Method for synthesizing Lamellarin key intermediate
By reacting 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives with phenylacetonitrile and copper compounds, the problems of complex and high cost in the synthesis route of Lamellarin compounds were solved, and efficient and low-cost large-scale production was achieved.
Patent Information
- Application Number
- CN202510741718.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-05
- Publication Date
- 2025-09-30
AI Technical Summary
The existing chemical synthesis routes of Lamellarin compounds are complex, with expensive raw materials, unsatisfactory yields, high costs, and difficulty in large-scale production.
Lamellarin key intermediates were prepared by reacting 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives with benzyl cyanide and copper compounds in a specific solvent. Lamellarin compounds were then synthesized through oxidation, hydrolysis and intramolecular cyclization steps.
The raw materials are readily available, the cost is low, the reaction conditions are mild, the yield is high, the purity is high, the process is simple, and it is suitable for large-scale production, providing a cheap source of Lamellarin compounds.
Smart Images
Figure CN120718014A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a key intermediate of Lamellarin. Background Art
[0002] Lamellarin compounds are a class of polyaromatic pyrrole alkaloids isolated from marine mollusks. Many of these compounds and their analogs exhibit promising anti-tumor drug candidates, including inhibition of tumor cell proliferation and reversal of p-glycoprotein-mediated multidrug resistance. For example, at non-cytotoxic doses, lamellarin I can directly inhibit p-glycoprotein-mediated drug efflux, thereby reversing multidrug resistance. Lamellarin D exhibits potent anti-tumor activity and is an inhibitor of human topoisomerase I. Furthermore, researchers have studied the immunomodulatory effects of lamellarin K and L in the micromolar range, and lamellarin α-20-sulfate is a promising candidate for inhibiting HIV integrase at non-cytotoxic concentrations.
[0003] Lamellarin compounds have such excellent pharmacological activity, but their content in marine organisms is extremely low, and it is unrealistic to obtain them solely through extraction. Therefore, obtaining them through chemical synthesis is a very valuable direction.
[0004] The main synthetic methods for lamellarins include the N-ylide method, the Michael addition method, and the Hinsberg pyrrole synthesis. The Michael addition method uses benzyldihydroisoquinoline as the starting material. The Michael addition method completes the pyrrole cyclization, followed by deprotection and lactonization to synthesize a variety of lamellarins. This method offers the highest yield of 61% and is the most convenient compared to other methods. However, the starting materials are complex, difficult to obtain, and expensive. The Hinsberg pyrrole synthesis method uses substituted phenylethylamines as starting materials. After N-disubstitution with methyl bromoacetate, the pyrrole is cyclized with dimethyl oxalate to form a pyrrole. Lamellarins D, N, and L are synthesized using a Pd-catalyzed Suzuki-Miyaura coupling reaction. The overall yield is 50%, which is not ideal, and the expensive metal Pd catalyst is used. The remaining methods also face the same dilemma: complex synthetic routes, low yields, and expensive starting materials or catalysts. Summary of the Invention
[0005] In response to the problems existing in the prior art, the present invention provides a method for preparing a key intermediate of Lamellarin. The method comprises reacting 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or a derivative thereof, benzyl cyanide and a copper compound in the presence of a solvent at 70°C-150°C to prepare the key intermediate of Lamellarin.
[0006] The preparation reaction formula of the key intermediate of Lamellarin found in this study is as follows: ; wherein R1 is selected from hydrogen, C 1-3 Saturated chain alkyl, methoxy, bis-ethyleneoxy, halogen, trifluoromethyl, benzene ring; R2 is selected from hydrogen, C 1-3 Alkyl, halogen.
[0007] The molar ratio of 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives:phenylacetonitrile is 1:(1.5-2.5), and the molar ratio of 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives:copper compound is 1:(0.5-2).
[0008] The copper compound is selected from CuI, [(CH3CN)4Cu]PF6, CuBr, CuCl, CuTc, CuOAc, CuCN, Cu2O, CuSCN, CuBr2, Cu(CF3SO3)2, and Cu2(OH)2CO.
[0009] The solvent is selected from N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene, acetonitrile, 1,4-dioxane, and N-methyl-2-pyrrolidone.
[0010] The 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives are prepared according to the method in the document "Acid-Promoted Redox-Annulation toward 1,2-Disubstituted-5,6-dihydropyrrolo[2,1-α]isoquinolines: Synthesis of the Lamellarin Core".
[0011] The above compound II can be synthesized into Lamellarin and its derivatives through the steps of oxidation, hydrolysis, and intramolecular cyclization: .
[0012] The beneficial effects of the present invention are: The starting material, 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives, is prepared according to the method described in the literature "Acid-Promoted Redox-Annulation toward 1,2-Disubstituted-5,6-dihydropyrrolo[2,1-α]isoquinolines: Synthesis of the Lamellarin Core." The raw materials are readily available. The cyanation reagent used is commercially available benzyl cyanide, which is harmless, inexpensive, and highly soluble in common organic solvents. The subsequent synthetic route is simple, requiring only hydrolysis, intramolecular cyclization, and deprotection.
[0013] The present invention has low cost, readily available raw materials, relatively mild reaction conditions, high reaction yield, high purity, simple and easy process, is relatively environmentally friendly, safe and reliable, is suitable for large-scale synthesis, can be used to prepare related products in the fields of biology, pesticides and medicine, and provides Lamellarin compounds with abundant sources and low prices. DETAILED DESCRIPTION
[0014] The present invention will be further described below with reference to the examples. However, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. The instruments, reagents, and materials involved in the following examples, unless otherwise specified, are all conventional instruments, reagents, and materials already in the prior art and can be obtained through regular commercial channels; the experimental methods, detection methods, etc. involved in the following examples, unless otherwise specified, are all conventional experimental methods and detection methods already in the prior art; The chemical reaction formula for preparing the key intermediate of Lamellarin in the embodiment is as follows: Example 1
[0015] 1. 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline (0.2 mmol), benzyl cyanide (0.4 mmol), and cuprous iodide (0.24 mmol) were placed in a reaction tube, and DMF (2 mL) was added. The mixture was heated to 130°C for 12 hours. After the reaction was completed, the solvent was removed by TLC. The reaction product was distilled off under reduced pressure at 40°C and purified by flash chromatography using petroleum ether-ethyl acetate (volume ratio 4:1) as the eluent to obtain compound IIa as a white solid (52.7 mg, 76%). IIa ; 1HNMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 3H), 7.25 (s, 1H), 7.24 -7.18(m, 7H), 7.15 (dd,J = 7.7, 4.1 Hz, 1H), 6.97 (d, J = 4.3 Hz, 2H), 4.28 (t, J= 6.6 Hz, 2H), 3.20 (t, J = 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 134.5,134.3, 132.5, 132.0, 131.1, 130.8, 129.2,128.8, 128.3, 128.2, 127.7, 127.4,127.0, 125.1, 121.5, 114.4, 101.7, 43.2, 29.3. 2. Compound IIa (0.1 mmol) was dissolved in dichloromethane (6 mL), and DDQ (0.051 g, 0.2 mmol) was added. The mixture was stirred at room temperature for 4 hours, quenched with water, extracted with dichloromethane, washed with brine, and the combined dichloromethane phases were collected and dried over anhydrous sodium sulfate. The concentrate was concentrated under reduced pressure at 40°C, and purified by preparative thin-layer chromatography (P-TLC) (developing solvent: ethyl acetate: n-hexane = 1:1.5) to obtain compound III (32.7 mg, 95%). ; 3. Compound III (1 mmol) was added to water (808.6 mg, 44.61 mmol) and stirred. Sodium hydroxide solution (30%, 1.1 mol) was slowly added at 80°C. The temperature was raised to 100°C and refluxed for 3 h. Dilute hydrochloric acid (30%, 1.1 mol) was slowly added thereto. The mixture was then cooled in an ice-water bath for crystallization for 1 h. The filter cake was washed with a small amount of water and dried at 60°C to obtain compound IV (345.3 mg, 95%). ; 4. Compound IV (0.2 mmol), Pd(OAc)2 (0.01 mmol, 5 mol%), acetylglycine (0.03 mmol), KOAc (0.4 mmol), PhI(OAc)2 (0.4 mmol), and tert-butanol (4.0 mL) were added to a sealed tube. The reaction tube was sealed and stirred at 80°C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure at 40°C to remove the solvent. The product was purified by silica gel column chromatography using petroleum ether-ethyl acetate-dichloromethane = 8:2:1 as eluent. The eluate was collected and dried to obtain Lamellarin (67.2 mg, 93%). . Example 2
[0016] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline in step 1 is replaced with 5,6-dihydro-2-(4-methylphenyl)-1-phenylpyrrolo[2,1-a]isoquinoline to obtain compound IIb as a white solid (53.3 mg, 74%). IIb ; 1H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 3H), 7.24 (s, 1H), 7.23-7.20(m, 2H), 7.15 (td, J = 4.9, 4.2, 2.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 7.05(d, J = 8.2 Hz, 2H), 6.98-6.92 (m, 2H), 4.26 (dd, J = 7.1, 6.0 Hz, 2H), 3.19(t, J = 6.6 Hz, 2H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 137.1, 134.6,134.5, 132.6, 131.0, 130.9, 129.1, 129.0, 129.0, 128.8, 128.2, 127.7, 127.7,127.4, 127.0, 125.1, 121.3, 114.6, 101.6, 43.2, 29.3, 21.3. Example 3
[0017] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 5,6-dihydro-2-(4-propylphenyl)-1-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound IIc as a white solid (54.4 mg, 70%). IIc ; 1H NMR (300 MHz, CDCl3) δ 7.32 (ddt, J = 5.3, 3.8, 2.2 Hz, 3H), 7.25-7.19 (m, 3H), 7.28-7.18 (m, 3H), 7.14 (dd, J = 8.2 Hz, 2H), 7.10-6.99 (m,2H), 4.27 (d, J = 7.1, 6.0 Hz, 2H), 3.21 (t, J = 6.6 Hz, 2H), 2.52 (dd, J =8.7, 6.7 Hz, 2H), 1.69-1.53 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75MHz, CDCl3) δ 161.8, 144.6, 144.4, 142.5, 141.0, 136.8, 136.1, 134.9, 132.7,131.4, 130.2, 127.7, 127.6, 127.3, 126.9, 125.1, 121.3, 114.6, 101.5, 43.1,37.7, 29.3, 24.3, 13.9. Example 4
[0018] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 5,6-dihydro-2-(3,5-dimethylphenyl)-1-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound IId as a white solid (42.7 mg, 57%). IId ; 1H NMR (300 MHz, CDCl3) δ 7.35-7.28 (m, 3H), 7.25-7.19 (m, 3H), 7.15(ddd, J = 7.5, 5.1, 3.5 Hz, 1H), 6.98 (dd, J = 3.7, 1.0 Hz, 2H), 6.89 (dd, J = 1.6 Hz, 1H), 6.79 (dd, J = 1.6 Hz, 2H), 4.27 (d, J = 6.9, 6.0 Hz, 2H), 3.20 (t, J = 6.6 Hz, 2H), 2.19 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 147.6, 144.7,144.5, 139.5, 138.7, 135.9, 135.8, 132.1, 131.6, 131.2, 127.8, 127.6, 127.3,127.0, 127.0, 125.1, 121.5, 114.5, 101.6, 43.2, 29.3, 21.3. Example 5
[0019] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 5,6-dihydro-2-(4-bromophenyl)-1-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound IIe as a white solid (62.9 mg, 74%). Ⅱe ; 1H NMR (300 MHz, CDCl3) δ 7.41-7.28 (m, 5H), 7.26-7.15 (m, 4H), 7.11-7.01 (m, 2H), 6.89 (d, J = 6.2 Hz, 2H), 4.31 (t, J = 6.6 Hz, 2H), 3.19 (t, J= 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 147.5, 134.0, 133.2, 132.5, 131.5,131.2, 131.0, 130.9, 130.8, 130.7, 128.9, 128.2, 127.9, 127.6, 127.5, 127.1,125.1, 121.6, 121.4, 114.2, 101.6, 43.3, 29.2. Example 6
[0020] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 5,6-dihydro-2-(4-trifluoromethylphenyl)-1-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound IIf as a yellow solid (59.7 mg, 72%). IIf ; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 8.4 Hz, 2H), 7.41-7.28 (m,6H), 7.23-7.13 (m, 3H), 7.03-6.92 (m, 2H), 4.30 (t, J = 6.6 Hz, 2H), 3.22 (t,J = 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 145.7, 145.7, 143.8, 142.8, 142.5,141.3, 139.7, 139.3, 139.0, 138.3, 135.0, 132.9, 131.7, 131.4, 130.1, 125.9,125.4, 125.3, 125.3, 125.2, 125.1, 122.3, 121.5, 114.0, 101.9, 43.3, 29.2.19FNMR (282 MHz, CDCl3)δ =62.5. Example 7
[0021] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 5,6-dihydro-2-(4-methoxyphenyl)-1-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound II g as a white solid (51.9 mg, 69%). Ⅱg ; 1H NMR (300 MHz, CDCl3) δ 7.35-7.29 (m, 3H), 7.24-7.19 (m, 3H), 7.18-7.10 (m, 3H), 6.99-6.93 (m, 2H), 6.81-6.75 (m, 2H), 4.26 (dd, J = 7.1, 6.0Hz, 2H), 3.76 (s, 3H), 3.19 (t, J = 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ158.8, 154.4, 144.3, 142.5, 141.0, 136.8, 136.3, 134.7, 134.2, 131.7, 127.6,127.3, 126.9, 125.0, 124.3, 121.2, 114.6, 113.7, 101.4, 55.1, 43.1, 29.3. Example 8
[0022] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline in step 1 is replaced with 5,6-dihydro-2-(1,3-benzodioxole)-1-phenylpyrrolo[2,1-a]isoquinoline to obtain compound IIh, a colorless liquid (31.7 mg, 40%). IIh ; 1H NMR (300 MHz, CDCl3) δ 7.78 (dt, J = 7.9, 3.4 Hz, 3H), 7.35 (dtd,J = 14.3, 6.9, 3.8 Hz, 4H), 7.26-7.14 (m, 3H), 7.09 (q, J = 2.4, 1.9 Hz, 5H), 6.99 (td, J = 7.6, 1.4 Hz, 1H), 4.36-4.21 (m, 2H), 3.23 (dd, J = 7.9, 5.4 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 144.1, 143.5, 143.4, 138.5, 137.1, 134.6,133.1, 129.8, 128.8, 128.4, 128.3, 128.3, 128.1, 127.7, 127.7, 127.0, 125.9,125.7, 125.1, 125.1, 123.2, 113.7, 103.5, 43.3, 29.3. Example 9
[0023] The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 5,6-dihydro-2-(1,3-benzodioxole)-1-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound IIi, a colorless liquid (32.1 mg, 41%). Ⅱi ; 1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 3H), 7.25-7.12 (m, 4H), 7.01-6.91 (m, 2H), 6.72 (t, J = 1.2 Hz, 2H), 6.63 (t, J = 1.0 Hz, 1H), 5.91 (s,2H), 4.26 (dd, J = 7.1, 6.0 Hz, 2H), 3.20 (t, J = 6.6 Hz, 2H). 13C NMR (75MHz, CDCl3) δ 147.4, 146.9, 144.3, 144.2, 138.5, 137.0, 136.8, 131.8, 130.2,127.7, 127.6, 127.4, 127.0, 125.7, 125.1, 123.0, 121.3, 114.4, 109.6, 108.3,101.6, 101.0, 43.2, 29.3. Example 10 The method of this example is the same as that of Example 1, except that 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 9-methyl-5,6-dihydro-1,2-phenylpyrrolo[2,1-a]isoquinoline in step 1 to obtain compound IIj, a white solid (51.1 mg, 71%). IIj ; 1H NMR (300 MHz, CDCl3) δ 7.36-7.28 (m, 3H), 7.23 (s, 7H), 7.13 (d, J= 7.7 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.74 (s, 1H), 4.26 (t, J = 6.8 Hz, 2H), 3.25 (t, J = 6.6 Hz, 2H), 2.13 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 146.5,144.4, 142.0, 141.3, 138.9, 136.5, 134.2, 131.6, 130.4, 130.3, 129.0, 128.5,127.3, 125.8, 121.4, 114.5, 101.6, 43.4, 28.9, 21.1. Example 11 The method of this example is the same as that of Example 1, except that in step 1, 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline is replaced with 9-chloro-5,6-dihydro-1-(4-methoxyphenyl)-2-phenylpyrrolo[2,1-a]isoquinoline to obtain compound IIk as a white solid (57.5 mg, 70%). Ⅱk ; 1H NMR (300 MHz, CDCl3) δ 7.15 (dd, J = 1.3 Hz, 3H), 7.13 (dd, J =3.8 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.25 – 7.16 (m, 3H), 6.98 (d, J = 2.0Hz, 1H), 6.93 – 6.84 (m, 2H), 4.27 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.16(t, J = 6.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 159.1, 144.6, 142.8, 139.8,136.7, 130.7, 129.8, 129.4, 129.3, 129.2, 128.4, 127.5, 125.6, 124.9, 121.8,114.4, 114.2, 102.1, 55.3, 43.1, 28.8. Example 12 The method of this embodiment is the same as that of Example 1, except that 130°C in step 1 is replaced by 110°C. The product is 43.0 mg, 62%.
[0024] Example 13 The method of this example is the same as that of Example 1, except that DMF in step 1 is replaced by N-Methyl-2-pyrrolidone, and the product is 42.3 mg, 61%.
[0025] Example 14 The method of this example is the same as that of Example 1, except that CuI (0.24 mmol) in step 1 is replaced by CuI (0.4 mmol), and the product is 51.3 mg, 74%.
[0026] Example 15 The method of this embodiment is the same as that of Example 1, except that CuI in step 1 is replaced by Cu2O, and the target product is 26.3 mg, 38%.
Claims
1. A method for synthesizing a key intermediate of Lamellarin, characterized in that: Lamellarin key intermediate is prepared by reacting 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives, benzyl cyanide and copper compound in the presence of a solvent at 70°C-150°C; ； wherein R1 is selected from hydrogen, C 1-3 Alkyl, methoxy, bis(ethyleneoxy), halogen, trifluoromethyl, benzene ring; R2 is selected from hydrogen, C 1-3 Alkyl, halogen.
2. the method for the synthetic Lamellarin key intermediate according to claim 1, is characterized in that: The molar ratio of 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives:phenylacetonitrile is 1:(1.5-2.5), and the molar ratio of 5,6-dihydro-1,2-diphenylpyrrolo[2,1-a]isoquinoline or its derivatives:copper compound is 1:(0.5-2).
3. the method for the synthetic Lamellarin key intermediate according to claim 1, is characterized in that: The copper compound is selected from CuI, [(CH3CN)4Cu]PF6, CuBr, CuCl, CuTc, CuOAc, CuCN, Cu2O, CuSCN, CuBr2, Cu(CF3SO3)2, and Cu2(OH)2CO.
4. the method for the synthetic Lamellarin key intermediate according to claim 1, is characterized in that: The solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, toluene, acetonitrile, 1,4-dioxane, and N-methyl-2-pyrrolidone.