A method for preparing a fluoroisoquinolinone compound

Abstract

The application discloses a preparation method of a fluoroisoquinolinone compound, which comprises the following steps: mixing a compound shown in formula (I), a compound shown in formula (II), a rhodium catalyst, a ligand of the rhodium catalyst and a solvent to react, so as to obtain a fluoroisoquinolinone compound shown in formula (III); wherein, the compound shown in formula (I), the compound shown in formula (II) and the fluoroisoquinolinone compound shown in formula (III) have the structural formula as follows: wherein, n is greater than or equal to 1, R 1 is selected from hydrogen, a substituted or unsubstituted C 1～6 alkyl, a C 1～10 alkoxy, halogen, a C 1～5 ester group, aryl and nitro. The preparation raw material of the application is simple, environment-friendly and low in price; the reaction condition is mild, the operation is simple, the yield is high, the post-treatment is simple and the application is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing fluoroisoquinoline ketone compounds. Background Technology

[0002] Fluoroquinolinones are a special class of nitrogen-containing benzo[a]hexacyclic compounds, serving as important skeletons for natural products and possessing numerous physiological activities, such as antibacterial, anti-inflammatory, and anticancer properties; especially in recent years. Currently, fluoroquinolinones are mainly constructed through hydrocarbon activation reactions of benzamides and alkenes / alkynes, but these methods still face many challenges. How to construct fluoroquinolinones from inexpensive and readily available raw materials using simple and rapid methods is a pressing issue in this field.

[0003] In summary, there is a need for a new method for preparing fluoroisoquinolinone compounds that is simple to operate and has a high yield. Summary of the Invention

[0004] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention provides a method for preparing fluoroisoquinoline ketone compounds, which is simple to operate and has a high yield.

[0005] A method for preparing a fluoroisoquinoline ketone compound according to a first aspect embodiment of the present invention includes the following steps:

[0006] The compound shown in formula (I), the compound shown in formula (II), the rhodium catalyst, the ligand of the rhodium catalyst and the solvent are mixed and reacted to obtain the fluoroisoquinoline ketone compound shown in formula (III);

[0007] The structural formulas of the compounds represented by formula (I), (II), and (III) are as follows:

[0008]

[0009] Where n≥1, R 1 Selected from hydrogen, substituted or unsubstituted C 1～6 alkyl, C 1～10 alkoxy, halogen, C 1～5 Ester group, aryl group, nitro group.

[0010] The preparation method according to embodiments of the present invention has at least the following beneficial effects:

[0011] In this invention, the compound represented by formula (I) in the raw materials undergoes CH activation under the catalysis of a rhodium catalyst and the action of a ligand, and directly cyclizes with the compound represented by formula (II) to construct fluoroisoquinolinone compounds. The raw materials of this invention are simple, readily available, environmentally friendly, and inexpensive; the reaction conditions are mild, the operation is simple, and the yield is high; the post-reaction processing is convenient and suitable for industrial production. The compounds prepared by this invention can be further used in anti-inflammatory, antibacterial, and anticancer applications.

[0012] According to some embodiments of the present invention, the rhodium catalyst is selected from at least one of [Cp*RhCl2]2, [Cp*Rh(CH3CN)3(SbF6)2], and Cp*Rh(OAc)2. Thus, after the compound of formula (I) undergoes hydrocarbon activation, it undergoes cyclization addition with the compound of formula (II) to obtain the target product.

[0013] According to some embodiments of the present invention, the ligand of the rhodium catalyst is selected from inorganic or organic bases. Thus, the role of the inorganic or organic base is to activate the rhodium catalyst and improve the yield.

[0014] According to some embodiments of the present invention, the inorganic base is selected from at least one of sodium acetate, cesium acetate, cesium pivalate, or cesium carbonate.

[0015] According to some embodiments of the present invention, the molar ratio of the compound represented by formula (I), the compound represented by formula (II), the rhodium catalyst, and the ligand of the rhodium catalyst is 1:(1-3):(0.025-0.05):(1-3). According to some embodiments of the present invention, the molar ratio of the compound represented by formula (I), the compound represented by formula (II), the rhodium catalyst, and the ligand of the rhodium catalyst is approximately 1:2:0.05:2. Therefore, the reactants react completely in this reaction, resulting in a high yield.

[0016] According to some embodiments of the present invention, the solvent is selected from at least one of water, trifluoroethanol, tetrahydrofuran, and toluene. According to some embodiments of the present invention, when the solvent is selected from water, the reaction is more environmentally friendly and the yield is higher.

[0017] According to some embodiments of the present invention, the reaction temperature is 60°C to 150°C. Thus, as the reaction temperature increases, the yield gradually increases and then remains constant.

[0018] According to some embodiments of the present invention, the reaction time is 8h to 12h.

[0019] According to some embodiments of the present invention, the volume molar ratio of the solvent to the compound represented by formula (I) is (6-20) mL / mmol.

[0020] According to some embodiments of the present invention, after the reaction is completed, quenching, extraction, washing, concentration and column chromatography are also included.

[0021] According to some embodiments of the present invention, after the reaction is completed, ethyl acetate is added to quench the reaction, followed by washing with ethyl acetate, separation to obtain an organic phase, extraction of the aqueous phase with ethyl acetate, combining the organic phases, drying, removing the solvent by vacuum distillation, and then performing column chromatography.

[0022] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention.

[0023] Definitions and general terms

[0024] "C replaced or not replaced" 1-6 "alkyl" indicates an alkyl group with a total number of 1-6 carbon atoms, including C64. 1-6 straight-chain alkyl, C 1-6 Branched alkyl groups and C 3-6 The alkyl group is a cycloalkyl group, wherein at least one H in the alkyl group is substituted by a corresponding group as defined herein. The substituted group may be halogen, phenyl, or nitro.

[0025] “C 1-10 "alkoxy group" refers to an alkoxy group with a total number of carbon atoms of 1-10, including C. 1-10 straight-chain alkoxy, C 1-10 Branched alkoxy groups and C 2-10 The cycloalkoxy group can be, for example, a straight-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; a branched-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; or a cycloalkoxy group with a total number of carbon atoms of 2, 3, 4, 5, 6, 7, 8, 9 or 10, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0026] "Halogen" includes any one or more of fluorine, chlorine, bromine, and iodine.

[0027] "Ester group" indicates the structural formula is The ester group, wherein C 1～5 The ester group is represented by an ester group with a total number of carbon atoms of 1 to 5. Representative examples include methyl formate, ethyl formate, ethyl acetate, methyl acetate, etc.

[0028] "Aryl" indicates an all-carbon monocyclic or fused polycyclic group with a fully conjugated π-electron system. Detailed Implementation

[0029] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0030] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0031] The yield calculation method of this invention is as follows: Yield = Product mass / (Molecular weight * Amount of material fed).

[0032] Example 1

[0033] Example 1 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0034]

[0035] Take a 15 mL pressure-resistant tube and add 30.2 mg (0.20 mmol) of N-methoxybenzamide (CAS No.: 2446-51-7), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 6.2 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7732-1). 8-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.23). The purified product weighs 30.4 mg and is a white powder with a yield of 76%.

[0036] The product's characterization data are as follows:

[0037] 1 H NMR (500MHz, Methanol-d4) δ8.05 (d, J = 7.9 Hz, 1H), 7.76 (m, 2H), 7.70 (t, J = 7.9 Hz, 1H), 5.13 (dd, J = 6.3, 3.7 Hz, 1H).

[0038] 13C NMR (126MHz, Methanol-d4) δ163.92, 133.07 (d, J = 2.3Hz), 131.47 (dd, J = 27.5, 22.1Hz), 131.13 (d, J = 2.8Hz), 127.61 ,127.46(dd,J=8.4,3.7Hz),124.64–123.86(m),114.36(dd,J=245.5,237.9Hz),76.01(dd,J=39.2,30.1Hz),29.37.

[0039] 19 F NMR (471 MHz, Methanol-d4) δ -94.26 (d, J = 263.5 Hz), -125.61 (d, J = 263.5 Hz). Examples 2-8

[0040] Examples 2-8 provide a series of methods for preparing fluoroisoquinoline ketone compounds. The steps are the same as in Example 1, except that the solvents are different, as detailed in Table 1.

[0041] Table 1

[0042]

[0043] Examples 9-14 and Comparative Example 1

[0044] Examples 9-14 and Comparative Example 1 provide a series of methods for preparing fluoroisoquinolone compounds, with the same steps as in Example 1, except that the additive ligands are different, as detailed in Table 2.

[0045] Table 2

[0046]

[0047] Examples 15-21 and Comparative Example 2

[0048] Examples 15-21 and Comparative Example 2 provide a series of methods for preparing fluoroisoquinolone compounds, with the same steps as in Example 1, except for different temperatures or catalysts, as detailed in Table 3.

[0049] Table 3

[0050]

[0051] a Reaction conditions: N-methoxysubstituted benzamide (0.10 mmol), catalyst (5 mol%), 2,2-difluoroethylene-4-methylbenzenesulfonic acid (0.2 mmol), 10 h, H2O (1 mL), NaOAc (0.2 mmol).

[0052] Example 22

[0053] Example 22 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 6-ethyl-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0054]

[0055] Take a 15 mL pressure-resistant tube and add 35.8 mg (0.20 mmol) of 4-ethyl-N-methoxybenzamide (CAS No.: 1455238-82-0), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 77). 32-18-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.33). The purified product weighs 32.2 mg and is a white powder with a yield of 71%.

[0056] The product's characterization data are as follows: 1 H NMR(500MHz,Methanol-d4)δ7.98(d,J=8.0Hz,1H),7.62(s,1H),7.55(d,J=8.0H z,1H),5.13(dd,J=6.3,3.6Hz,1H),2.81(q,J=7.6Hz,2H),1.30(t,J=7.6Hz,3H).

[0057] 13C NMR (126MHz, Methanol-d4) δ165.5, 151.9 (d, J = 2.3Hz), 132.9 (dd, J = 26.9, 22.0Hz), 132.0 (d, J = 2.7Hz), 129.3, 126.4 (dd,J=7.8,3.8Hz),124.8(dd,J=5.6,1.8Hz),115.9(dd,J=245.6,237.9Hz),77.47(dd,J=39.2,30.2Hz),29.9,15.7.

[0058] 19 F NMR (471 MHz, Methanol-d4) δ -94.14 (dd, J = 263.0, 5.8 Hz), -125.54 (d, J = 263.2 Hz). Example 23

[0059] Example 23 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-6-isopropyl-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0060]

[0061] Take a 15 mL pressure-resistant tube and add 38.6 mg (0.20 mmol) of 4-isopropyl-N-methoxybenzamide (CAS No.: 1326667-51-9), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7). 732-18-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.33). The purified product weighs 32.2 mg and is a white powder with a yield of 34%.

[0062] The product's characterization data are as follows: 1H NMR (500MHz, Methanol-d4) δ7.99(d,J=8.0Hz,1H),7.64(t,J=1.8Hz,1H),7.59(dt,J=8.0,1 .6Hz,1H),5.13(dd,J=6.4,3.7Hz,1H),3.08(hept,J=6.9Hz,1H),1.33(s,3H),1.32(s,3H).

[0063] 13 C NMR (126MHz, Methanol-d4) δ 164.1, 155.0 (d, J = 2.2Hz), 131.5 (dd, J = 26.7, 22.0Hz), 129.3 (d, J = 2.8Hz), 127.9, 125. 2(dd,J=7.5,3.7Hz),122.0(d,J=6.0Hz),114.5(dd,J=245.9,237.9Hz),76.1(dd,J=39.4,30.2Hz),34.3,22.6,22.5.

[0064] 19 F NMR (471MHz, Methanol-d4) δ-94.02 (dd, J = 263.4, 6.7Hz), -125.23--125.85 (m).

[0065] Example 24

[0066] Example 24 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-7-methyl-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0067]

[0068] Take a 15 mL pressure-resistant tube and add 30.4 mg (0.20 mmol) of N-methoxy-3-methylbenzamide (CAS No.: 72755-11-4), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 773). 2 mL (0.10 M) of 2-18-5 solution was added at 80 °C for 10 h. After the reaction was complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) was added to quench the reaction and 5 mL of saturated brine was added for washing. The organic phase was collected in layers, and the aqueous phase was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The product was then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.53). The purified product weighed 31.5 mg and was a white powder with a yield of 74%.

[0069] The product's characterization data are as follows: 1 H NMR (500MHz, Methanol-d4) δ7.88(s,1H),7.66(dd,J=7.8,2.2Hz,1H),7.58(d,J=7.9Hz,1H),5.11(dd,J=6.4,3.6Hz,1H),4.65(s,1H),2.48(d,J=2.2Hz,3H).

[0070] 13 C NMR(126MHz,Methanol-d4)δ165.5,143.2(d,J=3.1Hz),135.0(d,J=2.1Hz),130.1(dd,J=27.4,22.3Hz),129.3,12 8.7 (dd, J=8.1, 3.8Hz), 125.6 (dd, J=5.3, 1.4Hz), 116.0 (dd, J=245.7, 237.4Hz), 77.46 (dd, J=39.6, 30.1Hz), 21.4.

[0071] 19 F NMR (471MHz, Methanol-d4) δ -93.63 (d, J = 265.2Hz), -125.29 (d, J = 262.3Hz).

[0072] Example 25

[0073] Example 25 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 6-(tert-butyl)-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0074]

[0075] Take a 15 mL pressure-resistant tube and add 41.4 mg (0.20 mmol) of 4-(tert-butyl)-N-methoxybenzamide (CAS No.: 57139-24-9), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7). 732-18-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.56). The purified product weighs 35.7 mg and is a white powder with a yield of 70%.

[0076] The product's characterization data are as follows:

[0077] 1 H NMR (500MHz, Methanol-d4) δ8.00(d,J=7.9Hz,1H),7.77(m,2H),5.16–5.10(m,1H),4.64(s,1H),2.03(s,1H),1.40(s,9H).

[0078] 13 C NMR(126MHz,Methanol-d4)δ164.1,157.2(d,J=1.8Hz),131.2(dd,J=26.6,21.9Hz),128.2(d,J=2.5Hz),127.7,12 0.9 (d, J = 4.8Hz), 114.6 (dd, J = 245.7, 238.0Hz), 76.1 (dd, J = 39.1, 30.2Hz), 47.6 (dp, J = 42.9, 21.4Hz), 34.9, 30.0.

[0079] 19 F NMR (471MHz, Methanol-d4) δ -93.90 (d, J = 263.0Hz), -125.58 (d, J = 263.2Hz).

[0080] Example 26

[0081] Example 26 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named methyl 4,4-difluoro-3-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, and the preparation method is as follows:

[0082]

[0083] Take a 15 mL pressure-resistant tube and add 41.8 mg (0.20 mmol) of methyl 4-(methoxycarbamoyl)benzoate (CAS No.: 137042-75-2), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7). 732-18-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.28). The purified product weighs 21.6 mg and is a white powder with a yield of 42%.

[0084] The product's characterization data are as follows:

[0085] 1 H NMR(500MHz,Methanol-d4)δ8.35(t,J=1.6Hz,1H),8.32(dt,J=8.1,1.6Hz,1H) ,8.18(d,J=8.0Hz,1H),5.18(dd,J=6.1,3.6Hz,1H),4.67(s,1H),3.99(s,3H).

[0086] 13C NMR (126MHz, Methanol-d4) δ165.4, 162.8, 134.3 (d, J = 1.8Hz), 131.8 (d, J = 2.5Hz), 128.2, 125.2 (d, J=4.8Hz), 114.0 (dd, J=246.3, 238.6Hz), 75.9 (dd, J=38.5, 30.1Hz), 51.9, 47.6 (m, J=42.9, 21.4Hz).

[0087] 19 F NMR (471 MHz, Methanol-d4) δ -94.93 (d, J = 263.7 Hz), -125.83 (d, J = 263.7 Hz). Example 27

[0088] Example 27 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 6-bromo-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0089]

[0090] Take a 15 mL pressure-resistant tube and add 46.1 mg (0.20 mmol) of 4-bromo-N-methoxybenzamide (CAS No.: 72755-10-3), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 773). 2 mL (0.10 M) of 2-18-5 solution was added at 80 °C for 10 h. After the reaction was complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) was added to quench the reaction and 5 mL of saturated brine was added for washing. The organic phase was collected in layers, and the aqueous phase was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The product was then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.44). The purified product weighed 36.5 mg and was a white powder with a yield of 66%.

[0091] The product's characterization data are as follows: 1H NMR (500MHz, Methanol-d4) δ7.97(d,J=8.3Hz,1H),7.93(t,J=1.9Hz,1H),7.90(m,J=8.3,1.8Hz,1H),5.15(dd,J=6.1,3.6Hz,1H),4.65(s,1H),.

[0092] 13 C NMR (126MHz, Methanol-d4) δ 163.1, 134.5 (d, J = 2.6Hz), 133.3 (dd, J = 27.6, 22.6Hz), 129.7, 127. 4,127.3,126.59(dd,J=8.0,3.5Hz), 113.72(dd,J=247.3,239.2Hz), 75.96(dd,J=38.4,29.8Hz).

[0093] 19 F NMR (471 MHz, Methanol-d4) δ -95.13 (dd, J = 263.9, 5.6 Hz), -125.49 (dd, J = 263.9, 8.3 Hz). Example 28

[0094] Example 28 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 6-chloro-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0095]

[0096] Take a 15 mL pressure-resistant tube and add 37.2 mg (0.20 mmol) of 4-chloro-N-methoxybenzamide (CAS No.: 25563-14-8), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 773). 2 mL (0.10 M) of 2-18-5 solution was added at 80 °C for 10 h. After the reaction was complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) was added to quench the reaction and 5 mL of saturated brine was added for washing. The organic phase was collected in layers, and the aqueous phase was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The product was then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.26). The purified product weighed 30.3 mg and was a white powder with a yield of 65%.

[0097] The product's characterization data are as follows:

[0098] 1 H NMR (500MHz, Methanol-d4) δ8.05(d,J=8.3Hz,1H),7.78(t,J=2.0Hz,1H),7.74(dt,J=8.3,1.8Hz,1H),5.16(dd,J=6.1,3.6Hz,1H),4.66(s,2H).

[0099] 13 C NMR (126MHz, Methanol-d4) δ162.92, 139.19 (d, J = 2.4Hz), 133.19 (dd, J = 27.6, 22.4Hz), 131.41 (d, J = 2 .4Hz), 129.66, 126.21 (dd, J=7.4, 3.7Hz), 113.78 (dd, J=246.5, 238.9Hz), 75.98 (dd, J=38.2, 30.0Hz).

[0100] 19 F NMR (471MHz, Methanol-d4) δ-95.20 (ddd, J = 264.2, 27.0, 9.3Hz), -124.72–-126.11 (m).

[0101] Example 29

[0102] Example 29 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 7-benzoyl-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0103]

[0104] Take a 15 mL pressure-resistant tube and add 51.1 mg (0.20 mmol) of 3-benzoyl-N-methoxybenzamide, 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7732-18-5). 2 mL (0.10 M), 80 °C, reaction time 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.33). The purified product weighs 35.0 mg and is a white powder with a yield of 58%.

[0105] The product's characterization data are as follows:

[0106] 1 H NMR (500MHz, Methanol-d4) δ8.23(d,J=7.9Hz,1H),8.10(t,J=1.9Hz,1H),8.06(dt,J=7.9,1.7Hz,1H ),7.88–7.81(m,2H),7.75–7.68(m,1H),7.65–7.56(m,2H),5.21(dd,J=6.0,3.5Hz,1H),4.66(s,3H).

[0107] 13C NMR (126MHz, Methanol-d4) δ195.25,162.89,141.63,136.43,133.14,132.17,132.15,131.75(dd,J=27.5,22.4Hz),130.47( dd,J=7.9,2.8Hz),129.72,128.43,128.01,125.31(d,J=5.1Hz),114.06(dd,J=245.9,238.8Hz),75.96(dd,J=38.6,30.1Hz).

[0108] 19 F NMR(471MHz, Methanol-d4)δ-94.49–-95.24(m),-125.82(dd,J=263.7,2.4Hz).

[0109] Example 30

[0110] Example 30 provides a method for preparing a fluoroisoquinoline one compound, chemically named 6-(chloromethyl)-4,4-difluoro-3-hydroxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0111]

[0112] Take a 15 mL pressure-resistant tube and add 39.9 mg (0.20 mmol) of 4-(chloromethyl)-N-methoxybenzamide (CAS No.: 1498124-71-2), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7732-18-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.32). The purified product weighs 36.5 mg and is a white powder with a yield of 74%.

[0113] The product's characterization data are as follows: 1H NMR (500MHz, Methanol-d4) δ8.06(d,J=8.0Hz,1H),7.84(d,J=1.7Hz,1H),7.76(dd,J=8.0,1.6Hz,1H),5.15(dd,J=6.2,3.6Hz,1H),4.80(s,2H),4.66(s,1H).

[0114] 13 C NMR (126MHz, Methanol-d4) δ163.4, 143.7, 131.9 (dd, J = 27.3, 22.2Hz), 131.2 (d ,J=2.6Hz),128.2,124.3(m),116.2–112.2(m),76.0(dd,J=38.9,30.1Hz),44.2.

[0115] 19 F NMR (471 MHz, Methanol-d4) δ -94.54 (dd, J = 263.6, 6.1 Hz), -125.62 (dd, J = 263.6, 8.1 Hz). Example 31

[0116] Example 31 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-6-iodo-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0117]

[0118] Take a 15 mL pressure-resistant tube and add 55.4 mg (0.20 mmol) of 4-iodo-N-methoxybenzamide (CAS No.: 2446-51-7), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7732). -18-5) 2mL (0.10M), temperature 80℃, reaction for 10h. After the reaction is complete, 10mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.32). The purified product weighs 40.0mg and is a white powder with a yield of 62%.

[0119] The product's characterization data are as follows:

[0120] 1 H NMR (500MHz, Methanol-d4) δ8.10(d,J=8.5Hz,1H),8.09(s,1H),7.77(d,J=8.5Hz,1H),5.11(dd,J=6.1,3.6Hz,1H).

[0121] 13 C NMR (126MHz, Chloroform-d) δ 167.2, 144.6, 137.2 (d, J = 5.3Hz), 133.2, 117.6 (dd, J = 246.4, 238.9Hz), 103.3, 79.9 (dd, J = 38.2, 30.0Hz).

[0122] 19 F NMR (471 MHz, Methanol-d4) δ -95.05 (d, J = 269.7 Hz), -125.51 (d, J = 266.2 Hz). Example 32

[0123] Example 32 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-6-methoxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0124]

[0125] Take a 15 mL pressure-resistant tube and add 36.2 mg (0.20 mmol) of N,4-dimethoxybenzamide (CAS No.: 24056-08-4), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7732). -18-5) 2mL (0.10M), temperature 80℃, reaction for 10h. After the reaction is complete, 10mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5mL of ethyl acetate each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.20). The purified product weighs 31.0mg and is a white powder with a yield of 68%.

[0126] The product's characterization data are as follows:

[0127] 1 H NMR (500MHz, Methanol-d4) δ7.99(d,J=8.6Hz,1H),7.23(s,1H),7.20(d,J=8.6Hz,1H),5.09(dd,J=6.3,3.7Hz,1H),3.92(s,3H).

[0128] 13 C NMR (126MHz, Chloroform-d) δ 167.9, 167.7, 134.0, 120.3 (d, J = 2.5Hz), 118.2 (dd, J = 246.6, 238.8Hz), 113.2, 80.09 (dd, J = 38.8, 30.1Hz), 58.93.

[0129] 19 F NMR (471 MHz, Methanol-d4) δ -94.75 (d, J = 263.0 Hz), -125.28 (d, J = 263.2 Hz). Example 33

[0130] Example 33 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-5,7-dimethyl-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0131]

[0132] Take a 15 mL pressure-resistant tube and add 35.8 mg (0.20 mmol) of N-methoxy-3,5-dimethylbenzamide (CAS No.: 1202932-70-4), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 7732-18-5) 2 mL (0.10 M), temperature 80℃, reaction for 10 h. After the reaction is complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) is added for quenching and 5 mL of saturated brine is added for washing. The organic phase is collected in layers, and the aqueous phase is extracted twice with ethyl acetate, 5 mL each time. The organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The product is then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.30). The purified product weighs 13.6 mg and is a white powder with a yield of 30%.

[0133] The product's characterization data are as follows:

[0134] 1 H NMR (500MHz, Methanol-d4) δ7.74(s,1H),7.35(s,1H),5.04(dd,J=7.4,4.5Hz,1H),2.53(d,J=3.9Hz,3H),2.40(s,3H).

[0135] 13 C NMR(126MHz, Methanol-d4)δ164.6,141.2(d,J=2.5Hz),137.3,136.9,129.9,128.2,12 6.1,116.6(dd,J=245.6,240.0Hz),76.4(dd,J=39.2,31.7Hz),19.8,18.8(d,J=9.3Hz).

[0136] 19 F NMR (471 MHz, Methanol-d4) δ -94.85 (d, J = 270.7 Hz), -115.96 (d, J = 270.8 Hz). Example 34

[0137] Example 34 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0138]

[0139] Take a 15 mL pressure-resistant tube and add 42.2 mg (0.20 mmol) of N,3,4-trimethoxybenzamide (CAS No.: 25563-13-7), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 773). 2 mL (0.10 M) of 2-18-5 solution was added at 90 °C for 10 h. After the reaction was complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) was added to quench the reaction and 5 mL of saturated brine was added for washing. The organic phase was collected in layers, and the aqueous phase was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The product was then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.13). The purified product weighed 24.0 mg and was a white powder with a yield of 46%.

[0140] The product's characterization data are as follows:

[0141] 1 H NMR (500MHz, Methanol-d4) δ7.57(s,1H),7.26(d,J=1.5Hz,1H),5.10(dd,J=6.7,3.6Hz,1H),3.97(s,3H),3.94(s,3H).

[0142] 13 C NMR(126MHz,MeOD)δ164.0,153.2,151.3,129.9,128.2,117.79(dd,J=238.5,2 44.8Hz), 109.7, 106.45 (d, J = 5.6Hz), 76.30 (dd, J = 40.1, 29.8Hz), 55.4, 55.2.

[0143] 19F NMR (471MHz, Methanol-d4) δ -93.09 (dd, J = 262.0, 11.3Hz), -123.60 (dd, J = 262.0, 2.6Hz).

[0144] Example 35

[0145] Example 35 provides a method for preparing a fluoroisoquinoline ketone compound, chemically named 4,4-difluoro-3-hydroxy-6-nitro-3,4-dihydroisoquinoline-1(2H)-one, and the preparation method is as follows:

[0146]

[0147] Take a 15 mL pressure-resistant tube and add 39.2 mg (0.20 mmol) of N-methoxy-4-nitrobenzamide (CAS No.: 1613-79-2), 93.6 mg (0.40 mmol) of 2,2-difluorovinyl-4-methylbenzenesulfonic acid (CAS No.: 185739-14-4), 32.0 mg (0.40 mmol) of NaOAc (CAS No.: 6131-90-4), 8.4 mg (0.01 mmol) of [Cp*RhCl2]2 catalyst (CAS No.: 125357-42-8), and water (CAS No.: 773). 2 mL (0.10 M) of 2-18-5 solution was added at 90 °C for 10 h. After the reaction was complete, 10 mL of ethyl acetate (CAS No.: 141-78-6) was added to quench the reaction and 5 mL of saturated brine was added for washing. The organic phase was collected in layers, and the aqueous phase was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The product was then obtained by column chromatography with a mixture of petroleum ether and ethyl acetate as the eluent (PE / EA = 1 / 1, Rf = 0.28). The purified product weighed 20.0 mg and was a white powder with a yield of 41%.

[0148] The product's characterization data are as follows:

[0149] 1 H NMR (500MHz, Methanol-d4) δ8.55(s,1H),8.53(d,J=8.3Hz,1H),8.30(d,J=8.3Hz,1H),5.21(dd,J=5.8,3.6Hz,1H).

[0150] 13C NMR (126MHz, Methanol-d4) δ161.7, 150.6, 129.7, 126.0 (d, J = 2.4Hz), 119.6, 113.6 (dd, J = 247.5, 239.5Hz), 75.90 (dd, J = 37.8, 29.9Hz).

[0151] 19 F NMR (471MHz, Methanol-d4) δ -95.65 (dd, J = 264.3, 11.4Hz), -125.58 (d, J = 264.3Hz).

[0152] As can be seen from Examples 1 to 35 above, the substrates suitable for this reaction are mainly isoindolinone compounds substituted with alkyl, alkoxy, halogroups, ester groups, or phenyl groups. This reaction constructs fluoroisoquinolinone compounds by cyclizing N-methoxybenzamide compounds with 2,2-difluorovinyl-4-methylbenzenesulfonic acid under the catalysis of [Cp*RhCl2]2. Therefore, compared with the synthesis of other fluoroisoquinolinone compounds, this invention is simple to operate, uses environmentally friendly water as a solvent, and the reaction raw materials are inexpensive and readily available. The wide range of applicable substrates indicates good tolerance of its functional groups, thus broad applicability; the reaction yield is high; the reaction process is fast, simple, and safe to operate, and has the potential for large-scale production.

[0153] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing a fluoroisoquinoline ketone compound, characterized in that, Includes the following steps: The compound shown in formula (I), the compound shown in formula (II), the rhodium catalyst, the ligand of the rhodium catalyst and the solvent are mixed and reacted to obtain the fluoroisoquinoline ketone compound shown in formula (III); The solvent is selected from water; the rhodium catalyst is selected from at least one of [Cp*RhCl2]2, [Cp*Rh(CH3CN)3(SbF6)2], and Cp*Rh(OAc)2; the ligand of the rhodium catalyst is selected from at least one of sodium acetate, cesium acetate, cesium pivalate, or cesium carbonate; the reaction temperature is 60℃~150℃; and the reaction time is 8h~12h. The structural formulas of the compounds represented by formula (I), (II), and (III) are as follows: ； Where n≥1, R 1 Selected from hydrogen, C 1~6 alkyl, C 1~10 alkoxy, halogen, C 1~5 Ester group, nitro group.

2. The method for preparing fluoroisoquinoline ketone compounds according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I), the compound shown in formula (II), the rhodium catalyst, and the ligand of the rhodium catalyst is 1:1~3:0.02~0.05:1~3.

3. The method for preparing fluoroisoquinoline ketone compounds according to claim 1, characterized in that, The volume molar ratio of the solvent to the compound shown in formula (I) is 6 to 20 mL / mmol.

4. The method for preparing fluoroisoquinoline ketone compounds according to claim 1, characterized in that, After the reaction is completed, the process also includes quenching, extraction, washing, concentration, and column chromatography.

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