KR100457732B1 - The preparation of asymmetric furofuranelignan compound - Google Patents

Abstract

The present invention relates to an optical synthesis propranlignan compound represented by the following general formula (1) having a blood pressure lowering, anticancer and antioxidant effect, and a novel method for producing the enantiomer thereof.

Wherein R ¹ , R ² , R ³ represent the same or different hydrogen or methoxy groups, or methylenedioxy groups together with adjacent groups.

Description

New Preparation of Asymmetric Furofuranignan Compounds in Optical Synthesis {The preparation of asymmetric furofuranelignan compound}

The present invention relates to a novel method for preparing a compound represented by the following general structural formula (1), which is an optical synthetic furofuran lignan compound having various pharmacological activities such as a blood pressure lowering agent, an anticancer agent, and an antioxidant.

(One)

Wherein R ¹ , R ² , R ³ represent the same or different hydrogen, methoxy groups or methyleneoxydi groups together with adjacent groups.

Sesamin Yanggambin

Eudemin

Conventional methods for preparing (-), (+)-sesamine, (-), (+)-udesamine, (-), and (+)-yanggambin are preferred to produce mercaptosuccinic acid in the presence of a base. Condensation reaction with an aldehyde gives a mixture which is a 4-aryllactone isomer compound. These were separated, and condensation reaction of aromatic aldehydes was carried out, followed by reduction and dialkoxylation to prepare (-)-udesmine. Such a conventional manufacturing method is not only low in yield because it is obtained as an isomer mixture, but also has many problems in separating the isomers. In addition, (-)-sesamine was synthesized by using an intramolecular heterodiels-Alder reaction as a main reaction using L-tartaric acid ethyl ester (diethyl L-tartrate) as a starting material. This manufacturing method has a difficulty in preparing (-)-sesamin in 22 reaction pathways.

The present invention solves this problem, and furthermore, high purity (-), (+)-sesamine, (-), (+)-udesamine, (-), (+)-yanggambin are respectively in optically active form. Research of the manufacturing technology method has resulted in the completion of the present invention.

Accordingly, an object of the present invention is to use (-), (+)-sesamine, (-), (+)-oil represented by General Structural Formula (1) in an easy manufacturing process using inexpensive and readily available raw materials. It is to provide a method for preparing desmin, (-), (+)-yanggambin in an optically active form.

The invention is explained in detail in the following.

The present invention provides a method for synthesizing (+)-sesamin, (+)-udesamine, (+)-yanggambin and their enantiomers represented by general formula (I).

(One)

Wherein R ¹ , R ² , R ³ represent the same or different hydrogen, methoxy groups or methylenedioxy groups together with adjacent groups.

First, the compound represented by the general formula (2) is mixed with a general organic solvent (tetrahydrofuran, diethyl ether), stirred under the conditions of a base (butyllithium, sodium hydride), and then represented by the general formula (3). After adding a compound (XCOCH ₂ CH ₂ COX: X represents a halogen atom), the mixture is stirred at low temperature to obtain a compound represented by the general formula (4). An organic solvent (toluene, benzene , Dichloromethane, chloroform, carbon tetrachloride) and dialkylboron triplate are added under the conditions of base (diisopropylethylamine) to obtain boronenolate. Arylaldehyde is added to the reaction mixture under low temperature conditions, followed by stirring. A weak acid (dilute sulfuric acid, dilute hydrochloric acid) is added thereto to form a compound represented by the general formula (5). The compound represented by the general formula (5) is mixed with a general organic solvent (tetrahydrofuran, diethyl ether, benzene, dichloromethane, chloroform, carbon tetrachloride), reduced with DIBAL (diisobutyl aluminum hydride) to give a general formula ( Make the compound represented by 6). The compound represented by the general formula (6) was mixed with a general organic solvent (dichloromethane, chloroform), and then reduced to triethylsilane-boron trifluoride to give the compound represented by the general formula (1) in an optically active form. Get into. In addition, the enantiomer of the compound represented by General formula (1) was obtained in the optically active form from the enantiomer of the compound represented by General formula (2).

This is shown in Scheme 1.

Scheme 1

In the above formula, R ¹ , R ² , R ³ represent a methylenedioxy group together with hydrogen, a methoxy group or an adjacent group, R represents a benzyl, phenyl or isopropyl group, and X represents a halogen atom.

The present invention is described in detail in the following examples, but the present invention is not limited to the following examples.

A) Example of a process for preparing sesamin

Synthesis of 1,4-bis (4 (S) -benzyl-2-oxazolidin-3-yl) butane-1,4-dione

Example 1

To a THF (66 mL) solution of 4 (S) -benzyl-2-oxazolidinone (3.90 g, 22.0 mmol) was added 1.6 M n -butyllithium (13.2 mL, 21.0 mmol) at -76 ° C under a nitrogen stream and Stir at temperature for 20 minutes. A solution of succinic chloride (1.55 g, 10.0 mmol) in THF (5 mL) was added thereto over 10 minutes, stirred at the same temperature for 30 minutes, and then stirred at 0 ° C. for 2 hours. Saturated ammonium chloride (100 mL) was added to the reaction mixture, followed by extraction three times with ethyl acetate (70 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine. The mixture was dried, filtered and distilled under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 1: 3 mixed solvent] to give a white product (3.87 g, 89%).

mp: 55-57 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.19 (m, 10 H), 4.67 (br s, 2 H), 4.16 (t, J = 8.8 Hz, 4 H), 3.32 (s, 4 H) , 3.22 (d, J = 13.3 Hz, 2 H), 2.82 (dd, J = 12.9, J = 9.3 Hz, 2 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 172.36, 154.01, 135.71, 129.91, 129.74,

129.32, 127.69, 66.77, 55.43, 38.04, 30.49

IR (νmax, KBr) 1781, 1697, 1376 cm ^-1

[α] ²⁰ D (c = 1.0, MeOH) +104

Example 2

Of 3 (S), 4 (S) -bis (benzo [1,3] dioxol-5-yl) tetrahydrofuran [3 (S), 4 (S) -c] furan-1,4-dione synthesis

A solution of 1,4-bis (4 (S) -benzyl-2-oxazolidin-3-yl) butane-1,4-dione (2.0 g, 4.6 mmol) in dichloromethane (18 mL) After cooling to 0 ° C. under nitrogen stream, 1.0 M (in dichloromethane) dibutylboron triflate (10.0 mL, 10.0 mmol) was added over 10 minutes, and after 10 minutes, diisopropylethyl amine was dissolved in dichloromethane (4.6 mL). The solution was added over 10 minutes. The mixture was stirred at the same temperature for 30 minutes, cooled to -78 ° C, and a solution of piperonal (1.8 g 12.0 mmol) in dichloromethane (4.6 mL) was added over 10 minutes. The reaction mixture was stirred at the same temperature for 20 minutes and then stirred until it reached 0 ° C. Methanol (27 mL), saturated potassium dihydrogen phosphate (18 mL) and 28% hydrogen peroxide solution (18 mL) were added sequentially to the reaction mixture, followed by vigorous stirring at room temperature for 8 hours. The reaction mixture was extracted three times with dichloromethane (30 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 1: 4 mixed solvent] to give a white product (1.60 g, 91%).

mp. 124-126 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.81 (s, 4 H), 6.75 (s, 2 H), 5.99 (s, 4 H),

5.82 (s, 2 H), 3.54 (s, 4 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 175.33, 149.22, 148.99, 132.36, 119.18,

109.41, 105.87, 102.28, 82.48, 48.94

IR (νmax, KBr) 1772, 1498, 1247, 1038 cm ^-1

MS m / z (relative intensity) 382 (M +), 307, 154 (base peak)

[α] ²⁰ D (c = 1.0, MeOH) +69

Example 3

3 (S), 6 (S) -bis (benzo [1,3] dioxol-5-yl) tetrahydrofuro [3 (S), 4 (S) -c] furan-1,4-diol Synthesis of

3 (S), 6 (S) -bis (benzo [1,3] dioxol-5-yl) tetrahydro [3 (S), 4 (S) -c] furan-1,4-dione (1.40 g, 3.67 mmol) in tetrahythrofuran (30 mL) was cooled to -25 ° C under nitrogen stream, and then 1.0 M (in dichloromethane) diisobutylaluminium hydride (14.7 mL, 14.7 mmol)) was added slowly, stirred at the same temperature for 1 h and then slowly added water (30 mL). Dichloromethane (100 mL) was added to the reaction mixture, which was then filtered and extracted five times with dichloromethane (20 mL). The extract was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a product. This product was subjected to column chromatography [ethyl acetate: hexane = 1: 2 mixed solvent] to give a white product (0.63 g, 45%).

mp. 152-154 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.05-6.76 (m, 6 H), 5.97 (s, 4 H), 5.82 (s, 2 H), 4.95 (d, J = 7.2 Hz 2 H), 3.19 (br s, 2 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 154.77, 1141.72, 133.87, 119.81, 110.14,

105.85, 102.33, 101.23, 82.48, 46.44

IR (νmax, KBr) 3329, 3197, 1493, 1250 cm-1

MS m / z (relative intensity) 386 (M +), 307, 154 (base peak)

Example 4

(+)-Sesamin

3 (S), 6 (S) -bis (benzo [1,3] dioxol-5-yl) tetrahydrofuran [3 (S), 4 (S) -c] furan-1,4-diol ( 200 mg, 0.52 mmol) in dichloromethane (30 mL) was cooled to -10 ° C under a stream of nitrogen, then triethyl silane (0.25 mL, 1.56 mmol) was added, and boroncrofluoride diethyl ether (0.1 mL, 1.1 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at the same temperature for 2 hours, then saturated aqueous sodium carbonate solution (20 mL) was added and extracted three times with dichloromethane (15 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography [ethyl acetate: hexane = 1: 4 mixed solvent] to give the product (110 mg, 60%). Got it.

mp. 121-122 ℃

¹ H NMR (300 MHZ, CDCl ₃ ) δ 6.85-6.77 (m, 6 H), 5.95 (s, 4 H), 5.39 (s, 1 H)

, 4.33-4.39 (m, 1H), 4.18 (dd, J = 9.2, J = 6.0 Hz, 2H), 3.91 (d = 9.2 Hz 1H), 3.57 (dd, J = 9.2 Hz, J = 7.4 Hz, 1 H),

13 C NMR (75.47 MHz, CDCl ₃₎ δ 175.33, 149.22, 148.99, 132.36, 119.18,

109.41, 105.87, 102.28, 82.48, 48.94

IR (νmax, KBr) 3020, 2930, 2891 cm ^-1

MS m / z (relative intensity)

[α] ²⁰ D (c = 1.0, MeOH) +68

B) Example of the preparation method of the two sense bean

Example 5

3 (S), 6 (S) -bis (3,4,5-trimethoxyphenyl-5-yl) tetrahydro-1 H , 3 H Furo [3 (R), 4 (R) -c] furan-1,4-dione

A solution of 1,4-bis (4 (S) -benzyl-2-oxazolidin-3-yl) butane-1,4-dione (1.1 g, 2.5 mmol) in dichloromethane (10 mL) After cooling to 0 ° C. under nitrogen stream, 1.0 M (in dichloromethane) dibutylboron triflate (5.5 mL, 5.5 mmol) was added over 10 minutes, and after 10 minutes, diacisopropyl amine was added to dichloromethane (2.5 mL). The dissolved solution was added over 10 minutes. The mixture was stirred at the same temperature for 30 minutes, cooled to -78 ° C, and a solution of triethoxybenzaldehyde (1.4 g 7.0 mmol) in dichloromethane (5 mL) was added over 10 minutes. The reaction mixture was stirred at the same temperature for 20 minutes and then stirred until it reached 0 ° C. Methanol (15 mL), saturated aqueous potassium hydrogen phosphate solution (10 mL), and 28% hydrogen peroxide solution (10 mL) were added sequentially to the reaction mixture, followed by vigorous stirring at room temperature for 4 hours. The reaction mixture was extracted three times with dichloromethane (25 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 2: 3 mixed solvent] to give a product (759 mg, 64%).

mp. 170 to 171 ° C

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.51 (s, 4 H), 5.87 (s, 2 H), 3.87 (s, 12 H), 3.81 (s, 6 H), 3.57 (s, 2 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 174.94, 153.94, 138.30, 133.64, 101.25,

81.58, 60.86, 56.34, 48.47

IR (νmax, KBr) 1778, 1600, 1520, 1261 cm ^-1

MS m / z (relative intensity) 474 (M +), 307, 55 (base peak)

[α] ²⁰ D (c = 1.0, CHCl 3) +39

Example 6

3 (S), 6 (S) -bis (3,4,5-trimethoxyphenyl-5-yl) tetrahydro-1 H , 3 H Furo [3 (S), 4 (S) -c] furan-1,4-diol

3 (S), 6 (S) -bis (3,4,5-trimethoxyphenyl-5-yl) tetrahydro- 1H , 3H -furo- [3 (S), 4 (S) -c ] The solution of furan-1,4-dione (400 mg, 0.84 mmol) in tetrahydrofuran (11 mL) was cooled to -25 ° C under nitrogen stream, and then 1.0 M (in dichloromethane) diisobutylaluminum hydride. (3.8 mL, 3.8 mmol) was added slowly, stirred at the same temperature for 1 hour, and then slowly added water (10 mL). Dichloromethane (60 mL) was added to the reaction mixture, which was then filtered and extracted five times with dichloromethane (10 mL). The extract was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 3: 1 mixed solvent] to give a product (265 mg, 66%).

mp. 202-203 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.74 (s, 4 H), 5.63 (s, 2 H), 4.98 (s, 2 H),

3.88 (s, 12 H), 3.83 (s, 6 H), 3.28 (s, 2 H),

3.14 (br s, 2 H),

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 153.01, 139.40, 136.71, 103.81, 100.62,

84.51, 61.12, 60.22, 56.03

IR (νmax, KBr) 3415, 3384, 1593, 1133 cm ^-1

MS m / z (relative intensity) 478 (M +), 307, 154 (base peak)

Example 7

(+)-Yangambin

3 (S), 6 (S) -bis (3,4,5-trimethoxyphenyl-5-yl) tetrahydro- 1H , 3H -furo- [3 (S), 4 (S) -c ] The solution of furan-1,4-diol (147 mg, 0.31 mmol) in dichloromethane (60 mL) was cooled to −10 ° C. under a stream of nitrogen, and triethyl silane (0.11 mL, 0.93 mmol) was added thereto. , Borontrifluoride ether (62 μL, 0.68 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at the same temperature for 2 hours, then saturated aqueous sodium carbonate solution (15 mL) was added and extracted three times with dichloromethane (10 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 1: 1 mixed solvent] to give a product (48 mg, 35%).

mp. 117-119 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.57 (s, 4 H), 4.76 (d, J = 4.3 Hz, 2 H), 4.31 (dd, J = 9.1 Hz, J = 6.9 Hz, 2 H), 3.94 (dd, J = 9.1 Hz, J = 3.6 Hz, 2 H), 3.88 (s, 12 H), 3.84 (s, 6 H), 3.11 (ddd, J = 6.9 Hz, J = 4.3 Hz, J = 3.9 Hz, 2 H)

¹³ C NMR (75.47 MHZ, CDCl ₃ ) δ 175.33, 153.25, 137.37, 102.52, 85.94, 71.97, 60.85, 56.07, 54.51

IR (νmax, KBr) 2927, 1759, 1593, 1461, 1126 cm ^-1

MS m / z (relative intensity) 446 (M +, base peak), 154, 181

[α] ²⁰ D (c = 1.0, MeOH) +104

C) Example of the process for producing jusmin

Example 8

3 (S), 6 (S) -bis (3,4-dimethoxyphenyl-5-yl) tetrahydro-1 H , 3 H Furo [3 (S), 4- (S) -c] furan-1,4-dione

A solution of 1,4-bis (4 (S) -benzyl-2-oxazolidin-3-yl) butane-1,4-dione (2.2 g, 5.0 mmol) in dichloromethane (20 mL) was prepared. After cooling to 0 ° C. under nitrogen stream, 1.0 M (in dichloromethane) dibutylboron triflate (11.0 mL, 11.0 mmol) was added over 10 minutes, and after 10 minutes diisopropylethyl amine was added to dichloromethane (5.0 mL). The solution dissolved in was added over 10 minutes. The mixture was stirred at the same temperature for 30 minutes, cooled to -78 ° C, and a solution of dimethoxybenzaldehyde (2.3 g 14.0 mmol) in dichloromethane (10 mL) was added over 10 minutes. The reaction mixture was stirred at the same temperature for 20 minutes and then stirred until it reached 0 ° C. Methanol (30 mL), saturated potassium hydrogen phosphate (20 mL), and 28% hydrogen peroxide solution (20 mL) were added sequentially to the reaction mixture, followed by vigorous stirring at room temperature for 4 hours. The reaction mixture was extracted five times with dichloromethane (40 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 1: 1 mixed solvent] to give a product (1.13 g, 65%).

mp. 203-204 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.86 (s, 4 H), 6.79 (s, 2 H), 5.89 (s, 2 H), 3.90 (s, 6 H), 3.87 (s, 6 H) , 3.57 (s, 2 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 174.96, 149.62, 130.38, 116.72, 111.39, 107.88, 81.79, 56.11, 56.03, 48.38

IR (νmax, KBr) 1780, 1490, 1242, 1045 cm ^-1

MS m / z (relative intensity) 414 (M +), 307, 154 (base peak)

[α] ²⁰ D (c = 1.0, CHCl 3) +53

Example 9

3 (S), 6 (S) -bis (3,4-dimethoxyphenyl-5-yl) tetrahydro-1 H , 3 H -Furo [3 (S), 4- (S) -c] furan-1,4-diol

3 (S), 6 (S) -bis (3,4-dimethoxyphenyl-5-yl) tetrahydro- 1H , 3H -furo [3- (S), 4 (S) -c]- A solution of furan-1,4-dione (500 mg, 1.2 mmol) dissolved in dichloromethane (20 mL) was cooled to -25 ° C. under a stream of nitrogen, followed by 1.0 M (in dichloromethane) diisobutylaluminum hydride ( 4.8 mL, 4.8 mmol) was added slowly, stirred at the same temperature for 1 hour, and then slowly added water (20 mL). Dichloromethane (120 mL) was added to the reaction mixture, which was filtered and then extracted five times with dichloromethane (20 mL). The extract was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 3: 1 mixed solvent] to give a product (300 mg, 63%).

mp. 181-182 ℃

1 H NMR (300 MHz, CDCl ₃ ) δ 7.01 (d, J = 9.8 Hz, 4 H), 6.91 (s, 2 H), 4.83 (d, J = 5.8 2 H), 3.96 (s, 6 H), 3.87 (s, 6 H), 3.10 (br s, 2 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 152.99, 137.39, 135.70, 103.80, 100.67, 84.33, 65.07, 60.00, 55.30

IR (νmax, KBr) 3345, 3301, 1245

MS m / z (relative intensity) 478 (M +), 307, 154 (base peak)

Example 10

(+)-Eudesmin

3 (S), 6 (S) -bis (3,4-dimethoxyphenyl-5-yl) tetrahydro- 1H , 3H -furo [3- (S), 4 (S) -c] furan A solution of -1,4-diol (320 mg, 0.77 mmol) in dichloromethane (150 mL) was cooled to -10 ° C under a stream of nitrogen, followed by addition of triethyl silane (0.19 mL, 1.16 mmol), and boron. Trifluoride ether (78 μL, 0.85 mmol) was added dropwise at the same temperature. The reaction mixture was stirred at the same temperature for 2 hours, then saturated aqueous sodium carbonate solution (30 mL) was added and extracted three times with dichloromethane (20 mL). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. This crude product was subjected to column chromatography [ethyl acetate: hexane = 1: 4 mixed solvent] to give a product (132 mg, 44%).

mp. 67-68.5 ℃

¹ H NMR (300 MHz, CDCl ₃ ) δ 6.91 (d, J = 2.0 Hz, 2 H), 6.88 (dd, J = 8.3 Hz, J = 2.0 Hz, 2 H), 6.84 (d, J = 8.3 Hz , 2H) 4.76 (d, J = 4.4 Hz, 2H), 4.26 (dd, J = 9.5 Hz, J = 7.3 Hz, 2H), 3.91 (dd, J = 9.5 Hz, J = 3.9 Hz, 2 H), 3.88 (s, 6 H), 3.90 (s, 6 H), 3.12 (ddd, J = 7.3 Hz, J = 4.4 Hz, J = 3.9 Hz, 2 H)

¹³ C NMR (75.47 MHz, CDCl ₃ ) δ 149.22, 148.99, 132.36, 130.12, 119.18, 109.41, 105.87, 102.28, 82.48, 48.94

IR (νmax, KBr) 1772, 1498, 1247, 1038 cm ^-1

MS m / z (relative intensity) 386, 154 (base peak), 136

[α] ²⁰ D (c = 1.0, MeOH) +84

The present invention is an easy and simple reaction process, high optical purity of (-), (+)-sesamine, (-), (+)-udesamine, (-), (+)-yanggambin in high yield As a result, excellent effects can be expected in industrial applicability.

Claims (3)

A method for producing the compound represented by the general formula (1) of the optical synthesis and its enantiomer by reducing the compound of the general formula (6) with triethylsilin-borontripulolide. Wherein R ¹ , R ² , R ³ represent the same or different hydrogen, methoxy groups or methylenedioxy groups together with adjacent groups. A method for producing the compound represented by the general formula (6) and the enantiomer thereof by reducing the compound of the general formula (5) with DIBAL (diisobutyl aluminum hydride). Wherein R 1, R 2, R 3 represent the same or different hydrogen, methoxy groups or methylenedioxy groups together with adjacent groups. Compound of general formula (4) is reacted with dialkyl boron triplate under basic conditions to obtain boron enolate, and the reaction mixture is reacted with arylaldehyde of general formula (7), acid is added and treated to general synthesis of optical synthesis. A method for producing the compound represented by Structural Formula (5) and its enantiomer.