WO2010010578A2

WO2010010578A2 - A key intermediate for the preparation of stilbenes

Info

Publication number: WO2010010578A2
Application number: PCT/IN2009/000313
Authority: WO
Inventors: Venkata Subbaraju Gottumukkala; Mahesh Masna; Rama Mohan Hindupur; Suresh Thatipally
Original assignee: Aptuit Laurus Private Limited
Priority date: 2008-07-23
Filing date: 2009-06-01
Publication date: 2010-01-28
Also published as: WO2010010578A3

Abstract

The present invention provides a scalable process for the preparation of Stilbenes by (i) condensing 3,5-dialkylbenzyl phosphonates with 4'-O-tetrahydropyranyl benzaldehyde to get 3,5-alkyl-4'-O-tetrahydropyranyl Stilbene (ii) deprotecting the obtained 3,5-Dialkyl- 4'-O-tetrahydropyranylstilbene yields Stilbenes. The present invention also provides a novel intermediate 3,5-Dialkyl-4'-O-tetrahydropyranylstilbene, which is a key intermediate for the synthesis of Stilbenes such as Pterostilbene and Resveratrol.

Description

"A key intermediate for the preparation of Stilbenes"

Field of the invention:

The present invention relates to the preparation of 3,5-Dimethoxy-4'-O- tetrahydropyranylstilbene, which is a key intermediate for the synthesis of Stilbenes such as Pterostilbene and Resveratrol.

Background of the invention:

Methods for preparing Stilbenes such as Pterostilbene and Resveratrol are known in the art. JMC, 2002, 45 (12), 2534-2542 discloses a process for preparing Pterostilbene by;

• Condensing 3,5-Dύnethoxybenzyltriphenylphosphonium bromide with 4-(tert- butyldimethylsilyloxy) benzaldehyde in tetrahydrofuran yields 4'-(tert- butyldimethyl silyloxy)-3,5-dimethoxystilbene. • Treating 4'-(tert-Butyldimethylsilyloxy)-3,5-dimethoxystilbene with tetrabutyl ammonium fluoride affords Pterostilbene

CN 1948274 discloses a process for preparing Pterostilbene by;

• Condensing 4-benzyloxybenzaldehyde with 3,5-dimethoxybenzyl phosphonate in presence of sodium hydride yields 3,5-dimethoxy-4'-benzyloxystilbene and

• Debenzylating 3,5-dimethoxy-4'-benzyloxystilbene with aluminum chloride and iVJV-dimethylaniline in dichloromethane yields Pterostilbene.

CN 1955153 discloses a process for preparing Pterostilbene by; • Condensing 3,5-Dimethoxybenzyl phosphonic acid diethyl esters with hydroxy benzaldehyde methoxymethyl ethers affords the substituted 3, 5-Dimethoxy-4'- methoxymethyloxystyrylbenzene.

• Treating 3, 5-Dimethoxy-4'- methoxymethyloxystyrylbenzene dissolved in methanol with Pyridiniump-toluene sulfonate (PPTS) yields Pterostilbene.

Indian Journal of Chemistry, Section B: 2002, 41B (11), 2395-2398 discloses a process for preparing Resveratrol by;

• Treating Tri-O-methyl(-OMe) or tri-0-benzyl (-OCH₂Ph) Resveratrol with BBr₃ in CH₂Cl₂ yields Resveratrol. US 7,253,324 discloses a process for preparing Resveratrol by;

• Treating Tri-O-methyl(-OMe) or tri-O-benzyl (-OCH₂Ph) Resveratrol with AICI₃/N, iV-dimethylaniline yields Resveratrol. The limitations of the above methods are scalability and difficulty in selective deprotection to prepare Pterostilbene and use of expensive reagents for protection and/or low yields obtained in the process. So there is a need of the industry to have a process that is scalable and without using expensive reagents.

According to the present invention there is provided a convenient process for the preparation of Stilbene with desired purity and yield by using a novel intermediate 3 ,5-Dialkyl-4 ' -0-tetrahydropyranylstilbene.

Summary of the invention:

The main object of the present invention is to provide a process to prepare Stilbenes.

Another object of the present invention is to provide a process for the preparation of Stilbenes by deprotection 3,5-Dialkyl-4'-O-tetrahydropyranylstilbene of formula 1,

Wherein R¹ & R² independently represent hydrogen, lower alkyl or aralkyl.

Another object of the present invention is to provide a process for the preparation of 3,5- Dialkyl-4 ' -O-tetrahydropyranylstilbene . Detailed description of the invention:

Thus in accordance with the present invention preparation of Stilbenes comprising the steps of:

• condensing 3,5-dialkylbenzyl phosphonates with 4'-O-tetrahydropyranyl benzaldehyde to get 3,5-dialkyl-4'-O-tetrahydropyranyl Stilbene • deprotecting the obtained 3,5-Dialkyl-4'-O-tetrahydropyranylstilbene yields

Stilbene The reaction steps are illustrated in scheme- 1.

Scheme 1

Wherein R¹ & R independently represent hydrogen, lower alkyl or aralkyl.

The process as described above wherein the preferable Stilbenes are Pterostilbene and Resveratrol.

Condensation of 3,5-dialkylbenzyl phosphonates with 4'-O-tetrahydropyranyl benzaldehyde is carried out in presence of a base, preferably sodium hydride at a temperature ranging from room temperature to reflux temperature of the solvent used.

Deprotection of the above obtained compound i.e. 3,5-Dialkyl-4'-O-tetrahydro pyranylstilbene is carried out in presence of a suitable deprotecting agent selecting from PPTS, aluminum chloride, N,N-dimethylaniline and mixtures thereof. In a specific embodiment of the present invention 3,5-Dialkyl-4'-O- tetrahydropyranylstilbene is found to be novel and it can be a key intermediate for the preparation of Stilbenes, preferably Pterostilbene and Resveratrol.

In another embodiment of the present invention 3,5-Dialkyl-4'-O- tetrahydropyranylstilbene is prepared by; • condensing 3,5-dialkylbenzyl phosphonates with 4'-O-tetrahydropyranyl benzaldehyde to get 3,5-alkyl-4'-O-tetrahydropyranyl Stilbene

The process as described above wherein the condensation is carried in presence of a base, wherein the preferred base is sodium hydride. And the reaction is carried out in a solvent preferably tetrahydrofuran. In another embodiment of the present invention Pterostilbene can be prepared by deprotecting the 3,5-Dimethoxy-4'-O-tetrahydropyranylstilbene using pyridinium p-toluene sulfonate (PPTS) in an alcoholic solvent, preferably methanol. The reaction is carried out at room temperature to reflux temperature of the solvent used. In another embodiment of the present invention Resveratrol can be prepared by deprotecting the 3,5-Dimethoxy-4'-O-tetrahydropyranylstilbene using Aluminum chloride and N,iV-Dimethylaniline in an organic solvent, preferably toluene. The reaction is carried out at room temperature to reflux temperature of the solvent used. Examples:

The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results. Example-1: Synthesis of Pterostilbene:

Step-1.1:

To the sodium hydride (1.66 g, 0.0694 mol) suspension in tetrahydrofuran (40 ml) at O⁰C was added diethyl-3,5-dimethoxy benzyl phosphonate (10 g, 0.0347 mol) and resulting dark solution was stirred under nitrogen at room temperature for 30 min. A solution of 4'-O-tetrahydropyranyl benzaldehyde (7.84 g, 0.0381 mol) , in tetrahydrofuran (20 ml) was added at 18-2O⁰C and the mixture stirred at room temperature for about 2-3 hours. After completing the reaction added methanol (10 ml) drop wise at 0-5⁰C, resulting solution was poured into ice-water and extracted with ethyl acetate (50 ml). Organic layer washed with water (10 ml) and dried over sodium sulfate and removed ethyl acetate under reduced pressure at 4O⁰C to obtain semi solid and which on treating with methanol given pure solid compound (8.2 g, purity by HPLC 98.4%).

Step-1.2:

To a solution of 3,5-Dimethoxy-4'-O-tetrahydropyranylstilbene (10 g, 0.0294 mol) in methanol (50 ml) at RT was added PPTS (0.369 g, 0.264 mol) under stirring and contents were heated under reflux for 1 h. After completion of the reaction, solvent was distilled off under reduced pressure to get residue. The residue was dissolved in ethyl acetate and treated with 5% HCl, then with 5% NaHCθ₃, finally with water and separated organic phase. Removal of solvent in vacuo from the organic phase yielded the crude Pterostilbene, which was purified further by washing with 10% ethyl acetate and hexanes (10 ml) to get pure Pterostilbene (5.5- 6.7 g, purity by HPLC 99%).

Example-2: Synthesis of Resveratrol: Step-2.1:

To the sodium hydride (1.66 g, 0.0694 mol) suspension in tetrahydrofuran (40 ml) at O⁰C was added diethyl-3,5-dimethoxy benzyl phosphonate (10 g, 0.0347 mol) and resulting dark solution was stirred under nitrogen at room temperature for 30 min. A solution of 4'-O-tetrahydropyranyl benzaldehyde (7.84 g, 0.0381 mol) in tetrahydrofuran (20 ml) was added at 18-2O⁰C and the mixture stirred at room temperature for about 2-3 hours. After completing the reaction added methanol (10 ml) drop wise at 0-5⁰C, resulting solution was poured into ice-water and extracted with ethyl acetate (50 ml). Organic layer washed with water (10 ml) and dried over sodium sulfate and removed ethyl acetate under reduced pressure at 4O⁰C to obtain semi solid and which on treating with methanol given pure solid compound ( 8.2 g, purity by HPLC 98.4%).

Step-2.2: To a solution of Λ^-Dimethylaniline (32 g, 0.264 mol) in 500 ml RB flask at RT, was added slowly Aluminum chloride (35.2 g, 0.264 mol) under stirring, over a period of 15 min. The temperature of the reaction rose to 7O⁰C during the addition and toluene (50 ml) was added after 30 min and heated to 8O⁰C for another 30 min. To the reaction mixture at 80⁰C, was added drop wise, 3,5-Dimethoxy-4'-O-tetrahydropyranylstilbene (10 g, 0.0294 mol) in toluene (50 ml) under stirring and the contents were heated under reflux for further 3 h. After completion of the reaction, the contents were cooled to room temperature and the solvent was decanted. The residue was treated with dil.HCl (30 ml) and extracted the product into ethyl acetate (2 x 50 ml), solvent was distilled off under reduced pressure to obtain crude Resveratrol which was purified further by washing with dichloromethane (10 ml) to get pure Resveratrol (4.7- 6.0 gm, purity by HPLC 99%).

Claims

We claim;

1. A compound of the formula 1

Wherein R¹ & R² independently represent hydrogen, lower alkyl or aralkyl

2. A process for the preparation of compound of the formula 1, by condensing 3,5- Dialkylbenzyl phosphonates with 4'-O-tetrahydropyranyl benzaldehyde in presence of a base.

3. The process as claimed in claim 2, wherein the preferable base is sodium hydride 4. A process for the preparation of Stilbene of general formula 2,

Wherein R¹ & R² independently represent hydrogen, lower alkyl or aralkyl, Comprising the steps of;

• condensing Dialkylbenzyl phosphonates with 4'-O-tetrahydropyranyl benzaldehyde to get 3,5-alkyl-4'-O-tetrahydropyranyl Stilbene

• deprotecting the obtained 3,

5-Dialkyl-4'-O-tetrahydropyranylstilbene yields Stilbene 5. The process as claimed in claim 4, wherein the Stilbene is Pterostilbene.

6. The process as claimed in claim 4, wherein the Stilbene is Resveratrol.

7. A process for the preparation of Pterostilbene comprising the steps of;

• condensing 3,5-dimethoxybenzyl phosphonic acid diethyl ester with 4'-O- tetrahydropyranyl benzaldehyde to get 3,5-dimethoxy-4'-O- tetrahydropyranyl Stilbene • deprotecting the obtained 3,5-Dimethoxy-4'-O-tetrahydropyranylstilbene yields Pterostilbene

8. The process as claimed in claim 7, wherein the deprotection is carried out using Pyridinium p-toluene sulphonate.

9. A process for the preparation of Resveratrol, comprising the steps of; • condensing 3,5-dimethoxybenzyl phosphonic acid diethyl ester with 4'-O- tetrahydropyranyl benzaldehyde to get 3,5-dimethoxy-4'-O- tetrahydropyranyl Stilbene

• deprotecting the obtained 3,5-Dimethoxy-4'-O-tetrahydropyranylstilbene yields Resveratrol 10. The process as claimed in claim 9, wherein the deprotection is carried out using

Aluminum chloride and N,N- dimethylaniline.