Synthesis method of Peniterpheyl A
The synthesis of Peniterphenyl A via an organic synthesis route solves the problems of limited quantity and source in existing technologies, and realizes an efficient and simple synthesis method suitable for large-scale production.
Patent Information
- Application Number
- CN202511114605.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-11
- Publication Date
- 2025-11-28
AI Technical Summary
Current technology can only isolate and obtain Peniterphenyl A from microbial metabolites, but the amount is small and the source is limited, which affects subsequent research.
Peniterphenyl A was synthesized via a simple and efficient synthetic route using a series of organic synthesis steps, including silicon protection, bromination, methylation, and oxidative coupling. The intramolecular direct oxidative coupling of the two benzene rings was achieved using a Pd/Ag catalytic system to form a furan ring.
This method enables the large-scale synthesis of Peniterphenyl A, simplifies the production process, avoids dependence on specific strain screening and fermentation conditions, and is suitable for scale-up production to meet the needs of subsequent research.
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Abstract
Description
TECHNICAL FIELD
[0001] The application relates to the technical field of chemical synthesis, in particular to a synthesis method of Peniterphenyl A. BACKGROUND
[0002] Peniterphenyl A is a derivative with a 4-phenyl-dibenzofuran structure skeleton isolated from marine microorganisms by a research group, and the compound has strong anti-herpes virus (HSV1 and 2) activity (J. Nat. Prod. 2021, 84, 2822-2831). The compound is widely present in secondary metabolites of terrestrial plants and marine-derived microorganisms, and has activities such as anti-tumor, antibacterial, glucosidase inhibition, neuroaminidase inhibition, non-alcoholic fatty liver enzyme inhibition, etc. (Mar. Life Sci. Technol. 2022, 4, 62-73). The compound is mainly isolated from the metabolites of microorganisms in the early stage, and the obtained amount is small, which affects the subsequent research. SUMMARY
[0003] The application aims to provide a synthesis method of Peniterphenyl A, and solves the problem that the prior art can only separate and obtain the compound from metabolites of microorganisms, and the amount is small and the source is very limited.
[0004] The application is implemented through the following technical scheme:
[0005] The synthesis method of Peniterphenyl A is as follows:
[0006]
[0007] The method comprises the following steps:
[0008] Step 1: 2,5-dihydroxybenzaldehyde (compound 1) is reacted with triisopropylsilyl at room temperature to obtain a single-silyl-protected intermediate 2;
[0009] Step 2: Intermediate 2 is subjected to a bromination reaction with liquid bromine at 0 DEG C under alkaline conditions to obtain an intermediate 3;
[0010] Step 3: Intermediate 3 is subjected to a methylation reaction with methyl iodide at 5 DEG C, and then a triisopropylsilyl protecting group is removed by using tetrabutylammonium fluoride (TBAF) to obtain an intermediate 4;
[0011] Step 4: Intermediate 4 is reacted with an intermediate 5 at 80-120 DEG C to obtain an intermediate 6;
[0012] Step 5: At 60–100 °C and under the catalysis of palladium catalyst and in a nitrogen atmosphere, intermediate 6 reacts with p-tert-butyl ether phenylboronic acid (compound 7) to obtain intermediate 8;
[0013] Step 6: Intermediate 8 is oxidized by m-chloroperoxybenzoic acid (mCPBA), then hydrolyzed under alkaline conditions, and then reacted with pivaloyl chloride to obtain intermediate 9;
[0014] Step 7: Under heating conditions of 100-160°C in pivalic acid, intermediate 9 is cyclized in a palladium / silver catalyst system to obtain intermediate 10;
[0015] Step 8: Intermediate 10 is first deprotected by the tert-butyl protecting group under acidic conditions, then hydrolyzed by the tert-valerate group under alkaline conditions, and then the benzyl protecting group is removed by the Pd / C reduction system to obtain the final target compound Peniterphenyl A (compound 11).
[0016] The alkaline conditions in the second step include reagents such as triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, imidazole, etc.
[0017] The reaction solvent in the fourth step is one of acetone, DMF, and DMA, with DMF being preferred.
[0018] The palladium catalyst in the fifth step reaction is one of Pd(PPh3)4, Pd(OAc)2 / PPh3, Pd(PPh3)2Cl2, etc.
[0019] The alkaline conditions in steps six and eight include one of the following reagents: Na₂CO₃, K₂CO₃, LiOH, NaOH, KOH, etc.
[0020] The palladium / silver catalysts in step seven are Pd(OAc)2 / AgOAc, Pd(TFA)2 / AgOAc, and Pd(OC)2 / AgOAc. t One of Bu)2 / AgOAc, Pd(acac)2 / AgOAc, etc.
[0021] The Pd / C reduction system in step eight includes one of the reduction systems formed by using 5% or 10% Pd / C with hydrogen, ammonium formate, or ammonium acetate, respectively.
[0022] In step 8, the acidic conditions used are one of dilute hydrochloric acid, dilute sulfuric acid, and trifluoroacetic acid, with trifluoroacetic acid being preferred.
[0023] The beneficial effects of this invention are as follows: This invention proposes a simple and efficient synthesis process for the first time. The key structural unit, the furan ring, is synthesized by first achieving the synthesis of diphenyl ether through a simple heating substitution reaction of a phenol derivative with a fluorobenzene derivative. Then, under a Pd / Ag catalytic system, the intramolecular diphenyl ring is directly oxidatively coupled by C-C to synthesize the furan ring. Due to steric hindrance and directing group effects, the product has high selectivity, requiring no harsh reaction conditions. The synthesis steps are simple and suitable for scale-up production. Compared with obtaining low-quantity target compounds from microbial fermentation, it does not require extensive screening of specific strains and fermentation conditions. Moreover, it is simple and efficient, ensuring a large number of compounds required for subsequent research and development. Detailed implementation method:
[0024] The following is a further description of the invention, but not a limitation thereof.
[0025] Example 1: Synthesis of Intermediate 2
[0026]
[0027] At room temperature (25°C), 3.7 g (55.55 mmol, 3 equivalents) of imidazole, 2.76 g (20 mmol, 1.1 equivalents) of 2,5-dihydroxybenzaldehyde, and 444 mg (3.64 mmol, 0.2 equivalents) of DMAP were dissolved in dichloromethane, and 3.89 mL (18 mmol, 1 equivalent) of triisopropylchlorosilane (TIPSCl) was added dropwise to the above solution. After the reaction was complete, dichloromethane was added, the organic phase was washed three times with water, dried over anhydrous MgSO4, and the residue after solvent removal was purified by silica gel column chromatography to obtain 4.12 g of the target compound (77% yield).
[0028] Example 2: Synthesis of Intermediate 3
[0029]
[0030] At 0 °C, 860 mg (2.9 mmol, 1.0 equivalent) of intermediate 2 and 0.47 mL (5.8 mmol, 2.0 equivalent) of pyridine were dissolved in dichloromethane. 2.9 mL (5.8 mmol, 2 equivalent) of liquid bromine was dissolved in dichloromethane and then slowly added dropwise to the above solution. After completion, a saturated solution of Na₂S₂O₃ was added to remove residual Br₂, followed by the addition of dichloromethane. The organic phase was washed three times with water, dried over anhydrous MgSO₄, and the residue after solvent removal was purified by silica gel column chromatography to obtain 760 mg (70% yield).
[0031] Example 3: Synthesis of Intermediate 4
[0032]
[0033] At 5°C, 1.5 g (4 mmol, 1 equivalent) of intermediate 3 was dissolved in DMF, and 1.1 g (8 mmol, 2 equivalents) of K2CO3 and 0.5 mL (8 mmol, 2 equivalents) of iodomethane (MeI) were added. After the reaction was complete, ethyl acetate was added to the reaction solution and stirring was continued. Then, distilled water was added, the organic layer was washed three times with water, dried over MgSO4, and ethyl acetate and DMF were removed under reduced pressure. The residue was dissolved in THF, and 4 mL of 1 M (4 mmol, 1 equivalent) tetrabutylammonium fluoride (TBAF) solution was slowly added dropwise at room temperature (25°C). After the reaction was complete, the solvent was removed under reduced pressure, ethyl acetate was added, the organic layer was washed three times with water, dried over anhydrous MgSO4, and the residue after solvent removal was purified by silica gel column chromatography to give 700 mg (yield 76%).
[0034] Example 4: Synthesis of Intermediate 6
[0035]
[0036] 448 mg (1.95 mmol, 1 equivalent) of intermediate 4 and 807 mg (3.51 mmol, 1.8 equivalent) of intermediate 5 were mixed and dissolved in DMF, and 807 mg (5.85 mmol, 3 equivalent) of K2CO3 was added. The mixture was stirred overnight (16 hours) at 100 °C. After the reaction was complete, the solvent was removed under reduced pressure, ethyl acetate was added, the organic layer was washed three times with water, dried over anhydrous MgSO4, and the residue after solvent removal was purified by silica gel column chromatography to give 1.05 g (yield 93%).
[0037] Example 5: Synthesis of Intermediate 8
[0038]
[0039] 300 mg (0.68 mmol, 1 equivalent) of intermediate 6 and 265 mg (1.36 mmol, 2 equivalents) of compound 7 were mixed and dissolved in a DMF / H2O (v / v = 4 / 1) solvent system. 282 mg (2.04 mmol, 3 equivalents) of K2CO3, 30 mg (0.136 mmol, 0.2 equivalents) of Pd(OAc)2, and 90 mg (0.34 mmol, 0.5 equivalents) of PPh3 were added. The reaction system was subjected to nitrogen atmosphere and reacted overnight (16 hours) at 80 °C. After the reaction was complete, the solvent was removed under reduced pressure, ethyl acetate was added, the organic layer was washed three times with water, dried over anhydrous MgSO4, and the residue after solvent removal was purified by silica gel column chromatography to give 300 mg (yield 86%).
[0040] Example 6: Synthesis of Intermediate 9
[0041]
[0042] At room temperature (25°C), 95 mg (0.48 mmol, 4 equivalents, 85% content) of m-chloroperoxybenzoic acid (mCPBA) was added in portions to a dichloromethane system containing 60 mg (0.12 mmol, 1 equivalent) of intermediate 8, and the reaction was allowed to proceed overnight (16 hours). After the reaction was complete, saturated Na2S2O3 aqueous solution was added to remove excess mCPBA, followed by the addition of dichloromethane. The organic layer was washed three times with water, and the residue after solvent removal was dissolved in methanol. 0.48 mL (0.96 mmol, 8 equivalents) of 2M NaOH solution was added to hydrolyze the formyl group. After the reaction was complete, the solvent was removed, and the residue was rapidly passed through a short silica gel column using ethyl acetate / petroleum ether (10 / 1 = v / v) as the mobile phase. The crude product obtained was dissolved in dichloromethane. At 0 °C, 65 μL (0.48 mmol, 4 equivalents) of triethylamine and a catalytic amount (1 mg) of DMAP were added. 59 μL (0.48 mmol, 4 equivalents) of pivaloyl chloride was slowly added dropwise to the above solution. After the reaction was complete, the solvent was removed under reduced pressure, ethyl acetate was added, and the organic layer was washed three times with water. The residue was dried over anhydrous MgSO4. The residue after solvent removal was purified by silica gel column chromatography to obtain 300 mg (overall yield 38%).
[0043] Example 7: Synthesis of Intermediate 10
[0044]
[0045] 16 mg (0.0245 mmol, 1 equivalent) of intermediate 9 was dissolved in tervaline, and 2.4 mg (7.35 μmol, 0.3 equivalent) of palladium trifluoroacetate (Pd(TFA)2) and 8.2 mg (0.049 mmol, 2 equivalent) of silver acetate (AgOAc) were added. The mixture was reacted at 130 °C for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water and dried over anhydrous MgSO4. The residue after solvent removal was purified by silica gel column chromatography to obtain 9.6 mg (overall yield 60%).
[0046] Example 8: Synthesis of Penyterphenyl A(11)
[0047]
[0048] At room temperature (25℃), 20 mg (0.031 mmol, 1 equivalent) of intermediate 10 was dissolved in dichloromethane, and 30 μL of trifluoroacetic acid was added and stirred. After the reaction was completed, the solvent and excess trifluoroacetic acid were removed under reduced pressure. The residue was dissolved in methanol, and 0.12 mL (0.25 mmol, 8 equivalent) of 2M NaOH solution was added to hydrolyze the penyteryl group. After the reaction was completed, the solvent was removed, and the residue was dissolved in ethyl acetate. The organic layer was washed three times with water and dried over anhydrous MgSO4. The residue after removing the solvent was dissolved in methanol, and 4 mg (20%, mass fraction) of 10% Pd / C and 6 mg (0.093 mmol, 3 equivalent) of ammonium formate were added. The reaction was carried out at 85℃ for 1 hour. After the reaction was completed, the methanol was removed under reduced pressure, and ethyl acetate was added. The organic layer was washed three times with water and dried over anhydrous MgSO4. The residue after removing the solvent was purified by silica gel column chromatography to obtain 6.5 mg (total yield 64%) of Penyterphenyl A (11). 1 HNMR (500MHz, MeOD) δ7.48 (s, 1H), 7.47 (d, J = 8.8Hz, 2H), 6.93 (s, 1H), 6.88–6.83 (m, 3H), 3.40 (s, 3H). 13 CNMR(126MHz,MeOD)δ157.9,155.0,152.0,146.5,145.8,143.0,141.2,133.8 ,131.3,116.6,116.1,113.9,108.6,103.7,98.9,61.0.HRMS-ESI(m / z):Calcd for C 19 H 13 O6[MH] + 337.0718, Found 337.0726.
Claims
1. A method for synthesizing PeniterphenylA, characterized in that, The synthesis route is as follows: Includes the following steps: Step 1: At room temperature, 2,5-dihydroxybenzaldehyde reacts with triisopropylsilyl groups to obtain intermediate 2 protected by a monosilyl group; Step 2: Under alkaline conditions, intermediate 2 reacts with liquid bromine at 0°C to produce intermediate 3; Step 3: At 5°C, intermediate 3 undergoes a methylation reaction with iodomethane, and then the triisopropylsilyl protecting group is removed using tetrabutylammonium fluoride to obtain intermediate 4; Step 4: At 80-120℃, intermediate 4 reacts with intermediate 5 to obtain intermediate 6; Step 5: At 60–100 °C and under the catalysis of palladium catalyst and in a nitrogen atmosphere, intermediate 6 reacts with p-tert-butyl ether phenylboronic acid to obtain intermediate 8; Step 6: Intermediate 8 is oxidized by m-chloroperoxybenzoic acid, then hydrolyzed under alkaline conditions, and then reacted with pivaloyl chloride to obtain intermediate 9; Step 7: Under heating conditions of 100-160°C in pivalic acid, intermediate 9 is cyclized in a palladium / silver catalyst system to obtain intermediate 10; Step 8: Intermediate 10 is first deprotected by the tert-butyl protecting group under acidic conditions, then hydrolyzed by the tert-valerate group under alkaline conditions, and finally deprotected by the benzyl protecting group using a Pd / C reduction system to obtain the final target compound PeniterphenylA.
2. The method according to claim 1, characterized in that, The alkaline conditions in the second step include one of the following reagents: triethylamine, N,N-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and imidazole.
3. The method according to claim 1, characterized in that, The reaction solvent in step four is one of acetone, DMF, or DMA.
4. The method according to claim 1, characterized in that, The palladium catalyst in the fifth step reaction is one of Pd(PPh3)4, Pd(OAc)2 / PPh3, or Pd(PPh3)2Cl2.
5. The method according to claim 1, characterized in that, The alkaline conditions in steps six and eight include one of the following reagents: Na₂CO₃, K₂CO₃, LiOH, NaOH, and KOH.
6. The method according to claim 1, characterized in that, The palladium / silver catalyst in step seven is one of Pd(OAc)2 / AgOAc, Pd(TFA)2 / AgOAc, Pd(OCtBu)2 / AgOAc, and Pd(acac)2 / AgOAc.
7. The method according to claim 1, characterized in that, The Pd / C reduction system in step 8 includes reduction systems formed by using 5% or 10% Pd / C with hydrogen, ammonium formate, or ammonium acetate, respectively.
8. The method according to claim 1, characterized in that, In step eight, the acidic conditions used are one of dilute hydrochloric acid, dilute sulfuric acid, or trifluoroacetic acid.