3-fluoroisoquinoline-4-alcohol compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a 3-fluoroisoquinoline-4-alcohol compound and a preparation method and application thereof.The preparation method comprises the steps that substituted 2-azido-2-fluoro-2, 3-dihydro-1H-indene-1-ketone reacts with a solvent; adding an extracting agent for extraction, taking an organic phase, drying, filtering and concentrating to obtain a crude product; and purifying to obtain the 3-fluoroisoquinoline-4-alcohol compound. The solvent is prepared from dimethyl sulfoxide, N, N-dimethyl formamide, acetonitrile, isopropanol, tetrahydrofuran, 1, 4-dioxane, dichloromethane and chloroform. Compared with the prior art, the invention solves the problems that the synthesis of isoquinoline compounds in the prior art needs multi-step reaction, the reaction conditions are harsh, and the tolerance of functional groups is poor. According to the scheme, the 3-fluoroisoquinoline-4-alcohol compound is obtained through one-step chemical reaction, and the method has the advantages that raw materials are simple and easy to obtain, the substrate range is wide, the reaction is mild, the yield is high and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and in particular relates to a 3-fluoroisoquinoline-4-ol compound, its preparation method and application. Background Technology

[0002] Isoquinoline compounds are an important class of nitrogen-containing heterocyclic compounds, widely found in natural alkaloids, and possess a variety of biological activities, including antibacterial, antitumor, anti-inflammatory, anticancer, antioxidant, cholesterol-lowering, anti-hyperglycemic, and neuroprotective effects. Isoquinoline alkaloids, as lead compounds in drug discovery and development, have a high success rate, as seen in drugs such as the analgesic morphine, the antibacterial berberine, the antitussive codeine, and the acetylcholinesterase inhibitor galantamine. Therefore, developing new isoquinoline compounds as promising drug leads remains an active area of ​​research in organic synthetic chemistry and medicinal chemistry.

[0003] Currently, the main synthetic methods for isoquinoline derivatives reported in the literature are: (1) Bischler-Napieralski, Pomeranz-Fritsch, Pictet-Gams, and Pictet-Spengler reactions; (2) intramolecular cyclization reactions of ortho-alkynyl oximes, imines, and amides; (3) intermolecular cyclization reactions of alkynyl ketones with nitriles or amines, 2-halobenzomidines or ketimines with alkynes, CH / NH activated aryl imines, amides or oximes with alkynes; and multi-component reactions of aldehydes or ketones with amines and isocyanates. In addition, patent CN118026930A uses commercially available nitriles and carbonyl-functionalized aryl halides as raw materials to synthesize isoquinoline derivatives using a reductive coupling strategy; patent CN116813611A obtains three berberine-type isoquinoline alkaloids from the whole herb of Coptis chinensis through extraction, separation, and purification.

[0004] However, most of the reported methods currently available suffer from the need for multi-step preparation of raw materials, demanding reaction conditions (such as the use of precious metals like silver, rhodium, palladium, and gold), or strong acids and bases, and poor functional group tolerance. Therefore, developing new reaction types with broad substrate applicability using readily available substrates and inexpensive metal catalysts to efficiently and selectively synthesize structurally diverse isoquinoline derivatives remains of significant scientific importance and holds promising application prospects. Summary of the Invention

[0005] The purpose of this invention is to address at least one of the aforementioned problems by providing a 3-fluoroisoquinoline-4-ol compound, its preparation method, and its applications. This addresses the issues of existing isoquinoline compound synthesis requiring multiple steps, demanding reaction conditions, and poor functional group tolerance. This method uses substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one as a starting material to obtain 3-fluoroisoquinoline-4-ol compounds through a one-step chemical reaction. This method offers advantages such as readily available and simple starting materials, a broad substrate range, mild reaction conditions, and high yield.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] The first aspect of this invention discloses a method for preparing 3-fluoroisoquinoline-4-ol compounds, comprising the following steps:

[0008] The substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one was mixed with a solvent, and the reaction occurred.

[0009] After the reaction is complete, an extractant is added for extraction. The organic phase is dried with a drying agent, filtered, and concentrated to obtain the crude product.

[0010] The crude product was purified to obtain the 3-fluoroisoquinoline-4-ol compounds described above.

[0011] The solvents include dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, and chloroform.

[0012] Preferably, the substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one has the structural formula shown in Formula I:

[0013]

[0014] In the formula, R is benzyloxy, methoxy, dimethoxy, methyl, tert-butyl, chloro, fluoro, bromine, or no group.

[0015] Preferably, the solvent is one or more selected from dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, and chloroform.

[0016] Preferably, the ratio of the substituted 2-azido-2-fluoro-2,3-dihydro-1H-indene-1-one to the solvent is 1 g: 1-100 mL.

[0017] Preferably, the reaction temperature is 1-100℃ and the time is 1-12 hours.

[0018] Preferably, the reaction is carried out at a temperature of 80°C for 12 hours.

[0019] Preferably, the reaction process is monitored by thin-layer chromatography (TLC).

[0020] Preferably, the extractant is water and ethyl acetate, and the drying agent is anhydrous sodium sulfate.

[0021] Preferably, the extraction is performed at least three times, and the organic phases obtained from each extraction are collected, combined, and dried.

[0022] Preferably, the purification is performed by: purifying the crude product by silica gel column chromatography, followed by elution with petroleum ether / ethyl acetate as the eluent to obtain the 3-fluoroisoquinoline-4-ol compound.

[0023] The second aspect of this invention discloses a 3-fluoroisoquinoline-4-ol compound, which is prepared by the preparation method described in any of the preceding claims;

[0024] The structural formula of the 3-fluoroisoquinoline-4-ol compounds is shown in Formula II:

[0025]

[0026] In the formula, R is benzyloxy, methoxy, dimethoxy, methyl, tert-butyl, chloro, fluoro, bromine, or no group.

[0027] The third aspect of this invention discloses the use of 3-fluoroisoquinoline-4-ol compounds as described above in the preparation of alkaloid drugs.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) This invention provides a method for synthesizing 3-fluoroisoquinoline-4-ols. Using substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one as a starting material, 3-fluoroisoquinoline-4-ols are synthesized in one step in a solvent. Previously reported methods require multiple steps due to the complex structure of isoquinoline products, involving the construction of aromatic rings and the introduction of nitrogen atoms. This method improves atom economy and step economy compared to previously reported methods, and reduces synthesis costs.

[0030] (2) Avoid using strong acids and strong bases during the reaction process, which reduces the restrictions on functional groups and increases the diversity of functional groups in the product.

[0031] (3) The synthesis method of the present invention can yield many new isoquinoline derivatives with new compound structures, which enriches the isoquinoline compounds and is beneficial for screening lead compounds with better activity.

[0032] (4) The synthesis method of the present invention is simple and efficient and has good application prospects. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be described in detail below with reference to specific embodiments, but this is by no means a limitation of the invention.

[0034] Unless otherwise specified, the reagents used in the following description are conventional commercial products, the methods used are known in the art, and any other matters not covered herein may be handled using existing technology.

[0035] A method for synthesizing 3-fluoroisoquinoline-4-ols involves reacting a substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one (the synthesis method of this starting material is supplemented at the end of the specification) with a solvent. The reaction progress is monitored by TLC. After the reaction is complete, water and ethyl acetate are added for three extractions. The organic phases after the three extractions are collected, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product compound. The compound is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent to obtain the 3-fluoroisoquinoline-4-ol compound. The reaction equation for this synthesis method, Formula III, is:

[0036]

[0037] Wherein R is 7-benzyloxy, 4-methoxy, 6-methoxy, 5,6-dimethoxy, 4-methyl, 5-methyl, 6-methyl, 5-tert-butyl, 4-chloro, 5-chloro, 6-chloro, 4-fluoro, 5-fluoro, 6-fluoro, 4-bromo, 5-bromo, 6-bromo, or no group.

[0038] Furthermore, the solvent is selected from any one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane, and chloroform.

[0039] Furthermore, the reaction temperature is 1-100℃, and the reaction time is 1-12 hours.

[0040] Furthermore, the reaction temperature was 80°C and the reaction time was 12 hours.

[0041] Furthermore, the volume of the solvent used is in the mass ratio (1-100 mL) of the substituted 2-azido-2-fluoro-2,3-dihydro-1H-indene-1-one to 1 g.

[0042] Example 1

[0043] Synthesis of compound 3-fluoroisoquinoline-4-ol.

[0044]

[0045] 0.2 mmol of 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoroisoquinoline-4-ol. The yield was 85% and the purity was 99.7%.

[0046] The basic parameters of this product are as follows:

[0047] 1H NMR (401MHz, DMSO-d6): δ10.50(s,1H),8.51(s,1H),8.19(d,J=8.6Hz,1H),8.08(d,J=8.3Hz,1H),7.59(ddd,J=8.2,6.7,1.2Hz,1H).

[0048] 13C NMR: (101MHz, DMSO-d6): δ148.86(d,1JC-F=223.1Hz), 139.15(d,3JC-F=14.1Hz), 132.46(d,2JC-F=28.4Hz ),131.07(d,3'JC-F=6.0Hz),130.10,128.83,127.76,126.91(d,4JC-F=2.5Hz),121.57(d,4'JC-F=7.1Hz).

[0049] 19F NMR (377MHz, DMSO-d6): δ-98.48. (s, 1F).

[0050] HRMS(ESI)m / z calcd[M+H]+=for C9H7FNO:164.0512,found:164.0511.

[0051] Example 2

[0052] Synthesis of compound 3-fluoro-6-methoxyisoquinoline-4-ol.

[0053]

[0054] 0.2 mmol of 2-azido-2-fluoro-6-methoxy-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoro-6-methoxyisoquinoline-4-ol. The yield was 91% and the purity was 98.6%.

[0055] The basic parameters of this product are as follows:

[0056] 1H NMR (401MHz, DMSO-d6): δ10.28(s,1H),8.37(s,1H),7.98(d,J=9.0Hz,1H),7.43(d,J=2.5Hz,1H),7.20(dd,J=9.1,2.5Hz,1H),3.92(s,3H).

[0057] 13C NMR (101MHz, DMSO-d6): δ160.71,149.44(d,1JC-F=222.6Hz), 138.70(d,3JC-F=15.1Hz), 133.01(d,3'JC-F=6 .3Hz),131.46(d,2JC-F=29.1Hz),129.72,124.70,120.10(d,4JC-F=1.9Hz),99.35(d,4'JC-F=7.2Hz),56.02.

[0058] 19F NMR19F NMR (377MHz, DMSO-d6): δ-98.38. (s, 1F).

[0059] HRMS(ESI)m / z calcd[M+H]+=for C10H9FNO2:194.0617,found:194.0616.

[0060] Example 3

[0061] Synthesis of compound 3-fluoro-6-methylisoquinoline-4-ol.

[0062]

[0063] 0.2 mmol of 2-azido-2-fluoro-6-methyl-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoro-6-methylisoquinoline-4-ol. The yield was 93% and the purity was 98.3%.

[0064] The basic parameters of this product are as follows:

[0065] 1H NMR (401MHz, DMSO-d6): δ10.37(s,1H),8.44(s,1H),8.11-7.85(m,2H),7.41(dd,J=8.6,1.6Hz,1H),2.52(s,3H).

[0066] 13C NMR (101MHz, DMSO-d6): δ149.02(d,1JC-F=222.4Hz), 140.17, 138.81(d,3JC-F=14.3Hz), 131.87(d,2JC-F=28. 6Hz),131.36(d,3'JC-F=6.0Hz),129.18(d,4JC-F=2.6Hz),127.57,127.35,120.25(d,4'JC-F=7.1Hz),22.21.

[0067] 19F NMR(377MHz,DMSO-d6)δ-98.73.(s,1F).

[0068] HRMS(ESI)m / z calcd[M+H]+=for C10H9FNO:178.0668,found:178.0661.

[0069] Example 4

[0070] Synthesis of compound 7-tert-butyl-3-fluoroisoquinoline-4-ol.

[0071]

[0072] 0.2 mmol of 2-azido-5-(tert-butyl)-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 7-tert-butyl-3-fluoroisoquinoline-4-ol. The yield was 71% and the purity was 97.6%.

[0073] The basic parameters of this product are as follows:

[0074] 1H NMR (401MHz, DMSO-d6): δ10.41(s,1H),8.46(s,1H),8.12(d,J=8.9Hz,1H),7.94(d,J=2.0Hz,1H),7.81(dd,J=9.0,1.9Hz,1H),1.33(s,9H).

[0075] 13C NMR (101MHz, DMSO-d6): δ149.21,148.66(d,1JC-F=222.3Hz), 138.92(d,3JC-F=14.1Hz), 132.30(d,2JC-F=28.6Hz ),129.35(d,3'JC-F=5.7Hz),129.08,129.02(d,4JC-F=1.7Hz),122.18,121.47(d,4'JC-F=7.0Hz),35.13,31.18.

[0076] 19F NMR(377MHz,DMSO-d6)δ-99.36.(s,1F).

[0077] HRMS(ESI)m / z calcd[M+H]+=for C13H15FNO2:220.1138,found:220.1137.

[0078] Example 5

[0079] Synthesis of compound 3-fluoro-7-methylisoquinoline-4-ol.

[0080]

[0081] 0.2 mmol of 2-azido-2-fluoro-5-methyl-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoro-7-methylisoquinoline-4-ol. The yield was 96% and the purity was 98.5%.

[0082] The basic parameters of this product are as follows:

[0083] 1H NMR (401MHz, DMSO-d6): δ10.42(s,1H),8.38(s,1H),8.07(d,J=8.6Hz,1H),7.79(s,1H),7.54(dd,J=8.7,1.7Hz,1H),2.45(s,3H).

[0084] 13C NMR (101MHz, DMSO-d6): δ148.49(d,1JC-F=221.9Hz), 138.20(d,3JC-F=13.9Hz), 136.33, 132.49(d,2JC-F=24. 7Hz), 132.35, 129.35 (d, 3'JC-F = 5.8Hz), 129.14 (d, 4JC-F = 2.0Hz), 126.10, 121.48 (d, 4'JC-F = 7.1Hz), 21.53.

[0085] 19F NMR (377MHz, DMSO-d6): δ-99.61 (s, 1F).

[0086] HRMS(ESI)m / z calcd[M+H]+=for C10H9FNO:178.0668,found:178.0668.

[0087] Example 6

[0088] Synthesis of compound 7-chloro-3-fluoroisoquinoline-4-ol.

[0089]

[0090] 0.2 mmol of 2-azido-5-chloro-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 7-chloro-3-fluoroisoquinoline-4-ol. The yield was 90% and the purity was 98.8%.

[0091] The basic parameters of this product are as follows:

[0092] 1H NMR (401MHz, DMSO-d6): δ10.78 (s, 1H), 8.47 (s, 1H), 8.33-8.10 (m, 2H), 7.70 (dd, J = 9.0, 2.1Hz, 1H).

[0093] 13C NMR (101MHz, DMSO-d6) δ148.97(d,1JC-F=224.6Hz), 138.18(d,3JC-F=14.4Hz), 132.91(d,2JC-F=29.0Hz) ,131.52(d,3'JC-F=2.9Hz), 130.61,129.46,129.41(d,4JC-F=2.1Hz), 126.34,124.09(d,4'JC-F=7.1Hz).

[0094] 19F NMR(377MHz,DMSO-d6)δ-97.51.(s,1F).

[0095] HRMS(ESI)m / z calcd[M+H]+=for C9H6ClFNO:198.0122,found:198.0117.

[0096] Example 7

[0097] Synthesis of compound 3-fluoro-6,7-dimethoxyisoquinoline-4-ol.

[0098]

[0099] 0.2 mmol of 2-azido-2-fluoro-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoro-6,7-dimethoxyisoquinoline-4-ol. The yield was 83% and the purity was 99.3%.

[0100] The basic parameters of this product are as follows:

[0101] 1H NMR (401MHz, DMSO-d6): δ10.19(s,1H),8.21(d,J=1.3Hz,1H),7.38(d,J=10.3Hz,2H),3.93(s,3H),3.88(s,3H).

[0102] 13C NMR (101MHz, DMSO-d6): δ152.94, 150.00, 148.42 (d, 1JC-F = 220.3Hz), 136.30 (d, 3JC-F = 14.7Hz), 131.47 ( d,2JC-F=29.4Hz),127.39(d,3'JC-F=5.5Hz), 125.08(d,4JC-F=1.0Hz), 105.45,99.76(d,4'JC-F=7.0Hz).

[0103] 19F NMR (377MHz, DMSO-d6): δ-100.50. (s, F).

[0104] HRMS(ESI)m / z calcd[M+H]+=for C11H11FNO3:224.0723,found:224.0727.

[0105] Example 8

[0106] Synthesis of compound 3-fluoro-8-methylisoquinoline-4-ol.

[0107]

[0108] 0.2 mmol of 2-azido-2-fluoro-4-methyl-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoro-8-methylisoquinoline-4-ol. The yield was 93% and the purity was 99.7%.

[0109] The basic parameters of this product are as follows:

[0110] 1H NMR (401MHz, DMSO-d6) δ10.46(s,1H),8.57(d,J=1.2Hz,1H),8.03(d,J=8.6H z,1H),7.57(dd,J=8.6,6.9Hz,1H),7.35(dt,J=6.9,1.2Hz,1H),2.68(s,3H).

[0111] 13C NMR (101MHz, DMSO-d6) δ148.85(d,1JC-F=222.9Hz), 136.21(d,3JC-F=14.3Hz), 135.60, 132.53(d,2JC-F=28. 4Hz), 131.48 (d, 3'JC-F=5.8Hz), 129.85, 127.91 (d, 4JC-F=1.9Hz), 127.41, 119.75 (d, 4'JC-F=6.9Hz), 18.90.

[0112] 19F NMR (377MHz, DMSO-d6): δ-98.40. (s, 1F).

[0113] HRMS(ESI)m / z calcd[M+H]+=for C10H9FNO:178.0668,found:178.0660.

[0114] Example 9

[0115] Synthesis of compound 3,7-difluoroisoquinoline-4-ol.

[0116]

[0117] 0.2 mmol of 2-azido-2,5-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3,7-difluoroisoquinoline-4-ol. The yield was 81% and the purity was 99.6%.

[0118] The basic parameters of this product are as follows:

[0119] 1H NMR (401MHz, DMSO-d6): δ10.75(s,1H),8.43(s,1H),8.24-8.20(m,1H),7.83(dd,J=9.6,2.6Hz,1H),7.60(td,J=9.0,2.6Hz,1H).

[0120] 13C NMR (101MHz, DMSO-d6): δ160.41(d,J=245.5Hz), 148.67(d,1JC-F=221.2Hz), 137.91(dd,3JC-F=14.1,5.8Hz), 133.02(d,2JC-F=29. 0Hz), 129.52 (d, J = 9.0Hz), 128.24 (d, 3'JC-F = 5.7Hz), 124.91 (t, 4JC-F = 8.1Hz), 120.63 (d, J = 26.3Hz), 110.45 (d, 4'JC-F = 21.4Hz).

[0121] 19F NMR (377MHz, DMSO-d6): δ-99.42 (d, J=5.0Hz, 1F), -113.82 (tt, J=9.7, 5.2Hz, 1F).

[0122] HRMS(ESI)m / z calcd[M+H]+=for C9H6F2NO:182.0417,found:182.0415.

[0123] Example 10

[0124] Synthesis of compound 3-fluoro-8-methoxyisoquinoline-4-ol.

[0125]

[0126] 0.2 mmol of 2-azido-2-fluoro-4-methoxy-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3-fluoro-8-methoxyisoquinoline-4-ol. The yield was 94% and the purity was 99.1%.

[0127] The basic parameters of this product are as follows:

[0128] 1H NMR (401MHz, DMSO-d6): δ10.45(s,1H),8.61(t,J=1.0Hz,1H),7.70(d,J=8.5Hz,1H),7.61(t,J=8.1Hz,1H),3.98(s,3H).

[0129] 13C NMR (101MHz, DMSO-d6): δ156.24, 149.49 (d, 1JC-F = 223.3Hz), 133.84 (d, 3JC-F = 14.8Hz), 132.54 (d, 3'JC-F = 5. 8Hz), 132.26 (d, 2JC-F=28.6Hz), 131.08, 120.97 (d, 4JC-F=2.0Hz), 113.48 (d, 4'JC-F=6.8Hz), 105.21, 56.33.

[0130] 19F NMR (377MHz, DMSO-d6): δ-97.83. (s, 1F).

[0131] HRMS(ESI)m / z calcd[M+H]+=for C10H9FO2:194.0617,found:194.0616.

[0132] Example 11

[0133] Synthesis of compound 3,8-difluoroisoquinoline-4-ol.

[0134]

[0135] 0.2 mmol of 2-azido-2,4-difluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3,8-difluoroisoquinoline-4-ol. The yield was 95% and the purity was 97.2%.

[0136] The basic parameters of this product are as follows:

[0137] 1H NMR (401MHz, DMSO-d6): δ10.86(s,1H),8.58(s,1H),7.98(d,J=8.6Hz,1H),7.69(td,J=8.1,5.5Hz,1H),7.37(dd,J=11.0,7.7Hz,1H).

[0138] 13C NMR (101MHz, DMSO-d6): δ 158.69 (d, J = 253.4Hz), 149.50 (d, 1JC-F = 224.8Hz), 132.86 (dd, 2JC-F = 21.0, 3.9Hz), 132.69 (d, J = 3.0Hz), 132.3 5(dd,3JC-F=14.8,5.7Hz), 130.74(d,J=8.7Hz), 119.29(d,4JC-F=16.5Hz), 118.13(dd,3'JC-F=6.8,4.6Hz), 110.68(d,4'JC-F=18.7Hz).

[0139] 19F NMR(377MHz,DMSO-d6)δ-96.52(s,1F),-122.34(dt,J=10.2,4.6Hz1F)

[0140] HRMS(ESI)m / z calcd[M+H]+=for C9H6F2NO:182.0417,found:182.0417.

[0141] Example 12

[0142] Synthesis of compound 3,6-difluoroisoquinoline-4-ol.

[0143]

[0144] 0.2 mmol of 2-azido-2,6-difluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 3,6-difluoroisoquinoline-4-ol. The yield was 92% and the purity was 97.8%.

[0145] The basic parameters of this product are as follows:

[0146] 1H NMR (401MHz, DMSO-d6): δ10.62(s,1H),8.53(s,1H),8.19(dd,J=9.1,5.6Hz,1H),7.79(dd,J=10.3,2.5Hz,1H),7.48(td,J=8.9,2.6Hz,1H).

[0147] 13C NMR(101MHz,DMSO-d6)δ162.92(d,J=249.7Hz),149.33(d,1JC-F=224.1Hz),139.31(d,3JC-F=14.8Hz),132.47(dd,3'JC-F=10.1,6.6Hz),132 .23(dd,2JC-F=29.1,5.5Hz), 131.62(d,J=10.3Hz), 126.27(d,4JC-F=1.8Hz), 117.57(dd,J=26.1,3.0Hz), 105.20(dd,4'JC-F=23.2,7.5Hz).

[0148] 19F NMR (377MHz, DMSO-d6) δ-97.64 (s, 1F), -107.73 (q, J = 8.4Hz, 1F).

[0149] HRMS(ESI)m / z calcd[M+H]+=for C9H6F2NO:182.0417,found:182.0412.

[0150] Example 13

[0151] Synthesis of compound 8-chloro-3-fluoroisoquinoline-4-ol.

[0152]

[0153] 0.2 mmol of 2-azido-4-chloro-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 8-chloro-3-fluoroisoquinoline-4-ol. The yield was 64% and the purity was 97.1%.

[0154] The basic parameters of this product are as follows:

[0155] 1H NMR (401MHz, DMSO-d6): δ10.90 (s, 1H), 8.62 (t, J = 1.1Hz, 1H), 8.13 (dt, J = 8.0, 1.2Hz, 1H), 8.02-7.47 (m, 2H).

[0156] 13C NMR (101MHz, DMSO-d6): δ149.22(d,1JC-F=225.2Hz), 135.17(d,3JC-F=14.8Hz), 132.87(d,2JC-F=29.0Hz) ,132.52(d,3'JC-F=6.2Hz), 131.12,130.21,127.40,125.62(d,4JC-F=2.3Hz), 121.33(d,4'JC-F=6.9Hz).

[0157] 19F NMR(377MHz,DMSO-d6)δ-96.24.(s,1F).

[0158] HRMS(ESI)m / z calcd[M+H]+=for C9H6ClFNO:198.0122,found:198.0119.

[0159] Example 14

[0160] Synthesis of compound 6-chloro-3-fluoroisoquinoline-4-ol.

[0161]

[0162] 0.2 mmol of 2-azido-6-chloro-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 6-chloro-3-fluoroisoquinoline-4-ol. The yield was 71% and the purity was 97.9%.

[0163] The basic parameters of this product are as follows:

[0164] 1H NMR (401MHz, DMSO-d6): δ10.75 (s, 1H), 8.52 (s, 1H), 8.22-8.01 (m, 2H), 7.57 (dd, J = 8.9, 2.1Hz, 1H).

[0165] 13C NMR (101MHz, DMSO-d6): δ149.37(d,1JC-F=224.9Hz), 139.25(d,3JC-F=14.3Hz), 135.48, 131.94(d,2JC-F= 29.3Hz), 131.71 (d, 3'JC-F=6.6Hz), 130.26, 127.63 (d, 4JC-F=2.8Hz), 127.12, 120.43 (d, 4'JC-F=7.3Hz).

[0166] 19F NMR (377MHz, DMSO-d6): δ-96.70. (s, 1F).

[0167] HRMS(ESI)m / z calcd[M+H]+=for C9H6ClFNO:198.0122,found:198.0123.

[0168] Example 15

[0169] Synthesis of compound 6-bromo-3-fluoroisoquinoline-4-ol.

[0170]

[0171] 0.2 mmol of 2-azido-6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 6-bromo-3-fluoroisoquinoline-4-ol. The yield was 82% and the purity was 98.3%.

[0172] The basic parameters of this product are as follows:

[0173] 1H NMR (401MHz, DMSO-d6): δ10.75(s,1H),8.52(s,1H),8.32(d,J=1.9Hz,1H),8.03(d,J=8.8Hz,1H),7.69(dd,J=8.8,1.9Hz,1H).

[0174] 13C NMR (101MHz, DMSO-d6): δ149.30(d,1JC-F=224.7Hz), 139.34(d,3JC-F=14.4Hz), 132.01(d,3'JC-F=6.5Hz) ,131.80(d,2JC-F=29.4Hz),130.15,130.10,127.23(d,4JC-F=2.3Hz),124.46,123.72(d,4'JC-F=7.2Hz).

[0175] 19F NMR (377MHz, DMSO-d6): δ-96.51. (s, 1F).

[0176] HRMS(ESI)m / z calcd[M+H]+=for C9H6BrFNO:241.9617,found:241.9618

[0177] Example 16

[0178] Synthesis of compound 7-bromo-3-fluoroisoquinoline-4-ol.

[0179]

[0180] 0.2 mmol of 2-azido-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 7-bromo-3-fluoroisoquinoline-4-ol. The yield was 79% and the purity was 98.7%.

[0181] The basic parameters of this product are as follows:

[0182] 1H NMR (401MHz, DMSO-d6): δ10.79(s,1H),8.46(s,1H),8.33(d,J=1.9Hz,1H),8.09(d,J=9.0Hz,1H),7.79(dd,J=9.1,2.0Hz,1H).

[0183] 13C NMR (101MHz, DMSO-d6): δ148.93(d,1JC-F=224.7Hz), 138.14(d,3JC-F=14.3Hz), 132.99, 132.95(d,2JC-F= 28.9Hz), 129.84 (d, 4JC-F = 2.0Hz), 129.63, 129.55, 124.08 (d, 4'JC-F = 7.3Hz), 119.99 (d, 3'JC-F = 3.2Hz).

[0184] 19F NMR (377MHz, DMSO-d6): δ-97.18. (s, 1F).

[0185] HRMS(ESI)m / z calcd[M+H]+=for C9H6BrFNO:241.9617,found:241.9620.

[0186] Example 17

[0187] Synthesis of compound 8-bromo-3-fluoroisoquinoline-4-ol.

[0188]

[0189] 0.2 mmol of 2-azido-4-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 8-bromo-3-fluoroisoquinoline-4-ol. The yield was 90%, and the purity was 99.4%.

[0190] The basic parameters of this product are as follows:

[0191] 1H NMR (401MHz, DMSO-d6): δ10.93(s,1H),8.59(s,1H),8.20(d,J=8.5Hz,1H),7.89(d,J=7.3Hz,1H),7.59(t,J=8.0Hz,1H).

[0192] 13C NMR (101MHz, DMSO-d6): δ149.14(d,1JC-F=225.8Hz), 137.65(d,3JC-F=14.5Hz), 132.66(d,2JC-F=28.8Hz) ,132.58(d,3'JC-F=6.0Hz),131.22(d,4JC-F=1.9Hz),130.65,126.71,121.99(d,4'JC-F=6.9Hz),121.31.

[0193] HRMS(ESI)m / z calcd[M+H]+=for C9H6FNOBr:241.9617,found:241.9618.

[0194] Example 18

[0195] Synthesis of compound 7-benzyloxy-3-fluoroisoquinoline-4-ol.

[0196]

[0197] 0.2 mmol of 2-azido-5-benzyloxy-2-fluoro-2,3-dihydro-1H-inden-1-one and 2.0 mL of dimethyl sulfoxide solvent were mixed and heated at 80 °C for 12 hours. After the reaction was complete, 30 mL of water and ethyl acetate were added for three extractions. The mixture was dried over anhydrous Na₂SO₄ for 30 minutes, filtered, and concentrated. The residue was purified by silica gel column chromatography using petroleum ether / ethyl acetate (10:1 to 3:1) as eluent to give the product 7-benzyloxy-3-fluoroisoquinoline-4-ol. The yield was 81% and the purity was 97.8%.

[0198] The basic parameters of this product are as follows:

[0199] 1H NMR: 1H NMR (401MHz, DMSO-d6) δ10.51(s,1H),8.35(s,1H),8.10(d,J=9.2Hz,1H),7.57(d,J=2. 5Hz,1H),7.51(d,J=7.4Hz,2H),7.47-7.39(m,3H),7.35(t,J=7.2Hz,1H),5.23(s,2H).

[0200] 13C NMR (101MHz, DMSO-d6) δ 156.93, 148.05 (d, 1JC-F = 220.8Hz), 137.05 (d, 3JC-F = 13.8Hz), 137.04, 132.80 (d, 2JC-F = 28. 9Hz),130.25,129.00,128.53,128.41,126.52(d,3'JC-F=5.4Hz),123.54,123.37(d,4'JC-F=7.1Hz),106.21,70.05.

[0201] 19F NMR(377MHz,DMSO-d6)δ-101.15.(s,1F).

[0202] HRMS(ESI)m / z calcd[M+Na]+=for C16H12FNO2:292.0744,found:292.0749.

[0203] The synthetic method for 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivatives is as follows:

[0204]

[0205] The synthesis method of 2-bromo-2-fluoro-2,3-dihydro-1H-indone derivatives is described in the literature Cheng Zheng, Xuhui Cui, Jingjing Wu, Pingjie Wu, Yanyan Yu, Hanwen Liu, Fanhong Wu. Synthesis and Application of Monofluoroalkyl Building Blocks: α-Halo-α-fluoroketones[J]. European Journal of Organic Chemistry. 2022(32), e202200137. In this scheme, the method disclosed in the literature is used to prepare 2-bromo-2-fluoro-2,3-dihydro-1H-indone derivatives. 1.00 mmol, l eq. of 2-fluoro-2-bromo-2,3-dihydro-1H-indone derivative, 1.05 eq. of tetrabutylammonium azide, and 5 ml of dimethyl sulfoxide are added to the reaction tube. The reaction tube was placed at room temperature (25±2℃) and stirred for 1-1.5 hours. After the reaction progress was monitored by thin-layer chromatography (TLC), 20 mL of water and 10 mL of ethyl acetate were added for three extractions. The organic phases were combined and then extracted once more with water. The organic phase was dried over anhydrous Na2SO4 for 15 minutes, filtered, and concentrated by rotary evaporation to obtain the 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one derivative.

[0206] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A process for the preparation of a 3-fluoroisoquinolin-4-ol compound, characterized by, The method comprises the following steps: a substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one and a solvent are mixed to react; after the reaction is completed, an extractant is added to extract, the organic phase is dried with a drying agent, filtered and concentrated to obtain a crude product; the crude product is purified to obtain the 3-fluoroisoquinolin-4-ol compound; the solvent comprises dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane and chloroform.

2. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one has a structural formula as shown in formula I: in the formula, R is benzyloxy, methoxy, dimethoxy, methyl, tert-butyl, chloro, fluoro, bromo or no group.

3. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the solvent is one or more of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, isopropanol, tetrahydrofuran, 1,4-dioxane, dichloromethane and chloroform.

4. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the substituted 2-azido-2-fluoro-2,3-dihydro-1H-inden-1-one and the solvent are used in a ratio of 1 g:1-100 mL.

5. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the reaction is carried out at a temperature of 1-100 ℃ for 1-12 hours.

6. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the reaction is carried out at a temperature of 80 ℃ for 12 hours.

7. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the extractant is water and ethyl acetate, and the drying agent is anhydrous sodium sulfate.

8. The method for preparing a 3-fluoroisoquinoline-4-ol compound according to claim 1, characterized in that, the purification is that the crude product is purified by chromatography on a silica gel column, and then eluted using petroleum ether / ethyl acetate as an eluent to obtain the 3-fluoroisoquinolin-4-ol compound.

9. A 3-fluoroisoquinoline-4-ol compound, characterized in that, is prepared by using the preparation method according to any one of claims 1-8; the 3-fluoroisoquinolin-4-ol compound has a structural formula as shown in formula II: in the formula, R is benzyloxy, methoxy, dimethoxy, methyl, tert-butyl, chloro, fluoro, bromo or no group.

10. Use of the 3-fluoroisoquinolin-4-ol compound according to claim 9 in the preparation of an alkaloid drug.

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