Isoquinoline sulfonamide compound intermediate as well as preparation method and application thereof

Abstract

The invention provides compounds as shown in a formula D-1 and a formula E-1 as well as a preparation method and application thereof. The preparation method comprises one or more of the following steps: (1) reacting a compound shown as a formula C or a salt thereof with an isothiourea compound or a salt thereof to generate a compound shown as a formula D-1; (2) reacting the compound in the formula D-1 with dichlorohydantoin or pypocholoride to obtain a compound in a formula E-1; wherein R1 represents a C1-C4 alkyl group, X2 represents halogen, and R2 represents a C1-C4 alkyl group, or a C1-C4 alkyl group substituted by one or more C6-C12 aryl groups. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to an isoquinoline sulfonamide 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, resulting in a small amount of raw materials not being fully reacted. 2. In the preparation of Compound C, the yield is only about 40%, and the purity is only about 80%. Incompletely reacted B and excessively brominated impurities will remain. 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. In the preparation of Compound I, the reaction yield is only 35%. Summary of the Invention

[0007] In order to solve at least one technical problem existing in the prior art, the present invention provides an isoquinoline sulfonamide compound intermediate and a preparation method thereof.

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

[0009] (1) reacting a compound of formula C or a salt thereof with an isothiourea compound or a salt thereof to produce a compound of formula D-1;

[0010]

[0011] (2) reacting the compound of formula D-1 with dichlorohydantoin or hypochlorite to obtain the compound of formula E-1;

[0012]

[0013] Wherein, in Formula C, Formula D-1, and Formula E-1, R1 represents a C1-C4 alkyl group, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group; X2 represents a halogen group, preferably a bromine group or an iodine group;

[0014] In formula D-1, R2 represents a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more C6-C12 aryl groups (eg, phenyl group).

[0015] In some embodiments, R2 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl. In some embodiments, R2 represents methyl, ethyl or benzyl.

[0016] According to some embodiments of the present invention, the salt of the compound of formula C includes but is not limited to: a sulfate salt of the compound of formula C.

[0017] According to some embodiments of the present invention, the isothiourea compound includes a C1-C4 alkylisothiourea, wherein the C1-C4 alkylisothiourea is optionally substituted by one or more C6-C12 aromatic groups (eg, phenyl).

[0018] According to some embodiments of the present invention, the isothiourea compound includes at least one of benzylisothiourea, methylisothiourea, and ethylisothiourea.

[0019] According to some embodiments of the present invention, the salt of the isothiourea compound includes but is not limited to: hydrochloride and hydrobromide of the isothiourea compound.

[0020] According to some embodiments of the present invention, in Formula C, X2 represents Br.

[0021] According to some embodiments of the present invention, the salt of the compound of formula C includes the compound represented by formula C-1:

[0022]

[0023] In formula C-1, R1 and X2 are defined the same as in formula C.

[0024] According to some embodiments of the present invention, step (1) comprises: reacting a compound of formula C-1-1 with a hydrobromide salt of benzyl isothiourea to produce a compound of formula D-1-1;

[0025]

[0026] In some embodiments, the preparation method of the compound represented by formula C-1 comprises the following steps:

[0027] (S1) reacting a compound of formula A with a C1-C4 alkylboronic acid in the presence of a catalyst and a first alkaline substance in a first solvent to produce a compound of formula B; wherein X1 in formula A represents a halogen, such as fluorine, chlorine, bromine, iodine, etc., preferably bromine or iodine;

[0028] (S2) reacting the compound of formula B with sulfuric acid to produce the compound of formula B-1;

[0029]

[0030] (S3) reacting the compound of formula B-1 with a brominating agent or an iodinating agent to produce a compound of formula C-1;

[0031]

[0032] Wherein, in formula B, formula B-1 and formula C-1, R1 represents a C1-C4 alkyl group, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group;

[0033] In formula C-1, X2 represents Br or I.

[0034] In some embodiments, in step (S1), the C1-C4 alkyl boronic acid includes but is not limited to: methyl boronic acid, ethyl boronic acid, propyl boronic acid, isopropyl boronic acid, butyl boronic acid, etc.

[0035] In some embodiments, in step (S1), the molar ratio of the compound of formula A to the C1-C4 alkyl boronic acid is 1:(2-4).

[0036] 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.

[0037] In some embodiments, in step (S1), the first alkaline substance includes at least one of alkali metal carbonates, alkali metal phosphates, and alkali metal acetates, such as sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium acetate, potassium acetate, cesium carbonate, etc.

[0038] In some embodiments, in step (S1), the first 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, 1.5:1, 1.8:1, 2:1, or any value therebetween. In some specific embodiments, the first solvent comprises toluene and water.

[0039] In some embodiments, in step (S1), the reaction temperature is 90-100°C.

[0040] In some embodiments, in step (S2), the sulfuric acid is concentrated sulfuric acid.

[0041] According to some embodiments of the present invention, in step (S2), 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.

[0042] In some embodiments, in step (S2), the reaction temperature is -5 to 5°C.

[0043] In some embodiments, in step (S3), the bromination reagent includes at least one of NBS, DBH, liquid bromine, DBI, SMBI, and NBP.

[0044] In some embodiments, in step (S3), 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.

[0045] In some embodiments, in step (S3), the reaction temperature is 20-35°C.

[0046] According to some embodiments of the present invention, in step (1), the molar ratio of the compound of formula C or its salt to the isothiourea compound or its salt is 1:(1-2), for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, etc.

[0047] According to some embodiments of the present invention, in step (1), the reaction temperature is 80-90°C.

[0048] According to some embodiments of the present invention, in step (1), the reaction is carried out in a second solvent in the presence of a second alkaline substance. In some embodiments, the second alkaline substance comprises an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, etc. In some embodiments, the mass ratio of the second alkaline substance to compound C or its salt is 1: (1 to 1.5). In some embodiments, the second solvent comprises an amide organic solvent, such as N,N-dimethylformamide.

[0049] According to some embodiments of the present invention, step (1) further comprises: cooling the reaction solution after the reaction and performing solid-liquid separation, and washing and drying the solid phase to obtain a compound of formula D-1. In some embodiments, the reaction solution after the reaction is cooled to below 40°C. In some embodiments, the solid phase is washed with water. In some embodiments, the drying temperature is 40 to 60°C.

[0050] According to some embodiments of the present invention, in step (2), the hypochlorite comprises an alkali metal salt of hypochlorous acid, such as sodium hypochlorite.

[0051] According to some embodiments of the present invention, in step (2), the molar ratio of the compound of formula D-1 to dichlorohydantoin or hypochlorite is 1:(1-3), for example, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2.0, 1:2.2, 1:2.5, 1:2.8, 1:3.0 or any value therebetween.

[0052] According to some embodiments of the present invention, in step (2), the reaction temperature is 15 to 35°C.

[0053] According to some embodiments of the present invention, in step (2), the reaction time is 10 to 20 hours.

[0054] According to some embodiments of the present invention, in step (2), the reaction is carried out in a third solvent in the presence of an acid. In some embodiments, the acid comprises a monobasic or polybasic organic acid, such as glacial acetic acid. In some embodiments, the volume ratio of the mass of the compound of formula D-1 to the acid is 2 to 4 kg / L. In some embodiments, the third solvent comprises a nitrile organic solvent and water. In some specific embodiments, the third solvent comprises acetonitrile and water.

[0055] According to some embodiments of the present invention, in step (2), the third solvent is first mixed with the acid and the compound of formula D-1, cooled to 0-10° C., and then dichlorohydantoin or hypochlorite is added under heat preservation conditions.

[0056] According to some embodiments of the present invention, step (2) further comprises: after the reaction, subjecting the obtained reaction solution to solid-liquid separation, and washing and drying the solid phase to obtain the compound of formula E-1. In some embodiments, the solid phase is washed with an ether solvent such as methyl tert-butyl ether. In some embodiments, the drying temperature is 40 to 60°C.

[0057] In a second aspect, the present invention provides an intermediate compound having a structure as shown in the following formula E-1, or a compound as shown in the following formula D-1 or a salt thereof:

[0058]

[0059] In Formula D-1 and Formula E-1,

[0060] R1 is independently selected from C1-C4 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl;

[0061] R2 is selected from C1-C4 alkyl, C1-C4 alkyl substituted by one or more C6-C12 aryl groups, preferably C1-C4 alkyl, C1-C4 alkyl substituted by one or more phenyl groups, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl.

[0062] According to some embodiments of the present invention, the intermediate compound is selected from the following structures:

[0063]

[0064]

[0065] In a third aspect, the present invention provides use of the intermediate compound described in the second aspect in the preparation of isoquinoline sulfonamide compounds.

[0066] Compared with the prior art, the present invention has the following beneficial effects:

[0067] 1. The synthesis method of the intermediate of formula D-1 of the present invention avoids the use of the malodorous reagent sodium methyl mercaptan, and the post-reaction treatment is relatively simple. The product is solid, which is convenient for the next step of feeding, and the product yield is as high as over 90%.

[0068] 2. The synthesis method of the intermediate of formula E-1 of the present invention avoids the use of concentrated hydrochloric acid as a solvent, reduces the corrosiveness to the equipment, and the post-reaction treatment is relatively simple.

[0069] 3. The intermediate compound of the present invention can be used to prepare isoquinoline sulfonamide compounds with high product yield and high purity. DETAILED DESCRIPTION

[0070] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0071] Unless otherwise specified, the reagents used in the following examples and comparative examples of the present invention are 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.

[0072] Example 1 Preparation of Compound B-1:

[0073] The synthetic route is:

[0074]

[0075] 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.

[0076] 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; 1HNMR(500MHz,CD3Cl)δ9.11(s,1H),8.35(s,1H),8.08–7.86(m,2H),7.72(dd d,J=8.5,7.0,1.5Hz,1H),7.59(ddd,J=8.0,7.0,1.0Hz,1H),2.59(s,3H)ppm.

[0077] Example 2 Preparation of Compound C-1:

[0078] The synthetic route is:

[0079]

[0080] 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.

[0081] Comparative Example 1 Preparation of Compound D (Refer to WO2022135421A1)

[0082]

[0083] To a 50 L reactor, add N,N-dimethylacetamide (10 L) and stir. Add compound C (1003.60 g). Keeping the internal temperature below 55°C, slowly add sodium methyl mercaptan (1277.0 g) in portions to the 50 L reactor. Stir the reaction mixture at 50°C for 30 minutes. Raise the reactor temperature to 120°C, at which point the internal temperature is 109°C, and stir under these conditions for 12 hours. Adjust the reactor temperature to 50°C to lower the reaction liquid temperature to 40-50°C. Filter the reaction liquid through celite and wash with ethyl acetate (10 L). Add water (10 L) to the filtrate, and extract the aqueous phase with ethyl acetate (5 L x 2). Adjust the pH of the aqueous phase to 7 with concentrated hydrochloric acid. Extract the aqueous phase with ethyl acetate (5 L x 2). Combine the organic phases, wash with water (10 L x 3), and concentrate under reduced pressure until the weight remains unchanged to obtain solid compound D (0.597 kg) in a yield of 75.4%.

[0084] Example 3 Preparation of Compound D-1:

[0085] The synthetic route is:

[0086]

[0087] Under nitrogen protection, compound C-1 (3 kg) prepared in Example 2, benzyl isothiourea hydrobromide (2.1 kg), sodium hydroxide (2.63 kg), and DMF (60 L) were added to the reactor in sequence and heated to 80-90°C for 2 hours. The reaction solution was cooled to below 40°C, purified water (120 L) was slowly added, and the temperature was maintained below 40°C and stirred for 16 hours. The mixture was filtered, and the filter cake was washed twice with purified water (10 L x 2) and dried at 50°C for 24 hours to obtain compound D-1 (2.27 kg) with a yield of 91.45% and a purity of 97.1%. MS-ESI calculated value [M+H] + 266.37, measured value 266.1.

[0088] 1 H NMR (500MHz, CD3Cl) δ8.73 (dd, J=8.0, 1.5Hz, 1H), 7.76 (dd, J=7.5, 1.5Hz, 1H), 7.54 (t, J= 8.0Hz,1H),7.34(td,J=12.0,10.0,4.5Hz,6H),6.98(s,1H),5.19(s,2H),2.10(s,3H)ppm.

[0089] Compared with the process in the prior art, the synthesis method of compound D-1 of the present invention avoids the use of the malodorous reagent sodium methyl mercaptan, and the post-reaction treatment is relatively simple. The product is solid, which is convenient for the next step of feeding, and the yield is as high as over 90%.

[0090] Comparative Example 2 Preparation of Compound E (Refer to WO2022135421A1)

[0091] The synthetic route is:

[0092]

[0093] Add dichloromethane (8L) to a clean 50L high and low temperature reactor and start stirring. Add D (1474g) to the reactor and adjust the oil bath temperature to control the temperature in the reactor at 0-10°C. Add concentrated hydrochloric acid (4.4L) slowly to the reactor in batches, and control the internal temperature at 5-15°C. After the concentrated hydrochloric acid is added dropwise, lower the internal temperature of the reactor to -5°C. Add sodium hypochlorite aqueous solution (21.4L) slowly dropwise to the reactor in batches, and control the temperature at 0-10°C throughout the process. Filter the reaction solution, wash the filter cake with methyl tert-butyl ether (2L×2), and collect the filter cake. Place the collected filter cake in an oven and dry to obtain E with a yield of 57.43%.

[0094] Example 4 Preparation of Compound E-1:

[0095] The synthetic route is:

[0096]

[0097] To the reactor, acetonitrile (42.15 L), glacial acetic acid (1.69 L), purified water (1.12 kg) and compound D-1 (5.62 kg) prepared in Example 3 were added in sequence, stirred and cooled to 0-10 ° C. Dichlorohydantoin (1.04 kg × 8) was added in batches, the temperature was controlled to 0-10 ° C. After the addition was completed, the temperature was naturally raised to 25 ° C and stirred for 14 hours. Filtered, the filter cake was washed twice with methyl tert-butyl ether (5 L × 2). Acetone (45 L) and the above filter cake were added to the reactor, stirred and slurried at room temperature for 21 hours, filtered, and the filter cake was washed twice with methyl tert-butyl ether (5 L × 2). It was dried at 45 ° C for 18 hours to obtain compound E-1 (4.38 kg), with a yield of 74.36% and a purity of 98.53%.

[0098] MS-ESI calculated value [M+H] + 242.69, measured value 242.0.

[0099] 1H NMR (400MHz, DMSO) δ9.75 (s, 1H), 8.94-8.96 (m, 1H), 8.53 (dd, J = 7.6, 1.2Hz, 2H), 7.96 (t, J = 7.6Hz, 1H), 3.35 (s, 3H) ppm.

[0100] The synthesis method of the present invention avoids using concentrated hydrochloric acid as a solvent, reduces corrosion to equipment, and has simple post-reaction treatment and high product yield.

[0101] 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 formula D-1 and formula E-1, comprising one or more of the following steps: (1) reacting a compound of formula C or a salt thereof with an isothiourea compound or a salt thereof to produce a compound of formula D-1; (2) reacting the compound of formula D-1 with dichlorohydantoin or hypochlorite to obtain the compound of formula E-1; in, In formula C, formula D-1, and formula E-1, R1 represents a C1-C4 alkyl group, and X2 represents a halogen; In formula D-1, R2 represents a C1-C4 alkyl group or a C1-C4 alkyl group substituted with one or more C6-C12 aryl groups.

2. The preparation method according to claim 1, characterized in that In formula C, formula D-1, and formula E-1, R1 represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; and / or, In formula C, X2 represents Br or I; and / or, In formula D-1, R2 represents a C1-C4 alkyl group, a C1-C4 alkyl group substituted by one or more phenyl groups; preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group or a benzyl group; and / or, The salt of the compound of formula C includes the sulfate of the compound of formula C; and / or, The isothiourea compound comprises a C1-C4 alkyl isothiourea, wherein the C1-C4 alkyl isothiourea is optionally substituted by one or more C6-C12 aryl groups, preferably phenyl groups; preferably, the isothiourea compound comprises at least one of benzyl isothiourea, methyl isothiourea, and ethyl isothiourea; and / or, The salt of the isothiourea compound includes at least one of a hydrochloride and a hydrobromide of the isothiourea compound.

3. The preparation method according to claim 1 or 2, characterized in that Salts of the compound of formula C include compounds represented by formula C-1; In formula C-1, R1 and X2 are defined the same as in formula C; Preferably, the preparation method of the compound represented by formula C-1 comprises the following steps: (S1) reacting a compound of formula A with a C1-C4 alkylboronic acid in the presence of a catalyst and a first alkaline substance in a first solvent to produce a compound of formula B; wherein X1 represents fluorine, chlorine, bromine or iodine, preferably bromine or iodine; (S2) reacting the compound of formula B with sulfuric acid to produce the compound of formula B-1; (S3) reacting the compound of formula B-1 with a brominating agent or an iodinating agent to produce a compound of formula C-1; Wherein, in formula B, formula B-1 and formula C-1, R1 represents a C1-C4 alkyl group, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a tert-butyl group; In formula C-1, X2 represents Br or I.

4. The preparation method according to claim 3, characterized in that In step (S1), the C1-C4 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 molar ratio of the compound of formula A to the C1-C4 alkyl boronic acid is 1:(2-4); 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 first alkaline substance includes at least one of alkali metal carbonate, alkali metal phosphate, alkali metal acetate, and / or, The first solvent includes an aromatic organic solvent and water; and / or, In step (S1), the reaction temperature is 90-100°C; and / or, In step (S2), the sulfuric acid is concentrated sulfuric acid; and / or, In step (S2), 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, In step (S2), the reaction temperature is -5 to 5°C; and / or, In step (S3), the bromination reagent includes at least one of NBS, DBH, liquid bromine, DBI, SMBI, and NBP; 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; In step (S3), the reaction temperature is 20-35°C; Preferably, in the first solvent, the volume ratio of the aromatic hydrocarbon organic solvent to water is (1-2):1; preferably, the first solvent comprises toluene and water; Preferably, the first alkaline substance includes at least one of sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, and cesium carbonate.

5. The preparation method according to any one of claims 1 to 4, characterized in that In step (1): The molar ratio of the compound of formula C or its salt to the isothiourea compound or its salt is 1:(1-2); and / or the reaction temperature is 80-90° C.; and / or the reaction is carried out in the presence of a second alkaline substance in a second solvent; Preferably, the second alkaline substance comprises an alkali metal hydroxide, preferably sodium hydroxide and / or potassium hydroxide; Preferably, the mass ratio of the second alkaline substance to compound C or its salt is 1:(1-1.5); Preferably, the second solvent comprises an amide organic solvent, preferably N,N-dimethylformamide.

6. The preparation method according to any one of claims 1 to 5, characterized in that Step (1) further comprises: cooling the reaction solution after the reaction and performing solid-liquid separation, and washing and drying the solid phase to obtain a compound of formula D-1; Preferably, the reaction solution after the reaction is cooled to below 40°C; Preferably, the solid phase is washed with water; Preferably, the drying temperature is 40-60°C.

7. The preparation method according to claim 6, characterized in that In step (2): The hypochlorite comprises an alkali metal salt of hypochlorous acid, preferably sodium hypochlorite; and / or, the molar ratio of the compound of formula D-1 to dichlorohydantoin or hypochlorite is 1:(1-3); and / or, the reaction temperature is 15-35° C.; and / or, the reaction time is 10-20 hours; and / or, the reaction in step (2) is carried out in the presence of an acid in a third solvent; Preferably, the acid comprises a monobasic or polybasic organic acid, preferably comprises glacial acetic acid; Preferably, the mass ratio of the compound of formula D-1 to the volume ratio of the acid is 2 to 4 kg / L; Preferably, the third solvent comprises a nitrile organic solvent and water; more preferably comprises acetonitrile and water; Preferably, in step (2), the third solvent is first mixed with the acid and the compound of formula D-1, cooled to 0-10° C., and then dichlorohydantoin or hypochlorite is added under heat preservation conditions.

8. The preparation method according to any one of claims 1 to 7, characterized in that Step (2) further comprises: after the reaction, performing solid-liquid separation on the obtained reaction solution, and washing and drying the solid phase to obtain the compound of formula E-1; Preferably, the solid phase is washed with an ether solvent, preferably methyl tert-butyl ether; Preferably, the drying temperature is 40-60°C.

9. An intermediate compound having a structure as shown in the following formula E-1, or a compound as shown in the following formula D-1 or a salt thereof: In Formula D-1 and Formula E-1, R1 is independently selected from C1-C4 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; R2 is selected from C1-C4 alkyl, C1-C4 alkyl substituted by one or more C6-C12 aryl groups, preferably C1-C4 alkyl, C1-C4 alkyl substituted by one or more phenyl groups, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl; Preferably, the intermediate compound is selected from the following structures:

10. Use of the intermediate compound according to claim 9 in the preparation of isoquinoline sulfonamide compounds.

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