Preparation method of pterostilbene

Abstract

The invention relates to a preparation method of a natural product pterostilbene. The method comprises the following steps: (1) carrying out bromination reaction on a compound 1 (the chemical name is 3, 5-dimethoxybenzyl alcohol) to obtain an intermediate compound 2; (2) reacting the compound 2 with triethyl phosphite to obtain an intermediate compound 3; (3) reacting the compound 4 (the chemical name is 4-hydroxybenzaldehyde) with a corresponding protecting group to obtain a compound 5; (5) obtaining pterostilbene 6 from the compound 3 and a compound 5 under the action of strong base; the process route provided by the invention has the advantages of cheap and easily available raw materials, short reaction route, simple operation, high yield, no use of a heavy metal catalyst, and suitableness for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical manufacturing, and in particular to a method for preparing pterostilbene. Background Art

[0002] Pterostilbene (English name: Pterostilbene) belongs to the polyhydroxystilbene class of compounds and is a homologue of resveratrol. It has rich medicinal value and can be anti-cancer, anti-inflammatory, and antioxidant, especially in the treatment and protection of skin diseases. In addition, in terms of pharmacological effects, pterostilbene is partially similar to resveratrol and also has strong antifungal activity. Its chemical name is (E)-4-[2-(3,5-dimethoxyphenyl)-vinyl]-phenol, CAS registration number: 537-42-8, and the structural formula is as follows:

[0003]

[0004] The main synthetic routes of pterostilbene reported so far are as follows. The first route is shown in Scheme 1: 3,5-dimethoxybenzyl bromide and 4-hydroxybenzaldehyde are used as raw materials to prepare phosphonate and protect phenolic hydroxyl groups, respectively, and then the diphenylethylene skeleton is constructed by Horner-Wadsworth-Emmons reaction, and finally the target product pterostilbene is obtained by hydrolysis with hydrochloric acid.

[0005]

[0006] The above route obtains the final product through four reactions. However, in the last step of removing the protecting group, pterostilbene is easily polymerized under acidic conditions, resulting in a very low final yield, which is not suitable for industrial production. In addition, when the protecting group is methoxymethyl, the highly toxic carcinogenic substance chloromethyl methyl ether is required, which poses a safety problem.

[0007] The second route is shown in Scheme 2: 4-hydroxybenzaldehyde is used as the raw material, and 4-acetoxybenzaldehyde is generated through acetylation reaction; then 4-acetoxystyrene is generated through Wittig reaction; then 4-hydroxystyrene is hydrolyzed; finally, the target product pterostilbene is obtained through Heck reaction.

[0008]

[0009] The above route obtains the final product through four steps of reaction, but the last step requires the reaction conditions to be oxygen-free. There are also problems such as poor enantioselectivity and the generation of triphenylphosphine oxide impurities that are difficult to remove, which makes the product difficult to purify. In addition, palladium acetate is used in this step, which increases the risk of heavy metal residues in the final product. Enterprises need to remove palladium, detect palladium residues, and include palladium element detection in the quality standards of finished products, which increases production costs. Therefore, this route is not suitable for industrial production.

[0010] The third route is shown in Scheme 3: 3,5-dimethoxybenzaldehyde and 4-nitrotoluene are used as raw materials, and 3,5-dimethoxy-4'-nitrostilbene is generated by Wittig reaction, and then reduced to obtain 3,5-dimethoxy-4'-aminostilbene, and finally hydrolyzed by diazotization reaction to obtain the target product pterostilbene.

[0011]

[0012] The above route obtains the final product through three steps of reaction, but the second step uses the explosive chemical hydrazine hydrate, which has high toxicity and strong corrosiveness. The conditions of the last step, diazotization, are relatively stringent and the yield is very low. The target product can only be obtained through column chromatography, resulting in high production costs and is not suitable for industrial production. Summary of the invention

[0013] In order to overcome the shortcomings of the above technical route, the present invention provides a new method for synthesizing pterostilbene, in which the hydroxyl group is protected by tert-butyloxycarbonyl or dimethylaminoformyl, and the protective group is removed while the diphenylethylene skeleton is constructed by Horner-Wadsworth-Emmons reaction with phosphonate. The purpose is to use relatively readily available raw materials to provide a synthetic route that is simple to operate, cheap and readily available raw materials, does not require heavy metal removal detection, has high enantioselectivity, and is suitable for industrial production:

[0014]

[0015] The following steps are involved:

[0016] S1: Synthesis of compound 2

[0017] Dissolve compound 1 in an organic solvent, slowly add a bromination reagent at 0°C, then stir and react within a certain temperature range, perform TLC detection until compound 1 reacts completely, slowly add the reaction solution into ice water at 0°C, add an organic solvent for separation and extraction 3 times, dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to remove the solvent to obtain compound 2;

[0018] The bromination reagent used is one or more of phosphorus tribromide, phosphorus pentabromide, hydrogen bromide, and N-bromosuccinimide, preferably phosphorus tribromide; the molar ratio of compound 1 to phosphorus tribromide is 1.00:0.40-1.02, and the preferred molar ratio of compound 1 to phosphorus tribromide is 1.00:0.40-0.50; the reaction temperature is 25°C-40°C.

[0019] S2: Synthesis of compound 3

[0020] Compound 2 was added to triethyl phosphite, and the mixture was refluxed and stirred at 120°C for reaction, and the reaction of compound 3 was completed by TLC detection, followed by concentration under reduced pressure to remove the solvent, thereby obtaining compound 3;

[0021] Wherein, in the synthesis of compound 3, the molar ratio of compound 2 to triethyl phosphite is 1.00:1.00-1.10.

[0022] S3: Synthesis of compound 5

[0023] Compound 4 was dissolved in an organic solvent, 4-dimethylaminopyridine was added at 0°C, followed by di-tert-butyl dicarbonate or dimethylcarbamoyl chloride, and the mixture was stirred to react within a certain temperature range. TLC was performed until the reaction of compound 4 was complete. Water was added to the reaction solution, and an organic solvent was added for separation and extraction for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, thereby obtaining compound 5.

[0024] The organic solvent used is one or more of dichloromethane and methyl tert-butyl ether, preferably dichloromethane; the molar ratio of compound 4, 4-dimethylaminopyridine and di-tert-butyl dicarbonate is 1.00:0.01:1.00-1.20; the molar ratio of compound 4, triethylamine, 4-dimethylaminopyridine and dimethylcarbamoyl chloride is 1.00:1.20-1.40:0.01:1.20-1.40; and the reaction temperature is 25°C-40°C.

[0025] S4: Synthesis of Compound 6 (Pterostilbene)

[0026] Compound 3 is dissolved in an organic solvent, a strong base and compound 5 are added at 0°C, and then the mixture is stirred and reacted within a certain temperature range. When the reaction of compound 5 is complete, the mixture is filtered by suction, water is added to the reaction solution, and the organic solvent is removed by concentrating under reduced pressure. An organic solvent is added for separation and extraction for 3 times, and the organic layer is dried with anhydrous magnesium sulfate, filtered, and the solvent is removed by concentrating under reduced pressure. The mixture is recrystallized with a mixed solvent of n-hexane and ethyl acetate to obtain pterostilbene.

[0027] The organic solvent used is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and N,N-dimethylformamide, preferably tetrahydrofuran and 2-methyltetrahydrofuran; a method for synthesizing pterostilbene as claimed in claim 1, characterized in that the base used is one or more of potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium bistrimethylsilylamide, lithium diisopropylamide, preferably potassium tert-butoxide; the molar ratio of compound 5 to potassium tert-butoxide is 1.00:2.50-4.00, and the preferred molar ratio of compound 5 to potassium tert-butoxide is 1.00:3.00-4.00; during the recrystallization process, the volume ratio of n-hexane to ethyl acetate is 3:1.

[0028] Compared with the prior art, the beneficial effects of the present invention include:

[0029] 1. The present invention provides a new synthesis method of pterostilbene, the raw materials used in the method are cheap and readily available, the route is short, the operation is simple, and it is easy to industrialize production;

[0030] 2. The common hydroxyl protecting groups tert-butyloxycarbonyl and dimethylaminoformyl are used in the route to construct trans-olefins through the Horner-Wadsworth-Emmons reaction. At the same time, the above protecting groups can also be directly removed under the reaction conditions, avoiding the problem of polymerization of pterostilbene under acidic conditions, thereby obtaining pterostilbene in a shorter route and with a higher yield;

[0031] 3. This method avoids the use of heavy metal Pd in ​​the last three steps of synthesizing the final product, thereby eliminating the need to remove Pd from the product and to include palladium element testing in the finished product quality standards, thereby reducing production testing costs. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the experimental method of the present invention is further described in detail below through examples.

[0033] The experimental methods in the present invention are all conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0034] The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the starting material is generally regarded as the reaction endpoint.

[0035] Embodiment 1:

[0036] Example 1 of the present invention provides a method for preparing intermediate 2, and its synthetic route is as follows:

[0037]

[0038] The specific preparation method is as follows:

[0039] Compound 1 (36.50 g, 0.297 mol) was dissolved in dichloromethane (180 mL), and a solution of phosphorus tribromide (8.16 mL, 0.119 mol) in dichloromethane (100 mL) was slowly added at -10 ° C. After the addition was completed, the mixture was transferred to room temperature for reaction for 4 h. TLC detected that the reaction of compound 1 was complete, and the reaction solution was slowly dripped into ice water (300 mL), and 2 mol / L sodium hydroxide solution (70 mL) was dripped at 0 ° C to adjust the pH to 7, and DCM was added for separation and extraction, washed with saturated brine, and dried over anhydrous magnesium sulfate. Filtered and dried, and dichloromethane was removed under reduced pressure to obtain compound 2.

[0040] 33.50 g of a white solid was obtained by this method, with a yield of 70%.

[0041] The intermediate 2 obtained in this example was identified, and the following results were obtained:

[0042] 1 H NMR(400MHz, DMSO-d6)δ9.60(s,1H),7.46–7.36(m,2H),7.16(d,J=16.4Hz,1H),6.94(d,J= 16.4Hz,1H),6.80–6.74(m,2H),6.71(d,J=2.3Hz,2H),6.37(t,J=2.2Hz,1H),3.76(s,6H).

[0043] Embodiment 2:

[0044] Example 2 of the present invention provides a method for preparing intermediate 3, and its synthetic route is as follows:

[0045]

[0046] The specific preparation method is as follows:

[0047] Compound 2 (32.50 g, 0.141 mol) was added to triethyl phosphite (25.50 mL, 0.148 mol), followed by stirring at 130° C. for 4 h. TLC showed that the reaction of compound 2 was complete, and triethyl phosphite was removed under reduced pressure to obtain compound 3.

[0048] 40.20 g of yellow oily liquid was obtained by this method, and the yield was 99%.

[0049] The intermediate 3 obtained in this example was identified, and the following results were obtained:

[0050] 1 H NMR (400MHz, DMSO-d6) δ6.45(t,J=2.4Hz,2H),6.37(q,J=2.2Hz,1H),3.95(dq,J =8.1,7.0Hz,4H),3.71(s,6H),3.17(s,1H),3.12(s,1H),1.17(t,J=7.1Hz,6H).

[0051] Embodiment 3:

[0052] Example 3 of the present invention provides a method for preparing intermediate 5, and its synthetic route is as follows:

[0053]

[0054] The specific preparation method is as follows:

[0055] Compound 4 (50.00 g, 0.409 mol) was dissolved in dichloromethane (250 mL), dimethylaminopyridine (0.50 g, 4.09 mmol) was added, di-tert-butyl dicarbonate (96.00 mL, 0.418 mol) was slowly added dropwise at 0°C, and after addition, the mixture was transferred to room temperature for reaction for 4 h. TLC detected that compound 4 had reacted completely, water (250 mL) was added to wash the organic layer, and then 2 mol / L sodium hydroxide solution (120 mL) was added to wash the organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and dried to obtain compound 5a.

[0056] 71.30 g of a white solid was obtained by this method, with a yield of 78%.

[0057] The intermediate 5a obtained in this example was identified, and the following results were obtained:

[0058] 1 H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 1.51 (s, 9H). Example 4:

[0059] Example 4 of the present invention provides a method for preparing intermediate 5a:

[0060] Compound 4 (20.00 g, 0.164 mol) was dissolved in methyl tert-butyl ether (100 mL), dimethylaminopyridine (0.20 g, 1.64 mmol) was added, di-tert-butyl dicarbonate (45.20 mL, 0.196 mol) was slowly added dropwise at 0°C, and after the addition was completed, the mixture was transferred to room temperature for reaction. TLC detected that compound 4 was completely reacted, water (100 mL) was added to wash the organic layer, and then 2 mol / L sodium hydroxide solution (50 mL) was added to wash the organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and dried to obtain compound 5a.

[0061] 27.1 g of a white solid was obtained by this method, with a yield of 74%.

[0062] Embodiment 5:

[0063] Example 5 of the present invention provides a method for preparing intermediate 5b, and its synthetic route is as follows:

[0064]

[0065] Compound 4 (10.00 g, 81.89 mmol) was dissolved in dichloromethane (50 mL), triethylamine (15.93 mL, 114.64 mmol) was added, dimethylaminopyridine (0.10 g, 0.82 mmol) was added, dimethylaminoformyl chloride (10.54 mL, 114.64 mmol) was slowly added dropwise at 0°C, and after the addition was completed, the mixture was transferred to room temperature for reaction for 12 h. TLC detected that compound 4 was completely reacted, water (50 mL) was added to wash the organic layer, and then 2 mol / L hydrochloric acid (16.5 mL) was added to wash the organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and dried to obtain compound 5b.

[0066] The method was used to prepare 15.6 g of a white solid with a yield of 98%.

[0067] Embodiment 6:

[0068] Example 6 of the present invention provides a method for preparing pterostilbene, and its synthetic route is as follows:

[0069]

[0070] The specific preparation method is as follows:

[0071] Compound 5a (30.52 g, 137.32 mmol) was dissolved in tetrahydrofuran (200 mL), and compound 3 (40.38 g, 140.07 mmol) and potassium tert-butoxide (46.23 g, 412.00 mmol) were slowly added at 0°C. After the addition was completed, the mixture was transferred to room temperature for reaction for 1 h. TLC detected that the reaction of compound 5a was complete, water was added to the reaction solution, tetrahydrofuran was removed by rotation, dichloromethane was added for separation and extraction, and dilute hydrochloric acid was added to adjust the pH to 6, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. Petroleum ether (150 mL) and ethyl acetate (50 mL) were added for recrystallization to obtain compound 6.

[0072] The method was used to prepare 25.58 g of a white solid with a yield of 73% and a HPLC purity of more than 98%.

[0073] The pterostilbene obtained in this example was identified, and the following results were obtained:

[0074] 1 H NMR(400MHz, DMSO-d6)δ9.59(s,1H),7.46–7.37(m,2H),7.15(d,J=16.4Hz,1H),6.94(d,J= 16.4Hz,1H),6.81–6.74(m,2H),6.71(d,J=2.3Hz,2H),6.37(t,J=2.2Hz,1H),3.76(s,6H).

[0075] 13 C NMR (75MHz, DMSO-d6) δ161.11,157.85,140.08,129.43,128.42,125.62,116.05,104.52,99.74,55.60.

[0076] Embodiment 7:

[0077] Example 7 of the present invention provides a method for preparing pterostilbene:

[0078] Compound 5a (1.00 g, 4.50 mmol) was dissolved in methyl tert-butyl ether (10 mL), and compound 3 (1.32 g, 4.59 mmol) and potassium tert-butoxide (1.51 g, 13.50 mmol) were slowly added at 0°C. After the addition was completed, the mixture was transferred to room temperature for reaction for 1 h. TLC detected that compound 5a was completely reacted, water was added to the reaction solution, methyl tert-butyl ether was added for separation and extraction, and dilute hydrochloric acid was added to adjust the pH to 6, washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. Petroleum ether (5.0 mL) and ethyl acetate (1.7 mL) were added for recrystallization to obtain compound 6.

[0079] The method was used to prepare 0.82 g of a white solid with a yield of 71% and a HPLC purity of more than 98%.

[0080] Embodiment 8:

[0081] Example 8 of the present invention provides a method for preparing pterostilbene, and its synthesis route is as follows:

[0082]

[0083] The specific preparation method is as follows:

[0084] Compound 5b (15.00 g, 77.64 mmol) was dissolved in tetrahydrofuran (100 mL), and compound 3 (22.83 g, 79.19 mmol) and potassium tert-butoxide (21.78 g, 194.10 mmol) were slowly added at 0°C. After the addition was completed, the mixture was transferred to room temperature for reaction for 1 h. TLC detected that the reaction of compound 5b was complete, water was added to the reaction solution, tetrahydrofuran was removed by rotation, dichloromethane was added for separation and extraction, and dilute hydrochloric acid was added to adjust the pH to 6, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. Petroleum ether (75.0 mL) and ethyl acetate (25.0 mL) were added for recrystallization to obtain compound 6.

[0085] The method was used to prepare 15.93 g of a white solid with a yield of 80% and a HPLC purity of more than 98%.

[0086] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing pterostilbene, characterized in that: This is accomplished by: S1: Synthesis of compound 2 Dissolve compound 1 in an organic solvent, slowly add a bromination reagent at 0°C, then stir and react within a certain temperature range, perform TLC detection until compound 1 reacts completely, slowly add the reaction solution into ice water at 0°C, add an organic solvent for separation and extraction 3 times, dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to remove the solvent to obtain compound 2; S2: Synthesis of compound 3 Compound 2 was added to triethyl phosphite, and the mixture was refluxed and stirred at 120°C for reaction, and the reaction of compound 3 was completed by TLC detection, followed by concentration under reduced pressure to remove the solvent, thereby obtaining compound 3; S3: Synthesis of compound 5 Compound 4 was dissolved in an organic solvent, 4-dimethylaminopyridine was added at 0°C, followed by di-tert-butyl dicarbonate or dimethylcarbamoyl chloride, and the mixture was stirred to react within a certain temperature range. TLC was performed until the reaction of compound 4 was complete. Water was added to the reaction solution, and an organic solvent was added for separation and extraction for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, thereby obtaining compound 5. S4: Synthesis of Compound 6 (Pterostilbene) Compound 3 was dissolved in an organic solvent, and a strong base and compound 5 were added at 0°C, followed by stirring and reacting within a certain temperature range. When the reaction of compound 5 was completed by TLC detection, the reaction solution was filtered, water was added to the reaction solution, and the organic solvent was removed by concentrating under reduced pressure. An organic solvent was added for separation and extraction for 3 times, and the organic layer was dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by concentrating under reduced pressure. The mixture was recrystallized with a mixed solvent of n-hexane and ethyl acetate to obtain pterostilbene.

2. A synthesis method according to claim 1, characterized in that: In the synthesis of compound 2, the organic solvent used is dichloromethane; the bromination reagent used is one or more of phosphorus tribromide, phosphorus pentabromide, hydrogen bromide, and N-bromosuccinimide; the molar ratio of compound 1 to phosphorus tribromide is 1.00:0.40-1.02; and the reaction temperature is 25°C-40°C.

3. A synthesis method according to claim 1, characterized in that: In the synthesis of compound 3, the molar ratio of compound 2 to triethyl phosphite is 1.00:1.00-1.

10.

4. A synthesis method according to claim 1, characterized in that: In the synthesis of compound 5, the organic solvent used is one or more of dichloromethane and methyl tert-butyl ether; the molar ratio of compound 4, 4-dimethylaminopyridine and di-tert-butyl dicarbonate is 1.00:0.01:1.00-1.20; the molar ratio of compound 4, triethylamine, 4-dimethylaminopyridine and dimethylaminoformyl chloride is 1.00:1.20-1.40:0.01:1.20-1.40; and the reaction temperature is 25°C-40°C.

5. A method for synthesizing pterostilbene as claimed in claim 1, characterized in that: The organic solvent used is one or more of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether and N,N-dimethylformamide.

6. A method for synthesizing pterostilbene as claimed in claim 1, characterized in that: The base used is one or more of potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilyl)amide, and lithium diisopropylamide; the molar ratio of compound 5 to potassium tert-butoxide is 1.00:2.50-4.00; during the recrystallization process, the volume ratio of n-hexane to ethyl acetate is 3:1.

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