Method for synthesizing stilbene and its intermediates

Abstract

The present invention discloses a process for preparing stilbenes, such as pterostilbene and resveratrol. More specifically, the present invention discloses the synthesis of stilbenes using novel intermediates, 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol and 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene.

Description

[Technical Field]

[0001] The present invention relates to a process 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. [Background technology]

[0002] Resveratrol and pterostilbene are both monomeric stilbenes with a 6-2-6 carbon skeleton, each containing two phenyl rings connected by a double-bond ethylene bridge. Resveratrol has three hydroxyl groups (-OH), while pterostilbene has two methoxy groups (-OCH3) and one -OH group on the aromatic ring connected by a double-bond ethylene bridge. Stilbenes exist in monomeric, dimeric, trimeric, oligomeric, and polymeric forms, or as glycosides. Stilbenes possess biological activities such as antioxidant, antidiabetic, antiobesity, cardioprotective, and neuroprotective effects. Resveratrol and pterostilbene represent two of the most well-studied monomeric stilbenes in the art.

[0003] JMC, 2002, 45 (12), 2534-2542 discloses a process for preparing pterostilbene by condensing 3,5-dimethoxybenzyltriphenylphosphonium bromide with 4-(tert-butyldimethylsilyloxy)benzaldehyde in tetrahydrofuran to produce 4'-(tert-butyldimethylsilyloxy)-3,5-dimethoxystilbene; and treating 4'-(tert-butyldimethylsilyloxy)-3,5-dimethoxystilbene with tetrabutylammonium fluoride to obtain pterostilbene.

[0004] CN 1948274 discloses a process for preparing pterostilbene by condensing 4-benzyloxybenzaldehyde with 3,5-dimethoxybenzylphosphonate in the presence of sodium hydride to produce 3,5-dimethoxy-4-benzyloxystilbene; and debenzylating 3,5-dimethoxy-4-benzyloxystilbene in the presence of aluminum chloride and N,N-dimethylaniline in dichloromethane to obtain pterostilbene.

[0005] CN 1955153 discloses a process for preparing pterostilbene by condensing 3,5-dimethoxybenzylphosphonic acid diethyl ester with hydroxybenzaldehyde methoxymethyl ether to obtain substituted 3,5-dimethoxy-4-methoxymethyloxystyrylbenzene; and treating 3,5-dimethoxy-4'-methoxymethyloxystyrylbenzene dissolved in methanol with pyridinium p-toluenesulfonate (PPTS) to obtain pterostilbene.

[0006] Indian Journal of Chemistry, Section B: 2002, 41B (11), 2395-2398, discloses a process for preparing resveratrol by treating tri-O-methyl (-OMe) resveratrol or tri-O-benzyl (-OCH2Ph) resveratrol with BBr3 in dichloromethane to produce resveratrol.

[0007] US7253324 discloses a process for preparing resveratrol by treating tri-O-methyl (OMe) resveratrol or tri-O-benzyl (OCH2Ph) resveratrol with AIC1 / N,N-dimethylaniline to obtain resveratrol.

[0008] Subbaraju et al., US 8,524,782 B2, discloses a process for preparing stilbene by (i) condensing 3,5-dialkyloxybenzylphosphonate with 4'-O-tetrahydropyranylbenzaldehyde to obtain 3,5-alkyl-4'-O-tetrahydropyranylstilbene; and (ii) subsequently deprotecting to obtain stilbene. However, this process has an insufficient yield.

[0009] The limitations of the above methods disclosed in the prior art are that they suffer from scalability, selective deprotection, use of expensive reagents and low yields.

[0010] Therefore, there remains a need in the art to provide a process that is cost-effective, industrially scalable, and involves inexpensive and readily available reagents. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] CN 1948274 [Patent Document 2] CN 1955153 [Patent Document 3] US7253324 [Non-patent literature]

[0012] [Non-Patent Document 1] JMC, 2002, 45 (12), 2534-2542 [Non-patent document 2] Indian Journal of Chemistry, Section B: 2002, 41B (11), 2395-2398 [Non-patent document 3] Subbaraju et al. US 8,524,782 B2 Summary of the Invention [Problem to be solved by the invention]

[0013] It is therefore an object of the present invention to provide a cost-effective and industrially scalable process for preparing stilbenes in desired purity and yield. [Means for solving the problem]

[0014] In accordance with the above objectives, the present invention provides a scalable process for preparing substituted stilbenes, including 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] Thus, in one aspect, the present invention provides a process for preparing a stilbene, the process comprising: (i) 4-(1-ethoxyethoxy)benzaldehyde in a reaction with a compound of Formula 3: [ka]

[0016] [In the formula, R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, aryl, and arylalkyl. and a compound represented by formula 4: [ka]

[0017] [In the formula, R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, alkyl, aryl, and arylalkyl. and (ii) Deprotecting the compound of formula 4 to give formula 5 [ka]

[0018] producing a stilbene represented by the formula: Contains:

[0019] The process according to the invention is depicted in the following scheme: [ka] DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will now be described in detail with reference to certain preferred and optional embodiments to provide a more complete understanding of its various aspects.

[0021] The present invention provides a scalable process for preparing substituted stilbenes, including 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).

[0022] Thus, in one aspect, the present invention provides a process for preparing a stilbene, the process comprising: (i) 4-(1-ethoxyethoxy)benzaldehyde in a reaction with a compound of Formula 3: [ka]

[0023] [In the formula, R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, alkyl, aryl, and arylalkyl. and a compound represented by formula 4: [ka]

[0024] [In the formula, R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, alkyl, aryl, and arylalkyl. and (ii) Deprotecting the compound of formula 4 to give formula 5 [ka]

[0025] producing a stilbene represented by the formula: Contains:

[0026] In one embodiment, the compound represented by formula 3 (benzylphosphonate) is selected from the group consisting of diethyl(3,5-dimethoxyphenyl)methylphosphonate, diethyl(3,5-dihydroxyphenyl)methylphosphonate, diethyl(3,5-diaryloxyphenyl)methylphosphonate, and diethyl(3,5-diarylalkoxyphenyl)methylphosphonate.

[0027] In another embodiment, the compound of formula 4 is (a) 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a), (b) 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b), (c) 1-(4-(1-ethoxyethoxy)styryl)-3,5-diaryloxybenzene (4c), and (d) 1-(4-(1-ethoxyethoxy)styryl)-3,5-diarylalkoxy-benzene (4d) is selected from the group consisting of:

[0028] In yet another embodiment, the compound of formula 5 is pterostilbene (R 1 and R 2 = methyl); and resveratrol (R 1 and R 2 =H);

[0029] The intermediate compound represented by the above formula 4 is an important intermediate for synthesizing stilbenes such as resveratrol and pterostilbene.

[0030] In a further embodiment, the present invention provides a compound of formula 4 [ka]

[0031] [In the formula, R 1 and R 2 independently represent hydrogen, methyl, alkyl, aryl, and arylalkyl. wherein the process comprises condensing a 3,5-dialkoxybenzyl phosphonate with 4'-O-ethyl vinyl ether benzaldehyde in the presence of a base.

[0032] In a further embodiment, the present invention provides a novel intermediate compound, namely, 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a). [ka]

[0033] [In the formula, R 1 and R 2 is hydrogen. This intermediate compound is prepared by a process comprising condensing diethyl(3,5-dihydroxyphenyl)methylphosphonate with 4'-O-ethylvinyletherbenzaldehyde in the presence of a base.

[0034] In yet another embodiment, the present invention provides a novel intermediate, namely, 1-(4-(1-ethoxyethoxy)-styryl)-3,5-dimethoxy-benzene (4b), wherein the intermediate is 1 It is characterized by spectral analysis using H NMR and mass spectrometry. 1H NMR and mass spectrometry are described below: 1 H 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 spectrum m / z: 329.2 (M+H) + . In yet another embodiment, the present invention provides 1-(4-(1-ethoxyethoxy)-styryl)-3,5-dimethoxy-benzene (4b) [ka]

[0035] [In the formula, R 1 and R 2 is methyl] wherein the process comprises condensing diethyl(3,5-dimethoxyphenyl)methylphosphonate with 4'-O-ethylvinyletherbenzaldehyde in the presence of a base.

[0036] Thus, the process for preparing stilbene involves 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 at room temperature under stirring to produce 4-(1-ethoxyethoxy)benzaldehyde, which was extracted into a suitable solvent and isolated in very good yield as an off-white solid.

[0037] Furthermore, the preparation of the novel intermediate 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b) involves reacting 4-(1-ethoxyethoxy)benzaldehyde with diethyl(3,5-dimethoxyphenyl)methylphosphonate in a polar aprotic solvent (e.g., DMF, DMSO, dioxane, etc.) in the presence of a base (e.g., NaOMe, K2CO3, LiHMDS, n-BuLi, or NaH) at room temperature with stirring for 12 hours. After completion of the reaction, the product is extracted into a suitable solvent (e.g., ethyl acetate), washed with saturated brine solution, and dried to obtain 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) as a colorless liquid. The product thus obtained, 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b), is then 1 It was characterized by 1 H NMR and mass spectrometry.

[0038] Similarly, the preparation of another novel intermediate, i.e., 5-(4-(1-ethoxyethoxy)-styryl)-benzene-1,3-diol (4a), involves reacting 4-(1-ethoxyethoxy)benzaldehyde with diethyl(3,5-dihydroxyphenyl)methylphosphonate in a polar aprotic solvent (e.g., DMF, DMSO, dioxane, etc.) in the presence of a base (e.g., NaOMe, KCO, LiHMDS, n-BuLi, or NaH) at room temperature with stirring for 12 hours. After completion of the reaction, the product was extracted into a suitable solvent (e.g., ethyl acetate), washed with saturated brine, and dried over sodium sulfate to give 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a) as a colorless liquid.

[0039] Furthermore, the preparation of 4-(3,5-dimethoxystyryl)phenol (5b, pterostilbene) involved the deprotection of 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) in the presence of pyridinium p-toluenesulfonate in an alcoholic solvent under reflux for 2 hours. The progress of the reaction was monitored by TLC, which showed the deprotection of the ethyl vinyl ether group in compound 4b. The reaction mixture was then cooled to room temperature, the volatiles were evaporated, and the product was extracted into a suitable solvent (e.g., ethyl acetate) and purified to give 4-(3,5-dimethoxystyryl)phenol (5b, pterostilbene) as an off-white solid.

[0040] In yet another embodiment, resveratrol was prepared using the above process. Here, a solution of 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a) in methanol and pyridinium p-toluenesulfonate was refluxed for 2 hours. The progress of the reaction was monitored by TLC, which showed the 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.

[0041] Therefore, the process proposed in the present invention provides stilbenes such as pterostilbene and resveratrol in good yields. Furthermore, the process 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).

[0042] The following examples, which include preferred embodiments, serve to illustrate the practice of this invention, it being understood that the details given are for illustrative purposes and for exemplary illustration of preferred embodiments of the invention. [Example]

[0043] Example 1: Preparation of 4-(1-ethoxyethoxy)benzaldehyde (2) 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, dried over sodium sulfate, and the dichloromethane was removed under reduced pressure to give 4-(1-ethoxyethoxy)benzaldehyde (2) as an off-white solid. Yield: 14.5 g (91%).

[0044] Example 2: Preparation of 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b) 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 was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 12 h, water was added, and the mixture was extracted with ethyl acetate (2 volumes), washed with saturated brine solution, and dried over sodium sulfate. The ethyl acetate was collected under reduced pressure to give 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxybenzene (4b) as a colorless liquid: 8.0 g (80%).

[0045] 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 spectrum m / z: 329.2 (M+H). Example 3: Preparation of 4-(3,5-dimethoxystyryl)phenol (pterostilbene, 5b) 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, which showed the deprotection of the ethyl vinyl ether from compound 3. The reaction mixture was cooled to room temperature, the volatiles evaporated, and treated with water. It was extracted with ethyl acetate (2 volumes), the phases separated, and the organic phase washed with aqueous sodium bicarbonate (2 volumes), followed by 3 N aqueous hydrochloric acid (2 volumes), and finally with saturated brine solution (50 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified to give 4-(3,5-dimethoxystyryl)phenol (5b) as an off-white solid. Yield: 1.9g (66%).

[0046] 1H NMR (400 MHz, CDCl3): δ 3.82 (6H, s), 4.99 (1H, bs), 6.38 (1H, t, J = 2.4 Hz), 6.64 (2H, d, J = 2.0 Hz), 6.82 (2H, d, J = 8.8 Hz), 6.89 (1H, d, J = 16.4 Hz), 7.02 (1H, d, J = 16.4 Hz), 7.39 (2H, d, J = 8.4 Hz), Mass spectrum m / z: 255 (MH) - . Example 2: Preparation of 5-(4-(1-ethoxyethoxy)-styryl)-benzene-1,3-diol (4a) Sodium methoxide (2.08 g, 38.5 mmol) was added to a stirred solution of diethyl (3,5-dihydroxyphenyl)methylphosphonate (10.03 g, 38.5 mmol) in DMF (30 mL). The reaction mixture was stirred at 0 °C for 1 h, and 4-(1-ethoxyethoxy)benzaldehyde (5.0 g, 25.7 mmol) in DMF was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 12 h, added with water, extracted with ethyl acetate (2 volumes), washed with saturated brine solution, and dried over sodium sulfate. The ethyl acetate was collected under reduced pressure to give 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a) as a colorless liquid: 5.8 g (75%).

[0047] 1 H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J = 7.2 Hz), 1.54 (3H, d, J = 5.2 Hz), 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 = 2.4 Hz), 6.55 (2H, d, J = 2.0 Hz), 6.71 (1H, d, J = 16.4 Hz), 7.05 (2H, d, J = 3.2 Hz), 7.12 (1H, d, J = 16.4 Hz), 7.33 (2H, d, J = 8.8 Hz), Mass spectrum m / z: 301.3 (M+H)+ . Example 4: Preparation of resveratrol A stirred solution of 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, which showed the deprotection of the ethyl vinyl ether from compound 3a. The reaction mixture was cooled to room temperature, the volatiles evaporated, and treated with water. It was extracted with ethyl acetate (2 volumes), the phases separated, and the organic phase washed with sodium bicarbonate solution (2 volumes), followed by 3 N aqueous HCl (2 volumes), and finally with saturated brine solution (50 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified to give resveratrol (4) as an off-white solid. Yield: 0.55g (65%).

[0048] 1 H 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 (MH) - .

Claims

1. 1. A process for preparing stilbene, comprising: (iii) 4-(1-ethoxyethoxy)benzaldehyde in the presence of a base is reacted with a compound of formula 3: 【Chemistry 1】 [In the formula, R １ and R ２ are independently selected from the group consisting of hydrogen, methyl, alkyl, aryl, and arylalkyl. and a compound represented by formula 4: 【Chemistry 2】 [In the formula, R １ and R ２ are independently selected from the group consisting of hydrogen, methyl, alkyl, aryl, and arylalkyl. and (iv) Deprotecting the compound of formula 4 to obtain a compound of formula 5 【Transformation 3】 producing a stilbene represented by the formula: The process comprising:

2. 2. The process of claim 1, wherein the compound of formula 3 (benzylphosphonate) is selected from the group consisting of diethyl(3,5-dimethoxyphenyl)methylphosphonate; diethyl(3,5-dihydroxyphenyl)methylphosphonate; diethyl(3,5-diaryloxyphenyl)methylphosphonate; and diethyl(3,5-diarylalkoxyphenyl)methylphosphonate.

3. The compound represented by formula 4 is (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); 2. The process of claim 1, wherein the hydroxyl group is selected from the group consisting of:

4. 10. The process of claim 1, wherein the base used in step (a) is sodium methoxide.

5. 2. The process of claim 1, wherein the deprotection in step (b) is carried out in the presence of pyridinium p-toluenesulfonate in an alcoholic solvent.

6. Formula 4: 【Chemistry 4】 [In the formula, R １ and R ２ is hydrogen or methyl. A compound represented by the formula:

7. below, (a) 5-(4-(1-ethoxyethoxy)styryl)-benzene-1,3-diol (4a); (b) 1-(4-(1-ethoxyethoxy)styryl)-3,5-dimethoxy-benzene (4b); 7. The compound of formula 4 according to claim 6, selected from the group consisting of:

8. Formula 4 【Transformation 5】 [In the formula, R １ and R ２ each independently represents hydrogen or methyl.

1. A process for synthesizing a compound represented by the formula:

9. 9. The process of claim 8, wherein the benzyl phosphonate is selected from the group consisting of 3,5-dimethoxybenzyl phosphonate (3b) and diethyl(3,5-dihydroxyphenyl)methyl phosphonate (3a).

10. 9. The process of claim 8, wherein the base is sodium methoxide.

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