WO2023185027A1 - Preparation method for isoquinoline compound - Google Patents

Abstract

The present invention relates to synthesis of drugs for preventing or treating Alzheimer's disease, Parkinson's disease and other related diseases, and in particular to a preparation method for an isoquinoline compound. In the process, compound II is used as a raw material to prepare compound VI (i.e. to the isoquinoline compound), so that industrial production of the isoquinoline compound on a large scale can be achieved, the yield is higher, and the purity is high.

Description

Preparation method of isoquinoline compounds

The present invention claims the priority of the Chinese patent application submitted to the China Patent Office on March 30, 2022, with the application number 202210324743.9 and the invention name "A preparation method of isoquinoline compounds", the entire content of which is incorporated by reference. in the present invention.

Technical field

The invention belongs to the technical field of drug synthesis and relates to the synthesis of drugs for preventing or treating Alzheimer's disease, Parkinson's disease and other related diseases, and specifically relates to a preparation method of isoquinoline compounds.

Background technique

The information in this Background section is disclosed solely for the purpose of increasing understanding of the general background of the invention and is not necessarily considered to be an admission or in any way implying that the information constitutes prior art that is already known to a person of ordinary skill in the art.

At present, some studies have shown that isoquinoline compounds have the effect of treating Parkinson's disease and Alzheimer's disease. However, the chemical synthesis method of isoquinoline compounds has not yet been disclosed. In particular, there are no relevant reports on preparation methods suitable for industrial large-scale production.

Contents of the invention

In order to solve the deficiencies of the existing technology, the object of the present invention is to provide a preparation method of isoquinoline compounds, which can realize large-scale industrial production of isoquinoline compounds.

In order to achieve the above objects, the technical solution of the present invention is:

On the one hand, a method for preparing isoquinoline compounds includes the process of using compound II as a raw material to prepare compound VI (i.e., isoquinoline compounds) according to the following reaction route:

Among them, R is an amino protecting group, and compound II is prepared through Buchwald-Hartwig coupling reaction to compound III.

The main ring of isoquinoline compounds is isoquinoline, and its 2-position N has little effect on the electron cloud distribution of 1 and 3-position C, so the substituted amination reaction at 1 and 3-position is difficult to proceed. When other isoquinoline When the C position is replaced by other elements, for example, the 4-position C of isoquinoline is replaced by N to form quinazoline, which causes a large change in the electron cloud in the main ring structure. At this time, the substituted amination reaction at positions 1 and 3 is easier. conduct. Under the premise that the electron cloud distribution of isoquinoline compounds makes it difficult to carry out the substituted amination reaction at positions 1 and 3, the connection of methoxy groups at positions 6 and 7 is even more unfavorable for amine substitution at positions 1 and 3 of isoquinoline. Studies have shown that when C at position 1 is connected to a primary amine group, continued amination substitution at position 3 will easily cause the primary amine group at position 1 to be consumed. In order to prevent the primary amino group from being consumed, the present invention uses an amino protecting group R to protect the amino group, that is, react with compound II.

Theoretically, compound II reacts directly with N-methyl-N'-tetrahydrofuranoylpropanediamine, making the operation simpler. However, the cost of N-methyl-N'-tetrahydrofuranoylpropanediamine is relatively high. Secondly, N-methyl-N'-tetrahydrofuranoylpropanediamine is an oily substance, which is difficult to purify. It contains many impurities and easily increases side reactions, resulting in a low yield. Therefore, the present invention uses N-methyl-3-aminopropionitrile as raw material to avoid the problems of high input cost and excessive impurities caused by the use of N-methyl-N'-tetrahydrofuranformylpropanediamine in industrial production. In addition, the present invention solves the problem of difficult amination substitution of chlorine at the 3-position C through Buchwald-Hartwig coupling reaction, and then obtains the target product isoquinoline compound through reduction, amidation and deprotection.

On the other hand, a method for preparing isoquinoline compounds includes using compound II as a raw material to prepare compound VI according to the following reaction route:

Among them, R is an amino protecting group, X is halogen or hydroxyl, and compound II is prepared through Buchwald-Hartwig coupling reaction to compound VII.

In order to solve the problems of high feeding cost and excessive side reactions caused by excessive impurities caused by the use of N-methyl-N'-tetrahydrofuranoylpropanediamine in industrial production, the present invention uses methylamine hydrochloride, which has lower feeding cost and higher purity. Higher, side effects are greatly reduced. At the same time, the problem of difficult amination substitution of chlorine at position 3 was solved through Buchwald-Hartwig coupling reaction, and the target product isoquinoline compound was obtained through substitution reaction and deprotection.

The technical solution of the present invention has shown that it is difficult to obtain this compound using existing preparation methods. Therefore, the third aspect of the present invention is an isoquinoline compound, and the isoquinoline compound is compound VI obtained by the above preparation method.

The beneficial effects of the present invention are:

Through the above preparation method, the present invention avoids directly using N-methyl-N'-tetrahydrofuranoylpropanediamine to carry out amination reaction on the 3-position of isoquinoline, thereby avoiding low yield and high cost in industrial production. question. Experiments have shown that the preparation method of the present invention can achieve the purpose of industrial large-scale production of isoquinoline compounds, and the isoquinoline compounds prepared have higher yield and high purity.

Description of drawings

The description and drawings that constitute a part of the present invention are used to provide a further understanding of the present invention. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.

Figure 1 is a graph showing the test results of rats in a Parkinson's disease model in which 6-OHDA was injected with Compound VI in a specific brain area in Example 25 of the present invention during adhesion and standing.

Figure 2 is a graph showing test results during exercise of rats in a Parkinson's disease model using Compound VI to inject 6-OHDA into specific brain areas in Example 25 of the present invention.

Figure 3 is a graph showing the test results of the grip strength and nervous system balance ability of mice in the Parkinson's disease model using Compound VI for intraperitoneal injection of MPTP in Example 26 of the present invention.

Figure 4 is a graph illustrating the survival number results of dopamine neurons in mice of the Parkinson's disease model in which MPTP was injected intraperitoneally with Compound VI in Example 26 of the present invention.

Detailed ways

It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It should be noted that the terms used herein are for the purpose of describing specific embodiments only, and are not intended to limit the exemplary embodiments according to the present invention. As used herein, the singular forms are also intended to include the plural forms unless the context clearly indicates otherwise. Furthermore, it will be understood that when the terms "comprises" and/or "includes" are used in this specification, they indicate There are features, steps, operations, means, components and/or combinations thereof.

In view of the problem of low yield of isoquinoline compounds in scale-up production, the present invention proposes a preparation method of isoquinoline compounds.

A typical embodiment of the present invention provides a method for preparing isoquinoline compounds, which includes the process of using compound II as a raw material to prepare compound VI (i.e., isoquinoline compounds) according to the following reaction route:

Among them, R is an amino protecting group, and compound II is prepared through Buchwald-Hartwig coupling reaction to compound III. The amino protecting group is an amino protecting group, such as benzyl, substituted benzyl, diphenylmethyl, substituted diphenylmethyl, trityl, substituted trityl, tert-butoxycarbonyl, etc. The substituted benzyl group is a benzyl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like. The substituted benzyl group is a benzyl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like. The substituted trityl group is a trityl group substituted by an alkoxy group, a halogen group, an alkyl group, an alkyl group, or the like.

Some examples of this embodiment also include the process of preparing compound II from compound I according to the following reaction route:

The present invention uses R-NH ₂ to carry out the reaction, which can solve the problem that the reaction temperature is too high and microwave heating is required due to the electron cloud distribution of isoquinoline and the methoxy groups at positions 6 and 7.

In one or more embodiments, the amino protecting group is alkoxy or alkyl substituted benzyl. This scheme can ensure a higher yield of compound II. The amino protecting group is preferably 2-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or 2,4-dimethoxy. Benzyl.

In one or more embodiments, during the preparation of Compound II from Compound I, the reaction temperature is 100-160°C, preferably 100-130°C.

In one or more embodiments, the solvent in the process of preparing compound II from compound I is N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) one or more of them.

In one or more embodiments, during the preparation of compound II from compound I, the molar ratio of compound I to R-NH ₂ is 1:2-5, preferably 1:2.5-4.

The Buchwald-Hartwig coupling reaction of the present invention is a cross-coupling reaction of an amine and an aromatic halide to form an N-arylation product of the amine under palladium catalysis.

Research shows that in the Buchwald-Hartwig coupling reaction, the choice of catalyst affects the product yield. In one or more embodiments, the catalyst is Pd(OAc) ₂ (palladium acetate), Pd ₂ (dba) ₃ (tri( Dibenzylideneacetone)dipalladium), Pd(dba) ₂ (dibenzylideneacetonepalladium), PdCl ₂ (cod) ((1,5-cyclooctadiene)palladium chloride), [Pd(allyl )Cl] ₂ (allylpalladium(II) chloride dimer), PdCl ₂ ·(CH ₃ CN) ₂ (bis(acetonitrile)palladium dichloride), Pd(acac) ₂ (palladium diacetylacetonate) , Pd(PPh ₃ ) ₂ Cl ₂ (1,1'-bisdiphenylphosphine ferrocene palladium dichloride), PdCl ₂ [P(o-Tol) ₃ ] (trans-dichlorobis(tri-O - one or more of toluenephosphine) palladium).

In the Buchwald-Hartwig coupling reaction, not only a catalyst but also a base needs to be added. In one or more embodiments, the base in the Buchwald-Hartwig coupling reaction is sodium tert-butoxide, cesium carbonate, potassium tert-butoxide, Potassium carbonate, potassium phosphate, lithium bistrimethylsilylamide, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or MTBD (7-methyl-1, 5,7-triazabicyclo[4.4.0]dec-5-ene).

In the Buchwald-Hartwig coupling reaction, it is also necessary to add a ligand and a catalyst for use together. In one or more embodiments, the ligand in the Buchwald-Hartwig coupling reaction is Xphos (2-bicyclohexylphosphine-2', 4',6'-triisopropylbiphenyl), BrettPhos (2-(dicyclohexylphosphine)3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-Biphenyl), t-BuBrettPhos (2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-bis phenyl), Me ₄ t-BuXphos (2-di-tert-butylphosphonium-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl), Bippyphos(5 -Di-tert-butylphosphine-1',3',5'-triphenyl-1'H-[1,4']dipyrazole), MorDalPhos, IPr·HCl (1,3-bis(2,6 -Diisopropylphenyl)imidazolium chloride), P(t-Bu) ₃ ·HBF ₄ (tri-tert-butylphosphine tetrafluoroborate), PCy ₃ (tricyclohexylphosphine), n-BuP(Ad) _2. PPh ₃ (triphenylphosphine), P(o-tolyl) ₃ (tris(o-methylphenyl)phosphorus), RuPhos (2-bicyclohexylphosphine-2',6'-diisopropoxy biphenyl), DPEPhos (bis(2-diphenylphosphine)phenyl ether), Dppf(1,1'-bis(diphenylphosphine)ferrocene), CyPFt-Bu, Dppp(1,3-bis( Diphenylphosphine)propane), JohnPhos (2-(di-tert-butylphosphine)biphenyl), CyJohnPhos (2-(dicyclohexylphosphino)biphenyl), P(t-Bu) ₃ (tri-tert-butyl Phosphine), DavePhos (2-bicyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl), SPhos (2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl) , BINAP (binaphthyl diphenylphosphine), One or more of 4',6'-triisopropylbiphenyl).

In one or more embodiments, the solvent in the Buchwald-Hartwig coupling reaction is toluene, 1,4-dioxane, N,N-dimethylformamide (DMF) and dimethyl sulfoxide ( DMSO) one or more. When using low boiling point solvents such as tetrahydrofuran, the reaction system needs to be sealed and microwave heated. When using the above solvents, only conventional heating is required.

In one or more embodiments, the temperature in the Buchwald-Hartwig coupling reaction is 90-130°C, preferably 100°C.

In one or more embodiments, in the Buchwald-Hartwig coupling reaction, the molar ratio of compound II and N-methyl-3-aminopropionitrile is 1:1~5, preferably 1:1.5~3.

In one or more embodiments, in the Buchwald-Hartwig coupling reaction, the molar ratio of compound II and catalyst is 1:0.0.05~0.5, preferably 1:0.05~0.2.

In one or more embodiments, in the Buchwald-Hartwig coupling reaction, the molar ratio of compound II and ligand is 1:0.1-1.1, preferably 1:0.1-0.4.

In one or more embodiments, in the Buchwald-Hartwig coupling reaction, the molar ratio of compound II to the base is 1:1˜4, preferably 1:2.

In one or more embodiments, the mass/volume ratio of compound II and reaction solvent is 1:5~100kg/L, preferably 1:10~20kg/L;

In some examples of this embodiment, compound III is heated to 60-80°C with hydrogen or hydrazine hydrate under the action of a catalyst to react to obtain compound IV.

In one or more embodiments, in the process of preparing compound IV from compound III, the catalyst is a Raney nickel catalyst (Raney Ni), platinum dioxide, rhodium catalyst or nickel catalyst, preferably a Raney nickel catalyst (Raney Ni).

In one or more embodiments, in the process of preparing compound IV from compound III, the mass/volume ratio of compound III to the reaction solvent is 1:5~1:100kg/L, preferably 1:10~1:20kg/ L.

In one or more embodiments, in the process of preparing compound IV from compound III and hydrogen, the reaction solvent is liquid ammonia ethanol solution, liquid ammonia methanol solution or methanol sodium hydroxide solution.

In some examples of this embodiment, the process of preparing compound V from compound IV is as follows: after mixing compound IV, 2-tetrahydrofurancarboxylic acid and a base evenly, 1-propyl phosphoric acid cyclic anhydride (T3P) is added dropwise and the reaction is carried out.

In one or more embodiments, in the process of preparing compound V from compound IV, the base is triethylamine, diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaminopyridine, piperidine, 2 ,6-dimethylpiperidine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

In one or more embodiments, in the process of preparing compound V from compound IV, the ratio of compound IV to 2-tetrahydrofurancarboxylic acid is 1:1-3; preferably 1:1.1-2.

In one or more embodiments, in the process of preparing compound V from compound IV, the ratio of compound IV to T3P is 1:1-3; preferably 1:1.5.

In one or more embodiments, in the process of preparing compound V from compound IV, the ratio of compound IV to triethylamine is 1:1-6; preferably 1:3.

In some examples of this embodiment, the process of preparing compound V from compound IV is as follows: heating compound IV, 2-tetrahydrofurancarboxylic acid and carbonyldiimidazole to 40-45°C for reaction to obtain.

In one or more embodiments, in the process of preparing compound V from compound IV, the ratio of compound IV to carbonyldiimidazole is 1:1-3; preferably 1:1.5.

In some examples of this embodiment, the process of preparing compound V from compound IV is as follows: performing an acid chlorination reaction on compound IV and a chlorine source, then lowering the temperature to 0-10°C, adding 2-tetrahydrofurancarboxylic acid, and a base at 0-30 The reaction is carried out at ℃ to obtain; the chlorine source is thionyl chloride, oxalyl chloride or phosphorus oxychloride.

The base selection is the same as described above.

In some examples of this embodiment, the process of preparing compound V from compound IV is: mixing pivaloyl chloride, ethyl chloroformate, acetic anhydride, isobutyl chloroformate or Boc anhydride and 2-tetrahydrofurancarboxylic acid at 0-10°C Evenly, then add base and compound IV to react at 0-30°C to obtain.

Taking pivaloyl chloride as an example, the molar ratio of compound IV to pivaloyl chloride is 1:1-2; preferably 1:1.2.

In some examples of this embodiment, the process of preparing compound V from compound IV is as follows: reacting 2-tetrahydrofurancarboxylic acid, a condensing agent and compound IV at 0-30°C; the condensing agent is HBTU, HATU, HCTU, TBTU , TPTU, HOBt/DCC, HOBt/EDCl, HOBt/DICL.

In one or more embodiments, the molar ratio of compound IV to the condensing agent is 1:1˜3; preferably 1:1.5.

In some examples of this embodiment, the process of preparing compound V from compound IV is as follows: mixing 2-tetrahydrofurancarboxylic acid, boric acid and compound IV, and then heating and refluxing to react.

In one or more embodiments, the molar ratio of compound IV to boric acid is 1:0.05-0.4; preferably 1:0.1-0.2.

In some examples of this embodiment, the process of removing the amino protecting group of Compound V to obtain Compound VI is: reacting Compound V in a reaction solvent, and then using a saturated NaHCO ₃ solution to adjust the pH to 7-8 to obtain; The reaction solvent is trifluoroacetic acid, triethylsilyl hydrogen, methanesulfonic acid, trifluoromethanesulfonic acid, a mixed solvent of trifluoroacetic acid/dichloromethane, a mixed solvent of methanesulfonic acid/dichloromethane, or triethylsilyl hydrogen. /trifluoroacetic acid mixed solvent.

Another embodiment of the present invention provides a method for preparing isoquinoline compounds, which includes the process of preparing compound VI using compound II as a raw material according to the following reaction route:

Among them, R is an amino protecting group, X is halogen or hydroxyl, and compound II is prepared through Buchwald-Hartwig coupling reaction to compound VII.

The process for preparing compound II from compound I is as described above.

The conditions for the Buchwald-Hartwig coupling reaction of compound II with methylamine hydrochloride are the same as the conditions for the Buchwald-Hartwig coupling reaction of compound II with N-methyl-3-aminopropionitrile.

In some examples of this embodiment, the process of preparing N-3-substituted propyl-2-tetrahydrofurancarboxamide according to the following reaction formula includes 2-tetrahydrofurancarboxylic acid and 3-substituted propylamine as raw materials:

Among them, X is as mentioned above.

In one or more embodiments, 2-tetrahydrofurancarboxylic acid, 3-substituted propylamine and alkali are reacted at 0 to 25°C, and then 1-propylphosphoric acid cyclic anhydride is added dropwise, and the reaction is continued to obtain. The base is preferably triethylamine or diisopropylethylamine (DIPEA).

In some examples of this embodiment, compound VII, N-3-substituted propyl-2-tetrahydrofurancarboxamide, sodium iodide and alkali are heated to 90-100°C under an inert atmosphere to react to obtain compound V.

The base is as previously described.

In one or more embodiments, the reaction solvent is N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene or 1,4-dioxane. Avoid the boiling point of the solvent being too low to reach the reaction temperature.

In one or more embodiments, the molar ratio of compound VII to the base is 1:1.1-4, preferably 1:2.

In one or more embodiments, the molar ratio of compound VII and sodium iodide is 1:0.1~1, preferably 1:0.2~0.5.

In one or more embodiments, the molar ratio of compound VII and N-3-chloropropyl-2-tetrahydrofurancarboxamide is preferably 1:1 to 4, preferably 1:1.5 to 2.0.

The process of removing the amino protecting group of compound V was as described above.

The third embodiment of the present invention provides an isoquinoline compound, which is compound VI obtained by the above preparation method.

In order to enable those skilled in the art to understand the technical solution of the present invention more clearly, the technical solution of the present invention will be described in detail below with reference to specific examples and comparative examples.

Example 1: Synthesis of compound II (in the example, R = p-methoxybenzyl)

Add compound I (5.0kg) and N-methylpyrrolidone (25L) to the 100L reaction kettle, stir and dissolve, add p-methoxybenzylamine (7.95kg), and heat up to 120°C. After 4 hours of reaction, the reaction is complete. Post-treatment, add water (80L) to quench the reaction, extract with dichloromethane three times (30L × 3), combine the organic phases, wash once with saturated brine (50L), add anhydrous sodium sulfate to dry, rotary evaporate the solvent and use Purification with ethyl acetate and n-heptane gave 5.8 kg of product compound II, with a yield of 83.4%.

The obtained compound II ¹ H NMR analysis results are as follows:

¹ H NMR: (400MHz, DMSO-d ₆ ) δ8.08-7.88 (m, 1H), 7.64 (s, 1H), 7.32 (d, J = 8.8Hz, 2H), 7.14 (s, 1H), 6.93 -6.80(m,3H),4.62(d,J＝6.0Hz,2H),3.87(d,J＝3.6Hz,6H),3.79-3.61(m,3H).

LC-MS (C ₁₉ H ₁₉ ClN ₂ O ₃ ): 359.1 [M+H] ⁺ .

Purity: 98.22% (230nm, HPLC)

Example 2: Synthesis of compound II (R=2-methylbenzyl)

Add compound I (1g) and N,N-dimethylformamide (DMF) to the reaction flask, stir to dissolve, add 2-methylbenzylamine (1.88g), raise the temperature to 120°C, react for 4 hours, and perform TLC Monitor the reaction with a plate (petroleum ether/ethyl acetate = 3/1). The reaction is complete. Add water (30 mL) to quench the reaction in post-processing. Extract with dichloromethane three times (20 mL × 3). Combine the organic phases and use saturated salt. Wash once with water (30 mL), add anhydrous sodium sulfate and dry. The solvent is evaporated and separated by column chromatography (SiO ₂ ) to obtain 1.01 g of product compound II with a yield of 76.0%.

LC-MS (C ₁₉ H ₁₉ ClN ₂ O ₂ ): 343.0 [M+H] ⁺ .

Example 3: Synthesis of compound II (R=3,4-dimethoxybenzyl)

Add compound I (1g) and N-methylpyrrolidone (10mL) to the reaction flask, stir to dissolve, add 3,4-dimethoxybenzylamine (2.58g), raise the temperature to 120°C, react for 4 hours, and perform TLC Monitor the reaction with a plate (petroleum ether/ethyl acetate = 2/1). If the reaction is complete, add water (50 mL) to quench the reaction. Extract with dichloromethane three times (30 mL × 3). Combine the organic phases and use saturated salt. Wash once with water (30 mL), add anhydrous sodium sulfate and dry. The solvent is evaporated and separated by column chromatography (SiO ₂ ) to obtain 1.29 g of product compound II with a yield of 85.5%.

LC-MS (C ₂₀ H ₂₁ ClN ₂ O ₄ ): 389.1 [M+H] ⁺ .

Example 4: Synthesis of compound II (R=2,4-dimethoxybenzyl)

Add compound I (1g) and N-methylpyrrolidone (10mL) to the reaction flask, stir to dissolve, add 2,4-dimethoxybenzylamine (2.58g), raise the temperature to 120°C, react for 4 hours, and perform TLC Monitor the reaction with a plate (petroleum ether/ethyl acetate = 2/1). If the reaction is complete, add water (50 mL) to quench the reaction. Extract with dichloromethane three times (30 mL × 3). Combine the organic phases and use saturated salt. Wash once with water (30 mL), add anhydrous sodium sulfate and dry. The solvent is evaporated and separated by column chromatography (SiO ₂ ) to obtain 1.35 g of product compound II with a yield of 89.6%.

LC-MS (C ₂₀ H ₂₁ ClN ₂ O ₄ ): 389.1 [M+H] ⁺ .

Example 5: Synthesis of compound Ш (in the example, R = p-methoxybenzyl)

Add toluene (60L), compound II (5.7kg), N-methyl-3-aminopropionitrile (2.7kg), sodium tert-butoxide (2.85kg), Pd ₂ (dba) ₃ ( 2.91kg), RuPhos (2.96kg), the system was heated to 100°C under N ₂ protection and reacted for 3 hours. After the reaction was completed, the post-treatment was cooled to 20-30°C, filtered directly, and water (60L) and ethyl acetate ( 50L) into the filtrate, collect the organic phase, add citric acid solution, adjust the pH value of the system to 3-4, separate the liquids, take the aqueous phase, extract the organic phase twice with water (30L×2), combine the aqueous phases, and use ethyl acetate to Wash once with ester (30L), add sodium carbonate solution and ethyl acetate (50L) to the aqueous phase, adjust the pH value of the system to 7-8, collect the organic phase by liquid separation, and extract the aqueous phase twice with ethyl acetate (30L ×2), combine the organic phases, use vacuum rotary evaporation, rotary evaporate the solvent, and then recrystallize with n-heptane and ethyl acetate to obtain 4.4 kg of product compound Ш, with a yield of 68.1%.

Purity: 94.78% (220nm HPLC)

LC-MS (C ₂₃ H ₂₆ N ₄ O ₃ ): 407.3[M+H] ⁺ .

Comparative Example 1: Synthesis of compound Ш (in the example, R = p-methoxybenzyl)

Add N,N-dimethylformamide (1mL), compound II (0.05g), and N-methyl-3-aminopropionitrile (0.05g) to the reaction bottle, and heat the system to 140°C under _N2 protection. The reaction was carried out at ℃ for 3 hours, and the TLC plate showed that most of the raw materials were unreacted.

Comparative Example 2: Synthesis of compound Ш (in the example, R = p-methoxybenzyl)

Add N,N-dimethylformamide (1mL), compound II (0.05g), N-methyl-3-aminopropionitrile (0.05g), and DIEA (0.04g) to the reaction bottle. _2. Heat to 120°C for 12 hours under protection. The TLC plate shows that most of the raw materials have not reacted.

Example 6, synthesis of compound Ш (in the example, R = p-methoxybenzyl)

Add 1,4-dioxane (15mL), compound II (1g), N-methyl-3-aminopropionitrile (0.35g), cesium carbonate (0.5g), and Pd(OAc) to the reaction bottle. ₂ ( _0.12g ), SiO ₂ ) was separated and eluted with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.81g of the product compound Ш was obtained with a yield of 71.5%.

Example 7, synthesis of compound Ш (in the example, R = p-methoxybenzyl)

Add DMF (15mL), compound II (1g), N-methyl-3-aminopropionitrile (0.70g), potassium tert-butoxide (0.94g), Pd(PPh ₃ ) ₂ Cl ₂ ( _0.39g ) _, ) was separated and eluted with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.83g of the product compound Ш was obtained, with a yield of 73.2%.

Example 8: Synthesis of compound IV (R=p-methoxybenzyl in the example)

Add liquid ammonia ethanol solution (100L), compound III (4.4kg), Raney Ni catalyst (Raney Ni) to a 200L pressurized kettle. After nitrogen replacement, add hydrogen, pressurize and react at 70°C. After the reaction is completed, the catalyst is filtered off, the solvent is concentrated, and the product is obtained after the concentration is completed. The product is directly used for the next reaction.

Example 9: Synthesis of Compound IV (R=p-methoxybenzyl in the example)

Methanol (10 mL), compound III (1 g), Pd/C (10%) were added to the pressurized kettle, and after nitrogen replacement, hydrogen was introduced, the reaction was carried out under pressure, and the reaction was carried out at room temperature. After the reaction is completed, the catalyst is filtered off, the solvent is concentrated, and the product is obtained after the concentration is completed. The product is directly used for the next reaction.

Example 10: Synthesis of compound V (in the example, R = p-methoxybenzyl)

In a 100L reaction kettle, add compound IV (4kg), 2-tetrahydrofurancarboxylic acid (1.25kg), triethylamine (3.0kg), and ethyl acetate (40L), stir and mix, keep the reaction temperature below 25°C, and stir Add 1-propyl phosphate cyclic anhydride (T3P, 6.7kg, 50% ethyl acetate solution) dropwise. After the addition is completed, stir at 40-50°C for 4 hours; after the reaction is completed, add the system to water (80L) Stir, extract with ethyl acetate (20L) three times, combine the organic phases, evaporate the solvent under reduced pressure, add n-heptane and ethyl acetate to recrystallize after the solvent is evaporated, and 3.8kg of the product compound V is obtained as a yellow oil, which is collected. The rate is 82.3%.

Purity: 96.50% (220nm, HPLC).

The ¹ H NMR analysis when R = methoxybenzylamine is as follows:

¹ H NMR: (400MHz, CDCl ₃ ) δ7.92-7.78 (m, 1H), 7.41-7.34 (m, 1H), 7.03 (d, J = 8.8Hz, 2H), 6.94-6.77 (m, 3H) ,4.46-4.25(m,1H),4.18-4.07(m,2H),4.04-4.00(m,1H),4.06-4.00(m,1H),3.98(s,2H),3.93-3.89(m, 4H),3.83(s,2H),3.76-3.66(m,2H),3.41-3.22(m,3H),3.02-2.87(m,3H),2.00-1.97(m,1H),1.99-1.73( m,10H).

LC-MS (C ₂₈ H ₃₆ N ₄ O ₅ ): 509.1[M+H] ⁺ , 531.1[M+Na] ⁺ .

Example 11: Synthesis of compound V (in the example, R = p-methoxybenzyl)

In a three-necked flask, add tetrahydrofuran (10mL), 2-tetrahydrofurancarboxylic acid (0.31g), carbonyldiimidazole (0.59g), and compound IV (1g) and stir at 40-45°C for at least 3 hours. After the reaction is completed, the system Cool the temperature to 20-30°C, add to water and stir, collect the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter. The solvent was evaporated under reduced pressure. After the solvent was rotary evaporated, it was separated by column chromatography (SiO ₂ ). It was eluted with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.75g of the product compound V was obtained, with a yield of 60.5%. .

Example 12: Synthesis of compound V (in the example, R = p-methoxybenzyl)

In a three-necked flask, add dichloromethane (10mL), add 2-tetrahydrofurancarboxylic acid (0.31g), add thionyl chloride (0.40mL), stir for 30 minutes, cool to 0-10°C, add triethylamine ( 0.30g), and compound IV (1g), and then the system was stirred at 0-30°C for at least 1 hour. After the reaction is completed, add to water and stir, collect the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter. The solvent was evaporated under reduced pressure, and then the solvent was rotary evaporated and separated by column chromatography (SiO ₂ ). Elute with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.85g of the product compound V was obtained, with a yield of 68.6%. .

Example 13: Synthesis of compound V (in the example, R = p-methoxybenzyl)

In a three-necked flask, add dichloromethane (10 mL), cool to 0-10°C, add 2-tetrahydrofurancarboxylic acid (0.31g), add pivaloyl chloride (0.35g), add triethylamine (0.30g), and stir for 30 minutes later, and compound IV (1 g), and the system was stirred at 0-30°C for at least 1 hour. After the reaction is completed, add to water and stir, collect the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter. The solvent was evaporated under reduced pressure. After the solvent was rotary evaporated, column chromatography (SiO ₂ ) was added for separation. The solvent was eluted with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.88g of the product compound V was obtained, with a yield of 71.0%. .

Example 14: Synthesis of compound V (in the example, R = p-methoxybenzyl)

In a three-necked flask, add dichloromethane (10mL), add 2-tetrahydrofurancarboxylic acid (0.31g), add HBTU (1.39mL), add triethylamine (0.50g), stir for 30 minutes, and compound IV (1g) , and then the system is stirred at 0-30°C for at least 1 hour. After the reaction is completed, add to water and stir, collect the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter. The solvent was evaporated under reduced pressure. After the solvent was rotary evaporated, it was separated by column chromatography (SiO ₂ ). It was eluted with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.93g of the product compound V was obtained, with a yield of 75.1%. .

Example 15: Synthesis of compound V (in the example, R = p-methoxybenzyl)

In a three-necked flask, add toluene (10 mL), 2-tetrahydrofurancarboxylic acid (0.31g), boric acid (0.02g), and compound IV (1g), and then the system is stirred at reflux temperature for at least 4 hours. After the reaction is completed, add to water and stir, collect the organic phase, extract the aqueous phase three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and filter. The solvent was evaporated under reduced pressure, and then the solvent was rotary evaporated and separated by column chromatography (SiO ₂ ). Elute with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.90g of the product compound V was obtained, with a yield of 72.6%. .

Example 16: Synthesis of Compound VII (R=p-methoxybenzyl in the example)

Add 1,4-dioxane (55L), compound II (5.5kg), methylamine hydrochloride (2.0kg), cesium carbonate (20kg), Pd(OAc) ₂ (330g), BrettPhos (1.65kg), the system is heated to 110°C under N ₂ protection for at least 3 hours to react. After the reaction is completed, the post-processing is cooled to 20-30°C, filtered directly, and water (60L) and ethyl acetate (50L) are added to In the filtrate, collect the organic phase, add citric acid solution, adjust the pH value of the system to 3-4, separate the liquids, take the aqueous phase, extract the organic phase twice with water (30L × 2), combine the aqueous phases, and use ethyl acetate (30L ), wash once, add sodium carbonate solution and ethyl acetate (50L) to the water phase, adjust the pH value of the system to 7-8, collect the organic phase by liquid separation, and extract the water phase twice with ethyl acetate (30L×2) , combine the organic phases, use vacuum rotary evaporation, rotary evaporate the solvent, and then purify with n-heptane and ethyl acetate to obtain 3.4 kg of product compound VII, with a yield of 62.7%.

Purity: 95.70% (220nm, HPLC)

LC-MS (C ₂₀ H ₂₃ N ₃ O ₃ ): 354.1[M+H] ⁺ , 366.1[M+Na] ⁺ .

Example 17. Synthesis of Compound VII (R=p-methoxybenzyl in the example)

Add toluene (DMF) (10mL), compound II (1g), methylamine hydrochloride (0.47g), potassium phosphate (2.37g), Pd ₂ (dba) ₃ (0.26g), RuPhos (0.26 g), the system is heated to 100°C under N ₂ protection for at least 3 hours to react. After the reaction is completed, the post-treatment is directly filtered. The filtrate is vacuum evaporated, and the solvent is evaporated and separated by column chromatography (SiO ₂ ). It is separated with petroleum ether. Elute with a mixed solution of ethyl acetate and ethyl acetate. After concentrating the eluent, 0.71 g of the product compound VII is obtained, with a yield of 72.0%.

Example 18. Synthesis of Compound VII (R=p-methoxybenzyl in the example)

Add N,N-dimethylformamide (DMF) (10mL), compound II (1g), methylamine hydrochloride (0.56g), potassium tert-butoxide (1.25g), Pd (PPh ₃ ) ₂ Cl ₂ (0.20g) _, Separate by column chromatography (SiO ₂ ), and elute with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.70 g of the product compound VII is obtained, with a yield of 71.1%.

Example 19: Preparation of N-3-chloropropyl-2-tetrahydrofurancarboxamide

In a three-necked flask, add compound 2-tetrahydrofurancarboxylic acid (3kg), 3-chloropropylamine (2.54kg), triethylamine (7.8g), and ethyl acetate (30L), stir and mix, and keep the reaction temperature below 25°C. 1-propyl phosphoric acid cyclic anhydride (T3P, 12.3kg, 50% ethyl acetate solution) was added dropwise under stirring. After the dropwise addition was completed, stir at 40-50°C for 4 hours. After the reaction, the system was added to water (50L) and stirred, extracted three times with ethyl acetate (10L), the organic phases were combined, the solvent was evaporated under reduced pressure, and after concentration, 3.56kg of N-3-chloropropyl- 2-Tetrahydrofurancarboxamide. Yield: 68.5%.

LC-MS (C ₈ H ₁₄ ClNO ₂ ): 192.0 (100%) [M+H] ⁺ , 193.9 (33%) [M+2+H] ⁺ .

Example 20: Preparation of N-3-bromopropyl-2-tetrahydrofurancarboxamide

In a three-necked flask, add compound 2-tetrahydrofurancarboxylic acid (2g), 3-bromopropylamine (2.49g), triethylamine (5.22g), and N,N-dimethylformamide (20mL), stir and mix, and maintain the reaction. When the temperature is below 25°C, 1-propylphosphoric acid cyclic anhydride (T3P, 8.21g, 50% ethyl acetate solution) is added dropwise with stirring. After the dropwise addition is completed, stir at 5-25°C for 4 hours. After the reaction, the system was added to water, stirred, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain 2.8 g of N-3-bromopropyl-2-tetrahydrofurancarboxamide. Yield: 68.8%.

LC-MS (C ₈ H ₁₄ BrNO ₂ ): 235.9 (100%) [M+H] ⁺ , 237.9 (100%) [M+2+H] ⁺ .

Example 21: Synthesis of compound V (in the example, R = p-methoxybenzyl)

Add N,N-dimethylformamide (35L), compound VII (3.3kg), N-3-chloropropyl-2-tetrahydrofurancarboxamide (2.7kg), and sodium iodide (330g) into a 100L reaction kettle. , anhydrous potassium carbonate (2.6kg), the system was heated to 90~100°C under N ₂ protection and reacted for 3 hours. The reaction was complete, and the post-processing was directly filtered. The filtrate was diluted with water (60L) and extracted with ethyl acetate (20L). Combine the organic phases three times, use vacuum rotary evaporation, rotary evaporate the solvent, and then purify with n-heptane and ethyl acetate to obtain 2.5 kg of product compound V, with a yield of 52.7%.

The ¹ H NMR analysis when R = p-methoxybenzyl is as follows:

¹ H NMR: (400MHz, CDCl ₃ ) δ7.92-7.78 (m, 1H), 7.41-7.34 (m, 1H), 7.03 (d, J = 8.8Hz, 2H), 6.94-6.77 (m, 3H) ,4.46-4.25(m,1H),4.18-4.07(m,2H),4.04-4.00(m,1H),4.06-4.00(m,1H),3.98(s,2H),3.93-3.89(m, 4H),3.83(s,2H),3.76-3.66(m,2H),3.41-3.22(m,3H),3.02-2.87(m,3H),2.00-1.97(m,1H),1.99-1.73( m,10H).

LC-MS (C ₂₈ H ₃₆ N ₄ O ₅ ): 509.1[M+H] ⁺ , 531.1[M+Na] ⁺ .

Purity: 96.15% (220nm, HPLC).

Example 22: Synthesis of compound V (in the example, R = p-methoxybenzyl)

Add dimethyl sulfoxide (10 mL), compound VII (1g), N-3-bromopropyl-2-tetrahydrofurancarboxamide (1.0g), sodium iodide (0.13g), and cesium carbonate (1.84 g), the system was heated to 90-100°C for 3 hours under the protection of _N2 . The TLC plate monitored the reaction for completeness. The post-treatment was directly filtered. The filtrate was diluted with water and extracted with ethyl acetate three times. The organic phases were combined and vortexed with vacuum vortex. Evaporate and rotary evaporate the solvent, then add column chromatography (SiO ₂ ) for separation, and elute with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.96g of the product compound V is obtained, with a yield of 66.7%.

Example 23: Synthesis of compound V (in the example, R = p-methoxybenzyl)

Add toluene (15mL), compound VII (1g), N-3-bromopropyl-2-tetrahydrofurancarboxamide (1.33g), sodium iodide (0.21g), and potassium tert-butoxide (0.63g) into the reaction bottle. , the system was heated to 90-100°C for 3 hours under the protection of N _2. The TLC plate monitored the reaction for completeness. The post-processing was directly filtered. The filtrate was diluted with water and extracted with ethyl acetate three times. The organic phases were combined and vacuum evaporated. After the solvent was rotary evaporated, column chromatography (SiO ₂ ) was added for separation, and the mixture was eluted with a mixed solution of petroleum ether and ethyl acetate. After concentrating the eluent, 0.94 g of the product compound V was obtained, with a yield of 65.3%.

Example 24: Synthesis of N-[3-[(1-amino-6,7-dimethoxy-3-isoquinolyl)methylamino]propyl]tetrahydro-2-furancarboxamide (implementation In the example, R = p-methoxybenzyl)

Under the protection of _N2 , add dichloromethane (20L) and compound V (3.5kg) to the 50L reaction kettle, add trifluoroacetic acid (7L) at a temperature below 20°C, and react for 2 hours below 20°C. The reaction is complete. , add saturated NaHCO ₃ solution to the reaction system to adjust the pH to 7-8, separate the liquids, take the organic phase, extract it 3 times with dichloromethane (5L), combine the organic phases, use vacuum rotary evaporation, rotary evaporate the solvent and use Recrystallization from ethyl acetate and n-heptane gave 1.62 kg of product compound VI, with a yield of 60.6%.

Purity: 99.44% (250nm, HPLC).

¹ H NMR: (400MHz, CDCl ₃ ) δ8.48(br s,1H),6.85(s,1H),6.79(s,1H),5.98(s,1H),5.38(s,2H),4.49( dd,J＝5.6,8.4Hz,1H),4.16-4.04(m,1H),4.01-3.93(m,6H),3.92-3.86(m,1H),3.58-3.50(m,1H),3.45- 3.32(m,1H),3.04(tdd,J＝4.4,9.2,13.6Hz,1H),2.92(s,3H),2.34-2.18(m,2H),1.98-1.86(m,2H),1.78( tdd,J＝4.8,9.6,14.4Hz,1H)

LC-MS (C ₂₀ H ₂₈ N ₄ O ₄ ): 389.1 [M+H] ⁺ .

Example 25: Effect of Compound VI in Rat 6-OHDA Parkinson's Disease Model

In the Parkinson's disease model of rats injected with 6-OHDA in specific brain areas, 6-OHDA was injected into the right striatum for 2-3 weeks, followed by drug treatment for two weeks. Use the cylinder experiment to study the asymmetric use of limbs when animals stand against the wall, as shown in Figure 1. After rats were treated with 6-OHDA, the proportion of rats using the affected side's forelimb decreased, which was reflected in the forelimb asymmetry index = (use of unaffected side - use of affected side)/(use of unaffected side + use of affected side + use of both sides) × 100 % increased, and the forelimb asymmetry index significantly decreased after treatment with compound VI (compound VI).

The motor function of rats was also evaluated using the fatigue rotarod. After treatment with 6-OHDA, the time the rats maintained on the fatigue rotarod was significantly reduced. After treatment with Compound VI, this ability was significantly improved, as shown in Figure 2 Show.

Example 26: Effect of Compound VI in the Parkinson's Disease Model of Mouse MPTP

The Parkinson's disease model of mice was injected intraperitoneally with MPTP. Seven days after the intraperitoneal injection of 20 mg/Kg MPTP, the Rotarod test was used for study. This experiment quantitatively measures mouse grip strength and nervous system balance. After MPTP treatment, this ability of mice was significantly reduced, but after compound VI treatment, as shown in Figure 3, this ability was significantly improved. Ten mice were tested in each group.

The substantia nigra compacta (SNpc) was stained with dopamine antibodies, and the results are shown in Figure 4. Compared with normal mice, the number of dopamine neurons after MPTP treatment was significantly reduced; while the number of dopamine neurons in mice treated with Compound VI orally (MPTP-treated mice + Compound VI) was significantly increased, indicating that MPTP treatment with Compound VI There was a significant difference in dopamine neuron survival rate between mice treated with MPTP and mice not given compound VI (p<0.01).

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (10)

A method for preparing isoquinoline compounds, which is characterized by including the process of preparing compound VI using compound II as a raw material according to the following reaction route:

Among them, R is an amino protecting group, and compound II is prepared through Buchwald-Hartwig coupling reaction to compound III. The preparation method of isoquinoline compounds as claimed in claim 1, characterized in that, in the Buchwald-Hartwig coupling reaction for preparing compound III, the catalyst is Pd(OAc) ₂ , Pd ₂ (dba) ₃ dipalladium), Pd(dba) ₂ , PdCl ₂ (cod), [Pd(allyl)Cl] ₂ , PdCl ₂ ·(CH ₃ CN) ₂ , Pd(acac) ₂ , Pd(PPh ₃ ) ₂ Cl ₂ , PdCl ₂ [P (o-Tol) ₃ ] one or more; Or, the base in the Buchwald-Hartwig coupling reaction for preparing compound III is sodium tert-butoxide, cesium carbonate, potassium tert-butoxide, potassium carbonate, potassium phosphate, lithium bistrimethylsilylamide, DBU or MTBD; Or, the ligands in the Buchwald-Hartwig coupling reaction to prepare compound III are Xphos, BrettPhos, t-BuBrettPhos, Me ₄ t-BuXphos, Bippyphos, MorDalPhos, IPr.HCl, P(t-Bu) _{3.HBF 4} , PCy ₃ , n-BuP(Ad) ₂ , PPh ₃ , P(o-tolyl) ₃ , RuPhos, DPEPhos, Dppf, CyPFt-Bu, Dppp, JohnPhos, CyJohnPhos, P(t-Bu) ₃ , DavePhos, SPhos, One or more of BINAP, Xantphos, t-BuXphos; Or, the solvent in the Buchwald-Hartwig coupling reaction for preparing compound III is toluene, one or more of 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide; Or, the temperature in the Buchwald-Hartwig coupling reaction for preparing compound III is 90 to 130°C, preferably 100°C; Or, in the Buchwald-Hartwig coupling reaction for preparing compound III, the molar ratio of compound II and N-methyl-3-aminopropionitrile is 1:1~5, preferably 1:1.5~3; Or, in the Buchwald-Hartwig coupling reaction for preparing compound III, the molar ratio of compound II and catalyst is 1:0.05~0.5, preferably 1:0.05~0.2; Or, in the Buchwald-Hartwig coupling reaction for preparing compound III, the molar ratio of compound II and ligand is 1:0.1~1.1, preferably 1:0.1~0.4; Or, in the Buchwald-Hartwig coupling reaction for preparing compound III, the molar ratio of compound II and base is 1:1 to 4, preferably 1:2; Or, the mass/volume ratio of compound II and reaction solvent is 1:5~100kg/L, preferably 1:10~20kg/L. The preparation method of isoquinoline compounds according to claim 1, characterized in that compound III and hydrogen or hydrazine hydrate are heated to 60-80°C under the action of a catalyst to react to obtain compound IV; Preferably, in the process of preparing compound IV from compound III, the catalyst is platinum dioxide, rhodium catalyst or nickel catalyst, preferably Raney nickel catalyst; Preferably, in the process of preparing compound IV from compound III, the mass/volume ratio of compound III to the reaction solvent is 1:5 to 1:100kg/L, preferably 1:10 to 1:20kg/L; Preferably, in the process of preparing compound IV from compound III and hydrogen, the reaction solvent is liquid ammonia ethanol solution, liquid ammonia methanol solution or methanol sodium hydroxide solution. The preparation method of isoquinoline compounds as claimed in claim 1, characterized in that the process of preparing compound V from compound IV is: after mixing compound IV, 2-tetrahydrofurancarboxylic acid and alkali, 1-propyl phosphoric acid is added dropwise React after cyclic anhydride; Preferably, in the process of preparing compound V from compound IV, the ratio of compound IV to 2-tetrahydrofurancarboxylic acid is 1:1~3; preferably 1:1.1~2; Preferably, in the process of preparing compound V from compound IV, the ratio of compound IV to T3P is 1:1 to 3; preferably 1:1.5; Preferably, in the process of preparing compound V from compound IV, the ratio of compound IV to triethylamine is 1:1 to 6; preferably 1:3; Or, the process of preparing compound V from compound IV is as follows: heating compound IV, 2-tetrahydrofurancarboxylic acid and carbonyldiimidazole to 40-45°C for reaction to obtain; Preferably, in the process of preparing compound V from compound IV, the ratio of compound IV to carbonyldiimidazole is 1:1 to 3; preferably 1:1.5; Or, the process of preparing compound V from compound IV is as follows: performing an acid chlorination reaction on compound IV and a chlorine source, then lowering the temperature to 0 to 10°C, adding 2-tetrahydrofurancarboxylic acid and a base to react at 0 to 30°C to obtain; The chlorine source is thionyl chloride, oxalyl chloride or phosphorus oxychloride; Or, the process of preparing compound V from compound IV is: mix pivaloyl chloride, ethyl chloroformate, acetic anhydride, isobutyl chloroformate or Boc anhydride and 2-tetrahydrofurancarboxylic acid at 0 to 10°C, and then add a base and the compound IV is obtained by reacting at 0~30℃; Or, the process of preparing compound V from compound IV is: react 2-tetrahydrofurancarboxylic acid, a condensing agent and compound IV at 0 to 30°C to obtain; the condensing agent is HBTU, HATU, HCTU, TBTU, TPTU, HOBt/DCC , HOBt/EDCl, HOBt/DICL; Preferably, the molar ratio of compound IV to the condensing agent is 1:1 to 3; preferably 1:1.5; Or, the process of preparing compound V from compound IV is as follows: mixing 2-tetrahydrofurancarboxylic acid, boric acid and compound IV, then heating and refluxing to react, and obtain; Preferably, the molar ratio of compound IV to boric acid is 1:0.05-0.4; preferably 1:0.1-0.2. A method for preparing isoquinoline compounds, including the process of preparing compound VI using compound II as a raw material according to the following reaction route:

Among them, R is an amino protecting group, X is halogen or hydroxyl, and compound II is prepared through Buchwald-Hartwig coupling reaction to compound VII. The preparation method of isoquinoline compounds as claimed in claim 1 or 5, characterized in that it also includes the process of preparing compound II from compound I according to the following reaction route:

Preferably, the amino protecting group is an alkoxy or alkyl substituted benzyl group; the amino protecting group is preferably 2-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl or 2, 4-Dimethoxybenzyl; Preferably, in the process of preparing compound II from compound I, the reaction temperature is 100-160°C, preferably 100-130°C; Preferably, the solvent used in the process of preparing compound II from compound I is one or more of N-methylpyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide; Preferably, in the process of preparing compound II from compound I, the molar ratio of compound I to R-NH ₂ is 1:2~5, preferably 1:2.5~4; Or, the process of removing the amino protecting group of compound V to obtain compound VI is as follows: reacting compound V in a reaction solvent, and then using saturated NaHCO ₃ solution to adjust the pH to 7-8 to obtain; the reaction solvent is trifluoroacetic acid, Triethylsilylhydrogen, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid/methylene chloride mixed solvent, methanesulfonic acid/methylene chloride mixed solvent or triethylsilylhydrogen/trifluoroacetic acid mixed solvent. The preparation method of isoquinoline compounds as claimed in claim 5, characterized in that, in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride, the catalyst is Pd(OAc) ₂ , Pd ₂ (dba) ₃ dispalladium), Pd(dba) ₂ , PdCl ₂ (cod), [Pd(allyl)Cl] ₂ , PdCl ₂ ·(CH ₃ CN) ₂ , Pd(acac) ₂ , Pd(PPh ₃ ) ₂ Cl ₂ , one or more of PdCl ₂ [P(o-Tol) ₃ ]; Or, the base in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride is sodium tert-butoxide, cesium carbonate, potassium tert-butoxide, potassium carbonate, potassium phosphate, lithium bistrimethylsilylamide, DBU or MTBD; Or, the ligands in the Buchwald-Hartwig coupling reaction between compound II and methylamine hydrochloride are Xphos, BrettPhos, t-BuBrettPhos, Me ₄ t-BuXphos, Bippyphos, MorDalPhos, IPr·HCl, P(t-Bu) ₃ ·HBF ₄ , PCy ₃ , n-BuP(Ad) ₂ , PPh ₃ , P(o-tolyl) ₃ , RuPhos, DPEPhos, Dppf, CyPFt-Bu, Dppp, JohnPhos, CyJohnPhos, P(t-Bu) ₃ , one or more of DavePhos, SPhos, BINAP, Xantphos, t-BuXphos; Or, the solvent in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride is toluene, one of 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide. species or species; Or, the temperature in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride is 90 to 130°C, preferably 100°C; Or, in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride, the molar ratio of compound II and N-methyl-3-aminopropionitrile is 1:1~5, preferably 1:1.5~3; Or, in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride, the molar ratio of compound II and catalyst is 1:0.1~0.5, preferably 1:0.2; Or, in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride, the molar ratio of compound II and ligand is 1:0.1~1.1, preferably 1:0.4; Or, in the Buchwald-Hartwig coupling reaction of compound II and methylamine hydrochloride, the molar ratio of compound II and base is 1:1 to 4, preferably 1:2; Or, the mass/volume ratio of compound II and reaction solvent is 1:5~100 kg/L, preferably 1:10~20 kg/L. The preparation method of isoquinoline compounds as claimed in claim 5, characterized by comprising 2-tetrahydrofurancarboxylic acid and 3-substituted propylamine as raw materials to prepare N-3-substituted propyl-2-tetrahydrofurancarboxamide according to the following reaction formula the process of:

Among them, X is as mentioned above; Preferably, 2-tetrahydrofurancarboxylic acid, 3-substituted propylamine and a base are reacted at 0 to 25°C, and then 1-propyl phosphoric acid cyclic anhydride is added dropwise, and the reaction is continued to obtain; the base is preferably triethylamine or diisopropylethylamine . The preparation method of isoquinoline compounds as claimed in claim 5, characterized in that compound VII, N-3-substituted propyl-2-tetrahydrofurancarboxamide, sodium iodide and alkali are heated to Compound V is obtained by reacting at 90~100℃; Preferably, the reaction solvent is N,N-dimethylformamide, dimethyl sulfoxide, toluene or 1,4-dioxane; Preferably, the molar ratio of compound VII to the base is 1:1.1-4, preferably 1:2; Preferably, the molar ratio of compound VII and sodium iodide is 1:0.1~1, preferably 1:0.2~0.5; Preferably, the molar ratio of compound VII and N-3-chloropropyl-2-tetrahydrofurancarboxamide is preferably 1:1 to 4, preferably 1:1.5 to 2.0. An isoquinoline compound, characterized in that the isoquinoline compound is compound VI obtained by the preparation method described in any one of claims 1 to 9.

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