Isoquinolinone compound intermediate as well as preparation method and application thereof

Abstract

The invention provides an intermediate of an isoquinolinone compound as well as a preparation method and application of the intermediate. The intermediate disclosed by the invention has structures shown as a formula B-1 and a formula C-1. The preparation method comprises one or more of the following steps: (1) reacting a compound in a formula A with C1-4 alkyl boric acid in a solvent in the presence of a catalyst and alkali to generate a compound in a formula B; (2) reacting the compound in the formula B with sulfuric acid to generate a compound in a formula B-1; (3) reacting the compound as shown in the formula B-1 with a bromination reagent or an iodination reagent to generate a compound as shown in a formula C-1; wherein in the formula A, X1 represents halogen; in the formula B, the formula B-1 and the formula C-1, R represents C1-4 alkyl; in the formula C-1, X2 represents Br or I. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to an isoquinolinone-type compound intermediate, a preparation method and an application thereof. Background Art

[0002] Isoquinoline sulfonamide compounds are an important class of ROCK kinase inhibitors. Both fasudil and K-115 (patent WO2006057397A1), currently on the market, are isoquinoline sulfonamide compounds. Fasudil is a novel drug with a broad range of pharmacological effects. As a RHO kinase inhibitor, it increases the activity of myosin light chain phosphatase, dilating blood vessels, reducing endothelial cell tension, improving brain microcirculation, and preventing the generation and exacerbation of cerebral blood steal. It also antagonizes inflammatory factors, protects neurons against apoptosis, and promotes neural regeneration. K-115 has a wide range of approved and potential applications, including glaucoma, elevated intraocular pressure, complications of diabetic retinopathy, age-related macular degeneration, corneal damage, and recovery after cataract and glaucoma surgery. It may also be further expanded to systemic use.

[0003] WO2022135421A1 discloses a salt form of an isoquinolinone-type compound as a ROCK protein kinase inhibitor and a preparation method thereof, and discloses a synthesis method of the following compound I:

[0004]

[0005] This synthesis method has the following disadvantages:

[0006] 1. In the preparation of Compound B, the sodium carbonate in the reaction will wrap around the raw materials and stick to the walls of the reactor as the reaction proceeds, and a small amount of raw materials will not react completely. 2. The yield in the preparation of Compound C is only about 40%, and the purity is only about 80%. There will be residual unreacted Compound B and excessively brominated impurities. 3. A high-purity sodium methyl mercaptan reagent is used in the preparation of Compound D. This reagent has a very strong odor, which is not conducive to scale-up production, and high-purity sodium methyl mercaptan is not easy to purchase. The reaction yield is only 70%. 4. In the preparation of Compound E, a large amount of concentrated hydrochloric acid is used as the reaction solvent, which is highly corrosive to the equipment. 5. The reaction yield in the preparation of Compound I is only 35%. Summary of the Invention

[0007] To address at least one technical problem existing in the prior art, the present invention provides an intermediate of an isoquinolinone-type compound and a method for synthesizing the same. The method of the present invention is simple, and the product (intermediate) is produced in high yield and purity. Furthermore, the use of the intermediate compound of the present invention can significantly improve the yield and purity of the isoquinolinone-type compound.

[0008] The first aspect of the present invention provides a method for preparing the compounds represented by the following formula B-1 and formula C-1, comprising one or more of the following steps:

[0009] (1) Compound A and C 1-4 The alkyl boronic acid is reacted in the presence of a catalyst and a base in a solvent to produce a compound of formula B; in formula A, X1 represents a halogen (such as F, Cl, Br, I, etc., preferably Br or I);

[0010]

[0011] (2) reacting the compound of formula B with sulfuric acid to produce the compound of formula B-1;

[0012]

[0013] (3) reacting the compound of formula B-1 with a brominating agent or an iodinating agent to produce a compound of formula C-1;

[0014]

[0015] In the above formula B, formula B-1 and formula C-1, R represents C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.; in formula C-1, X2 represents Br or I.

[0016] According to some embodiments of the present invention, in step (1), the compound of formula A and C 1-4 The molar ratio of the alkylboronic acid is 1:(2-4), for example, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, etc.

[0017] According to some embodiments of the present invention, in step (1), the C 1-4 The alkyl boronic acid is at least one selected from methyl boronic acid, ethyl boronic acid, propyl boronic acid, isopropyl boronic acid and butyl boronic acid.

[0018] According to some embodiments of the present invention, in step (1), the catalyst includes a combination of at least one of 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, XPhos (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl), RUphos (2-dicyclohexylphosphine-2',6'-diisopropyl-1,1'-biphenyl), and Mephos (2-dicyclohexylphosphine-2'-methylbiphenyl) and at least one of tris(dibenzylideneacetone)dipalladium, Pd(dppf)Cl2, PdCl2(PPh3)2, Pd(PPh3)4, and Pd(OAc)2.

[0019] According to some embodiments of the present invention, in step (1), the base includes at least one of alkali metal carbonates (such as sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal phosphates (such as potassium phosphate, sodium phosphate, etc.), and alkali metal acetates (such as potassium acetate, sodium acetate, etc.).

[0020] According to some embodiments of the present invention, in step (1), the solvent comprises an aromatic organic solvent and water. In some embodiments, the volume ratio of the aromatic organic solvent to water is (1-2):1, for example, 1:1, 1.2:1, 1.4:1, 1.5:1, 1.6:1, 1.8:1, 2:1, etc. In some embodiments, the aromatic organic solvent comprises toluene. In some embodiments, in step (1), the solvent comprises toluene and water.

[0021] According to some embodiments of the present invention, step (1) comprises: first mixing the aromatic hydrocarbon organic solvent with the compound of formula A, an alkyl boronic acid, a catalyst, and a base to obtain a mixed solution; and then adding water to the mixed solution to react. In some preferred embodiments, the mixed solution is first heated to 55-65° C. before adding water to react.

[0022] According to some embodiments of the present invention, in step (1), the reaction temperature is 90-100°C.

[0023] According to some embodiments of the present invention, in step (1), the reaction time is 10 to 20 hours.

[0024] According to some embodiments of the present invention, in step (1), the reaction is carried out in a protective atmosphere. In some embodiments, the protective atmosphere comprises at least one of nitrogen, helium, and argon.

[0025] According to some embodiments of the present invention, step (1) further comprises: after the reaction is completed, mixing the obtained reaction solution with water and performing solid-liquid separation to obtain a filtrate; separating the filtrate to obtain an organic phase, and washing, concentrating under reduced pressure and cooling the organic phase to obtain a compound of formula B. In some specific embodiments, the organic phase is washed with saturated salt water. In some specific embodiments, the concentrated solution obtained after the reduced pressure concentration is first mixed with C 1-6 In some embodiments, the temperature is lowered to -5 to 5°C.

[0026] According to some embodiments of the present invention, in step (2), the sulfuric acid is concentrated sulfuric acid.

[0027] According to some embodiments of the present invention, in step (2), the ratio of the mass of the sulfuric acid to the mass of the compound A is (0.4-0.8):1, for example, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, preferably (0.5-0.7):1.

[0028] According to some embodiments of the present invention, in step (2), the reaction temperature is -5 to 5°C.

[0029] According to some embodiments of the present invention, in step (2), the reaction time is 0.5 to 1.5 hours.

[0030] According to some embodiments of the present invention, step (2) further comprises: after the reaction of the compound of formula B with sulfuric acid is completed, the obtained reaction solution is subjected to solid-liquid separation to obtain a solid phase, and the solid phase is washed and dried to obtain the compound of formula B-1. In some specific embodiments, an ester organic solvent (preferably C 2-6 Ester solvents such as ethyl acetate) and / or halogenated hydrocarbon organic solvents (preferably C 1-6 The solid phase is washed with a halogenated hydrocarbon solvent such as dichloromethane. In some embodiments, the solid phase is dried at a temperature of 40 to 60°C.

[0031] According to some embodiments of the present invention, in step (3), the bromination reagent includes at least one of NBS, DBH, liquid bromine, DBI, SMBI, and NBP.

[0032] According to some embodiments of the present invention, in step (3), the iodination reagent includes at least one of NIS, NIP, NISac, DDH, CH3SO3I, CF3SO3I, NaI, KI, AgI, CHI3, iodobenzene, Dess-Martin reagent, hydroxy(toluenesulfonyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosobenzene, 2-iodobenzoic acid or iodobenzene dichloride.

[0033] According to some embodiments of the present invention, in step (3), the molar ratio of the compound of formula B-1 to the brominating agent or the iodinating agent is 1:(1 to 1.1), for example, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, etc.

[0034] According to some embodiments of the present invention, in step (3), the reaction temperature is 20-35°C.

[0035] According to some embodiments of the present invention, in step (3), the reaction time is 10 to 20 hours.

[0036] According to some embodiments of the present invention, in step (3), the reaction is carried out in the presence of sulfuric acid, preferably concentrated sulfuric acid.

[0037] According to some embodiments of the present invention, step (3) further comprises:

[0038] After the reaction is completed, the obtained reaction liquid is washed and separated, the pH of the aqueous phase is adjusted to 8-10 with alkali, and then extracted, washed, dried and concentrated to obtain a concentrated organic phase; the concentrated organic phase is mixed with sulfuric acid and reacted, and the obtained reaction liquid is subjected to solid-liquid separation to obtain a solid phase containing the compound of formula C-1; the solid phase containing the compound of formula C-1 is washed and dried to obtain the compound shown in formula C-1.

[0039] In some embodiments, step (3) further comprises:

[0040] After the reaction is completed, the obtained reaction solution is washed with a halogenated alkane solvent (such as dichloromethane) and separated, the aqueous phase is adjusted to pH 8-10 with a base (such as an alkali metal hydroxide, preferably sodium hydroxide), then extracted with a halogenated alkane solvent (such as dichloromethane), washed with saturated brine, dried and concentrated at 30-50° C. to obtain a concentrated organic phase; the concentrated organic phase is mixed with C 1-6 An alcohol solvent (such as ethanol) and concentrated sulfuric acid are mixed and reacted at 0-10° C. The obtained reaction solution is subjected to solid-liquid separation to obtain a solid phase containing the compound of formula C-1; the solid phase containing the compound of formula C-1 is subjected to C 1-6 Alcohol solvents (such as ethanol) and C 2-6 The product is washed with an ester solvent (such as ethyl acetate) and dried at 40-60°C to obtain the compound represented by formula C-1.

[0041] The second aspect of the present invention provides an intermediate compound of an isoquinolinone-type compound having a structure shown in the following formula B-1 or formula C-1:

[0042]

[0043] Wherein, in formula B-1 and formula C-1, R is independently selected from C 1-4 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; in formula C-1, X2 represents halogen, such as fluorine, chlorine, bromine, iodine, etc., preferably Br or I.

[0044] According to some embodiments of the present invention, the intermediate compound is selected from the following structures:

[0045]

[0046] The third aspect of the present invention provides use of the intermediate compound described in the second aspect in the preparation of an isoquinolinone-type compound.

[0047] The intermediate compound of the present invention can be used to prepare isoquinolinone compounds, especially isoquinoline sulfonamide compounds, with significantly improved product yield and product purity.

[0048] Compared with the prior art, the present invention has the following beneficial technical effects:

[0049] 1. The present invention adds water during the reaction process of preparing compound B to keep the reaction system in a loose state, thereby avoiding the adhesion of the added alkaline substance (sodium carbonate) to the wall during the reaction process, thereby improving the utilization rate and conversion rate of the reaction raw materials.

[0050] 2. The present invention prepares compound B in the form of a sulfate (compound B-1), thereby converting the product from a free liquid state into a loose solid, which is more conducive to the next step of feeding, and the purity and yield are significantly improved.

[0051] 3. Using the compound B-1 and compound C-1 synthesized in the present invention as intermediates to prepare isoquinolinone-type compounds can significantly improve the yield and product purity of the isoquinolinone-type compounds. DETAILED DESCRIPTION

[0052] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. The specific embodiments described herein are only used to illustrate the present invention and are not intended to constitute any limitation to the present invention.

[0053] Unless otherwise specified, the reagents used in the following examples and comparative examples of the present invention are all conventional commercial products or reagents prepared according to conventional methods. The instruments used in the examples and comparative examples, unless otherwise specified, can be obtained through commercial channels.

[0054] Comparative Example 1 Preparation of Compound B (Refer to WO2022135421A1)

[0055]

[0056] Toluene (24 L) was added to the reactor while maintaining the internal temperature at 25-35°C. Compound A (4000 g), sodium carbonate (6120 g), methylboric acid (3465 g), 2-dicyclohexylphosphine-2′,6′-dimethoxybiphenyl (98.66 g), and trisdibenzylideneacetone dipalladium (88.03 g) were then added sequentially with stirring. The reactor was purged with nitrogen three times, the internal temperature raised to 90°C, and stirred at 90-100°C for 13 hours (solid adhered to the wall during the reaction). Water (4 L) was added to the reactor to dissolve the solid. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with methyl tert-butyl ether (4 L). The washings and filtrate were combined and the pH was adjusted to 3 with concentrated hydrochloric acid (8 L). The mixture was allowed to stand for separation. The lower aqueous phase was extracted with methyl tert-butyl ether (5 L), the aqueous phase was adjusted to pH 9 with aqueous sodium hydroxide solution, the aqueous phase was extracted twice with ethyl acetate (12 L), and the combined organic phases were concentrated in vacuo until the weight no longer decreased to obtain compound B (liquid) with a yield of 80% and a purity of 98%.

[0057] Example 1 Preparation of Compound B-1:

[0058] The synthetic route is:

[0059]

[0060] The internal temperature was controlled at 25-35°C, and toluene (42 L) was added to the reactor. Compound A (7 kg), sodium carbonate (10.7 kg), methylboric acid (6.03 kg), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (0.164 kg), and trisdibenzylideneacetone dipalladium (0.154 g) were added to the reactor in sequence with stirring. The temperature was then raised. When the internal temperature of the reactor reached 55-65°C, purified water (28 L) was added. The reactor was purged with nitrogen three times, the internal temperature was raised to 90°C, and the mixture was stirred at 90-100°C for 13 hours to produce Compound B.

[0061] After stopping heating and cooling to room temperature, water (14 L) was added to the reactor to dissolve the solid, stirred for 1-2 hours, filtered, and the filtrate was separated into organic phase and aqueous phase. The organic phase was washed with saturated brine and concentrated under reduced pressure to remove toluene. After concentration, isopropanol (35 L) was added to the concentrate, cooled to 0 ° C, and concentrated sulfuric acid (3.955 kg) was slowly added dropwise to salt compound B. After the addition was complete, the mixture was stirred at 0 ° C for 1 hour, filtered, and the filter cake was washed twice with ethyl acetate (5 L * 2) and dried at 45 ° C for 20 hours to obtain solid compound B-1 (7.22 kg), with a yield of 88.9% and a purity of 97.78%; MS-ESI calculated value [M+H] + 144.19, measured value 144.2; 1H NMR (500MHz, CD3Cl) δ9.11(s,1H),8.35(s,1H),8.08–7.86(m,2H),7.72(ddd,J=8.5,7.0,1.5Hz,1H),7.59(ddd,J=8.0,7.0,1.0Hz,1H),2.59(s,3H)ppm.

[0062] The present invention adds water during the reaction process to keep the reaction system in a loose state and prevent it from adhering to the wall. In addition, the present invention prepares the product compound B into a sulfate, thereby converting the product from a free liquid state into a loose solid, which is more conducive to the next step of feeding and significantly improves the product yield.

[0063] Comparative Example 2 Preparation of Compound C (Refer to WO2022135421A1)

[0064]

[0065] Control the temperature inside the reactor to be lower than 30°C and slowly add concentrated sulfuric acid (13.36L) to a 50L reactor. Control the temperature inside the reactor to be lower than 50°C and slowly add compound B (2500g) to the reactor using a constant pressure dropping funnel. Control the temperature inside the reactor to be -10 to 0°C and slowly add N-bromosuccinimide (3070.25g) to the reactor in batches. The reaction solution is stirred at -10 to 8°C for 13 hours. Control the temperature inside the reactor to be lower than 50°C and slowly pour the reaction solution into ice water (8L). Control the temperature inside the reactor to be lower than 50°C and slowly add aqueous sodium hydroxide solution to the reaction solution to adjust the pH to 9. Add ethyl acetate (10L) to the reaction solution and stir for 10 minutes. Filter the reaction solution and wash the filter cake with ethyl acetate (12.5L). Extract the aqueous phase with ethyl acetate (10L×3) and concentrate the combined organic phases under reduced pressure at 45°C. n-Heptane (10 L) was added to the concentrated residue for slurrying, and suction filtration was performed to obtain a brown-red solid, which was placed in a vacuum drying oven (40° C.) to dry to obtain compound C with a yield of 40% and a purity of 80%.

[0066] Example 2 Preparation of Compound C-1:

[0067] The synthetic route is:

[0068]

[0069] Concentrated sulfuric acid (20 L) and compound B-1 (4 kg) prepared in accordance with Example 1 were added to the reactor, cooled to -10 ° C and stirred. When the internal temperature reached -10 ° C, NBS (406 g × 8) was added in batches, and the reaction was controlled at -10 ± 3 ° C, adding once every 30 minutes for about 4 hours. The refrigeration was stopped, and the temperature was slowly raised to 25 ° C and the reaction was completed for 14 hours. The reaction solution was slowly poured into ice (60 kg), washed twice with DCM (25 L × 2), and the organic phase was discarded. The aqueous phase was adjusted to pH = 9 with 40 wt% sodium hydroxide, the temperature was controlled at 30-40 ° C, and extracted twice with DCM (25 L × 2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness at 40 ° C. Ethanol (18.5 L) was added to the reactor, stirred to dissolve, and then cooled to 0-10 ° C. Slowly add concentrated sulfuric acid (1.8 kg) dropwise, control the temperature at 0-10°C, keep warm and stir for 30 minutes after the addition, filter, and wash the filter cake twice with ethyl acetate (7 L x 2). Add ethanol (26.7 L) to the reactor, add the filter cake under stirring, heat to 70-80°C, and stir for 2 hours. Stop heating and slowly raise the temperature to room temperature and stir for 13 hours, then cool to 0-10°C, stir for 2 hours, filter, wash the filter cake twice with ethyl acetate (7 L x 2), and dry with air at 45°C for 22 hours to obtain compound C-1 (3.55 kg), yield: 66.8%, purity 97.35%; MS-ESI calculated value [M+H] + 223.09, measured value 223.0; 1 H NMR (500MHz, CD3Cl) δ9.08(s,1H),8.43–8.32(m,1H),8.00(dd,J=7.5,1.3Hz,1H),7.89(dd,J=8.0,1.2Hz,1H),7.36(t,J=7.5Hz,1H),3.03(s,3H)ppm.

[0070] Compared with Comparative Example 2, the present invention can significantly improve the yield and purity of product C-1 by using the sulfate of compound B (ie, compound B-1).

[0071] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for preparing the compounds represented by the following formulas B-1 and C-1, comprising one or more of the following steps: (1) Compound A and C 1-4 The alkylboronic acid is reacted in a solvent in the presence of a catalyst and a base to produce a compound of formula B; (2) reacting the compound of formula B with sulfuric acid to produce the compound of formula B-1; (3) reacting the compound of formula B-1 with a brominating agent or an iodinating agent to produce a compound of formula C-1; in, In formula A, X1 represents a halogen, preferably Br or I; In Formula B, Formula B-1 and Formula C-1, R represents C 1-4 Alkyl; In formula C-1, X2 represents Br or I.

2. The preparation method according to claim 1, characterized in that In step (1): The compound of formula A and said C 1-4 The molar ratio of alkylboronic acid is 1:(2-4); and / or, The C 1-4 The alkyl boronic acid is selected from at least one of methyl boronic acid, ethyl boronic acid, propyl boronic acid, isopropyl boronic acid and butyl boronic acid; and / or, The catalyst comprises a combination of at least one of 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-diisopropyl-1,1'-biphenyl, and 2-dicyclohexylphosphine-2'-methylbiphenyl and at least one of tris(dibenzylideneacetone)dipalladium, Pd(dppf)Cl2, PdCl2(PPh3)2, Pd(PPh3)4, and Pd(OAc)2; and / or, The base includes at least one of alkali metal carbonates, alkali metal phosphates, and alkali metal acetates, and preferably includes at least one of sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium acetate, potassium acetate, and cesium carbonate; and / or, The solvent includes an aromatic organic solvent and water; preferably, the volume ratio of the aromatic organic solvent to water is (1-2):1; preferably, the solvent includes toluene and water.

3. The preparation method according to claim 2, characterized in that Step (1) includes: First, the aromatic hydrocarbon organic solvent is mixed with the compound of formula A, an alkylboronic acid, a catalyst and a base to obtain a mixed solution; then water is added to the mixed solution to react; Preferably, the mixed solution is first heated to 55-65° C. and then water is added to carry out the reaction.

4. The preparation method according to any one of claims 1 to 3, characterized in that In step (1), the reaction temperature is 90 to 100° C.; and / or the reaction time is 10 to 20 hours; Preferably, the reaction is carried out in a protective atmosphere; more preferably, the protective atmosphere comprises at least one of nitrogen, helium and argon.

5. The preparation method according to any one of claims 1 to 4, characterized in that Step (1) further includes: After the reaction is completed, the obtained reaction solution is mixed with water and solid-liquid separation is performed to obtain a filtrate; the filtrate is separated to obtain an organic phase, and the organic phase is washed, concentrated under reduced pressure and cooled to obtain a compound of formula B; Preferably, the organic phase is washed with saturated saline; Preferably, the concentrated solution obtained after reduced pressure concentration is firstly mixed with C 1-6 An alcohol solvent, preferably isopropyl alcohol, is mixed, and then cooled; Preferably, the temperature is lowered to -5 to 5°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that In step (2), the sulfuric acid is concentrated sulfuric acid; and / or the ratio of the mass of the sulfuric acid to the mass of the compound A is (0.4-0.8):1, preferably (0.5-0.7):1, and / or the reaction temperature is -5-5°C; and / or the reaction time is 0.5-1.5 hours; and / or, Step (2) further includes: After the reaction of the compound of formula B with sulfuric acid is completed, the obtained reaction solution is subjected to solid-liquid separation to obtain a solid phase; the solid phase is washed and dried to obtain the compound of formula B-1; Preferably, the solvent used for washing includes an ester organic solvent and / or a halogenated hydrocarbon organic solvent, and the ester organic solvent preferably includes ethyl acetate and / or isopropyl acetate; the halogenated hydrocarbon organic solvent preferably includes dichloromethane; Preferably, the drying temperature is 40-60°C.

7. The preparation method according to any one of claims 1 to 6, characterized in that In step (3): The bromination reagent includes at least one of NBS, DBH, liquid bromine, DBI, SMBI, and NBP; and / or The iodination reagent comprises at least one of NIS, NIP, NISac, DDH, CH3SO3I, CF3SO3I, NaI, KI, AgI, CHI3, iodobenzene, Dess-Martin reagent, hydroxy(toluenesulfonyloxy)iodobenzene, iodosobenzene diacetate, iodosobenzene bis(trifluoroacetate), iodosobenzene, 2-iodobenzoic acid or iodobenzene dichloride; and / or, The molar ratio of the compound of formula B-1 to the brominating agent or iodinating agent is 1:(1 to 1.1); and / or, The reaction temperature is 20-35°C; and / or, The reaction time is 10 to 20 hours; and / or, The reaction is carried out in the presence of sulfuric acid, preferably concentrated sulfuric acid.

8. The preparation method according to any one of claims 1 to 7, characterized in that Step (3) further includes: After the reaction is completed, the obtained reaction solution is washed and separated, the aqueous phase is adjusted to pH 8-10 with alkali, and then extracted, washed, dried and concentrated to obtain a concentrated organic phase; The concentrated organic phase is mixed with sulfuric acid and reacted to obtain a reaction solution; the reaction solution is subjected to solid-liquid separation to obtain a solid phase containing the compound of formula C-1; The solid phase containing the compound of formula C-1 is washed and dried to obtain the compound represented by formula C-1.

9. An intermediate compound having a structure represented by the following formula B-1 or formula C-1: in, In formula B-1 and formula C-1, R is independently selected from C 1-4 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; in formula C-1, X2 represents halogen, preferably Br or I; Preferably, the intermediate compound is selected from the following structures:

10. Use of the intermediate compound as claimed in claim 9 in the preparation of isoquinolinone-type compounds.

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