A method for synthesizing (E)-3,5-dihydroxy-4-isopropylstilbene

Abstract

This invention provides a ( E This invention relates to the field of pharmaceutical synthesis technology and provides a method for synthesizing 3,5-dihydroxy-4-isopropylstilbene. The method comprises three steps: starting with 3,5-dimethoxy-bromobenzene as a starting material, isopropylation is carried out under acidic conditions to obtain 3,5-dimethoxy-4-isopropylstilbene; further, a Heck reaction is performed with styrene under palladium catalysis to obtain (…). E )-3,5-dimethoxy-4-isopropylstilbene; demethylation reaction yields the ( E 3,5-Dihydroxy-4-isopropylstilbene. Compared to existing synthetic routes, the synthetic method of this invention significantly shortens the synthetic path, has higher atom utilization, higher product yield, and is environmentally friendly.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, and particularly to a ( E Synthetic method of 3,5-dihydroxy-4-isopropylstilbene. Background Technology

[0002] Benvitimod, its Chinese chemical name is ( E 3,5-Dihydroxy-4-isopropylstilbene, with the molecular formula C 17 H 18 O2 was first isolated in 1981 from the metabolites of symbiotic bacteria of *Nematoda* spp., and subsequently found in *Proteobacterium*, *Heterobacter pylori*, and *Heterobacter spp.*. Benvitimod was subsequently shown to possess a variety of excellent biological activities. Developed by Guanhao Biotech Co., Ltd., its cream is a Class I new drug in my country with complete independent intellectual property rights. It is mainly used to treat inflammatory reactions and autoimmune reactions, and can also inhibit the degranulation of mast cells and basophils associated with allergic reactions. It also shows good therapeutic effects on psoriasis. However, the total chemical synthesis of this compound was not reported until 2009. Currently, there are several synthetic routes for the total chemical synthesis of benvitimide, but many of them have drawbacks, such as a large amount of chemical waste (such as waste products generated by pyridine chlorochromate, diethyl phosphate, etc.), high pollution from active reagents (such as KBH4, SOCl2, Br2, LiAlH4, nBuLi, etc.), and long synthetic routes (more than 6 synthetic steps). These disadvantages are also the reason why the synthesis cost of benvitimide remains high.

[0003] Therefore, it is of great significance to find a synthetic method for benvitomod that has fewer steps and is more environmentally friendly. Summary of the Invention

[0004] In order to solve the problems existing in the prior art, the main objective of the present invention is to provide a ( E Synthetic method of 3,5-dihydroxy-4-isopropylstilbene.

[0005] To achieve the above objectives, the present invention proposes a ( E The method for synthesizing 3,5-dihydroxy-4-isopropylstilbene includes the following steps:

[0006] (1) 3,5-Dimethoxy-4-isopropylbenzene was obtained by isopropylation under acidic conditions using 3,5-dimethoxy-4-isopropylbenzene as the starting material.

[0007] (2) The 3,5-dimethoxy-4-isopropylbenzene bromide was reacted with styrene under palladium catalyst conditions to obtain (E )-3,5-dimethoxy-4-isopropylstilbene;

[0008] (3) Regarding the ( E The demethylation reaction of 3,5-dimethoxy-4-isopropylstilbene yields the (…). E )-3,5-dihydroxy-4-isopropylstilbene.

[0009] The synthesis path of the above synthesis method is as follows:

[0010]

[0011] The synthesis method provided in this invention uses 3,5-dimethoxybromobenzene as a starting material and requires only three steps to synthesize benvitimod. Compared with existing processes, this significantly shortens the synthesis route, has higher atom utilization, and achieves a higher yield of benvitimod. Furthermore, the synthesis method provided by this invention does not require the addition of substances such as pyridine chlorochromate or diethyl phosphate, nor does it require the addition of reactive reagents such as KBH4, SOCl2, Br2, LiAlH4, or nBuLi, making it more environmentally friendly than existing processes.

[0012] As a preferred embodiment of the synthesis method of the present invention, step (1) includes: dissolving 3,5-dimethoxy-4-isopropylbenzene in a concentrated acid, adding isopropanol under heating conditions to carry out isopropylation reaction, cooling the reaction solution to room temperature after the reaction is completed, and obtaining the 3,5-dimethoxy-4-isopropylbenzene after post-treatment.

[0013] In a preferred embodiment of the synthesis method of the present invention, the concentrated acid in step (1) is concentrated sulfuric acid, and the heating conditions correspond to a temperature of 70~85°C. o C, preferably 80 o C; and with reference to the amount of 3,5-dimethoxybromobenzene added, the amount of isopropanol added is 1.1 to 1.5 equivalents, preferably 1.2 equivalents, and the isopropylation reaction time is 3 to 5 hours, preferably 4 hours.

[0014] As a preferred embodiment of the synthesis method of the present invention, the post-processing in step (1) includes: cooling the reaction solution to room temperature, diluting it with water, extracting it with ethyl acetate, collecting the ethyl acetate layer, drying, concentrating, and column chromatography to obtain the 3,5-dimethoxy-4-isopropylbenzene bromide.

[0015] As a preferred embodiment of the synthesis method of the present invention, step (2) includes: mixing the 3,5-dimethoxy-4-isopropylbenzene bromide, the palladium catalyst, the solvent and the ligand, continuing to add styrene and an alkaline substance, and conducting the Heck reaction under heating conditions, followed by post-treatment to obtain the ( E )-3,5-dimethoxy-4-isopropylstilbene.

[0016] In a preferred embodiment of the synthesis method of the present invention, the palladium catalyst in step (2) includes at least one of palladium acetate, palladium chloride, and (1,5-cyclooctadiene)palladium dichloride, preferably (1,5-cyclooctadiene)palladium dichloride; the solvent includes at least one of N-methylpyrrolidone, N,N-dimethylformamide, and acetonitrile, preferably N-methylpyrrolidone; the ligand includes at least one of tris(o-tolyl)phosphine, triphenylphosphine, and tris(diethylamino)phosphine, preferably tris(diethylamino)phosphine; and the alkaline substance includes at least one of potassium carbonate, sodium carbonate, cesium carbonate, and triethylamine, preferably potassium carbonate.

[0017] In a preferred embodiment of the synthesis method described in this invention, the reaction temperature in step (2) is 120~140°C. o C, preferably 120 o C; and with reference to the amount of 3,5-dimethoxy-4-isopropyl bromide added, the amount of styrene added is 1.5 to 2 equivalents, preferably 1.5 equivalents.

[0018] As a preferred embodiment of the synthesis method of the present invention, the amount of palladium catalyst added in step (2) is 0.05~0.1% of 3,5-dimethoxy-4-isopropylbenzene bromide, preferably 0.1% in molar percentage; and the ratio of the amount of ligand added to the amount of palladium catalyst is 2:1.

[0019] As a preferred embodiment of the synthesis method of the present invention, the post-processing method in step (2) includes: cooling the reaction solution to room temperature, quenching with dilute hydrochloric acid solution, extracting with ethyl acetate, collecting the ethyl acetate layer, drying, concentrating, and column chromatography to obtain the (… E )-3,5-dimethoxy-4-isopropylstilbene.

[0020] In a preferred embodiment of the synthesis method of the present invention, step (3) includes: taking the ( E )-3,5-dimethoxy-4-isopropylstilbene was subjected to demethylation reaction with boron tribromide at low temperature to obtain the ( E )-3,5-dihydroxy-4-isopropylstilbene.

[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0022] (1) The synthesis method provided in the technical solution of the present invention uses 3,5-dimethoxybromobenzene as the starting material and only requires three steps to synthesize benvimod. Compared with the existing process route, the synthesis path is greatly shortened, the atom utilization rate is higher, the yield of benvimod is higher, and the operation is simple and suitable for industrialization.

[0023] (2) The synthesis method provided by the present invention does not require the addition of substances such as pyridine chlorochromate and diethyl phosphate, nor does it require the addition of active reagents such as KBH4, SOCl2, Br2, LiAlH4, nBuLi. Therefore, it is more green and environmentally friendly than the existing process routes. Attached Figure Description

[0024] Figure 1 The 3,5-dimethoxy-4-isopropylbenzene bromide prepared in Example 1 1 HNMR spectrum (400MHz, CDCl3);

[0025] Figure 2 The 3,5-dimethoxy-4-isopropylbenzene bromide prepared in Example 1 13 CNMR spectrum (100MHz, CDCl3);

[0026] Figure 3 The one prepared in Example 3 ( E )-3,5-dimethoxy-4-isopropylstilbene 1 HNMR spectrum (400MHz, CDCl3);

[0027] Figure 4 The one prepared in Example 3 ( E )-3,5-dimethoxy-4-isopropylstilbene 13 CNMR spectrum (100MHz, CDCl3);

[0028] Figure 5 The one prepared in Example 6 ( E )-3,5-dihydroxy-4-isopropylstilbene 1 HNMR spectrum (400MHz, CDCl3); and

[0029] Figure 6 The one prepared in Example 6 ( E )-3,5-dihydroxy-4-isopropylstilbene 13 CNMR spectrum (100MHz, CDCl3). Detailed Implementation

[0030] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below through specific embodiments.

[0031] Example 1 (Preparation of 3,5-dimethoxy-4-isopropylbenzene bromide)

[0032] Add 4.3 g (20 mmol) of 3,5-dimethoxybromobenzene to a three-necked flask. Under nitrogen protection, add 50 ml of 85% concentrated sulfuric acid, stir well, and heat to 80°C. o C. Then, 1.32 g (22 mmol) of isopropanol was slowly added dropwise. After reacting for 4 hours, the mixture was cooled to room temperature, 50 ml of water was added, followed by 100 ml of ethyl acetate. The mixture was extracted, the oil phase was evaporated to dryness, and the solution was passed through a silica gel column with petroleum ether to give 3.4 g of white solid.

[0033] Characterization data: 1 H NMR (400 MHz, Chloroform-d) δ 6.69 (s, 2H), 3.80 (s, 6H), 3.55 (p, J = 7.1 Hz, 1H), 1.26 (d, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ158.12, 122.53, 118.56, 107.27, 55.03, 23.10, 19.56.

[0034] The above white solid was subjected to 1 H NMR and 13 C NMR analysis, 1 H NMR spectrum as shown Figure 1 As shown, 13 The C NMR spectrum is as follows Figure 2 As shown, the white solid was identified as 3,5-dimethoxy-4-isopropylbenzene bromide. The calculated yield was 3.4 ÷ (20 × 259 × 10⁻⁶). -3 The yield of 3,5-dimethoxy-4-isopropylbenzene bromide in this example is 66% (100%).

[0035] Example 2 (Preparation of 3,5-dimethoxy-4-isopropylbenzene bromide)

[0036] Add 4.3 g (20 mmol) of 3,5-dimethoxybromobenzene to a three-necked flask. Under nitrogen protection, add 50 ml of 85% concentrated sulfuric acid, stir well, and heat to 80°C. oC. Then, 1.8 g (30 mmol) of isopropanol was slowly added dropwise. After reacting for 4 hours, the mixture was cooled to room temperature, 50 ml of water was added, followed by 100 ml of ethyl acetate. The mixture was extracted, the oil phase was evaporated to dryness, and the solution was passed through a silica gel column with petroleum ether to give 4.2 g of white solid.

[0037] The above white solid was subjected to 1 H NMR and 13 C10 NMR analysis confirmed that the white solid was 3,5-dimethoxy-4-isopropylbenzene bromide. The calculated yield was 4.2 ÷ (20 × 259 × 10⁻⁶). -3 The yield of 3,5-dimethoxy-4-isopropylbenzene bromide in this example is 81% (100%).

[0038] Example 3 (( E Preparation of 3,5-dimethoxy-4-isopropylstilbene

[0039] In a three-necked flask, 2.6 g (10 mmol) of 3,5-dimethoxy-4-isopropylbenzene bromide was added. Under nitrogen protection, 30 mL of N-methylpyrrolidone was added, followed by 0.05% (1,5-cyclooctadiene)palladium dichloride and 0.1% tris(diethylamino)phosphine. Then, 1.56 g (15 mmol) of styrene and 2.1 g (15 mmol) of potassium carbonate were added. The mixture was heated to 120 °C and reacted for 12 hours. After cooling to room temperature, 10 mL of 6% hydrochloric acid and 100 mL of ethyl acetate were added. The mixture was extracted, and the oil phase was evaporated to dryness. The solution was then passed through a silica gel column with petroleum ether to give 2.54 g of a white solid.

[0040] Characterization data: 1 H NMR (400 MHz, Chloroform-d) δ 7.57–7.49 (m, 2H), 7.38 (t,J = 7.7 Hz, 2H), 7.31–7.24 (m, 1H), 7.08 (s, 2H), 6.72 (s, 2H), 3.88 (s, 6H), 3.64–3.57 (m, 1H), 1.31 (d, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 158.87,137.52, 136.03, 129.18, 128.81, 128.16, 127.64, 126.58, 124.66, 103.08,55.93, 24.33, 20.84.

[0041] The above white solid was subjected to 1 H NMR and 13C NMR analysis, 1 H NMR spectrum as shown Figure 3 As shown and 13 The C NMR spectrum is as follows Figure 4 As shown, the white solid is determined to be ( E )-3,5-dimethoxy-4-isopropylstilbene. The calculated yield is 2.54 ÷ (10 × 282 × 10⁻⁶) / 2.54 ÷ 10⁻⁶. -3 )×100%, that is, in this embodiment ( E The yield of 3,5-dimethoxy-4-isopropylstilbene was 90%.

[0042] Example 4 (( E Preparation of 3,5-dimethoxy-4-isopropylstilbene

[0043] In a three-necked flask, 2.6 g (10 mmol) of 3,5-dimethoxy-4-isopropylbenzene bromide was added. Under nitrogen protection, 30 mL of N,N-dimethylformamide was added, followed by 0.05% (1,5-cyclooctadiene)palladium dichloride and 0.1% tris(diethylamino)phosphine. Then, 1.56 g (15 mmol) of styrene and 2.1 g (15 mmol) of potassium carbonate were added. The mixture was heated to 120 °C and reacted for 12 hours. After cooling to room temperature, 10 mL of 6% hydrochloric acid and 100 mL of ethyl acetate were added. The mixture was extracted, and the oil phase was evaporated to dryness. The solution was then passed through a silica gel column with petroleum ether to give 1.41 g of a white solid.

[0044] The above white solid was subjected to 1 H NMR and 13 C10 NMR analysis confirmed that the white solid was ( E )-3,5-dimethoxy-4-isopropylstilbene. The calculated yield is 1.41 ÷ (10 × 282 × 10⁻⁶) / (3,5-dimethoxy-4-isopropylstilbene). -3 )×100%, that is, in this embodiment ( E The yield of 3,5-dimethoxy-4-isopropylstilbene was 50%.

[0045] Example 5 (( E Preparation of 3,5-dimethoxy-4-isopropylstilbene

[0046] In a three-necked flask, 2.6 g (10 mmol) of 3,5-dimethoxy-4-isopropylbenzene bromide was added. Under nitrogen protection, 30 mL of N-methylpyrrolidone was added, followed by 0.1% (1,5-cyclooctadiene) palladium dichloride and 0.2% tris(diethylamino)phosphine. Then, 1.56 g (15 mmol) of styrene and 2.8 g (20 mmol) of potassium carbonate were added. The mixture was heated to 120 °C and reacted for 24 hours. After cooling to room temperature, 10 mL of 6% hydrochloric acid and 100 mL of ethyl acetate were added. The mixture was extracted, and the oil phase was evaporated to dryness. The solution was then passed through a silica gel column with petroleum ether to give 2.67 g of a white solid.

[0047] The above white solid was subjected to 1 H NMR and 13 C10 NMR analysis confirmed that the white solid was ( E )-3,5-dimethoxy-4-isopropylstilbene. The calculated yield is 2.67 ÷ (10 × 282 × 10⁻⁶) / 2. -3 )×100%, that is, in this embodiment ( E The yield of 3,5-dimethoxy-4-isopropylstilbene was 95%.

[0048] Example 6 (( E Preparation of 3,5-dihydroxy-4-isopropylstilbene

[0049] Add 1.41 g (5 mmol) to the three-necked flask. E 3,5-Dimethoxy-4-isopropylstilbene was reacted under nitrogen protection with 150 ml of dry dichloromethane. The mixture was cooled to -20°C, and then boron tribromide solution (8.5 g, 33.5 mmol, 30% in DCM) was slowly added dropwise. The mixture was stirred until it stabilized at room temperature, and the reaction was allowed to proceed for 4 hours. After the reaction was complete, the mixture was poured into a beaker containing 100 ml of water, extracted with dichloromethane (3 x 50 ml), washed with saturated brine, dried over anhydrous sodium sulfate, and then evaporated to dryness before column chromatography to obtain 1.04 g of white solid.

[0050] Characterization data: 1 H NMR (400 MHz, Chloroform-d) δ 7.54–7.43 (m, 2H), 7.37(dd, J = 8.4, 6.8 Hz, 2H), 7.32–7.23 (m, 1H), 6.96 (q, J = 16.3 Hz, 2H), 6.52(s, 2H), 4.85 (s, 2H), 3.48 (p, J = 7.1 Hz, 1H), 1.40 (d, J = 7.1 Hz, 6H);13 CNMR (101 MHz, CDCl3) δ 155.10, 137.34, 136.42, 128.83, 127.91, 127.79, 126.64, 120.49, 109.56, 107.05, 24.79, 20.90.

[0051] The above white solid was subjected to 1 H NMR and 13 C NMR analysis, 1 H NMR spectrum as shown Figure 5 As shown and 13 The C NMR spectrum is as follows Figure 6 As shown, the white solid is determined to be ( E 3,5-Dihydroxy-4-isopropylstilbene. The calculated yield is 1.04 ÷ (5 × 254 × 10⁻⁶). -3 )×100%, that is, in this embodiment ( E The yield of 3,5-dihydroxy-4-isopropylstilbene was 82%.

[0052] Synthesized using the above embodiments ( E The highest yield of 3,5-dihydroxy-4-isopropylstilbene was 81% * 95% * 82% = 63%.

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A kind of ( E The method for synthesizing 3,5-dihydroxy-4-isopropylstilbene is characterized by, Includes the following steps: (1) 3,5-Dimethoxy-4-isopropylbenzene was obtained by isopropylation of 3,5-dimethoxy-4-isopropylbenzene under acidic conditions. (2) The 3,5-dimethoxy-4-isopropylbenzene bromide was reacted with styrene under palladium catalyst conditions to obtain ( E 3,5-Dimethoxy-4-isopropylstilbene; (3) Regarding the ( E The ()-3,5-dimethoxy-4-isopropylstilbene was subjected to a demethylation reaction to obtain the () E 3,5-Dihydroxy-4-isopropylstilbene; Step (2) includes: mixing the 3,5-dimethoxy-4-isopropylbenzene bromide, the palladium catalyst, the solvent and the ligand, adding styrene and an alkaline substance, and conducting the Heck reaction under heating conditions. After post-treatment, the (E)-3,5-dimethoxy-4-isopropylstilbene is obtained. The palladium catalyst in step (2) is (1,5-cyclooctadiene)palladium dichloride; The solvent is N-methylpyrrolidone; The ligand is tris(diethylamino)phosphine and The alkaline substance is at least one of potassium carbonate, sodium carbonate, and cesium carbonate; The reaction temperature in step (2) is 120~140℃; and With reference to the amount of 3,5-dimethoxy-4-isopropyl bromide added, the amount of styrene added is 1.5 to 2 equivalents; The amount of palladium catalyst added in step (2) is 0.05-0.1% of 3,5-dimethoxy-4-isopropylbenzene bromide, based on molar percentage; and The ratio of the ligand to the palladium catalyst is 2:

1.

2. The synthesis method according to claim 1, characterized in that, Step (1) includes: dissolving 3,5-dimethoxy-4-isopropylbenzene in a concentrated acid, adding isopropanol under heating conditions to carry out isopropylation reaction, cooling the reaction solution to room temperature after the reaction is completed, and obtaining the 3,5-dimethoxy-4-isopropylbenzene after post-treatment.

3. The synthesis method as described in claim 2, characterized in that, The concentrated acid in step (1) is concentrated sulfuric acid, and the heating conditions correspond to a temperature of 70~85℃; and With reference to the amount of 3,5-dimethoxybromobenzene added, the amount of isopropanol added is 1.1 to 1.5 equivalents, and the isopropylation reaction time is 3 to 5 hours.

4. The synthesis method according to claim 2, characterized in that, The post-processing in step (1) includes: cooling the reaction solution to room temperature, diluting it with water, extracting it with ethyl acetate, collecting the ethyl acetate layer, drying, concentrating, and column chromatography to obtain the 3,5-dimethoxy-4-isopropylbenzene bromide.

5. The synthesis method as described in claim 1, characterized in that, The post-processing method in step (2) includes: cooling the reaction solution to room temperature, quenching it with dilute hydrochloric acid solution, extracting it with ethyl acetate, collecting the ethyl acetate layer, drying, concentrating, and column chromatography to obtain the (E)-3,5-dimethoxy-4-isopropylstilbene.

6. The synthesis method according to claim 1, characterized in that, Step (3) includes: treating (E)-3,5-dimethoxy-4-isopropylstilbene with boron tribromide at low temperature to obtain (E)-3,5-dihydroxy-4-isopropylstilbene by demethylation reaction.

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