Method for synthesizing stilbene and intermediate thereof

Abstract

The invention discloses a preparation method of stilbene such as pterostilbene and resveratrol. More particularly, the present invention discloses the synthesis of stilbene using the new intermediates 5-(4-(1-ethoxyethoxy) styryl)-benzene 1, 3 diol and 1-(4-(1-ethoxyethoxy) styryl)-3, 5-dimethoxy-benzene.

Description

Field of the Invention:

[0001] The present invention relates to a method for preparing stilbenes such as pterostilbene and resveratrol. More particularly, the present invention relates to the synthesis of stilbenes using novel intermediates, namely 5-(4-(1-ethoxyethoxy)styryl)benzene-1,3-diol and 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene.

[0002] Background and Prior Art:

[0003] Both resveratrol and pterostilbene are monomeric stilbenes having a 6-2-6 carbon skeleton, which contains two benzene rings connected by a double bond ethylene bridge. On the aromatic rings connected by the double bond ethylene bridge, resveratrol has three hydroxyl groups (-OH), while pterostilbene has two methoxy groups (-OCH3) and one -OH group. Stilbenes exist in the form of monomers, dimers, trimers, oligomers, and polymers, or as glycosides. Stilbenes have biological activities such as antioxidant, antidiabetic, anti-obesity, cardioprotective, and neuroprotective. Resveratrol and pterostilbene are two monomeric stilbenes that have been well studied in the art.

[0004] JMC, 2002, 45 (12), 2534-2542 discloses a method for preparing pterostilbene by condensing 3,5-dimethoxybenzyltriphenylphosphonium bromide with 4-(tert-butyldimethylsilyloxy)benzaldehyde in tetrahydrofuran to obtain 4'-(tert-butyldimethylsilyloxy)-3,5-dimethoxystilbene; and treating 4'-(tert-butyldimethylsilyloxy)-3,5-dimethoxystilbene with tetrabutylammonium fluoride to obtain pterostilbene.

[0005] CN1948274 discloses a method for preparing pterostilbene by condensing 4-benzyloxybenzaldehyde with 3,5-dimethoxybenzyl phosphonate in the presence of sodium hydride to obtain 3,5-dimethoxy-4-benzyloxystilbene; and debenzylating 3,5-dimethoxy-4-benzyloxystilbene in dichloromethane in the presence of aluminum chloride and N,N-dimethylaniline to obtain pterostilbene.

[0006] CN 1955153 discloses a method for preparing pterostilbene by condensing diethyl 3,5-dimethoxybenzylphosphonate with hydroxyphenylaldehyde methoxymethyl ether to obtain a substituted 3,5-dimethoxy-4-methoxymethoxystyrylbenzene; and treating 3,5-dimethoxy-4'-methoxymethoxystyrylbenzene dissolved in methanol with pyridinium p-toluenesulfonate (PPTS) to obtain pterostilbene.

[0007] Indian Journal of Chemistry, Section B: 2002, 41B(11), 2395 - 2398 discloses a method for preparing resveratrol as follows: treating tri - O - methyl (-OMe) or tri - O - benzyl (-OCH2Ph) resveratrol with BBr3 in dichloromethane to obtain resveratrol.

[0008] US 7253324 discloses a method for preparing resveratrol as follows: treating tri - O - methyl (-OMe) or tri - O - benzyl (-OCH2Ph) resveratrol with AIC1 / N,N - dimethylaniline to obtain resveratrol.

[0009] US 8,524,782 B2 by Subbaraju et al. discloses a method for preparing stilbene as follows: (i) condensing 3,5 - dialkyloxybenzyl phosphonate with 4’ - O - tetrahydropyranylbenzaldehyde to obtain 3,5 - alkyl - 4’ - O - tetrahydropyranyl stilbene, and (ii) then deprotecting to obtain stilbene. However, the yield of this method is low.

[0010] The limitations of the above - mentioned methods disclosed in the prior art are scalability, selective deprotection, use of expensive reagents, and low yield.

[0011] Therefore, there is still a need in the art to provide cost - effective, industrially scalable methods with cheaper and readily available reagents.

[0012] Accordingly, an object of the present invention is to provide a cost - effective and industrially scalable method for preparing stilbene with the desired purity and yield. Summary of the Invention:

[0014] To achieve the above object, the present invention provides a scalable method for preparing substituted stilbene, the method involving novel intermediate compounds, namely 5 - (4 - (1 - ethoxyethoxy)styryl)benzene - 1,3 - diol (4a) and 1 - (4 - (1 - ethoxyethoxy)styryl)-3,5 - dimethoxy - benzene (4b).

[0015] Accordingly, on the one hand, the present invention provides a method for preparing stilbene, which comprises:

[0016] (i) condensing 4 - (1 - ethoxyethoxy)benzaldehyde with a compound of formula 3;

[0017]

[0018] wherein R 1 and R 2 are each independently selected from hydrogen, methyl, aryl, and aralkyl to obtain a compound of formula 4; and

[0019]

[0020] wherein R1 and R 2 are each independently selected from hydrogen, methyl, alkyl, aryl, and aralkyl,

[0021] (ii) Deprotecting the compound of Formula 4 to obtain the stilbene of Formula 5

[0022]

[0023] 5a) R 1 & R 2 = H = resveratrol

[0024] 5b) R 1 & R 2 = methyl = pterostilbene

[0025] 5c & 5d) R 1 & R 2 = aryl, aralkyl.

[0026] The method of the present invention is shown as follows:

[0027] DETAILED DESCRIPTION OF THE INVENTION:

[0029] The present invention will now be described in detail in connection with certain preferred and optional embodiments so that various aspects of the present invention can be more fully understood and appreciated.

[0030] The present invention provides a scalable method for preparing substituted stilbenes, which involves novel intermediates, namely 5-(4-(1-ethoxyethoxy)styryl)benzene-1,3-diol (4a) and 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b).

[0031] Thus, in one aspect, the present invention provides a method for preparing stilbenes, which comprises:

[0032] (i) Condensing 4-(1-ethoxyethoxy)benzaldehyde with a compound of Formula 3;

[0033]

[0034] wherein R 1 and R 2 are each independently selected from hydrogen, methyl, alkyl, aryl, and aralkyl, to obtain a compound of Formula 4; and

[0035]

[0036] wherein R 1 and R 2 are each independently selected from hydrogen, methyl, alkyl, aryl, and aralkyl,

[0037] (ii) Deprotect the compound of Formula 4 to obtain the stilbene of Formula 5,

[0038]

[0039] 5a) R 1 & R 2 = H = resveratrol

[0040] 5b) R 1 & R 2 = methyl = pterostilbene

[0041] 5c & 5d) R 1 & R 2 = aryl, aralkyl.

[0042] In one aspect, the compound of Formula 3 (benzylphosphonate) is selected from diethyl (3,5 - dimethoxyphenyl)methylphosphonate; diethyl (3,5 - dihydroxyphenyl)methylphosphonate; diethyl (3,5 - diaryloxyphenyl)methylphosphonate and diethyl (3,5 - diarylalkoxyphenyl)methylphosphonate.

[0043] In another aspect, the compound of Formula (4) is selected from:

[0044] a) 5 - (4 - (1 - ethoxyethoxy)styryl) - benzene - 1,3 - diol (4a)

[0045] b) 1 - (4 - (1 - ethoxyethoxy)styryl) - 3,5 - dimethoxybenzene (4b)

[0046] c) 1 - (4 - (1 - ethoxyethoxy)styryl) - 3,5 - diaryloxybenzene (4c) and

[0047] d) 1 - (4 - (1 - ethoxyethoxy)styryl) - 3,5 - diarylalkoxy - benzene (4d).

[0048] In yet another aspect, the compound of Formula 5 is selected from pterostilbene (when R 1 and R 2 = methyl); and resveratrol (when R 1 and R 2 = H).

[0049] The above intermediate compound of Formula (4) is a key intermediate for the synthesis of stilbenes (e.g., resveratrol and pterostilbene).

[0050] In additional embodiments, the present invention provides a method for synthesizing a compound of Formula 4, the method comprising the step of condensing a 3,5 - dialkoxybenzylphosphonate with 4’ - O - ethylvinyl ether benzaldehyde in the presence of a base,

[0051]

[0052] wherein R 1 and R 2 independently represent hydrogen, methyl, alkyl, aryl, and aralkyl.

[0053] In a further embodiment, the present invention provides a new intermediate compound, namely 5-(4-(1-ethoxyethoxy)styryl)-benzene 1,3-diol (4a). This intermediate compound is prepared by a method comprising the steps of: condensing diethyl (3,5-dihydroxyphenyl)methylphosphonate with 4'-O-ethyl vinyl ether benzaldehyde in the presence of a base,

[0054]

[0055] wherein R 1 and R 2 are hydrogen.

[0056] In yet another embodiment, the present invention provides a new intermediate, namely 1-(4-(1-ethoxyethoxy)-styryl)-3,5-dimethoxy-benzene (4b), which is characterized by spectroscopic analysis by 1 1H NMR and mass spectrometry as described below.

[0057] 1 1H NMR (400 MHz, CDCl3): δ 1.21 (3H, t, J = 7.2 Hz), 1.51 (3H, d, J = 5.2 Hz), 3.57 - 3.53 (1H, m), 3.81 - 3.70 (1H, m), 3.82 (6H, s), 5.42 - 5.38 (1H, m), 6.37 (1H, t, J = 2.4 Hz), 6.65 (2H, d, J = 2.0 Hz), 6.91 (1H, d, J = 16.4 Hz), 7.00 (2H, d, J = 3.2 Hz), 7.02 (1H, d, J = 16.4 Hz), 7.43 (2H, d, J = 8.8 Hz); mass spectrometry m / z: 329.2 (M+H) + .

[0058] In another embodiment, the present invention provides a method for preparing 1-(4-(1-ethoxyethoxy)-styryl)-3,5-dimethoxy-benzene (4b), the method comprising: the step of condensing diethyl (3,5-dimethoxyphenyl)methylphosphonate with 4'-O-ethyl vinyl ether benzaldehyde in the presence of a base,

[0059]

[0060] wherein R 1 and R 2 are methyl.

[0061] Therefore, the preparation method of stilbene includes the preparation of 4-(1-ethoxyethoxy)benzaldehyde (2), which is prepared by reacting 4-hydroxybenzaldehyde and pyridinium p-toluenesulfonate in a suitable solvent with ethyl vinyl ether under stirring at room temperature to obtain 4-(1-ethoxyethoxy)benzaldehyde. The compound is extracted into a suitable solvent and isolated as an off-white solid in very good yield.

[0062] In addition, the preparation of the new intermediate 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b) involves reacting 4-(1-ethoxyethoxy)benzaldehyde with diethyl (3,5-dimethoxyphenyl)methylphosphonate in the presence of a base (such as NaOMe, K2CO3, LiHMDS, n-BuLi or NaH), in a polar aprotic solvent (such as DMF, DMSO, dioxane, etc.), under stirring at room temperature for 12 hours. After the reaction is completed, the product is extracted into a suitable solvent (such as ethyl acetate), washed with a saturated saline solution and dried to obtain 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) as a colorless liquid. Subsequently, the obtained product 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) is characterized by 1 HNMR and mass spectrometry.

[0063] Similarly, the preparation of another new intermediate, namely 5-(4-(1-ethoxyethoxy)-styryl)-benzene-1,3-diol (4a), involves reacting 4-(1-ethoxyethoxy)benzaldehyde with diethyl (3,5-dihydroxyphenyl)methylphosphonate in the presence of a base (such as NaOMe, K2CO3, LiHMDS, n-BuLi or NaH), in a polar aprotic solvent (such as DMF, DMSO, dioxane, etc.), under stirring at room temperature for 12 hours. After the reaction is completed, the product is extracted into a suitable solvent (such as ethyl acetate), washed with a saturated saline solution, and dried over sodium sulfate to obtain 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a) as a colorless liquid.

[0064] In addition, the preparation of 4-(3,5-dimethoxystyryl)phenol (5b, pterostilbene) involves the deprotection of 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) by refluxing in an alcohol solvent in the presence of pyridinium p-toluenesulfonate for 2 hours. The reaction progress is monitored by TLC, indicating the deprotection of the ethyl vinyl ether group in compound 4b. Subsequently, the reaction mixture is cooled to room temperature; the volatiles are evaporated, and the product is extracted into a suitable solvent (such as ethyl acetate) and purified to obtain 4-(3,5-dimethoxystyryl)phenol (5b, pterostilbene) as an off-white solid.

[0065] In another embodiment, resveratrol was prepared by the above method, wherein a solution of 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a) in methanol was refluxed with pyridinium p-toluenesulfonate for 2 hours. The reaction progress was monitored by TLC, showing deprotection of the ethyl vinyl ether group from compound 4a. The reaction mixture was cooled to room temperature, and the product was extracted into a suitable solvent (e.g., ethyl acetate) and purified to give resveratrol (5a) as an off-white solid.

[0066] Accordingly, the method proposed by the present invention gives stilbenes, such as pterostilbene and resveratrol, in good yields. In addition, the method proceeds via novel intermediates, such as 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a) and 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b).

[0067] The following examples, including preferred embodiments, will be used to illustrate the practice of the present invention. It should be understood that the details shown are by way of example only and are used to discuss the preferred embodiments of the present invention illustratively.

[0068] Example 1: Preparation of 4-(1-ethoxyethoxy)benzaldehyde (2)

[0069] Ethyl vinyl ether (17.71 g, 245.6 mmol) was added to a stirred solution of 4-hydroxybenzaldehyde (10.0 g, 81.8 mmol) and pyridinium p-toluenesulfonate (2.06 g, 8.18 mmol) in dichloromethane (1.0 L). The reaction mixture was stirred at room temperature for 12 hours. It was treated with water and extracted with dichloromethane (2 volumes). The organic phase was washed with saturated brine solution and dried over sodium sulfate, and dichloromethane was recovered under reduced pressure to give 4-(1-ethoxyethoxy)benzaldehyde (2) as an off-white solid. Yield: 14.5 g (91%).

[0070] Example 2: Preparation of 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b)

[0071] Sodium methoxide (2.49 g, 46.2 mmol) was added to a stirred solution of diethyl (3,5-dimethoxyphenyl)methylphosphonate (13.34 g, 46.2 mmol) in DMF (30 mL). The reaction mixture was stirred at 0 °C for 1 h, and 4-(1-ethoxyethoxy)benzaldehyde (6.0 g, 30.8 mmol) in DMF solution was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h, water was added, and it was extracted with ethyl acetate (2 volumes), washed with saturated brine solution, and dried over sodium sulfate. Ethyl acetate was recovered under reduced pressure to give 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) as a colorless liquid: 8.0 g (80%).

[0072] 1 HNMR (400 MHz, CDCl3): δ 1.21 (3H, t, J = 7.2 Hz), 1.51 (3H, d, J = 5.2 Hz), 3.57 - 3.53 (1H, m), 3.81 - 3.70 (1H, m), 3.82 (6H, s), 5.42 - 5.38 (1H, m), 6.37 (1H, t, J = 2.4 Hz), 6.65 (2H, d, J = 2.0 Hz), 6.91 (1H, d, J = 16.4 Hz), 7.00 (2H, d, J = 3.2 Hz), 7.02 (1H, d, J = 16.4 Hz), 7.43 (2H, d, J = 8.8 Hz), mass spectrum m / z: 329.2 (M + H).

[0073] Example 3: Preparation of 4-(3,5-dimethoxystyryl)phenol (stilbenoid, 5b)

[0074] A stirred solution of 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) (3.2 g, 9.74 mmol) and pyridinium p-toluenesulfonate (0.49 g, 1.94 mmol) in MeOH (32 mL) was refluxed for 2 h. The progress of the reaction was monitored by TLC, showing the deprotection of ethyl vinyl ether from compound 3. The reaction mixture was cooled to room temperature, the volatiles were evaporated and the residue was treated with water. It was extracted with ethyl acetate (2 volumes), the phases were separated and the organic phase was washed with sodium bicarbonate solution (2 volumes), then with 3N aqueous HCl solution (2 volumes), and finally with saturated brine solution (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified to give 4-(3,5-dimethoxystyryl)phenol (5b) as an off-white solid. Yield: 1.9 g (66%).

[0075] 1HNMR(400MHz, CDCl3): δ 3.82(6H, s), 4.99(1H, bs), 6.38(1H, t, J = 2.4Hz), 6.64(2H, d, J = 2.0Hz), 6.82(2H, d, J = 8.8Hz), 6.89(1H, d, J = 16.4Hz), 7.02(1H, d, J = 16.4Hz), 7.39(2H, d, J = 8.4Hz), Mass spectrum m / z: 255(M - H) - .

[0076] Example 2: Preparation of 5-(4-(1 - ethoxyethoxy)-styryl)-benzene - 1,3 - diol (4a)

[0077] To a stirred solution of diethyl (3,5 - dihydroxyphenyl)methylphosphonate (10.03 g, 38.5 mmol) in DMF (30 mL) was added sodium methoxide (2.08 g, 38.5 mmol). The reaction mixture was stirred at 0 °C for 1 hour and 4-(1 - ethoxyethoxy)benzaldehyde (5.0 g, 25.7 mmol) in DMF solution was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 hours, water was added, and the mixture was extracted with ethyl acetate (2 volumes), washed with saturated brine solution, and dried over sodium sulfate. Ethyl acetate was recovered under reduced pressure to give 5-(4-(1 - ethoxyethoxy)styryl)-benzene - 1,3 - diol (4a) as a colorless liquid: 5.8 g (75%).

[0078] 1 HNMR(400MHz, CDCl3): δ 1.23(3H, t, J = 7.2Hz), 1.54(3H, d, J = 5.2Hz), 3.47 - 3.43(1H, m), 3.61 - 3.54(1H, m), 5.01(2H, bs), 5.42 - 5.38(1H, m), 6.27(1H, t, J = 2.4Hz), 6.55(2H, d, J = 2.0Hz), 6.71(1H, d, J = 16.4Hz), 7.05(2H, d, J = 3.2Hz), 7.12(1H, d, J = 16.4Hz), 7.33(2H, d, J = 8.8Hz), Mass spectrum m / z: 301.3(M + H) + .

[0079] Example 4: Preparation of Resveratrol

[0080] A solution of stirred 5-(4-(1-ethoxyethoxy)-styryl)-benzene-1,3-diol (4a) (1.0 g, 3.33 mmol) and pyridinium p-toluenesulfonate (0.167 g, 0.66 mmol) in MeOH (10 mL) was refluxed for 2 h. The progress of the reaction was monitored by TLC, showing the deprotection of ethyl vinyl ether from compound 3a. The reaction mixture was cooled to room temperature, the volatiles were evaporated and the residue was treated with water. It was extracted with ethyl acetate (2 volumes), the phases were separated and the organic phase was washed with sodium bicarbonate solution (2 volumes), then with 3N aqueous HCl solution (2 volumes) and finally with saturated brine solution (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified to give resveratrol (4) as an off-white solid. Yield: 0.55 g (65%). 1 1H NMR (400 MHz, CDCl3): δ 4.99 (1H, bs), 5.01 (2H, bs), 6.32 (1H, t, J = 2.4 Hz), 6.68 (2H, d, J = 2.0 Hz), 6.72 (2H, d, J = 8.8 Hz), 6.81 (1H, d, J = 16.4 Hz), 7.00 (1H, d, J = 16.4 Hz), 7.31 (2H, d, J = 8.4 Hz), mass spectrum m / z: 227.2 (M-H) - 。

Claims

1. Method for preparing stilbene, which comprises: (iii) Condensing 4-(1-ethoxyethoxy)benzaldehyde with a compound of formula 3 in the presence of a base; wherein R 1 and R 2 are each independently selected from hydrogen, methyl, alkyl, aryl and aralkyl, To obtain a compound of formula 4; and wherein R 1 and R 2 are each independently selected from hydrogen, methyl, alkyl, aryl and aralkyl, (iv) Deprotecting the compound of formula 4 to obtain stilbene of formula 5, 5a)R 1 &R 2 = H = Resveratrol 5b)R 1 &R 2 = methyl = pterostilbene 5c&5d)R 1 &R 2 = aryl, aralkyl.

2. The method according to claim 1, wherein, The compound of formula 3 (benzylphosphonate) is selected from diethyl (3,5-dimethoxyphenyl)methylphosphonate; diethyl (3,5-dihydroxyphenyl)methylphosphonate; diethyl (3,5-diaryloxyphenyl)methylphosphonate and diethyl (3,5-diarylalkoxyphenyl)methylphosphonate.

3. The method according to claim 1, wherein The compound of formula (4) is selected from: a) 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a); b) 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b); c) 1-(4-(1-ethoxyethoxy)styryl)-3,5-diaryloxy-benzene (4c); and d) 1-(4-(1-ethoxyethoxy)styryl)-3,5-diarylalkoxy-benzene (4d).

4. The method according to claim 1, wherein, The base used in step a) is sodium methoxide.

5. The method according to claim 1, wherein the deprotection in step b) is carried out in an alcohol solvent in the presence of pyridinium p-toluenesulfonate.

6. Compound of formula 4, where R 1 and R 2 are hydrogen or methyl groups.

7. The compound of formula 4 according to claim 6, which is selected from: a) 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a); b) 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b).

8. Method for synthesizing a compound of formula 4, which method comprises the step of condensing a benzylphosphonate of formula 3 with 4'-O-ethylvinyl ether benzaldehyde (2) in the presence of a base, wherein R 1 and R 2 each independently represents hydrogen or methyl.

9. The method according to claim 8, wherein The benzylphosphonate is selected from 3,5-dimethoxybenzylphosphonate (3b) and diethyl (3,5-dihydroxyphenyl)methylphosphonate (3a).

10. The method according to claim 8, wherein the base is sodium methoxide.

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