Process for the preparation of 1-substituted isoquinolines

Abstract

The application discloses a preparation method of 1-substituted isoquinoline compounds. The application provides a preparation method of 1-substituted isoquinoline compounds, which comprises the following steps: step 1: coupling reaction of isoquinoline compounds and organic metal reagent containing M-C bond in an organic solvent to obtain mixture A; wherein the 1 position of the isoquinoline compounds is not substituted; step 2: quenching reaction of the mixture A and a quenching reagent to obtain mixture B; step 3: dehydrogenation reaction of the mixture B in the presence of a dehydrogenation reagent to obtain 1-substituted isoquinoline compounds, namely the preparation method is completed; the C in the organic metal reagent containing M-C bond is substituted in the 1 position of the isoquinoline compounds. The preparation method can improve the reaction yield, reduce the reaction cost and reduce the three waste emissions.

Description

Technical Field

[0001] This invention relates to a method for preparing 1-substituted isoquinoline compounds. Background Technology

[0002] In the biopharmaceutical field, isoquinoline alkaloids constitute the largest class of alkaloids. Isoquinolines and their derivatives, as important pharmaceutical and chemical intermediates, have been used to synthesize a range of important drugs. For example, isoquinoline alkaloids exhibit diverse biological activities, including antitumor, antibacterial, analgesic, immunomodulatory, antiplatelet aggregation, antiarrhythmic, and antihypertensive effects. Papaverine, a commonly used drug for cerebral thrombosis, is a typical 1-benzyl-substituted isoquinoline alkaloid. In the field of OLED luminescent materials, 1-substituted isoquinoline compounds have attracted widespread attention as ligands for metal-based luminescent materials.

[0003] Currently, the main methods for preparing 1-substituted isoquinolines are as follows:

[0004] The coupling method of 1-haloisoquinoline with arylboronic acid has a high yield, but it often uses palladium catalysts, which are difficult to recover, resulting in high costs. In addition, the preparation of 1-haloisoquinoline is difficult and costly.

[0005] The method of preparing 1-substituted isoquinoline by first forming an imine with aminoacetaldehyde dimethyl acetal and aryl ketone compounds and then cyclizing the imine is low-cost, but the yield is often less than 30% and generates a large amount of waste.

[0006] The tetrahydroisoquinoline dehydrogenation method has a high reaction temperature, uncertain conversion rate, and limited sources of tetrahydroisoquinoline.

[0007] In 2006, Chen Guoying et al. from the Dalian Institute of Chemical Physics, Chinese Academy of Sciences, proposed a method to obtain 1-substituted-1,2-dihydroisoquinoline compounds protected by 2-benzyloxycarbonyl by reacting isoquinoline compounds with Grignard reagents under the activation of benzyl chloroformate, followed by aromatization using a Pd / C / HCO2NH4 system to obtain 1-substituted isoquinoline compounds (Organic Chemistry, 26(11), 1548-1552, 2006). This method has problems such as poor reaction performance with aryl Grignard reagents, the use of protecting groups, the use of hydrogen donors during dehydrogenation, and the large amount of palladium on carbon.

[0008] In 2013, Fang-fang Zhuo et al. from Lanzhou University proposed a method for the direct reaction of aryl Grignard reagents with isoquinolines (Joc, 78(7), 3243-3249, 2013), which increased the yield of 1-aryl-substituted isoquinolines to 60%. This method noted the generation of 1,2-dihydroisoquinolines in the reaction and believed that dihydroisoquinolines could be converted into isoquinoline compounds after being exposed to air for 12 hours. This method yielded good results in milligram to gram-scale reactions, but the yield dropped significantly when scaled up, making it unsuitable for industrial production. The conversion of dihydroisoquinolines into isoquinoline compounds can be considered as oxidation or isomerization. If it is oxidation, there are problems of low reaction efficiency and low reaction yield, and a large amount of 4-hydroxyisoquinoline byproducts are generated. If it is isomerization, tetrahydroisoquinoline byproducts are generated simultaneously. The process of dihydroisoquinolines converting into isoquinolines is generally considered to be caused by oxidation by oxygen in the air. Therefore, it is more likely that people would use other oxidants to oxidize dihydroisoquinoline to prepare isoquinoline, rather than performing dehydrogenation. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the shortcomings of existing methods for preparing 1-substituted quinoline derivatives, such as narrow substrate adaptability, large catalyst dosage, and unsuitability for industrial production. The present invention provides a method for preparing 1-substituted isoquinoline compounds. The preparation method of the present invention can improve the reaction yield, reduce the reaction cost, and reduce the emission of waste.

[0010] Our research shows that the reaction of isoquinoline compounds with organometallic reagents first yields a metal salt of 1-substituted-1,2-dihydroisoquinoline. This metal salt, upon quenching, generates the 1-substituted-1,2-dihydroisoquinoline compound. The 1-substituted-1,2-dihydroisoquinoline compound is unstable and undergoes partial isomerization to form 1-substituted isoquinoline and 1-substituted-1,2,3,4-tetrahydroisoquinoline compounds, which coexist to form a mixture. If the 1-substituted-1,2-dihydroisoquinoline compound is exposed to air at room temperature, it reacts slowly with oxygen to form an aromatic 1-substituted-4-hydroxyisoquinoline compound. We used a dehydrogenating reagent to catalytically dehydrogenate the 1-substituted-1,2-dihydroisoquinoline compound, completely converting it to a 1-substituted isoquinoline compound. The 1-substituted-1,2,3,4-tetrahydroisoquinoline compound was also partially or completely converted to a 1-substituted isoquinoline compound. The final result was that isoquinoline compounds were only converted to 1-substituted isoquinolines, thus significantly improving the yield of 1-substituted isoquinolines. The dehydrogenating reagents, such as Pd / C, used in the reaction can be recovered. Gas chromatography-mass spectrometry (GC-MS) was used to determine the molecular weights of the 1-substituted isoquinoline, 1-substituted-1,2-dihydroisoquinoline, and 1-substituted-1,2,3,4-tetrahydroisoquinoline compounds. The structures of the 1-substituted isoquinoline and 1-substituted-1,2,3,4-tetrahydroisoquinoline compounds were determined using 1H NMR spectroscopy. This process is not commonly known in the art; it is our first discovery and verification, and based on this, we propose a green and efficient method for preparing 1-substituted isoquinolines.

[0011] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0012] This invention provides a method for preparing 1-substituted isoquinoline compounds, comprising the following steps:

[0013] Step 1: In an organic solvent, an isoquinoline compound is coupled with an organometallic reagent containing an MC (carbon) bond to obtain mixture A;

[0014] Wherein, the 1-position of the isoquinoline compound is not substituted; M is MgCl, MgBr, MgI, Li, Na, K, CuLi, ZnCl, ZnI, ZnBr;

[0015] Step 2: The mixture A is subjected to a quenching reaction with a quenching agent to obtain mixture B;

[0016] Step 3: In the presence of a dehydrogenating agent, the above mixture B is subjected to a dehydrogenation reaction to obtain a 1-substituted isoquinoline compound;

[0017] The 1-substituted isoquinoline compound is the organometallic reagent containing an MC bond in which the C is substituted at the 1-position of the isoquinoline compound.

[0018] Preferably, M is MgCl, MgBr, Li, or ZnBr; for example, MgCl, MgBr, or ZnBr.

[0019] In step 1, the conditions and operations of the coupling reaction can be the conventional conditions and operations for this type of coupling reaction in the art; preferably, the following are preferred in this invention:

[0020] In step 1, the organic solvent may be one or more of ether solvents, alkane solvents, and aromatic solvents; the ether solvent may be one or more of tetrahydrofuran (THF), dioxane, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and ethylene glycol dimethyl ether. The alkane solvent may be n-hexane. The aromatic solvent may be toluene.

[0021] In step 1, the organometallic reagent containing MC bonds can be used in a solution form conventional in the art, such as a solution formed with a portion of the organic solvent described above; or, for example, the molar concentration of the organometallic reagent containing MC bonds in the solution can be from 0.5M to 3.0M, such as 0.5M, 1.0M, 1.3M, 2.0M, or 3.0M.

[0022] In step 1, the molar ratio of the isoquinoline compound to the organometallic reagent containing the MC bond can be from 1:0.9 to 1:2.0; for example, 1:0.9, 1:1.3, 1:1.5, 1:1.8, or 1:2.0.

[0023] In step 1, the coupling reaction is carried out in an inert gas atmosphere, which may be nitrogen and / or argon.

[0024] In step 1, the temperature of the coupling reaction can be from -70°C to 150°C; for example, from 0°C to 60°C (or, for example, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C), preferably from 20°C to 60°C.

[0025] Step 1 can be as follows: Under an inert gas atmosphere, the solution of the organometallic reagent containing MC bonds and a portion of the organic solvent is added to the solution of the isoquinoline compound and the remaining organic solvent to carry out the coupling reaction, thereby obtaining mixture A; the addition can be dropwise or direct mixing; the addition temperature can be room temperature; the coupling reaction temperature can be -70℃ to 150℃, for example, 10℃ to 60℃.

[0026] In step 1, the raw materials for the coupling reaction are the isoquinoline compounds, the organometallic reagents containing MC bonds, and the organic solvents.

[0027] In step 1, the progress of the coupling reaction can be monitored by conventional detection methods (e.g., TLC, HPLC) until the isoquinoline compound stops reacting or disappears; the coupling reaction time is generally 2 to 24 hours, for example 6 hours, 8 hours, 10 hours, 15 hours, or 20 hours.

[0028] In step 2, the quenching agent can be a conventional quenching agent for this type of coupling reaction in the art, such as proton solvents, Lewis acids, complexes that can complex metal ions, etc., all of which can be used for quenching in this invention; or water, acid, Lewis acid, preferably an aqueous solution of ammonium chloride, such as 5% to saturated aqueous solution of ammonium chloride, preferably 20% aqueous solution of ammonium chloride.

[0029] In step 2, the quenching agent, in addition to quenching the active organometallic reagent and reaction intermediates, also dissolves the salts produced in the reaction. For example, the mass ratio of the quenching agent to the isoquinoline compound can be from 0.1:1 to 10:1; for example, 1:1, 1.6:1, 2:1 (the minimum amount of quenching agent is enough to completely quench the active intermediate; the preferred amount of quenching agent is enough to completely dissolve the salts produced in the reaction. Adding more quenching agent will not affect the subsequent reaction.)

[0030] In step 2, the quenching temperature can be between -10℃ and 30℃; for example, between 0℃ and 5℃.

[0031] In step 2, the quenching reaction is carried out in an inert gas atmosphere, which may be nitrogen and / or argon.

[0032] In step 2, the quenching can be performed as follows: under an inert gas atmosphere, the quenching reagent is added to the mixture A to carry out the quenching reaction, and the mixture B is obtained; the addition can be dropwise; the addition temperature can be room temperature; the temperature of the quenching reaction can be between -10℃ and 30℃, for example, between 0℃ and 5℃.

[0033] In step 2, the raw materials for the quenching reaction are the quenching reagent and the mixture A.

[0034] In step 2, the progress of the quenching reaction can be monitored by conventional detection methods (e.g., TLC, HPLC), for example, until the two phases are clear.

[0035] In step 3, the dehydrogenation reagent may be palladium on carbon, platinum on carbon, rhodium on carbon, ruthenium on carbon, Raney nickel, or other reagents with equivalent activity; for example, 5% or 10% palladium on carbon or Raney nickel.

[0036] In step 3, the mass percentage of the dehydrogenating agent to the isoquinoline compound can be from 1% to 50%; for example, 10%, 17%, 20%, or 33%. Preferably, it is from 5% to 10%.

[0037] In step 3, the temperature of the dehydrogenation reaction can be from -70°C to 150°C; for example, from 50°C to 80°C (or, for example, 50°C or 60°C).

[0038] In step 3, the dehydrogenation reaction is carried out in an inert gas atmosphere, which may be nitrogen and / or argon.

[0039] In step 3, the progress of the dehydrogenation reaction can be monitored by conventional detection methods (e.g., TLC, HPLC) until the 1-substituted isoquinoline compounds no longer increase; the time of the dehydrogenation reaction is generally 2 to 24 hours, for example 8 hours, 10 hours, 15 hours, 20 hours, or 24 hours.

[0040] Step 3 may further include a post-processing step, which may be: after the dehydrogenation reaction is completed, separation and purification are performed to obtain the 1-substituted isoquinoline compound; the separation and purification may be crystallization and / or column chromatography purification.

[0041] In one aspect of the present invention,

[0042] The isoquinoline compounds are shown in Formula I;

[0043] The organometallic reagent containing MC bonds is shown in formula RM;

[0044] Accordingly, the obtained 1-substituted isoquinoline compounds are shown in Formula V;

[0045]

[0046] Among them, X1, X2, X3, X4, X5, and X6 are independently hydrogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Alkyl-O-, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 nucleotide heteroaryl, fluorine, -NR 1 R 2 C1-C 10The alkyl-S-; in the substituted or unsubstituted 5-10-membered heteroaryl group, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3 or 4;

[0047] Alternatively, any two adjacent X1, X2, X3, X4, X5, and X6, together with their bonded carbon atoms, form: substituted or unsubstituted C3-C atoms. 10 cycloalkyl, substituted or unsubstituted C6-C 10 The aryl, substituted or unsubstituted 5-10 member heteroaryl; wherein the heteroatom in the substituted or unsubstituted 5-10 member heteroaryl is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0048] R 1 and R 2 Alkyl groups that are independently C1-C4;

[0049] R is C6-C 20 aryl, 5-10 membered heteroaryl, benzyl, monosubstituted or polysubstituted C6-C 20 aryl, monosubstituted or polysubstituted 5-10 heteroaryl, monosubstituted or polysubstituted benzyl, substituted or unsubstituted C3-C 10 cycloalkyl, C1-C 10 Alkyl, C2-C 10 alkenyl, or C2-C 10 The alkynyl group; in the 5-10 member heteroaryl group and the monosubstituted or polysubstituted 5-10 member heteroaryl group, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0050] The substituents in X1, X2, X3, X4, X5, X6, and R are independently selected from: C1-C4 alkyl groups, C1-C4 alkyl-O- groups, C1-C4 alkyl-S- groups, F, Cl, trifluoromethyl groups, and -NR groups. 3 R 4 ;

[0051] R 3 and R 4 It is an alkyl group that is independently C1-C4.

[0052] In certain preferred embodiments of the present invention, certain groups in the phosphine ligand compound represented by Formula V are defined as follows, and groups not mentioned are as described in any embodiment of this application (hereinafter referred to as "in a certain embodiment").

[0053] When X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C1-C 10Alkyl, substituted or unsubstituted C1-C 10 When alkyl-O-, the substituted or unsubstituted C1-C 10 Alkyl groups and substituted or unsubstituted C1-C 10 C1-C in alkyl-O- 10 The alkyl group can be a C1-C6 alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl), or a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl); for example, isopropyl.

[0054] In a given scheme, X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C3-C. 10 When cycloalkyl, the substituted or unsubstituted C3-C 10 C3-C in cycloalkyl groups 10 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0055] In a given scheme, X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C6-C. 10 When the aryl group is substituted or unsubstituted, the C6-C 10 The aryl group can be phenyl or naphthyl.

[0056] In one embodiment, when X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted 5-10-membered heteroaryl groups, the 5-10-membered heteroaryl group in the substituted or unsubstituted 5-10-membered heteroaryl group can be pyridine, furan, thiophene, benzofuran, or benzothiophene.

[0057] In one scheme, when any two adjacent X1, X2, X3, X4, X5, X6 together with their adjacent carbon atoms form: substituted or unsubstituted C3-C 10 When cycloalkyl, the substituted or unsubstituted C3-C 10 C3-C in cycloalkyl groups 10 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0058] In one scheme, when any two adjacent X1, X2, X3, X4, X5, X6 together with their adjacent carbon atoms form: substituted or unsubstituted C6-C 10 When the aryl group is substituted or unsubstituted, the C6-C 10 The aryl group can be phenyl or naphthyl.

[0059] In one embodiment, when any two adjacent X1, X2, X3, X4, X5, X6 together with the attached carbon atom form a substituted or unsubstituted 5-10 member heteroaryl, the 5-10 member heteroaryl in the substituted or unsubstituted 5-10 member heteroaryl can be pyridine, furan, thiophene, benzofuran, or benzothiophene.

[0060] In a certain scheme, when R is C6-C 20 aryl, monosubstituted or polysubstituted C6-C 20 When the aryl group is present, the C6-C 20 aryl and mono- or poly-substituted C6-C 20 C6-C in aryl 20 The aryl group can be phenyl, naphthyl, anthracene, phenanthryl, pyrene, peryl, fluorenyl, biphenyl, terphenyl, benzoanthryl, or benzophenanthryl; for example, phenyl.

[0061] In one embodiment, when R is a 5-10 ternary group, or a 5-10 ternary group in a monosubstituted or polysubstituted 5-10 ternary group, the 5-10 ternary group and the 5-10 ternary group in the monosubstituted or polysubstituted 5-10 ternary group can be pyridine, furan, thiophene, benzofuran, or benzothiophene.

[0062] In a certain scheme, when R is substituted or unsubstituted C3-C 10 When cycloalkyl, the substituted or unsubstituted C3-C 10 C3-C in cycloalkyl groups 10 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0063] In a certain scheme, when R is C1-C 10 When alkyl, the C1-C 10 The alkyl group can be a C1-C6 alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl or hexyl), or a C1-C4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl); for example, methyl, ethyl, isopropyl.

[0064] In a certain scheme, when R is C2-C 10 When the alkenyl group is present, the C2-C 10 The alkenyl group can be a C2-C3 alkenyl group, such as vinyl, propenyl, or allyl.

[0065] In a certain scheme, when R is C2-C 10 When the alkynyl group is present, the C2-C 10 The alkynyl group can be a C2-C3 alkynyl group, such as ethynyl, propynyl, or propynyl.

[0066] In one embodiment, when the substituents in X1, X2, X3, X4, X5, X6, and R are independently selected from C1-C4 alkyl groups, C1-C4 alkyl-O- groups, and C1-C4 alkyl-S- groups, the C1-C4 alkyl group in the C1-C4 alkyl group, C1-C4 alkyl-O- group, and C1-C4 alkyl-S- group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; for example, methyl or isopropyl.

[0067] In a certain scheme, when R 1 R 2 R 3 and R 4 When independently a C1-C4 alkyl group, the C1-C4 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0068] In one embodiment, the isoquinoline compound, the organometallic reagent, and the corresponding 1-substituted isoquinoline compound are selected from the group consisting of:

[0069]

[0070] The group positions on any molecule used in the definition can be any of the aforementioned groups, as long as they are chemically stable.

[0071] In this invention, the term "alkyl" is not specifically specified and refers to a saturated straight-chain or branched monovalent hydrocarbon group with a specified number of carbon atoms, such as C1-C2. 10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0072] In this invention, the term "cycloalkyl" or "cycloalkane" refers to a non-aromatic saturated or unsaturated cycloalkyl group having a specified number of ring carbon atoms. The cycloalkyl group can be monocyclic or polycyclic (e.g., bicyclic and tricyclic), and can have fused, spirocyclic, and bridged ring structures. The cycloalkyl group optionally contains one or more double or triple bonds. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyl groups also include polycyclic cycloalkyl structures, wherein the polycyclic structure optionally includes a saturated or partially unsaturated cycloalkyl group fused with a saturated or partially unsaturated cycloalkyl or heterocyclic or aryl or heteroaryl ring. Bicyclic carbon rings having 7 to 12 atoms can be arranged, for example, as bicyclic [4,5], [5,5], [5,6] or [6,6] systems, or as bridging ring systems such as bis[2.2.1]heptane, bicyclic [2.2.2]octane and bicyclic [3.2.2]nonane.

[0073] In this invention, the term "aryl" or "aromatic ring" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring containing up to seven atoms in each ring, wherein at least one ring is an aromatic ring. Examples of aryl include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindene, pyrene, peryl, fluorenyl, biphenyl, terphenyl, benzanthracene, benzo[a]phenanthrene, phenanthrene, anthracene, or acenaphthyl. It is understood that in cases where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage occurs through the aromatic ring.

[0074] In this invention, the term "heteroaryl" or "heteroary ring" refers to a stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbon ring containing up to seven atoms in each ring, wherein at least one ring is an aromatic ring and contains at least one heteroatom selected from O, N, and S. Heteroaryl groups can be linked to other parts of a molecule via heteroatoms or carbon atoms. Examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophene, benzofuranyl, benzothiophene, acridinel, carbazoyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, and furanyl.

[0075] The chemical groups used in the definition include all their isotopic groups. For example, hydrogen includes isotopes of H, D, and T; methyl groups include -CH3, CD3, CH2D, and CHD2.

[0076] When defining variables, the groups used include all their isomers. For example, propyl includes 1-propyl and 2-propyl; methyl-substituted phenyl includes 1-methylphenyl, 2-methylphenyl, and 3-methylphenyl.

[0077] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally determined according to national standards. If no corresponding national standard exists, then common international standards, conventional conditions, or conditions recommended by the manufacturer are followed. Unless otherwise stated, all parts are parts by weight, and all percentages are weight percentages.

[0078] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0079] The reagents and raw materials used in this invention are all commercially available.

[0080] The positive and progressive effects of this invention are as follows: the preparation method of this invention is green and efficient, greatly improving the yield of 1-substituted isoquinoline compounds; the dehydrogenation reagents such as Pd / C used in the reaction can be recovered. Detailed Implementation

[0081] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0082] Unless otherwise specified, the purity detection method in the examples is gas chromatography. Because dihydroisoquinoline is unstable, different intermediates exhibit different responses in gas chromatography; the sampling in the examples represents only one sampling result. Unless otherwise specified, the yields in the examples are reaction yields detected by gas chromatography. Unless otherwise specified, the palladium on carbon used in the examples is wet palladium on carbon containing 65-70% water. The 5% or 10% palladium on carbon used in the examples refers to a palladium content of 5% or 10% on a dry basis. The 10% w / w palladium on carbon used in the examples refers to the amount of palladium on carbon being 10% of the mass of the raw material isoquinoline compound.

[0083] Example 1

[0084] Preparation of 1-(3,5-dimethylphenyl)-6-isopropylisoquinoline as shown in Formula III

[0085] Under nitrogen protection, 876 ml of commercially available 0.5 M 3,5-dimethylphenyl magnesium bromide Grignard reagent THF solution (1.5 eq) was added to a 2 L four-necked flask. At room temperature, 50 g of commercially available 6-isopropylisoquinoline (1.0 eq) was added, stirred for 10 min, heated to 60 °C, and kept at this temperature for 20 h.

[0086] The contents were determined by gas chromatography as follows: 6-isopropylisoquinoline 5%, 1-(3,5-dimethylphenyl)-6-isopropylisoquinoline 40%, 1-(3,5-dimethylphenyl)-6-isopropyl-1,2-dihydroisoquinoline 45%, and 1-(3,5-dimethylphenyl)-6-isopropyl-1,2,3,4-tetrahydroisoquinoline 10%.

[0087] Under nitrogen protection, the reaction system was cooled to 0°C, and 100g of 20% ammonium chloride aqueous solution was added dropwise to quench the reaction. Then, 5.0g of commercially available 5% palladium on carbon (10% w / w of 6-isopropylisoquinoline) was added, and the temperature was raised to 50°C again and the reaction was stirred for 20h.

[0088] The contents were determined by gas chromatography as follows: 6-isopropylisoquinoline 5%, 1-(3,5-dimethylphenyl)-6-isopropylisoquinoline 91%, 1-(3,5-dimethylphenyl)-6-isopropyl-1,2-dihydroisoquinoline 0%, and 1-(3,5-dimethylphenyl)-6-isopropyl-1,2,3,4-tetrahydroisoquinoline 4%. Column chromatography purification yielded 68.5 g of 1-(3,5-dimethylphenyl)-6-isopropylisoquinoline with a purity of 99.0%, a yield of 85.2%; and 2.0 g of the byproduct 1-(3,5-dimethylphenyl)-6-isopropyl-1,2,3,4-tetrahydroisoquinoline with a purity of 98.5%.

[0089] Gas chromatography-mass spectrometry (GC-MS) was used to detect the following: 1-(3,5-dimethylphenyl)-6-isopropylisoquinoline, M + :275.2, 1-(3,5-dimethylphenyl)-6-isopropyl-1,2-dihydroisoquinoline, M + :277.3, 1-(3,5-dimethylphenyl)-6-isopropyl-1,2,3,4-tetrahydroisoquinoline, M + :279.3.

[0090] 1-(3,5-Dimethylphenyl)-6-isopropylisoquinoline: 1 H NMR (300MHz, CDCl3): δppm8.57-8.55(d,1H),8.07-8.05(d,1H),7.66(s,1H),7.58-7.57(d,1H), 7.45-7.42(dd,1H),7.31(s,2H),7.13(s,1H),3.12-3.08(m,1H),2.42(s,1H),1.37-1.35(d,2H).

[0091] 1-(3,5-Dimethylphenyl)-6-isopropyl-1,2,3,4-tetrahydroisoquinoline: 1H NMR (300MHz, CDCl3): δppm 7.01(s,1H),6.93-6.92(m,4H),6.72-6.70(d,2H),5.01(s,1H),3.34-3.27(m,1H), 3.14-3.02(m,2H),2.91-2.78(m,2H),2.31(s,6H),2.06(s,1H),1.27-1.25(m,6H).

[0092] The reaction formula is as follows:

[0093]

[0094] Example 2

[0095] Preparation of 6-isopropyl-1-methylisoquinoline

[0096] Under nitrogen protection, 10 ml of THF was added to a 50 ml four-necked flask, followed by 8.76 ml of commercially available 3.0 M methyl magnesium chloride Grignard reagent THF solution (0.9 eq), and then 5.0 g of 6-isopropylisoquinoline (1.0 eq). The mixture was stirred at room temperature for 10 min, then heated to 40 °C and maintained at this temperature for 4 h. Gas chromatography analysis revealed the following concentrations: 6-isopropyl-1-methylisoquinoline 40%, 6-isopropyl-1-methyl-1,2-dihydroisoquinoline 15%, and 6-isopropyl-1-methyl-1,2,3,4-tetrahydroisoquinoline 14%.

[0097] Under nitrogen protection, the reaction system was cooled to 0°C, 20 ml of methyl tert-butyl ether was added, and the reaction was quenched by adding 5 g of 20% ammonium chloride aqueous solution dropwise. Then, 1.0 g of commercially available 5% palladium on carbon (10% w / w 6-isopropylisoquinoline) was added, and the temperature was raised again to 50°C with stirring for 20 h. The content was determined by gas chromatography, and 6-isopropyl-1-methylisoquinoline was found to be 60%.

[0098] The gas chromatography-mass spectrometry (GC-MS) method was used to detect the following: ESI-MS (m / z): 6-isopropyl-1-methylisoquinoline, molecular weight: 185.

[0099] The reaction formula is as follows:

[0100]

[0101] Example 3

[0102] Preparation of 1-ethylisoquinoline mixture

[0103] Under nitrogen protection, 46.5 ml of commercially available 1.0 M ethyl magnesium bromide THF solution (2.0 eq) was added to a 250 ml four-necked flask, followed by 3.0 g of isoquinoline (1.0 eq). The mixture was stirred at room temperature for 10 min, then heated to 60 °C and maintained at this temperature for 10 h. Gas chromatography analysis revealed the following content: 1-ethylisoquinoline 60%, 1-ethyl-1,2-dihydroisoquinoline 25%, and 1-ethyl-1,2,3,4-tetrahydroisoquinoline 3%.

[0104] Under nitrogen protection, the reaction system was cooled to 0°C, 30 ml of methyl tert-butyl ether was added, and the reaction was quenched by adding 3 g of 20% ammonium chloride aqueous solution. The aqueous phase was separated. 0.3 g of commercially available 5% palladium on carbon was added to the organic phase, and the temperature was raised again to 50°C and stirred for 10 h. The content was determined by gas chromatography, and 1-ethylisoquinoline was 80%.

[0105] Detection by gas chromatography-mass spectrometry, ESI-MS (m / z): 1-ethylisoquinoline, molecular weight: 157.

[0106] The reaction formula is as follows:

[0107]

[0108] Example 4

[0109] Preparation of 1-benzylisoquinoline

[0110] Under nitrogen protection, 3.0 g of isoquinoline was added to a 250 ml four-necked flask and dissolved in 40 ml of tetrahydrofuran. Then, 41.8 ml of commercially available 1.0 M benzyl magnesium chloride THF solution (1.8 eq) was added dropwise at room temperature, and the mixture was stirred at 20°C for 6 h. Gas chromatography analysis revealed the following content: 1-benzylisoquinoline 27%, 1-benzyl-1,2-dihydroisoquinoline 54%, and 1-benzyl-1,2,3,4-tetrahydroisoquinoline 11%.

[0111] Under nitrogen protection, the reaction system was cooled to 0°C, 30 ml of methyl tert-butyl ether was added, and the reaction was quenched by adding 5 g of 20% ammonium chloride aqueous solution. The aqueous phase was separated. 0.6 g of commercially available 5% palladium on carbon was added to the organic phase, and the temperature was raised to 60°C with stirring for 24 h. The content was determined by gas chromatography, and 1-benzylisoquinoline was 86%.

[0112] Detection by gas chromatography-mass spectrometry, ESI-MS (m / z): 1-benzylisoquinoline, molecular weight: 219.

[0113] The reaction formula is as follows:

[0114]

[0115] Example 5

[0116] Preparation of 1-cyclohexylisoquinoline

[0117] Under nitrogen protection, 3.0 g of isoquinoline was added to a 250 ml four-necked flask and dissolved in 30 ml of tetrahydrofuran. Then, 32.2 ml of commercially available 1.3 M cyclohexyl magnesium chloride THF solution (1.8 eq) was added dropwise at room temperature. The mixture was stirred at 20°C for 10 min, then heated to 50°C and maintained at this temperature for 8 h. Gas chromatography analysis revealed the following content: 1-cyclohexylisoquinoline 21%, 1-cyclohexyl-1,2-dihydroisoquinoline 55%, and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline 13%.

[0118] Under nitrogen protection, the reaction system was cooled to 0°C, 30 ml of methyl tert-butyl ether was added, and 5 g of 20% ammonium chloride aqueous solution was added dropwise to quench the reaction. 0.5 g of commercially available 5% palladium on carbon was added, and the temperature was raised to 50°C with stirring for 8 hours. The content was determined by gas chromatography, and 1-cyclohexylisoquinoline was 95%.

[0119] Detection by gas chromatography-mass spectrometry, ESI-MS (m / z): 1-cyclohexylisoquinoline, molecular weight: 211.

[0120] The reaction formula is as follows:

[0121]

[0122] Example 6

[0123] Preparation of 1-isopropylisoquinoline

[0124] Under nitrogen protection, 20 ml of tetrahydrofuran, 21.0 ml of commercially available 2.0 M isopropyl magnesium chloride THF solution (1.8 eq), and 3.0 g of isoquinoline (1.0 eq) were added to a 100 ml four-necked flask. The mixture was stirred at room temperature for 10 min, then heated to 50 °C and maintained at that temperature for 15 h. The contents were determined by gas chromatography as follows: 1-isopropylisoquinoline 10%, 1-isopropyl-1,2-dihydroisoquinoline 78%, and 1-isopropyl-1,2,3,4-tetrahydroisoquinoline 2%.

[0125] Under nitrogen protection, the reaction system was cooled to 0°C, 30 ml of methyl tert-butyl ether was added, and the reaction was quenched by adding 5 g of 20% ammonium chloride aqueous solution. The aqueous phase was separated. 1.0 g of commercially available 5% palladium on carbon was added to the organic phase, and the mixture was heated to 50°C and stirred for 8 hours. The content was determined by gas chromatography, and 1-isopropylisoquinoline was 88%.

[0126] Detected by gas chromatography-mass spectrometry, ESI-MS (m / z): 1-isopropylisoquinoline, molecular weight: 171.

[0127] The reaction formula is as follows:

[0128]

[0129] Example 7

[0130] Preparation of 1-phenylisoquinoline

[0131] Under nitrogen protection, 5.0 g of isoquinoline was added to a 250 ml four-necked flask and dissolved in 20 ml of tetrahydrofuran. 29 ml of commercially available 2.0 M phenyl magnesium chloride THF solution (1.5 eq) was added dropwise at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated to 50 °C and stirred for 6 hours.

[0132] Under nitrogen protection, the reaction system was cooled to 0°C, 20 ml of methyl tert-butyl ether was added to aid dissolution, 5 g of 20% ammonium chloride aqueous solution was added dropwise to quench the reaction, 0.5 g of commercially available 5% Pt / C was added, and the temperature was raised to 60°C with stirring for 10 h. The content was determined by gas chromatography; 1-phenylisoquinoline was 90%.

[0133] The reaction formula is as follows:

[0134]

[0135] Example 8

[0136] Preparation of 1-benzylisoquinoline

[0137] Under nitrogen protection, 3.0 g of isoquinoline was added to a 250 ml four-necked flask and dissolved in 40 ml of tetrahydrofuran. 69.7 ml of commercially available 0.5 M benzyl zinc bromide THF solution (1.8 eq) was added dropwise at room temperature. The mixture was stirred at room temperature for 10 minutes and then heated to 50 °C and stirred for 6 hours.

[0138] Under nitrogen protection, the reaction system was cooled to 0°C, 30 ml of methyl tert-butyl ether was added, and the reaction was quenched by adding 5 g of 20% ammonium chloride aqueous solution. 0.6 g of commercially available Raney nickel was added, and the mixture was heated to 60°C and stirred for 40 h. The content was determined by gas chromatography, and 1-benzylisoquinoline was 86%.

[0139] The reaction formula is as follows:

[0140]

[0141] As shown in Tables 2 and 3 of the prior art (Organic Chemistry, 26(11), 1548-1552, 2006), the yield of compound 2a (1-methylisoquinoline) is only 35.7% (70% × 51%); the yield of compound 2b (1-ethylisoquinoline) is only 62.4% (78% × 80%); the yield of compound 2d (1-benzylisoquinoline) is only 64% (78% × 82%); and the yield of compound 2e (1-phenylisoquinoline) is only 60.8% (80% × 76%).

[0142] As can be seen from compound 25 in Table 3 of the prior art (Joc, 78(7), 3243-3249, 2013), the yield of 1-phenylisoquinoline is only 60%.

[0143] In Example 2 of this invention, 1-methylisoquinoline reaches 60%; in Example 3, 1-ethylisoquinoline reaches 80%; in Examples 4 and 8, 1-benzylisoquinoline reaches 86%; and in Example 7, 1-phenylisoquinoline reaches 90%. Compared with the above-mentioned prior art, these figures represent increases of 68%, 28%, 34%, and 48%, respectively.

[0144] In summary, we have discovered for the first time the problem of a large amount of "dihydroisoquinoline and tetrahydroisoquinoline byproducts" in Grignard reactions, thus providing a technical solution that differs from existing technologies and solving the technical problems of low yield in existing technologies.

Claims

1. A method for preparing a 1-substituted isoquinoline compound, characterized in that, It includes the following steps: Step 1: In an organic solvent, an isoquinoline compound is coupled with an organometallic reagent containing an MC bond to obtain mixture A; Wherein, the 1-position of the isoquinoline compound is not substituted; M is MgCl, MgBr, MgI, ZnCl, ZnI, or ZnBr; The organic solvent is an ether solvent; The molar ratio of the isoquinoline compound to the organometallic reagent containing the MC bond is 1:0.9 to 1:2; The coupling reaction is performed at a temperature ranging from 0°C to 60°C. Step 2: The mixture A is subjected to a quenching reaction with a quenching agent to obtain mixture B; Step 3: In the presence of a dehydrogenating agent, the above mixture B is subjected to a dehydrogenation reaction to obtain a 1-substituted isoquinoline compound; The dehydrogenating agent is palladium on carbon, platinum on carbon, rhodium on carbon, ruthenium on carbon, or Raney nickel; the mass percentage of the dehydrogenating agent to the isoquinoline compound is 1% to 50%. The dehydrogenation reaction is carried out at a temperature of 50-80℃; The isoquinoline compounds are shown in Formula I; The organometallic reagent containing MC bonds is shown in formula RM; Accordingly, the obtained 1-substituted isoquinoline compounds are shown in Formula V; ； Among them, X1, X2, X3, X4, X5, and X6 are independently hydrogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, C1-C 10 Alkyl-S-; Alternatively, any two adjacent X1, X2, X3, X4, X5, and X6, together with their adjacent carbon atoms, form a substituted or unsubstituted C3-C atom. 10 cycloalkyl, substituted or unsubstituted C6-C 10 aryl; R is C6-C 20 aryl, benzyl, monosubstituted or polysubstituted C6-C 20 aryl, monosubstituted or polysubstituted benzyl, substituted or unsubstituted C3-C 10 cycloalkyl, C1-C 10 Alkyl groups; The substituents in X1, X2, X3, X4, X5, X6, and R are independently selected from C1-C4 alkyl groups.

2. The preparation method according to claim 1, characterized in that, M is MgCl, MgBr, or ZnBr; Alternatively, in step 1, the organometallic reagent containing MC bonds is used in the form of a solution formed with a portion of the organic solvent; Alternatively, in step 1, the coupling reaction is carried out in an inert gas atmosphere; Alternatively, in step 1, the temperature of the coupling reaction is 10°C to 60°C; Alternatively, step 1 can be as follows: Under an inert gas atmosphere, the solution of the organometallic reagent containing MC bonds and a portion of the organic solvent is added to the solution of the isoquinoline compound and the remaining organic solvent to carry out the coupling reaction, thereby obtaining mixture A. Alternatively, in step 1, the raw materials for the coupling reaction are the isoquinoline compounds, the organometallic reagent containing MC bonds, and the organic solvent.

3. The preparation method according to claim 2, characterized in that, In step 1, when the organic solvent is an ether solvent, the ether solvent is one or more of tetrahydrofuran, dioxane, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, isopropyl ether, and ethylene glycol dimethyl ether. Alternatively, in step 1, the organometallic reagent containing MC bonds is used in the form of a solution formed with a portion of the organic solvent; wherein the molar concentration of the organometallic reagent containing MC bonds in the solution is 0.5 M to 3.0 M; Alternatively, in step 1, the molar ratio of the isoquinoline compound to the organometallic reagent containing the MC bond is 1:0.9, 1:1.3, 1:1.5, 1:1.8, or 1:2.

0. Alternatively, in step 1, the coupling reaction is carried out in an inert gas atmosphere; the inert gas is nitrogen and / or argon. Alternatively, in step 1, the temperature of the coupling reaction is 20°C to 60°C; Alternatively, step 1 can be as follows: Under an inert gas atmosphere, the solution of the organometallic reagent containing MC bonds and a portion of the organic solvent is added to the solution of the isoquinoline compound and the remaining organic solvent to carry out the coupling reaction, thereby obtaining mixture A; the addition can be done by dropwise addition or direct mixing. Alternatively, step 1 can be as follows: Under an inert gas atmosphere, the solution of the organometallic reagent containing MC bonds and a portion of the organic solvent is added to the solution of the isoquinoline compound and the remaining organic solvent to carry out the coupling reaction, thereby obtaining mixture A; the addition temperature is room temperature. Alternatively, step 1 can be performed as follows: Under an inert gas atmosphere, the solution of the organometallic reagent containing MC bonds and a portion of the organic solvent is added to the solution of the isoquinoline compound and the remaining organic solvent to carry out the coupling reaction, thereby obtaining mixture A.

4. The preparation method according to any one of claims 1-3, characterized in that, In step 2, the quenching agent is water or acid; Alternatively, in step 2, the mass ratio of the quenching reagent to the isoquinoline compound is 0.1:1 to 10:1; Alternatively, in step 2, the quenching temperature is -10℃ to 30℃; Alternatively, in step 2, the quenching reaction is carried out in an inert gas atmosphere; Alternatively, in step 2, the quenching is performed as follows: under an inert gas atmosphere, the quenching reagent is added to the mixture A to carry out the quenching reaction, thereby obtaining mixture B. Alternatively, in step 2, the raw materials for the quenching reaction are the quenching reagent and the mixture A.

5. The preparation method according to claim 4, characterized in that, In step 2, the quenching agent is a 5% to saturated ammonium chloride aqueous solution; Alternatively, in step 2, the mass ratio of the quenching reagent to the isoquinoline compound is 1:1, 1.6:1, or 2:

1. Alternatively, in step 2, the quenching reaction is carried out in an inert gas atmosphere, wherein the inert gas is nitrogen and / or argon. Alternatively, in step 2, the quenching is performed as follows: under an inert gas atmosphere, the quenching reagent is added to the mixture A to carry out the quenching reaction, thereby obtaining mixture B; the addition is done dropwise. Alternatively, in step 2, the quenching is performed as follows: under an inert gas atmosphere, the quenching reagent is added to mixture A to carry out the quenching reaction, thereby obtaining mixture B; the temperature at which the reagent is added is room temperature. Alternatively, in step 2, the quenching is performed as follows: under an inert gas atmosphere, the quenching reagent is added to the mixture A to carry out the quenching reaction, thereby obtaining mixture B; the temperature of the quenching reaction is between -10℃ and 30℃.

6. The preparation method according to any one of claims 1-3, characterized in that, In step 2, the quenching agent is a 20% ammonium chloride aqueous solution; Alternatively, in step 3, the dehydrogenation reaction is carried out under an inert gas atmosphere; Alternatively, step 3 may include a post-processing step, which involves separating and purifying the compound after the dehydrogenation reaction is complete to obtain the 1-substituted isoquinoline compound.

7. The preparation method according to claim 6, characterized in that, In step 3, the dehydrogenation reagent is 5% or 10% palladium on carbon or Raney nickel; Alternatively, in step 3, the mass percentage of the dehydrogenating agent to the isoquinoline compound is 5% to 10%. Alternatively, in step 3, the temperature of the dehydrogenation reaction is 50°C to 60°C. Alternatively, in step 3, the dehydrogenation reaction is carried out in an inert gas atmosphere, wherein the inert gas is nitrogen and / or argon. Alternatively, step 3 may include a post-processing step, which is: after the dehydrogenation reaction is completed, separation and purification are performed to obtain the 1-substituted isoquinoline compound; the separation and purification are performed by crystallization and / or column chromatography purification.

8. The preparation method according to any one of claims 1-3, characterized in that, in, When X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C1-C 10 When alkyl, the C1-C 10 The alkyl group is a C1-C6 alkyl group; Alternatively, when X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C3-C 10 When cycloalkyl, the substituted or unsubstituted C3-C 10 C3-C in cycloalkyl groups 10 The cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Alternatively, when X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C6-C 10 When the aryl group is substituted or unsubstituted, the C6-C 10 The aryl group is phenyl or naphthyl; Alternatively, when any two adjacent X1, X2, X3, X4, X5, X6, together with their bonded carbon atoms, form either substituted or unsubstituted C3-C atoms. 10 When cycloalkyl, the substituted or unsubstituted C3-C 10 C3-C in cycloalkyl groups 10 The cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Alternatively, when any two adjacent X1, X2, X3, X4, X5, X6, together with their bonded carbon atoms, form either substituted or unsubstituted C6-C atoms. 10 When the aryl group is substituted or unsubstituted, the C6-C 10 The aryl group is phenyl or naphthyl; Or, when R is C6-C 20 aryl, monosubstituted or polysubstituted C6-C 20 When the aryl group is present, the C6-C 20 aryl and mono- or poly-substituted C6-C 20 C6-C in aryl 20 The aryl groups are phenyl, naphthyl, anthracene, phenanthryl, pyrene, peryl, fluorenyl, biphenyl, terphenyl, benzoanthryl, and benzophenanthryl. Or, when R is substituted or unsubstituted C3-C 10 When cycloalkyl, the substituted or unsubstituted C3-C 10 C3-C in cycloalkyl groups 10 The cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Or, when R is C1-C 10 When alkyl, the C1-C 10 The alkyl group is a C1-C6 alkyl group; Alternatively, when the substituents in X1, X2, X3, X4, X5, X6, and R are independently selected from C1-C4 alkyl groups, the C1-C4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

9. The preparation method according to claim 8, characterized in that, in, When X1, X2, X3, X4, X5, and X6 are independently substituted or unsubstituted C1-C 10 When alkyl, the C1-C 10 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; Or, when R is C6-C 20 aryl, monosubstituted or polysubstituted C6-C 20 When the aryl group is present, the C6-C 20 aryl and mono- or poly-substituted C6-C 20 C6-C in aryl 20 The aryl group is phenyl; Or, when R is C1-C 10 When alkyl, the C1-C 10 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; Alternatively, when the substituents in X1, X2, X3, X4, X5, X6, and R are independently selected from C1-C4 alkyl groups, the C1-C4 alkyl groups are methyl or isopropyl.

10. The preparation method according to claim 9, characterized in that, in, The isoquinoline compounds, the organometallic reagents, and the corresponding 1-substituted isoquinoline compounds are selected from the group consisting of: 、 、 、 、 、 、 。

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