KR101122397B1 - An economical synthesis of ailanthoidol - Google Patents

Abstract

The present invention is a method for synthesizing the synthesis of ailanthoidol, which is expected to have an excellent anti-inflammatory activity, as an active ingredient of hawthorn locust tree, which is used as a folk remedy, from a vanillin compound in a short reaction and a high yield (72% in total). The present invention relates to the development of an economical ailanthoidol synthesis method in which a long reaction step and a low yield method, which are a problem in the conventional synthesis method, are solved by using a coupling-ring simultaneous reaction in which iodine is introduced.

Ailanthoidol, Anti-Inflammatory, Japanese Herb, Redwood, Coupling-ring Synchronization

Description

{An economical synthesis of ailanthoidol} Ａｉｌａｎｔｈｏｉｄｏｌ

The present invention relates to the development of a method of synthesizing a total of five steps from a vanillin compound with a short yield and a high yield as an economic synthesis method of the active ingredient ailanthoidol of the locust tree, which is expected to have strong anti-inflammatory action.

Bark and leaves of Zanthoxylum ailanthoides have long been used in various folk remedies, and ailanthoidol has been isolated as a major component [Phytochemistry, 1994, 36, 213]. Existing synthetic methods are described in vanillin [J. Org. Chem., 2002, 67, 6772; Tetrahedron Lett., 1998, 39, 6581] and 5-bromo-2-hydroxy-3-methoxybenzaldehyde [J. Org. Chem., 2003, 68, 2968] as a starting material to synthesize ailanthoidol in a low yield of 26-50%. In particular, the existing synthetic methods are very sensitive to the coupling group and benzofuran cyclization reaction depending on the substitution group, and the reactivity is very low, reducing the efficiency and economic efficiency of the synthesis. Ailanthoidol is a compound that has not been studied much yet. Therefore, there is an increasing demand for the development of efficient and economical synthetic methods for active ingredients that are difficult to obtain.

The following scheme 1 schematically illustrates the reaction.

Scheme 1

Synthesis of ailanthoidol was performed by synthesizing ortho-iodine phenol derivatives (Formula 2) by commercially inexpensive vanillin (Formula 1) using silver sulphate iodide, followed by synthesis of acetylene derivatives by Sonogashira coupling reaction using copper acetylide. At the same time, a cyclization reaction with an intramolecular hydroxy group occurs to synthesize the benzofuran compound (Formula 3) in high yield. Wittig reaction to synthesize a carbethoxyethenyl derivative (Formula 4). A benzofuran alcohol compound (Formula 5) is synthesized by a debenzylation reaction using TiCl ₄ , followed by synthesis of ailanthoidol (Formula 6) reduced in ester by a reduction reaction using DIBAL-H. Conventional synthesis method using vanillin as starting material [J. Org. Chem., 2002, 67, 6772] synthesized ailanthoidol in 26% yield in 11 steps, including coupling and cyclization using bromine.

Therefore, in order to solve this problem, the present invention introduces iodine into the benzene ring so that the Sonogashira coupling reaction can occur without the introduction of a protecting group, and the coupling and cyclization reactions can occur simultaneously in the same reaction conditions sequentially. To provide a synthetic method to increase the economics and efficiency of the system.

In accordance with the above object, the present invention provides a method of selectively introducing iodine at the ortho-phenol position of vanillin so that the Sonogashira coupling reaction occurs well without a protecting group, and the coupling and benzofuran cyclization reactions are sequentially and simultaneously highly reactive. .

In preparing the ailanthoidol of the formula (6) from the compound of the formula (1) by simplifying the reaction step in five steps through the formulas (2), (3), (4) and (5), it is the most efficient and highest yield synthesis method among the published ailanthoidol synthesis methods. (72% overall yield). In particular, the product of the Sonogashira coupling reaction with iodine group was simultaneously linked to the benzofuran cyclization reaction under the same reaction conditions, thereby simplifying the reaction step and improving the reaction yield.

Hereinafter, the present invention will be described in detail.

Vanillin used as a starting material in the present invention is represented by the following formula (1):

In the above formula, vanillin can be easily purchased from a reagent company such as Aldrich and used by dissolving in ethanol solvent.

In the above formula, 4-hydroxy-3-iodo-5-methoxybenzaldehyde is obtained from the starting material vanillin by iodide using silver sulfate.

In the above formula, 2- (4-benzyloxy-3-methoxyphenyl) -7-methoxybenzofuran-5-carbaldehyde is obtained by intramolecular cyclization reaction in which the product of Sonogashira coupling reaction with Chemical Formula 2 and acethylene derivatives is carried out simultaneously under the same conditions. .

In the above formula, 2- (4-benzyloxy-3-methoxyphenyl) -5- (carbethoxyethenyl) -7-methoxybenzofuran is obtained by Wittig reaction with Chemical Formula 3.

In the above formula, 2- (4-hydroxy-3-methoxyphenyl) -5- (carbethoxyethenyl) -7-methoxybenzofuran is obtained by debenzylation using Chemical Formula 4 and TiCl ₄ .

In the above formula, ailanthoidol is obtained by a reduction reaction between Formula 5 and DIBAL-H.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example

Example 1

Synthesis of Chemical Formula 2 from Vanillin (Formula 1)

Vanillin (1g, 6.57mmol), iodine (2.08g, 7.89mmol) and silver sulfate (2.46g, 7.89mmol) were dissolved in EtOH (50mL), stirred at room temperature for 1 hour and water was added to terminate the reaction. Extract with CH ₂ Cl ₂ . After extraction, the organic layer was washed with water and brine, dried using Na ₂ SO _4, and distilled under reduced pressure. The remaining material was separated by column chromatography (EtOAc: Hexane = 1: 2) to obtain the title compound 2 as a white solid.

Yield: 1.55 g, 85%

R _f 0.34 (EtOAc: Hexane = 1: 3); mp 178-181 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) d 3.97 (3H, s, OCH ₃ ), 6.69 (1H, s, OH), 7.36 (1H, d, J = 1.5 Hz, C6-H), 7.81 (1H, d, J = 1.5 Hz, C2-H), 9.75 (1H, s, CHO). ¹³ C NMR (75 MHz, CDCl ₃ ) d 56.8 (OMe), 80.7 (C3-I), 108.8 (C6), 131.2 (C1), 136.4 (C2), 146.6 (C5), 151.5 (C4), 189.7 ( C = O).

Example 2

Synthesis of Chemical Formula 3 from Chemical Formula 2

0.145 g (0.523 mmol) of a compound of Formula 2 was added to Pd (PPh ₃ ) ₄ (0.018 g, 0.026 mmol), 1-benzyloxy-4-ethynyl-2-methoxybenzene (0.187 g, 0.784 mmol), CuI (0.005 g, 0.026 mmol) and DMF (8 mL). Et ₃ N (0.146 mL, 1.046 mmol) was added thereto and stirred at room temperature under a nitrogen stream for 14 hours. After the reaction, add water and extract with CH ₂ Cl ₂ . After extraction, the organic layer was washed with water, dried over Na ₂ SO ₄ , and distilled under reduced pressure. The remaining material was separated by column chromatography (EtOAc: Hexane = 1: 4) to obtain the title compound 3 as a yellow solid.

R _f 0.3 (EtOAc: Hexane = 1: 2); mp 160-162; ¹ H NMR (300 MHz, CDCl ₃ ) d 3.98 (3H, s, C3′-OCH ₃ ), 4.06 (3H, s, C7-OCH ₃ ), 5.19 (2H, s), 6.91 (1H, s, C3 -H), 6.93 (1H, s, C2'-H), 7.29-7.45 (8H, m), 7.65 (1H, s, C4-H), 9.96 (1H, s, CHO). ¹³ C NMR (75 MHz, CDCl ₃ ) d 56.5 (x2), 71.2, 100.9, 104.5, 108.9, 114.0, 118.5, 119.2, 123,1, 127.5, 128.2, 128.8, 131.2, 133.6, 136.8, 146.0, 147.6, 149.3, 149.9, 158.0, 191.9 (C = O).

Example 3

Synthesis of Chemical Formula 4 from Chemical Formula 3

0.270 g (0.75 mmol) of the compound of Formula 3 and (carbethoxymethylene) triphenylphosphorane (0.264 g, 0.99 mmol) were added to CH ₂ Cl _2. Dissolve in (20mL). The mixture is refluxed under nitrogen stream for 6 hours and then cooled to room temperature. Add water and extract with CH ₂ Cl ₂ . After extraction, the organic layer was washed with brine, dried over Na ₂ SO _4, and distilled under reduced pressure. The remaining material was separated by column chromatography (EtOAc: Hexane = 1: 6) to obtain the title compound 4 as a white solid.

Yield: 0.341 g, 99%

R _f 0.2 (EtOAc: Hexane = 1: 4); mp 142-144 ^o C; ¹ H NMR (300 MHz, acetone- d ₆ ) d 1.28 (3H, t, J = 7.1 Hz, CH ₃ ), 3.92 (3H, s), 4.07 (3H, s), 4.20 (2H, q, J = 7.1 Hz, OCH ₂ ), 5.15 (2H, s), 6.52 (1H, d, J = 16.0 Hz, trans ethenyl C1-H), 6.52 (1H, d, J = 16 Hz), 7.12 (1H, d, J = 8.3 Hz), 7.15 (1H, s), 7.26 (1H, d, J = 1.4 Hz), 7.31- 7.52 (8H, m), 7.72 (1H, d, J = 16.0 Hz, trans ethenyl C2-H). ¹³ C NMR (75 MHz, acetone- d ₆ ) d 14.8 (CH ₃ ), 56.5 (OCH ₃ ), 56.7 (OCH ₃ ), 60.8 (OCH ₂ ), 71.5 (OCH ₂ ), 101.7, 106.5, 109.8, 115.1 , 118.1 ( trans ethenyl-C1), 118.8, 124.3, 128.7, 128.9, 129.4, 131.9, 132.5, 138.4, 146.1 ( trans ethenyl-C2), 146.1, 146.6, 150.5, 151.3, 158.1, 167.4 (C = O).

Example 4

Synthesis of Chemical Formula 5 from Chemical Formula 4

A compound 0.29g (0.63mmol) of the formula (4) in a nitrogen atmosphere CH ₂ Cl ₂ (20mL) and then at room temperature TiCl ₄ (0.7 mL, 0.7 mmol, 1.0 M in CH ₂ Cl ₂ ) was slowly added and stirred under nitrogen stream for 1 hour at room temperature. After completion of the reaction, MeOH was added at room temperature to terminate the reaction. The solvent was distilled off under reduced pressure, and the remaining material was separated by column chromatography (EtOAc: Hexane = 1: 4) to obtain the title compound 5 as a white solid.

Yield: 0.228 g, 98%

R _f 0.5 (EtOAc: Hexane = 1: 2); mp 149-151 ^o C; ¹ H NMR (300 MHz, acetone- d ₆ ) δ 1.27 (3H, t, J = 7.1 Hz, CH ₃ ), 3.91 (3H, s), 4.07 (3H, s), 4.20 (2H, q, J = 7.1 Hz, OCH ₂ ), 6.52 (1H, d, J = 16.0 Hz, trans ethenyl C1-H), 6.94 (1H, d, J = 8.2 Hz), 7.07 (1H, s), 7.24 (1H, d, J = 1.4 Hz), 7.41 (1H, dd, J = 8.2, 2.0 Hz) , 7.70 (1H, d, J = 16.0 Hz, t rans ethenyl C2-H), 8.07 (1 H, s). ¹³ C NMR (75 MHz, acetone- d ₆ ) δ 14.8 (CH ₃ ), 56.6 (OCH ₃ ), 56.6 (OCH ₃ ), 60.9 (OCH ₂ ), 100.1, 106.5, 109.4, 115.5, 116.6 ( trans ethenyl-C1), 118.0, 119.5, 123.0, 129.5, 131.9, 132.6, 146.1 ( trans ethenyl-C2), 146.6, 148.9 (x2), 158.4, 167.5 (C = O).

Example 5

Synthesis method of ailanthoidol (Formula 6) from Chemical Formula 5

0.17 g (0.46 mmol) of the compound of Formula 5 was dissolved in THF (10 mL), and DIBAL-H (0.25 mL, 1.9 mmol, 1.0 M in CH ₂ Cl ₂ ) was added thereto, and slowly added dropwise under nitrogen stream at -78. After slowly raising the temperature to room temperature and stirring for 12 hours, saturated Na ₂ CO _{3 ?} Aqueous 10H ₂ O solution was added and the resulting aluminum gel-like material was diluted with CH ₂ Cl ₂ (50 mL), and the aluminum gel material was filtered while washing with EtOAc. After distillation under reduced pressure, the remaining material was recrystallized with ethyl alcohol to obtain the title compound (6) as a white solid.

Yield: 0.143 g, 95%

R _f 0.6 (EtOAc: Hexane = 3: 1); mp 199-201 ^o C; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.87 (3H, s, C7-OCH ₃ ), 3.93 (3H, s, C3'-OCH ₃ ), 4.13 (2H, d, J = 4.7 Hz, CH ₂ OH), 5.59 (1H, s), 6.31 (1H, dt, J = 5.0, 15.8 Hz, trans ethenyl C2-H), 6.57 (1H, d, J = 15.8 Hz, trans ethenyl C1-H), 6.86 (1H, d, J = 8.2 Hz, C5'-H), 6.90 (1H, s, C2'-H), 7.03 (1H, d, J = 1.4 Hz, C3-H) , 7.10 (1H, s), 7.29 (1H, doublet of doublets, J = 1.4, 8.2 Hz, C6′-H), 7.33 (1H, s, C4-H). ¹³ C NMR (75 MHz, DMSO- d ₆ ) δ 55.7 (C3'-OCH ₃ , C7-OCH ₃ ), 61.6 (CH ₂ OH), 100.1 (C3), 104.3 (C4), 108.6 (C6), 110.8 (C2 '), 115.8 (C6'), 117.8 (C5 '), 121.0 ( trans ethenyl C2), 128.9 (C1 '), 129.5 (C3a), 130.7 ( trans ethenyl C1), 133.1 (C5), 142.3 (C7), 144.5 (C4'), 147.5 (C3 '), 147.8 (C7a), 156.1 (C2).

Claims (4)

In the method for synthesizing ailanthoidol represented by Chemical Formula 6 from vanillin represented by Chemical Formula 1, iodobenzaldehyde represented by Chemical Formula 2 is formed via Intermediate Compound 3 through Sonogashira coupling reaction and cyclization reaction under the same reaction conditions. Method characterized by Formula 1

Formula 2

Formula 3

6

The method of claim 1, wherein in the method for synthesizing the compound of Formula 6, the Wittig reaction using Formula 3 and (carbethoxymethylene) triphenylphosphorane is produced via Formula 4 as an intermediate compound. Formula 4

The method of claim 1, wherein in the method for synthesizing the compound of Chemical Formula 6, a debenzylation reaction using TiCl ₄ in Chemical Formula 4 is produced via Chemical Formula 5 as an intermediate compound. Formula 5

The method of claim 1, wherein in the method for synthesizing the compound of Chemical Formula 6, the final compound represented by Chemical Formula 6 is produced by a reduction reaction using DIBAL-H (Diisobuthylaluminum hydride) in Chemical Formula 5.