Synthetic method of drug intermediate

Abstract

The invention discloses a synthetic method of a drug intermediate 8, 8-dimethyl-2, 3-dihydro-4H, 8H-pyrano [2, 3-f] chromene-4-ketone, and belongs to the field of organic synthesis. Specifically, resorcinol is used as a raw material, a Friedel-Crafts acylation reaction is performed, then intramolecular cyclization is performed to obtain 7-hydroxychromene-4-ketone, and the intermediate is subjected to cyclization, condensation and alkylation reactions to obtain a target product. The method has the advantages of easy control of reaction conditions, simple operation, high yield, few reaction steps, strong industrial practicality, and wide application in organic chemistry and medicinal chemistry.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a pharmaceutical intermediate, specifically to a method for synthesizing the compound 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one, and belongs to the field of biomedicine. Background Art

[0002] 8,8-Dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one (molecular formula: C 14 H 14 O3, CAS: 130245-20-4) is a unique organic compound belonging to the pyranocoumarin class. It is a fused bicyclic system containing a pyran ring linked to a coumarin nucleus. The compound consists of a coumarin backbone, a 2,3-dihydropyran ring, and two methyl groups at the 8-position, as Figure 1 shown, which endows it with unique chemical and physical properties. In drug research, it has been found that oxacycles are more favored by medicinal chemists than thia- and aza-cycles because they are relatively less sensitive to inherent toxicity. Pyranocoumarins, including their derivatives, have important applications in organic and medicinal chemistry due to their diverse biological activities such as antioxidant, anti-inflammatory, and anticancer properties. The presence of the pyran ring fused to the coumarin system enhances the stability of the compound on the one hand and increases the potential for interaction with biological targets on the other hand. In addition, the 8,8-dimethyl substitution introduces steric and electronic effects, which can affect reactivity and binding affinity. The compound is also a valuable synthetic intermediate for the development of more complex heterocyclic systems and natural product analogs. Chromenone has various biological activities, including antitumor, antibacterial, anti-inflammatory, antiviral, antioxidant, etc. In terms of antitumor activity, chromenone exhibits multiple mechanisms, including cytotoxicity, chemoprevention, antimetastasis, anti-angiogenesis, immunomodulation, etc. 8,8-Dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one has a wide range of biological activities, including antioxidant, anticancer, and anti-inflammatory properties.

[0003] The literature "Synthesis of some novel pyrano[2,3-f]chromenone derivatives" (Alizadeh et al., J IRAN CHEM SOC (2015) 12:605-612) reported an effective preparation method for a novel pyrano[2,3-f]chromenone. This method uses resorcinol and 3-chloropropionic acid as starting materials, reacts in trifluoromethanesulfonic acid (CF3SO3H) to obtain an intermediate product, and the intermediate product is condensed in the presence of 2 M sodium hydroxide to obtain 7-hydroxycoumarin-4-one. Then, in the presence of 1,8-diazabicyclo(5,4,0)-7-undecene (DBU), trifluoroacetic anhydride ((CF3CO)2O) and copper(II) chloride dihydrate CuCl2·H2O, and in acetonitrile and in the presence of 2-methyl-3-butyn-2-ol, the phenolic hydroxyl group was alkylated at 0 °C to prepare 7-(2-methyl-3-butyn-2-yloxy)coumarin-4-one. This compound was then heated in N,N-dimethylaniline and polyethylene glycol-200 at 200 - 220 °C to obtain the cyclized product 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one, and no rearrangement occurred during the reaction, as Figure 2 shown. Subsequently, the authors reacted 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one with various aromatic aldehydes in tetrahydrofuran at -78 °C to prepare various pyrano[2,3-f]chromenone derivatives, such as flavonoids and rotenone. The above synthesis method obtains the target product through 4 steps of reactions. During the reaction process, a variety of toxic reagents are used, the reaction conditions are relatively harsh, the reaction temperature is relatively high, and it is not energy-saving and environmentally friendly enough.

[0004] The present invention aims to introduce a synthesis method for 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one with fewer preparation steps, energy-saving and environmental protection, and high yield, providing a new route for the synthesis of this pharmaceutical intermediate. It is worth noting that the present invention first uses 1,1-dimethoxy-3-methyl-2-butene for the pyran ring formation reaction, ensuring the efficient direct synthesis of the target product under controlled conditions. The reaction conditions are mild, and it does not require the high-temperature (200-220 °C) reaction conditions reported in the literature and the use of toxic reagents such as N,N-dimethylaniline, making it more environmentally friendly and energy-saving. Summary of the Invention

[0005] This synthetic method describes the Friedel-Crafts acylation reaction of resorcinol and 3-chloropropionic acid in the presence of the catalyst trifluoromethanesulfonic acid to synthesize the intermediate 2´,4´-dihydroxy-3-chloropropiophenone II, which is cyclized intramolecularly with 2 M NaOH to form compound III. The last step is a cyclization and condensation reaction to form the pyran ring. Using toluene as the solvent, compound III is cyclized with 1,1-dimethoxy-3-methyl-2-butene and alkylated with 3-methylpyridine, and refluxed to obtain compound IV, which is the target product 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one.

[0006] The present invention relates to a synthetic method of 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one, and the specific reaction route is as Figure 3 shown.

[0007] Step 1: A mixture of resorcinol and 3-chloropropionic acid is stirred at 5 °C to room temperature, trifluoromethanesulfonic acid is added dropwise, and the mixture is refluxed at 80 °C for 30 minutes. The reaction process is monitored by thin-layer chromatography TLC (petroleum ether: ethyl acetate (PE: EA) volume ratio = 3:1). After cooling to room temperature, it is extracted with dichloromethane. The organic layer is washed with brine, dried over anhydrous Na2SO4, filtered, and the solvent is removed to obtain an orange semi-solid compound II.

[0008] Step 2: Compound II is dissolved in 2 M NaOH at 5 °C, refluxed at room temperature for 2 hours, and then acidified with 12 M HCl. Monitored by TLC, the same as above. Extracted with ethyl acetate, the organic layer is washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation to obtain a brown solid. Dissolved in hexane, filtered, and purified by column chromatography to obtain a white compound III.

[0009] Step 3: Compound III is dissolved in an appropriate amount of toluene, 3 equivalents of 1,1-dimethoxy-3-methyl-2-butene and 2 equivalents of 3-methylpyridine are added dropwise, heated to 111 °C, and the reflux reaction is continued for 12 hours. The reaction process is monitored by TCL. After the reaction is completed, the excess 3-methylpyridine is removed by rotary evaporation. The organic phase is collected and washed with 1 M hydrochloric acid, and also washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography to obtain a yellow solid compound IV, which is the target product.

[0010] Figure 1 is the structural formula of 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one Figure 2The synthetic route reported in the literature J IRAN CHEM SOC (2015) 12:605-612 Figure 3 The synthetic route of this discovery Figure 4 The hydrogen spectrum of Compound II Figure 5 The carbon spectrum of Compound II Figure 6 The hydrogen spectrum of Compound III Figure 7 The carbon spectrum of Compound III Figure 8 The hydrogen spectrum of Compound IV Figure 9 The carbon spectrum of Compound IV Detailed implementation methods Examples

[0011] Synthesis of 2′,4′-dihydroxy-3-chloropropiophenone Take 10.00 g of resorcinol and add it to 10.10 g of 3-chloropropionic acid, and stir to dissolve at room temperature. Slowly add 41.7 g of trifluoromethanesulfonic acid (3 equiv.), stir the mixture, heat to 80 °C, keep warm for 1 hour, and then cool to room temperature. Monitor with TLC (PE:EA = 3:1). Pour the mixed solution into 200 ml of dichloromethane, and then add 200 ml of water for extraction. The aqueous phase is extracted again with 100 ml of dichloromethane. The organic phases of the two extractions are washed with brine, dried over anhydrous Na2SO4, and finally filtered. A highly viscous orange semi-solid compound II is obtained by vacuum concentration, with a mass of 12.74 g and a yield of 85%. The hydrogen spectrum and carbon spectrum data detected by NMR are as follows: ¹H-NMR (400 MHz, DMSO-d6): δ 11.84 (1H, s, J = 11.84), 10.23 (1H, s, J = 10.23), 7.36 - 7.33 (1H, d, J = 7.35), 5.96 - 5.93 (1H, dd, J = 5.95), 5.84 - 5.83(1H,d, J = 5.84), 3.49 - 3.48 (2H, d, J = 3.47), 3.46 - 3.32 (2H, t, J = 3.04); ¹³C-NMR (100 MHz, DMSO-d6): δ 200.39, 164.96, 163.97, 132.99, 112.82, 108.33,102.41, 40.31, 40.14

[0012] At 5 °C, 12.74 g of 2',4'-dihydroxy-3-chloropropiophenone was added to 300 mL of 2 M NaOH solution, stirred, and the mixed solution was refluxed at 40 °C for 2 hours. Then, the reaction mixture was cooled back to 5 °C, acidified with 46 mL of 12 M HCl, and the pH was adjusted to 2. Finally, it was extracted three times with ethyl acetate (3 × 100 mL), washed with brine, dried over anhydrous Na2SO4, and filtered. The crude product was dried in vacuo and concentrated to a brown solid. The crude product was refined by dissolving in hexane, filtered, concentrated by rotary evaporation, and purified by flash column chromatography to obtain 6.87 g of white compound III with a yield of 86%. The 1H-NMR and 13C-NMR data are as follows: 1H-NMR (400 MHz, DMSO-d6): δ 10.53 (1H, s, J = 10.53), 7.62 - 7.60 (1H, d, J = 7.62), 6.49 - 6.46 (1H, dd, J = 6.47), 6.30 (1H, d, J = 6.30), 4.47 - 4.44 (2H, t, J = 4.45), 2.67 - 2.64 (2H, t, J = 2.66); 13 13C NMR (150 MHz, DMSO-d6, 300K): δ (ppm) 190.3, 165.0, 163.9, 129.1, 114.5, 110.9, 102.9, 67.5, 37.4.

[0013] 2.01 g of 7-hydroxycoumarin-4-one was dissolved in 20.1 mL of toluene, heated to 111 °C, 5.6 mL of 1,1-dimethoxy-3-methyl-2-butene and 2.4 mL of 3-methylpyridine were added dropwise, and the reaction was heated under reflux for 12 hours, monitored by TLC (PE:EA = 2:1). The excess 3-methylpyridine was removed by rotary evaporation, washed twice with 100 mL of 1 M HCl, the organic phase was collected, washed with distilled water and brine, dried over anhydrous Na2SO4, filtered, concentrated by vacuum evaporation, and purified by flash column chromatography to obtain 1.92 g of yellow solid compound IV with a yield of 88%. The 1H-NMR and 13C-NMR data are as follows: ¹H-NMR (400 MHz, DMSO-d6): δ 7.57-7.55 (1H, d, J= 7.56), 6.57-6.54(1H, d, J= 6.56), 6.50-6.47 (1H, d, J= 6.48), 5.78-5.73 (1H, d, J= 5.77),4.57-4.54 (2H, t, J= 4.55), 2.73-2.70 (2H, t, J= 2.72), 1.40 (6H, s, J=1.40);13C NMR (150 MHz, DMSO-d6, 300 K): δ (ppm) 190.50, 158.94, 157.96, 130.14,127.90, 115.53, 110.82, 110.82, 109.33, 77.91, 67.87, 37.30, 28.29, 28.29.

[0014] 5.0 g of resorcinol and 5.03 g of 3-chloropropionic acid were stirred at 5 °C. 20.86 trifluoromethanesulfonic acid (3 equiv.) was slowly added to the stirred mixture, and the mixture was heated to 80 °C and kept warm for 30 minutes, then cooled to room temperature, and dichloromethane was added. Water was added for extraction, the organic layer was collected, washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to obtain 5.10 g of an orange crude product with a yield of 58%. The crude product was dissolved in 250 mL of 2 M NaOH solution and refluxed at room temperature for 2 hours. After cooling, it was acidified with 6 M H2SO4, washed with ethyl acetate, and the organic layer was washed with brine and aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated into a brown solid. It was dissolved in ethanol, filtered, and recrystallized from water to obtain 2.53 g of an orange semi-solid compound II with a yield of 70%.

[0015] 2.81 g of compound III was dissolved in 25 ml of xylene and heating was started at 140 °C. 9.18 g of 1,1-dimethoxy-3-methyl-2-butene was added dropwise and 4.22 g of 4-dimethylaminopyridine (DMAP) was added. The reaction mixture was refluxed for 8 hours and monitored by TLC. After the reaction was completed, the solution was cooled to room temperature and extracted three times with ethyl acetate (3 × 50 mL). The organic phase was washed twice with 1 M hydrochloric acid, water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a crude product. The crude product was purified by column chromatography to obtain 2.49 g of a yellow solid compound IV, namely 8,8-dimethyl-2,3-dihydro-4H, 8H -pyrano[2,3-f]chromen-4-one, with a yield of 73%.

[0016] The present invention describes a method for the efficient synthesis of 8,8-dimethyl-2,3-dihydro-4H,8H-pyrano[2,3-f]chromen-4-one. This method has fewer synthesis steps, a high yield, simple operation, low reagent prices, is conducive to academic research and industrial-scale production, and has broad application prospects in organic chemistry and medicinal chemistry. This method has higher efficiency, higher output, and a simplified purification process, has commercial application advantages, and provides a practical and scalable solution for the synthesis of this valuable compound.

Claims

1. A method for synthesizing a pharmaceutical intermediate, characterized in that: Using resorcinol as a raw material, through Friedel-Crafts acylation reaction, intramolecular cyclization, condensation reaction, further cyclization and alkylation reaction, the pharmaceutical intermediate, namely 8,8-dimethyl-2,3-dihydro-4H, 8H-pyrano[2,3-f]chromen-4-one, is obtained.

2. The synthesis method of a pharmaceutical intermediate according to claim 1, wherein It includes the following steps: Step 1: A mixture of resorcinol and 3-chloropropionic acid is stirred at 5 °C, trifluoromethanesulfonic acid is added dropwise, refluxed at 80 °C for 30 minutes, cooled to room temperature, extracted with dichloromethane, the organic layer is washed with brine, the organic layer is dried over anhydrous Na2SO4, filtered, the solvent is removed, and an orange semi-solid compound II is obtained; Step 2: Compound II is dissolved in 2 M NaOH at 5 °C, refluxed at room temperature for 2 hours, then acidified with 12 M HCl, extracted with ethyl acetate, the organic layer is washed with brine, and dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation to obtain a brown solid, dissolved and refined with hexane, filtered, purified by column chromatography, and a white compound III is obtained; Step 3: Compound III is dissolved in an appropriate amount of toluene, 3 equivalents of 1,1-dimethoxy-3-methyl-2-butene and 2 equivalents of 3-methylpyridine are added dropwise, heated to 111 °C, and the reflux reaction is continued for 12 hours. After the reaction is completed, the excess 3-methylpyridine is removed by rotary evaporation. Subsequently, the organic phase is collected after washing with 1 M hydrochloric acid, washed with distilled water and brine, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and purified by column chromatography to obtain a yellow solid compound IV, namely the target product, 8,8-dimethyl-2,3-dihydro-4H, 8H-pyrano[2,3-f]chromen-4-one.

3. The synthesis method of a pharmaceutical intermediate according to claim 2, wherein the reagent trifluoromethanesulfonic acid in step 1 is a catalyst.

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