mild, so the safety is high. In addition, according to the total synthesis, the yield of coptisine is very high in the final step, and the purification is easy.

Hereinafter, embodiments of the present invention will be described in detail.

<Intramolecular cyclization of the compound represented by formula (Ia)>
The berberine-type alkaloid, which is the final product, does not have a Br group. The compound represented by the formula (Ia) is intramolecularly cyclized with trifluoromethanesulfonic anhydride and 2,6-di-tert-butyl-4-methylpyridine to obtain the above-mentioned general formula (Ia′). It is important to reduce the represented compound to synthesize the compound represented by the general formula (Ib) and then debrominate it.

The intramolecular cyclization reaction is preferably performed at 12° C. or higher, and may be performed at room temperature. The temperature is more preferably 15°C or higher, further preferably 15 to 50°C, and particularly preferably 20 to 45°C. The reaction time is preferably 20 to 28 hours.
In the present specification, room temperature is 15°C to 30°C, preferably 20°C to 25°C. The same applies to the following.

As the reaction solvent for the intramolecular cyclization reaction, chloroform, 1,2-dichloroethane, or dichloromethane is preferably used, and dichloromethane is particularly preferably used, because a higher yield can be obtained.

The reducing agent used for the reduction after the intramolecular cyclization reaction is not particularly limited, and examples thereof include sodium borohydride (NaBH ₄ ), lithium aluminum hydride (LiAlH ₄ ), sodium cyanoborohydride (NaBH ₃ CN) and the like. It is preferable to use the reducing agent used for the hydride reduction of, and sodium borohydride is particularly preferable.

The reaction temperature for the reduction is not particularly limited, and the reaction is preferably performed at room temperature. The reaction time is preferably 1 to 4 hours, more preferably 1.5 to 2 hours.

<Debromination of Compound Represented by General Formula (Ib)>
The debromination of the compound represented by the general formula (Ib) is not particularly limited, and a known and commonly used debromination method may be applied. For example, debromination may be performed using a known and commonly used reducing agent such as palladium carbon (Pd-C).

The reaction temperature for the debromination is not particularly limited, and the reaction is preferably performed at room temperature. The reaction time is preferably 12 hours to 24 hours.

<Aromatic Cyclization of Compound Represented by General Formula (Ic)>
The aromatic cyclization of the compound represented by the general formula (Ic) is not particularly limited except that a quinone-based oxidizing agent is used, and known and commonly used oxidation conditions may be applied. As the quinone-based oxidant, it is preferable to use 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), which does not require strict anhydrous conditions and allows the intended product to be obtained by a simple operation. High yields can be achieved. The reaction solvent is not particularly limited, and acetonitrile, dioxane or the like may be used.

The reaction temperature for the aromatic cyclization is not particularly limited, and the reaction is preferably performed at 75 to 85°C. The reaction time is preferably 1.5 to 2.5 hours.

A berberine-type alkaloid can be easily obtained by treating with hydrochloric acid after the aromatic cyclization.

The reaction temperature of the treatment with hydrochloric acid is not particularly limited, and the reaction is preferably performed at room temperature. The reaction time is preferably 0.5 to 2.0 hours.

<Method for producing compound represented by general formula (Ia)>
The method for producing the compound represented by the general formula (Ia) is not particularly limited, and may be produced, for example, by formylating the compound represented by the general formula (II).

As the formylation, a known and commonly used method may be used. For example, by using N-formylsaccharin, the compound represented by the general formula (Ia) can be produced in good yield.

The reaction temperature for the formylation is not particularly limited, and the reaction is preferably performed at room temperature. The reaction time is preferably 5 to 30 minutes.

<Method for producing compound represented by general formula (II)>
The method for producing the compound represented by the general formula (II) is not particularly limited, but the compound represented by the general formula (III-1) is reacted with the compound represented by the general formula (IV-1). And cyclized, it can be produced in good yield.

The conditions for the reaction of the two compounds are not particularly limited, and for example, boron trifluoride/diethyl ether complex (BF ₃ OEt ₂ ) may be added dropwise in a mixed solvent of dichloromethane/chloroform. The reaction temperature is not particularly limited and is preferably −78° C. to −10° C. The reaction time is preferably 3 to 25 hours.

In addition, in the reaction of the above-mentioned two compounds, since both the Boc form and the deBoc form can be produced as cyclization products at the end of the reaction, in order to complete the deprotection, for example, after the reaction, treatment with an acid is required. Is preferred.

<Method for producing compound represented by general formula (III-1)>
The method for producing the compound represented by the general formula (III-1) is not particularly limited, but the amino group of the compound represented by the general formula (III-2) and di-tert-butyl dicarbonate (Boc ₂ It may be produced by reacting with O) to protect the amino group.

The reaction may be performed by using a known and conventional method for protecting an amino group with di-tert-butyl dicarbonate. The reaction temperature is not particularly limited, and the reaction is preferably performed at room temperature. The reaction time is preferably 6 to 24 hours.

<Method for producing compound represented by general formula (IV-1)>
The method for producing the compound represented by the general formula (IV-1) is not particularly limited, but by reacting the compound represented by the following general formula (IV-2) with trimethylsilyl chloride and sodium iodide. It can be produced in high yield. It can also be produced by reacting by deprotection with a protonic acid, a Lewis acid, or iodine.

The conditions of the reaction are not particularly limited, but the reaction is preferably performed at room temperature, for example. The reaction time is preferably 1 to 20 minutes.

<Method for producing compound represented by general formula (IV-2)>
The method for producing the compound represented by the general formula (IV-2) is not particularly limited, but a compound represented by the following general formula (IV-3) is reacted with triphenylphosphine methoxymethyl chloride (TPMCl). Thus, it can be produced in a high yield.

The reaction is not particularly limited, but the yield can be further improved by sufficiently heating the triphenylphosphine methoxymethyl chloride used as the Wittig reagent and drying it under vacuum, and extending the adjustment time of the Wittig reagent. Further, the base used for the preparation of the Wittig reagent is not particularly limited, but hexamethyldisilazane sodium (NaHMDS), potassium tert-butoxide (t-BuOK), lithium bis(trimethylsilyl)amide (LiHMDS), etc. may be used, Among them, hexamethyldisilazane sodium is preferable. The reaction solvent is not particularly limited, but tetrahydrofuran is preferable because a higher yield can be obtained.

The conditions of the reaction are not particularly limited, but the reaction is preferably performed at 0° C. to room temperature, for example. The reaction time is preferably 1.5 to 2.5 hours.

Hereinafter, in the process shown in FIG. 1, coptisine chloride was synthesized using 6-bromopiperonal and compound 3 (homopiperonylamine) as starting materials.

真空下で加熱乾燥したトリフェニルフォスフィンメトキシメチルクロリド（ＴＰＭＣｌ）（４．５４ｇ、１３．２ｍｍｏｌ）の無水テトラヒドロフラン（ＴＨＦ）懸濁液（２５ｍＬ）に、アルゴン雰囲気下、０℃で、１ｍｏｌ／Ｌのヘキサメチルジシラザンナトリウム（ＮａＨＭＤＳ）のテトラヒドロフラン（ＴＨＦ）溶液（１３ｍｌ、１３ｍｍｏｌ）を１５分かけて滴下して加えた。その後、反応混合物を０℃で２時間攪拌し（下記表１中の「調整条件」）、Ｗｉｔｔｉｇ試薬を調整した。
６−ブロモピペロナール（１．５２ｇ、６．６４ｍｍｏｌ）のテトラヒドロフラン（ＴＨＦ）溶液（２５ｍＬ）を、アルゴン雰囲気下、０℃で、上記Ｗｉｔｔｉｇ試薬に１０分かけて滴下して加え、その反応混合物を０℃で０．５時間及び室温で２時間攪拌した（表１中の「反応条件」）。
得られた反応混合物に水（１５０ｍＬ）を加え、この水相から酢酸エチル（４００ｍＬ）で抽出した。得られた有機相を塩水で洗い、硫酸ナトリウム（Ｎａ_２ＳＯ_４）（２０ｇ）で乾燥した。減圧下で有機溶媒を蒸発させた後、残渣をシリカゲルクロマトグラフィー（１００ｇ、ヘキサン／酢酸エチル＝３０／１）で精製し、白色の固体状の化合物１を１．９５ｇ得た（収率＝１００％）。 [Experimental Example 1-1]
<Synthesis of Compound 1>

1 mol/L of triphenylphosphine methoxymethyl chloride (TPMCl) (4.54 g, 13.2 mmol) in anhydrous tetrahydrofuran (THF) suspension (25 mL) dried by heating under vacuum at 0° C. under argon atmosphere. A solution of sodium hexamethyldisilazane (NaHMDS) in tetrahydrofuran (THF) (13 ml, 13 mmol) was added dropwise over 15 minutes. Then, the reaction mixture was stirred at 0° C. for 2 hours (“adjustment condition” in Table 1 below) to adjust the Wittig reagent.
A solution of 6-bromopiperonal (1.52 g, 6.64 mmol) in tetrahydrofuran (THF) (25 mL) was added dropwise to the Wittig reagent at 0° C. under an argon atmosphere over 10 minutes, and the reaction mixture was added. The mixture was stirred at 0° C. for 0.5 hours and at room temperature for 2 hours (“reaction conditions” in Table 1).
Water (150 mL) was added to the resulting reaction mixture, and this aqueous phase was extracted with ethyl acetate (400 mL). The organic phase obtained was washed with brine and dried over sodium sulfate (Na ₂ SO ₄ ) (20 g). After evaporating the organic solvent under reduced pressure, the residue was purified by silica gel chromatography (100 g, hexane/ethyl acetate=30/1) to obtain 1.95 g of white solid compound 1 (yield=100 %).

The data of the obtained compound 1 are as follows.
mp 45.0-47.0 ℃
¹ H-NMR (CDCl ₃ ,600 MHz) δ :3.70 (1.65H, s), 3.76 (1.35H, s) ,5.51 (0.45H, d, J = 7.2Hz), 5.94, 5.95 (2H, sx 2 ), 6.02 (0.55H, d, J = 12.6Hz), 6.15 (0.45H, d, J = 7.2Hz), 6.82 (0.55H, s), 6.85 (0.55H, d, J = 12.6Hz), 6.99 (1H, sx 2)

[Experimental Examples 1-2 to 1-8]
The same as in Experimental Example 1-1, except that the base used for the adjustment of the Wittig reagent, the solvent, the adjustment conditions thereof, and the reaction conditions of 6-bromopiperonal and the Wittig reagent were changed as shown in Table 1 below. The reaction was carried out. The yield of Compound 1 is shown in Table 1 below. In the following, "rt" in the table means room temperature.

ａ）それぞれ１．２５−１．５モル当量のＴＰＭＣｌ（メトキシメチルトリフェニルフォスホニウムクロリド）及び塩基を用いた。
ｂ）それぞれ２．０−３．０モル当量のＴＰＭＣｌ及び塩基を用いた。

a) 1.25-1.5 molar equivalents of TPMCl (methoxymethyltriphenylphosphonium chloride) and base respectively were used.
b) 2.0-3.0 molar equivalents of TPMCl and base respectively were used.

化合物１（２．０７ｇ、８．０５ｍｍｏｌ）及びヨウ化ナトリウム（１．３８ｇ、９．２ｍｍｏｌ）の無水アセトニトリル溶液（８０ｍＬ）に、アルゴン雰囲気下、室温で、トリメチルシリルクロリド（ＴＭＳＣｌ）（１．０２ｍＬ、８．０５ｍｍｏｌ）を加え、その混合物を室温で２０分攪拌した。得られた反応混合物にチオ硫酸ナトリウム（Ｎａ_２Ｓ_２Ｏ_３）水溶液を加え、この水相から酢酸エチルで抽出した。得られた有機相を硫酸ナトリウムで乾燥した。減圧下で有機溶媒を蒸発させた後、残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１）で精製し、無色透明の油状の化合物２を１．７２ｇ得た（収率＝８７．９％）。 [Experimental example 2-1]
<Synthesis of Compound 2>

To a solution of Compound 1 (2.07 g, 8.05 mmol) and sodium iodide (1.38 g, 9.2 mmol) in anhydrous acetonitrile (80 mL) at room temperature under argon atmosphere, trimethylsilyl chloride (TMSCl) (1.02 mL, 8.05 mmol) was added and the mixture was stirred at room temperature for 20 minutes. An aqueous sodium thiosulfate (Na ₂ S ₂ O ₃ ) solution was added to the obtained reaction mixture, and this aqueous phase was extracted with ethyl acetate. The organic phase obtained was dried over sodium sulfate. After evaporating the organic solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to obtain 1.72 g of colorless transparent oily compound 2 (yield=87.9). %).

The data of the obtained compound 2 are as follows.
mp 39.0-40.0 ℃
¹ H-NMR (CDCl ₃ , 600 MHz) δ: 3.77 (2H, s), 5.99 (2H, s), 6.71 (1H, s), 7.06 (1H, s), 9.71 (1H, t, J = 1.7 Hz).

[Experimental example 2-2]
The reaction was performed in the same manner as in Experimental Example 2-1, except that the reaction conditions after adding trimethylsilyl chloride (TMSCl) were changed as shown in Table 2 below. The yield of compound 2 is shown in Table 2 below.

ホモピペロニルアミン（化合物３）（４９９．６ｍｇ、３．０２ｍｍｏｌ）と炭酸水素ナトリウム（ＮａＨＣＯ_３）（１．０５ｇ、１２．５ｍｍｏｌ）の混合物のメタノール溶液（５ｍＬ）に、室温で、二炭酸ジ−ｔｅｒｔ−ブチル（Ｂｏｃ_２Ｏ）（１．５ｍＬ、６．５３ｍｍｏｌ）を加え、その混合物を室温で１８時間攪拌した。得られた反応混合物に水を加え、この水相から酢酸エチルで抽出した。得られた有機相を硫酸ナトリウムで乾燥した。減圧下で有機溶媒を蒸発させた後、残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝２０／１→１０／１）で精製し、白色の固体状の化合物４を６８５．９ｍｇ得た（収率＝７７．４％）。 [Experimental example 3-1]
<Synthesis of Compound 4>

A solution of homopiperonylamine (Compound 3) (499.6 mg, 3.02 mmol) and sodium hydrogencarbonate (NaHCO ₃ ) (1.05 g, 12.5 mmol) in methanol (5 mL) was added to dicarbonic acid dicarbonate at room temperature. -Tert-Butyl (Boc ₂ O) (1.5 mL, 6.53 mmol) was added and the mixture was stirred at room temperature for 18 hours. Water was added to the obtained reaction mixture, and this aqueous phase was extracted with ethyl acetate. The organic phase obtained was dried over sodium sulfate. After evaporating the organic solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane/ethyl acetate=20/1→10/1) to obtain 685.9 mg of a white solid compound 4 (yield = 77.4%).

The data of the obtained compound 4 are as follows.
mp 58.0-59.0 ℃
¹ H-NMR (CDCl ₃ ,600 MHz) δ: 1.44 (9H, s), 2.70 (2H, t, J = 6.6Hz), 3.33 (2H, brd), 6.64 (1H, d, J = 7.8Hz) , 6.68(1H, s), 6.74 (1H, d, J = 7.8Hz).

[Experimental example 3-2]
The reaction was performed in the same manner as in Experimental Example 3-1, except that the reaction conditions were changed as shown in Table 3 below. The yield of compound 4 is shown in Table 3 below.

＊Ｎ，Ｎ−ジイソプロピルエチルアミン
＊＊４−ジメチルアミノピリジン

*N,N-diisopropylethylamine **4-dimethylaminopyridine

化合物２（１．８５ｇ、７．６０ｍｍｏｌ）と化合物４（１．２０ｇ、４．１０ｍｍｏｌ）の混合物のジクロロメタン（ＣＨ_２Ｃｌ_２）（８０ｍＬ）及びクロロホルム（ＣＨＣｌ_３）（８０ｍＬ）溶液に、アルゴン雰囲気下、−７８℃で、三フッ化ホウ素・ジエチルエーテル錯体（ＢＦ_３ＯＥｔ_２）（０．９２ｍＬ、７．３４ｍｍｏｌ）を加え、その混合物を−７８℃で１時間攪拌し、３時間かけて徐々に−１０℃まで温めた。その後、反応混合物を−１０℃で２０時間攪拌した。得られた反応混合物に炭酸水素ナトリウム（ＮａＨＣＯ_３）水溶液（１００ｍＬ）を加え、この水相からクロロホルム（４００ｍＬ）で抽出した。得られた有機相を硫酸ナトリウム（２０ｇ）で乾燥した。減圧下で有機溶媒を蒸発させた後、蒸発残渣にメタノール（１０ｍＬ）、濃塩酸（５ｍＬ）、及び、水（１０ｍＬ）を加えた。得られた反応混合物を１時間還流しながら、メタノールを除去した。得られた反応混合物に、ジオキサン（１０ｍＬ）を加え、その混合物を１時間還流した。得られた反応混合物に、炭酸ナトリウム（Ｎａ_２ＣＯ_３）水溶液（２００ｍＬ）を加え、この水相から酢酸エチル（１００ｍＬ×３）で抽出した。得られた有機相を硫酸ナトリウム（２０ｇ）で乾燥した。減圧下で有機溶媒を蒸発させた後、残渣に１ｍｏｌ／Ｌ塩酸−酢酸エチル溶液（２０ｍＬ）を加え、その混合物を室温で１８時間攪拌した。得られた反応混合物を飽和炭酸ナトリウム（Ｎａ_２ＣＯ_３）水溶液（２００ｍＬ）に注ぎ、この水相から酢酸エチル（１００ｍＬ×３）で抽出した。得られた有機相を硫酸ナトリウム（２０ｇ）で乾燥した。減圧下で有機溶媒を蒸発させた後、残渣をシリカゲルクロマトグラフィー（２００ｇ、クロロホルム→クロロホルム／メタノール＝２０／１）で精製し、淡黄色の固体状の化合物５を１．５６ｇ得た（収率＝９７．３％）。 [Experimental Example 4-1]
<Synthesis of Compound 5>

A mixture of compound 2 (1.85 g, 7.60 mmol) and compound 4 (1.20 g, 4.10 mmol) in dichloromethane (CH ₂ Cl ₂ ) (80 mL) and chloroform (CHCl ₃ ) (80 mL) was added to an argon atmosphere. At −78° C., boron trifluoride/diethyl ether complex (BF ₃ OEt ₂ ) (0.92 mL, 7.34 mmol) was added, and the mixture was stirred at −78° C. for 1 hour and gradually added over 3 hours. It was warmed to -10°C. Then the reaction mixture was stirred at −10° C. for 20 hours. An aqueous sodium hydrogen carbonate (NaHCO ₃ ) solution (100 mL) was added to the obtained reaction mixture, and this aqueous phase was extracted with chloroform (400 mL). The obtained organic phase was dried over sodium sulfate (20 g). After evaporating the organic solvent under reduced pressure, methanol (10 mL), concentrated hydrochloric acid (5 mL), and water (10 mL) were added to the evaporation residue. Methanol was removed while the resulting reaction mixture was refluxed for 1 hour. Dioxane (10 mL) was added to the obtained reaction mixture, and the mixture was refluxed for 1 hr. Aqueous sodium carbonate (Na ₂ CO ₃ ) solution (200 mL) was added to the obtained reaction mixture, and this aqueous phase was extracted with ethyl acetate (100 mL×3). The obtained organic phase was dried over sodium sulfate (20 g). After evaporating the organic solvent under reduced pressure, 1 mol/L hydrochloric acid-ethyl acetate solution (20 mL) was added to the residue, and the mixture was stirred at room temperature for 18 hr. The obtained reaction mixture was poured into saturated aqueous sodium carbonate (Na ₂ CO ₃ ) solution (200 mL), and this aqueous phase was extracted with ethyl acetate (100 mL×3). The obtained organic phase was dried over sodium sulfate (20 g). After evaporating the organic solvent under reduced pressure, the residue was purified by silica gel chromatography (200 g, chloroform→chloroform/methanol=20/1) to obtain 1.56 g of pale yellow solid compound 5 (yield = 97.3%).

The data of the obtained compound 5 are as follows.
mp 120.0-121.0℃., ¹ H-NMR (CDCl ₃ ,600 MHz) δ:2.73 (2H, t, J = 5.4Hz), 2.84 (1H, dd, J = 10.8, 13.8Hz), 2.94(1H, td, J = 5.4, 12.6Hz), 3.20 (1H, m), 3.23 (1H, dd, J = 3.0, 13.8Hz), 4.17 (1H, dd, J = 3.0, 10.2Hz), 5.91 x 2 (1H , d, J = 1.8Hz), 5.97 (1H, d, J = 1.8Hz), 5.98 (1H, d, J = 1.8Hz), 6.57 (1H, s), 6.77 (1H, s), 6.81 (1H , s), 7.05 (1H, s)., ¹³ C-NMR (CDCl ₃ ,150 MHz) δ: 30.0, 39.9, 42.9, 55.5, 100.7, 101.7, 106.5, 108.8, 111.3, 112.9, 114.9, 128.2, 131.6 , 131.7, 145.8, 145.9, 147.2, 147.3., LRMS (+APCI) m/z: 390 [M+H] ⁺ , HRMS (+APCI) m/z: 390.0334 (Calcd for C ₁₉ H ₁₇ O ₅ NBr: 390.0335)., IR (KBr): cm ^-1 :3311.1, 2930.3, 2898.4, 1502.2, 1477.2, 1257.3, 1229.4, 1035.5, 931.4.

[Experimental Example 4-2]
After adding the boron trifluoride/diethyl ether complex, the reaction was performed in the same manner as in Experimental Example 4-1, except that the temperature and stirring conditions were changed as shown in Table 4 below. The yield of compound 5 is shown in Table 4 below.

化合物５（３．７８ｇ、９．６９ｍｍｏｌ）のテトラヒドロフラン（ＴＨＦ）懸濁液（４５ｍＬ）に、Ｎ−ホルミルサッカリン（２．７２ｇ、１２．９ｍｍｏｌ）を加え、その反応混合物を室温で０．５時間攪拌した。得られた反応混合物を飽和炭酸水素ナトリウム（ＮａＨＣＯ_３）水溶液（１５０ｍＬ）に注ぎ、この水相から酢酸エチル（４００ｍＬ）で抽出した。得られた有機相を硫酸ナトリウム（２０ｇ）で乾燥した。減圧下で有機溶媒を除去し、淡黄色の固体状の化合物６を４．１０ｇ得た（収率１００％％）。異性体比は３．２／１であった。 [Experimental Example 5]
<Synthesis of Compound 6>

N-formylsaccharin (2.72 g, 12.9 mmol) was added to a tetrahydrofuran (THF) suspension (45 mL) of compound 5 (3.78 g, 9.69 mmol), and the reaction mixture was stirred at room temperature for 0.5 hours. It was stirred. The resulting reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (NaHCO ₃ ) solution (150 mL), and the aqueous phase was extracted with ethyl acetate (400 mL). The obtained organic phase was dried over sodium sulfate (20 g). The organic solvent was removed under reduced pressure to obtain 4.10 g of pale yellow solid compound 6 (yield 100%). The isomer ratio was 3.2/1.

The data of the obtained compound 6 are as follows.
mp 140.5-141.5°C., ¹ H-NMR (CDCl ₃ ,600 MHz) δ:2.71-3.66 (5.48H, m), 4.47 (0.76H, ddd, J = 2.4, 6.0, 13.2Hz), 4.72 (0.76 H, dd, J = 3.6, 10.8Hz), 5.59 (0.24H, dd, J = 4.8, 9.6Hz), 5.93-5.98 (4H, m), 6.52 (0.76H, s), 6.55 (0.24H, s) ), 6.61 (0.76H, s), 6.64 (0.24H, s), 6.66 (0.24H, s), 6.81 (0.76H, s), 6.99 (0.24H, s), 7.04 (0.76H, s), 7.58 (0.76H, s), 8.03 (0.24H, s)., ¹³ C-NMR (CDCl ₃ ,150 MHz) δ: 28.2, 34.4, 43.2, 60.0, 101.1, 101.9, 106.6, 108.7, 111.3, 112.9, 114.6, 127.2, 128.5, 129.4, 146.4, 147.0, 147.6, 147.8, 161.3 (isomer 1). 29.7, 40.2, 41.9, 51.2, 101.0, 101.7, 107.2, 108.5, 110.7, 112.7, 115.4, 126.2, 130.0, 146.7, 147.2, 147.3 (isomer 2)., LRMS (+APCI) m/z: 418 [M+H] ⁺ , HRMS(+APCI) m/z: 402.0284 (Calcd for C ₁₉ H ₁₇ O ₅ NBr: 418.0285). , IR (KBr): cm ^-1 :2901.3, 2875.3, 1659.4, 1476.2, 1246.7, 1230.3, 1214.9, 1034.6, 936.2.

化合物６（１０．３ｍｇ、０．０２４６ｍｍｏｌ）及び２，６−ジ−ｔｅｒｔ−ブチル−４−メチルピリジン（ＤＴＢＭＰ）（５８．３ｍｇ、０．２８４ｍｍｏｌ）のジクロロメタン溶液（１．０ｍＬ）に、０℃で、トリフルオロメタンスルホン酸無水物（Ｔｆ_２Ｏ）（２０μＬ、０．１２ｍｍｏｌ）を滴下して加えた。その後、反応混合物を２４時間攪拌した（下記表５中の「反応条件１」）。減圧下で過剰な溶媒を蒸発させた後、残渣をメタノール（２ｍＬ）に溶解した。得られた溶液に、０℃で、水素化ホウ素ナトリウム（ＮａＢＨ_４）（７３．９ｍｇ、１．９５ｍｍｏｌ）を加え、その反応混合物を室温で２時間攪拌した。得られた反応混合物に飽和炭酸ナトリウム（Ｎａ_２ＣＯ_３）水溶液を加え、この水相からクロロホルムで抽出した。得られた有機相を硫酸ナトリウムで乾燥した。減圧下で有機溶媒を蒸発させた後、残渣を分取薄層クロマトグラフィー（ＴＬＣ）（３％メタノールのジクロロメタン溶液）にかけて、化合物７を５．３ｍｇ（収率＝５３．６％）、並びに、化合物６を１．４ｍｇ（収率＝１３．６％）及び下記に示す化合物８−ｉｓｏを２．１ｍｇ（収率＝２６．４％）をそれぞれ精製して得た。 [Experimental Example 6-1]
<Synthesis of Compound 7>

A solution of compound 6 (10.3 mg, 0.0246 mmol) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) (58.3 mg, 0.284 mmol) in dichloromethane (1.0 mL) was added at 0°C. At this point, trifluoromethanesulfonic anhydride (Tf ₂ O) (20 μL, 0.12 mmol) was added dropwise. Then, the reaction mixture was stirred for 24 hours ("Reaction condition 1" in Table 5 below). After evaporation of excess solvent under reduced pressure, the residue was dissolved in methanol (2 mL). Sodium borohydride (NaBH ₄ ) (73.9 mg, 1.95 mmol) was added to the obtained solution at 0° C., and the reaction mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium carbonate (Na ₂ CO ₃ ) solution was added to the obtained reaction mixture, and the aqueous phase was extracted with chloroform. The organic phase obtained was dried over sodium sulfate. After evaporating the organic solvent under reduced pressure, the residue was subjected to preparative thin layer chromatography (TLC) (3% methanol in dichloromethane) to give 5.3 mg of compound 7 (yield=53.6%), and The compound 6 was obtained by purifying 1.4 mg (yield=13.6%) and 2.1 mg (yield=26.4%) of the compound 8-iso shown below, respectively.

The data of the obtained compound 7 are as follows.
dp 198.0-199.0°C., ¹ H-NMR (CDCl ₃ ,600 MHz) δ: 2.58 (1H, ddd, J = 1.2, 11.4, 16.8Hz), 2.61 (1H, td, J = 10.8, 3.6Hz), 2.67 (1H, d, J = 15.6Hz), 3.09 (1H, ddd, J = 4.8, 10.8, 15.6Hz), 3.15 (1H, ddd, J = 1.8, 4.8, 10.8Hz), 3.28 (1H, dd, J = 3.6, 16.8Hz), 3.51 (1H, d, J = 15.0Hz), 3.55 (1H, dd, J = 3.6, 11.4Hz), 4.05 (1H, d, J = 15.6Hz), 5.93 (1H, d, J = 1.2Hz), 5.94 (1H, d, J = 1.2Hz), 5.95 (1H, d, J = 1.8Hz), 5.98 (1H, d, J = 1.8Hz), 6.60 (1H, s) , 6.79 (1H, s), 6.95 (1H, s)., ¹³ C-NMR (CDCl ₃ ,150 MHz) δ: 29.5, 37.7, 51.1, 50.9, 52.9, 59.7, 100.9, 101.7, 105.6, 108.4, 110.9 , 114.8, 118.3, 127.5, 127.6, 130.3, 143.1, 145.7, 146.1, 146.3., LRMS (+APCI) m/z: 402 [M+H] ⁺ ,HRMS (+APCI) m/z: 402.0338 (Calcd for C ₁₉ H ₁₇ O ₄ NBr: 402.335)., IR (KBr): cm ^-1 :2948.6, 2910.0, 2891.7, 2849.3, 2772.1, 2755.7, 1503.2, 1457.9, 1242.9, 1226.5, 1036.5.

[Experimental Examples 6-2 to 6-12]
The reaction was performed in the same manner as in Experimental Example 6-1, except that the additives, the reaction temperature and the time, and the reaction solvent were changed as shown in Table 5 below. The yield of compound 7 is shown in Table 5 below.

♯収率は^１Ｈ−ＮＭＲで計算
＊密閉したチューブ内

# Yield calculated by ¹ H-NMR *In a sealed tube

化合物７（５１６．１ｍｇ、１．２８ｍｍｏｌ）、１０％パラジウム炭素（Ｐｄ−Ｃ）（２８１．６ｍｇ）、及び、トリエチルアミン（Ｅｔ_３Ｎ）（１．７ｍＬ、１６．９ｍｍｏｌ）のメタノール−クロロホルム懸濁液（４４ｍＬ）を、水素雰囲気下、室温で２４時間攪拌した。反応混合物の沈殿物をセライトでクロロホルム（２００ｍＬ）とメタノール（１５０ｍＬ）で溶出しながら濾去し、濾液を減圧濃縮し、飽和炭酸ナトリウム（Ｎａ_２ＣＯ_３）水溶液（７０ｍＬ）及び酢酸エチル（２００ｍＬ）に分けて、有機相を硫酸ナトリウム（１５ｇ）で乾燥した。硫酸ナトリウムを濾去した後、濾液を減圧濃縮して、黄色の固体状の化合物８を４２４．２ｍｇ得た（収率＞９９％）。 [Experiment 7]
<Synthesis of Compound 8>

Methanol-chloroform suspension of compound 7 (516.1 mg, 1.28 mmol), 10% palladium carbon (Pd-C) (281.6 mg), and triethylamine (Et ₃ N) (1.7 mL, 16.9 mmol). The liquid (44 mL) was stirred under a hydrogen atmosphere at room temperature for 24 hours. The precipitate of the reaction mixture was filtered off with Celite eluting with chloroform (200 mL) and methanol (150 mL), the filtrate was concentrated under reduced pressure, saturated aqueous sodium carbonate (Na ₂ CO ₃ ) solution (70 mL) and ethyl acetate (200 mL). The organic phase was dried over sodium sulfate (15 g). After removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure to obtain 424.2 mg of yellow solid compound 8 (yield >99%).

The data of the obtained compound are as follows.
dp 203.0-205.0 °C., ¹ H-NMR (CDCl ₃ ,600 MHz) δ: 2.61-2.67 (2H, m), 2.80 (1H, dd, J = 11.4, 15.6Hz), 3.08-3.16 (2H, m ), 3.23 (1H, dd, 3.6, 16.2Hz), 3.54 (1H, d, 15.0Hz), 3.57 (1H, dd, J = 3.6, 11.4Hz), 4.10 (1H, d, J = 15.0Hz), 5.92 (2H, s), 5.93 (1H, d, J = 1.2Hz), 5.96 (1H, d, J = 1.2Hz), 6.59 (1H, s), 6.63 (1H, d, J = 7.8Hz), 6.68 (1H, d, J = 7.8Hz), 6.73 (1H, s)., ¹³ C-NMR (CDCl ₃ ,150 MHz) δ: 29.6, 36.5, 51.2, 52.9, 59.8, 100.8, 101.0, 105.5, 106.8 , 108.4, 116.8, 121.0, 127.8, 128.5, 130.7, 143.3, 145.0, 146.0, 146.2. LRMS (+APCI) m/z: 324 [M+H] ⁺ ,HRMS (+APCI) m/z: 324.1221 (Calcd for C ₁₉ H ₁₈ O ₄ N: 324.1230)., IR (KBr): cm ^-1 :2911.9, 2799.1, 2747.1, 1499.3, 1485.8, 1458.8, 1264.1, 1246.7, 1226.5, 1038.4.

化合物８（２５．０ｍｇ、７７．３μｍｏｌ）と、２，３−ジクロロ−５，６−ジシアノ−ｐ−ベンゾキノン（ＤＤＱ）（８７．４ｍｇ、０．３８５ｍｍｏｌ）の混合物の無水アセトニトリル（ＭｅＣＮ）溶液（２．５ｍＬ）を、アルゴン雰囲気下、２時間還流した。
得られた反応混合物をメタノール（５ｍＬ）に溶解し、得られた溶液をセライト（０．９３ｇ）に吸収させた。得られたセライト混合物を、ＮＨ−シリカゲルを用いてクロマトグラフィー（５０ｇ、クロロホルム→メタノールのみ）で精製した。メタノール分画をメンブレンフィルター（ＰＴＦＥ、０．５μＭ）で濾過し、コプチシンの水酸化物塩を得た。得られた水酸化物塩をメタノールに溶解し、１ｍｏｌ／Ｌの塩酸／酢酸エチルで処理し、黄色の固体状のコプチシン塩化物（化合物９）を得た。得られたコプチシン塩化物を、減圧下で乾燥した（６０℃、１．４×１０^０ｈＰａ、１ｈ）。収量は３１．４ｍｇ（収率＝１００％）であった。 [Experimental example 8-1]
<Synthesis of coptisine chloride (compound 9)>

Anhydrous acetonitrile (MeCN) solution of a mixture of compound 8 (25.0 mg, 77.3 μmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (87.4 mg, 0.385 mmol) ( (2.5 mL) was refluxed for 2 hours under an argon atmosphere.
The obtained reaction mixture was dissolved in methanol (5 mL), and the obtained solution was absorbed in Celite (0.93 g). The obtained Celite mixture was purified by chromatography (50 g, chloroform→methanol only) using NH-silica gel. The methanol fraction was filtered through a membrane filter (PTFE, 0.5 μM) to obtain a hydroxide salt of coptisine. The obtained hydroxide salt was dissolved in methanol and treated with 1 mol/L hydrochloric acid/ethyl acetate to obtain a yellow solid coptisine chloride (compound 9). The coptisine chloride obtained was dried under reduced pressure (60° C., 1.4×10 ⁰ hPa, 1 h). The yield was 31.4 mg (yield=100%).

The data of the obtained compound are as follows.
dp 286 ℃., ¹ H-NMR (DMSO-d6, 600 MHz) δ: 3.20 (2H, t, J = 6.4Hz), 4.88 (2H, t, J = 6.4Hz), 6.18 (2H, s), 6.54 (2H, s), 7.08 (1H, s), 7.79 (1H, s), 7.83 (1H, d, J = 8.6Hz), 8.04 (1H, d, J = 8.6Hz), 8.97 (1H, s) ), 9.96 (1H, s)., ¹³ C-NMR (DMSO-d6, 150 MHz) δ: 26.2, 55.0, 102.0, 104.4, 105.2, 108.3, 111.5, 120.4, 120.8, 120.9, 121.6, 130.5, 132.2, 136.7, 143.7, 144.4, 147.0, 147.6, 149.7., LRMS (+APCI) m/z: 320 [M-Cl] ⁺ , HRMS (+APCI) m/z: 320.0919 (Calcd for C ₁₉ H ₁₄ O ₄ N : 320.0917), IR (KBr): cm ^-1 : 338.3, 3036.3, 2911.9, 1619.9, 1605.4, 1506.1, 1364.3, 1323.8, 1056.8, 1036.5.

[Experimental Examples 8-2, 8-3]
The reaction was performed in the same manner as in Experimental Example 8-1 except that the additives, the reaction time, and the reaction solvent were changed as shown in Table 6 below. The yield of compound 9 is shown in Table 6 below.

As shown in the above experimental example, according to the method for producing a berberine-type alkaloid of the present invention, total synthesis of coptisine chloride could be achieved with a total yield of about 54%. In particular, in the synthesis of compound 7, compound 6 having a Br group introduced at a specific position is used as a reaction product, and trifluoromethanesulfonic anhydride and 2,6-di-tert-butyl-4-methylpyridine are used. This enabled intramolecular cyclization reaction with excellent regioselectivity. Further, in the synthesis of Compound 9, it was possible to highly efficiently perform the aromatic cyclization by using a quinone-based oxidizing agent.

Claims (12)

A method for producing a berberine-type alkaloid represented by the following general formula (I),

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)
A compound represented by the following general formula (Ia) obtained by an intramolecular cyclization reaction of a compound represented by the following general formula (Ia) using trifluoromethanesulfonic anhydride and 2,6-di-tert-butyl-4-methylpyridine. A compound represented by the following general formula (Ib) is reduced by using a reducing agent to reduce the compound represented by

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)
Debrominating the compound represented by the general formula (Ib) to synthesize a compound represented by the following general formula (Ic),

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.)
A production method comprising a step of subjecting the compound represented by the general formula (Ic) to an aromatic cyclization using a quinone-based oxidizing agent. The production method according to claim 1, wherein the intramolecular cyclization reaction of the compound represented by the general formula (Ia) is performed at 15°C to 50°C. The production method according to claim 1, wherein dichloromethane is used as a reaction solvent for the intramolecular cyclization reaction of the compound represented by the general formula (Ia). The production method according to claim 1, wherein the reducing agent used for reducing the compound represented by the general formula (Ia′) is a reducing agent used for hydride reduction. The quinone-based oxidizing agent used for the aromatic cyclization of the compound represented by the general formula (Ic) is 2,3-dichloro-5,6-dicyano-p-benzoquinone. The manufacturing method described. The method according to claim 1, wherein the aromatic cyclized compound is treated with hydrochloric acid after the step of aromatic cyclization. 7. The method according to claim 1, further comprising a step of synthesizing the compound represented by the general formula (Ia) by formylating the compound represented by the following general formula (II) with N-formylsaccharin. The manufacturing method according to one paragraph.

(Wherein R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group, and R ³ and R ⁴ are each a methoxy group. , Or R ³ and R ⁴ combine to form a methylenedioxy group.) A step of synthesizing a compound represented by the general formula (II) by reacting a compound represented by the following general formula (III-1) with a compound represented by the following general formula (IV-1) The manufacturing method according to claim 7, which comprises.

(In the formula, R ¹ and R ² are each a methoxy group, or R ¹ and R ² are bonded to each other to form a methylenedioxy group, and Boc is a protective group derived from di-tert-butyl dicarbonate. Indicates a group.)

(In the formula, R ³ and R ⁴ are each a methoxy group, or R ³ and R ⁴ are combined to form a methylenedioxy group.) 9. A step of synthesizing a compound represented by the general formula (III-1) by reacting a compound represented by the following general formula (III-2) with di-tert-butyl dicarbonate. The manufacturing method described.

(In the formula, R ¹ and R ² are each a methoxy group, or R ¹ and R ² are combined to form a methylenedioxy group.) 9. The production according to claim 8, comprising a step of synthesizing the compound represented by the general formula (IV-1) using a compound represented by the following general formula (IV-2), trimethylsilyl chloride and sodium iodide. Method.

(In the formula, R ³ and R ⁴ are each a methoxy group, or R ³ and R ⁴ are combined to form a methylenedioxy group.) 11. The method comprising the step of synthesizing the compound represented by the general formula (IV-2) by reacting the compound represented by the following general formula (IV-3) with triphenylphosphine methoxymethyl chloride. The manufacturing method described.

(In the formula, R ³ and R ⁴ are each a methoxy group, or R ³ and R ⁴ are combined to form a methylenedioxy group.) The method according to any one of claims 1 to 11, wherein the compound represented by the general formula (I) is a berberine-type alkaloid selected from the group consisting of berberine, palmatin and coptisine.

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