A green synthesis method of 1-alkoxyisoquinoline compound

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a green synthesis method of a 1-alkoxyisoquinoline compound, wherein a benzonitrile compound and an alcohol are used as starting raw materials for the reaction, a low eutectic is used as a solvent, an addition reaction occurs, and then an intramolecular C-H activation / cyclization reaction occurs with vinylene carbonate under the action of a cobalt catalyst and an additive, so as to prepare the 1-alkoxyisoquinoline compound. The starting raw materials of the invention are simple and easy to obtain, low in price, high in reaction selectivity and product yield, excellent in substrate functional group compatibility, and the low eutectic solvent / cobalt salt catalytic system can be recycled for multiple times, thereby greatly reducing production costs.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis and relates to a green synthesis method of a 1-alkoxyisoquinoline compound. Background Art

[0002] Isoquinoline structure is an important organic structure. Most compounds containing this structure fragment have excellent biological and pharmacological activities, such as antifungal, antitumor, antiviral activities, etc., and therefore have a wide range of applications in medicine and other related fields. Among them, 1-alkoxyisoquinoline compounds have good clinical applications. For example, quinicaine can be used for topical anesthesia, and its anesthetic is more than 1,000 times stronger than cocaine, and has low toxicity. Therefore, in recent years, the research on the synthesis of 1-alkoxyisoquinoline compounds has increased both at home and abroad.

[0003] The traditional synthesis of nitrogen heterocyclic ethers mainly involves the reaction of nitrogen heterocyclic halides with alcohols under the action of strong bases. However, the temperature of such reactions is high and the yield is low. Londregan et al. reported that N-oxides of isoquinoline were used as raw materials and tripyrrolidinophosphonium bromide hexafluorophosphate (PyBroP) was used as a promoter to achieve the synthesis of 1-alkoxyisoquinoline compounds under alkaline conditions (Org. Lett., 2016, 18: 1362–1365). This method requires the use of relatively expensive tripyrrolidinophosphonium bromide hexafluorophosphate (Aldrich, 280 yuan / g), and the N-oxide raw materials of isoquinoline containing substituents require multi-step synthesis.

[0004]

[0005] In recent years, intramolecular CH activation / cyclization through the "one-pot method" has received widespread attention from researchers. For example, Hua Ruimao et al. used diphenylacetylene, nitrile and alcohol as raw materials, and achieved 1-alkoxy-3,4-diaryl substituted isoquinoline compounds under the action of rhodium catalyst (J.Org.Chem., 2021, 86, 8862-8872). This reaction requires the use of expensive rhodium catalysts, and the alkyne needs to be a symmetrical structure.

[0006]

[0007] In addition, the 1-alkoxyisoquinoline compounds reported in the above methods all have corresponding substituent groups at positions 3 and 4, while there are few reports on the general synthesis method of 1-alkoxyisoquinoline compounds without substituent groups at positions 3 and 4. The synthesis method of 1-alkoxyisoquinoline compounds in the prior art usually requires the use of toxic and volatile organic solvents as reaction media, and the catalysts used are expensive. Organic solvents, catalysts and additives are difficult to recycle, which not only causes environmental pollution but also leads to high reaction costs. In view of the important characteristic that 1-alkoxyisoquinoline compounds without substituents at positions 3 and 4 can be introduced through other reactions, it is very necessary to develop a green synthesis method for 1-alkoxyisoquinoline compounds without substituents at positions 3 and 4, which has simple raw materials, high reaction activity, good versatility, low reaction cost and is environmentally friendly. Summary of the invention

[0008] In view of the defects of the synthesis method of 1-alkoxyisoquinoline compounds in the prior art, the purpose of the present invention is to provide a green synthesis method for preparing 1-alkoxyisoquinoline compounds, which comprises taking a benzonitrile compound and an alcohol as the starting raw materials for the reaction, taking a low eutectic as a solvent, carrying out an addition reaction, and then carrying out an intramolecular CH activation / cyclization reaction with vinylene carbonate under the action of a cobalt catalyst and an additive. The method has a high yield of the target product, low raw material cost, is environmentally friendly, and is conducive to industrial production and application.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is:

[0010] A green synthesis method of a 1-alkoxyisoquinoline compound, which uses a benzonitrile compound and an alcohol as starting materials for the reaction, uses a low eutectic as a solvent, performs an addition reaction, and then performs an intramolecular CH activation / cyclization reaction with vinylene carbonate under the action of a cobalt catalyst and an additive to prepare the 1-alkoxyisoquinoline compound;

[0011] The reaction route is as follows:

[0012]

[0013] In the 1-alkoxyisoquinoline compound of the present invention, R 1 It can be hydrogen, methyl, methoxy, halogen, cyano, ester, trifluoromethyl, nitro, etc. The position of the substituent is not limited and can be ortho, meta or para.

[0014] Furthermore, R 2 It is a C1-C4 straight chain or branched alkyl, trifluoroethyl, allyl, etc. There is no substituent at the 3 and 4 positions of 1-alkoxyisoquinoline. 1 and R 2The choice of substituent type and position does not have a significant effect on the yield of the target product. Experiments show that all types of substituents can basically ensure that the yield of the target product is above 80%.

[0015] As a preferred scheme, the low eutectic solvent is selected from any one of choline chloride / acetic acid, choline chloride / malonic acid, choline chloride / glycerol, and betaine / hexafluoroisopropanol. The preferred choline chloride / acetic acid low eutectic solvent is composed of choline chloride and acetic acid in a molar ratio of 1:1 to 3. The preferred choline chloride / malonic acid low eutectic solvent is composed of choline chloride and malonic acid in a molar ratio of 1:1 to 3. The preferred choline chloride / glycerol low eutectic solvent is composed of choline chloride and glycerol in a molar ratio of 1:1 to 3. The preferred betaine / hexafluoroisopropanol low eutectic solvent is composed of betaine and hexafluoroisopropanol in a molar ratio of 1:1 to 3. In these types of low eutectic solvents, 1-alkoxyisoquinoline compounds can be successfully generated, and the yield of the target product is more than 60%, and betaine / hexafluoroisopropanol is the best low eutectic solvent for the reaction, especially when betaine / hexafluoroisopropanol is composed of a molar ratio of 1:2, the yield of the target product obtained is the best. The amount of the low eutectic solvent used in the present invention is based on the amount of conventional solvents added, such as the concentration of 1-alkoxyisoquinoline in the low eutectic solvent is 0.05 to 0.2 mol / L, preferably 0.05 to 0.1 mol / L.

[0016] Furthermore, the cobalt catalyst is one of cobalt acetate, Cp*Co(CO)I2 and [CoCp*(CH3CN)3](SbF6)2. A further preferred technical solution is that the amount of the cobalt salt catalyst is at least 2.5% of the molar amount of benzonitrile. The optimal amount of the cobalt salt catalyst is 5% equivalent. When the amount of the cobalt salt catalyst is increased, the yield of the target product does not increase significantly; when the amount of the cobalt salt catalyst is reduced, the yield of the target product decreases significantly; further preferably 2.5-10%.

[0017] The additive is used as an oxidant and is one of cupric acetate, cupric oxide, silver acetate and silver carbonate. A further preferred technical solution is that the amount of the additive is 10-30 mol% of benzonitrile, and the optimal amount of the additive is 20 mol%.

[0018] The green synthesis method of a 1-alkoxyisoquinoline compound comprises the following steps: the molar ratio of benzonitrile: alcohol: vinylene carbonate is 1:10-20:3-5.

[0019] A further preferred technical solution is that the molar ratio of benzonitrile:alcohol:vinyl carbonate is 1:20:3.

[0020] The intramolecular CH activation / cyclization reaction conditions are: reaction at 90-120°C for 12-24h. The temperature is most preferably around 110°C, and the time is optimally 12h. Further increase in temperature or extension of reaction time does not increase the yield of the target product.

[0021] After the intramolecular CH activation / cyclization reaction is completed, an organic solvent is used for extraction to separate the 1-alkoxyisoquinoline compound, and the raffinate is a low eutectic solvent, a cobalt salt catalyst and an additive, which can be reused. The organic solvent is ethyl acetate, etc.

[0022] The advantages and beneficial effects of the present invention are:

[0023] 1. The present invention provides a universal green synthesis method of 1-alkoxyisoquinoline compounds, which provides a new idea for the actual synthesis of such compounds.

[0024] 2. The present invention uses a biomass low eutectic solvent as a reaction medium and a cobalt salt as a catalyst, which is inexpensive, readily available, environmentally friendly, and the low eutectic solvent / cobalt salt system can be recycled more than 6 times.

[0025] 3. The sources of reaction substrates used in the present invention are convenient, and benzonitrile, alcohol and vinylene carbonate are all industrial products with very low prices. The functional group compatibility is good, the substrate has a wide range of application, and the yield is high.

[0026] 4. The present invention provides a green synthesis method for 1-alkoxyisoquinoline compounds which are unsubstituted at positions 3 and 4. New functional groups can be introduced at positions 3 and 4 by other organic reaction means, thereby realizing the construction of a series of 1-alkoxyisoquinoline compounds and satisfying product diversity. DETAILED DESCRIPTION

[0027] The present invention is not limited to the following specific embodiments. A person skilled in the art can implement the present invention in various other specific embodiments according to the contents disclosed in the present invention, or any simple changes or modifications made to the design structure and ideas of the present invention fall within the protection scope of the present invention. It should be noted that the embodiments and features in the embodiments of the present invention can be combined with each other without conflict.

[0028] Comparative Example:

[0029] The following reaction formula is an intramolecular CH activation / cyclization reaction under optimal conditions in a deep eutectic solvent and a cobalt catalyst (as a standard reaction):

[0030]

[0031] The specific operation steps are as follows: benzonitrile (0.5 mmol), methanol (10 mmol), vinylene carbonate (1.5 mmol), Cp*Co(CO)I2 (5 mol%), copper acetate (20 mol%), and low eutectic solvent betaine / hexafluoroisopropanol (5 mL) are added in sequence into a clean and dry 25 mL round-bottom flask, and the resulting mixed solution is heated at 110°C for 12 h. After the reaction is completed, the reaction solution is cooled to room temperature, the reactant is extracted with ethyl acetate, and petroleum ether (PE) / ethyl acetate (EA) is used as an eluent, and column chromatography purification is performed using silica gel (200 300 mesh sieve).

[0032] The following control experimental groups 1 to 19 are based on standard reaction conditions for comparison and explanation:

[0033]

[0034]

[0035] Experimental groups 1 to 5 in the above table investigated the effects of different catalysts on the reaction. From the experimental data, it can be seen that the three cobalt catalysts have a certain catalytic activity for the reaction, and the yields are all above 65%. When the dosage of Cp*Co(CO)I2 is 5 mol%, the best reaction effect is 92%.

[0036] Experimental groups 6 to 9 investigated the effects of additives on the reaction, among which copper acetate had the best effect.

[0037] Experimental groups 10 to 16 investigated the effects of different low eutectic solvents, compositions and dosages on the reaction. Among them, betaine / hexafluoroisopropanol has the best effect as a solvent. The optimal molar ratio of betaine and hexafluoroisopropanol in the low eutectic solvent is 1:2. Too high or too low will reduce the yield of the target product, indicating that there is an obvious synergistic effect between betaine and hexafluoroisopropanol. In addition, the dosage of betaine / hexafluoroisopropanol also has a certain effect on the reaction. Too high a dosage will not reduce the yield of the target product, but too low a dosage will reduce the yield of the target product to a certain extent. It is best to ensure that the concentration of the reactants is within the concentration range of 0.05 to 0.1 mol / L.

[0038] Experimental groups 17 to 19 investigated the effects of different reaction times and temperatures on the reaction. The most preferred reaction temperature was around 110°C. When the temperature was further increased, the yield of the target product did not increase; when the reaction temperature was lowered, the yield of the target product decreased significantly; and when the reaction time was further extended, the yield of the target product did not increase.

[0039] The following Examples 1 to 6 were carried out according to the above standard reaction:

[0040]

[0041] The specific operation steps are as follows: aromatic nitrile (0.5 mmol), alcohol (10 mmol), vinylene carbonate (1.5 mmol), Cp*Co(CO)I2 (5 mol%), copper acetate (20 mol%), and low eutectic solvent betaine / hexafluoroisopropanol (5 mL) are added in sequence into a clean and dry 25 mL round-bottom flask, and the resulting mixed solution is heated at 110°C for 12 h. After the reaction is completed, the reaction solution is cooled to room temperature, the reactant is extracted with ethyl acetate, and petroleum ether (PE) / ethyl acetate (EA) is used as an eluent, and column chromatography purification is performed using silica gel (200300 mesh sieve).

[0042] Example 1

[0043] 1-Methoxyisoquinoline, yield 92%.

[0044] 1 H NMR(500MHz, CDCl3)δ8.26(ddd,J=0.8,2.0,8.2Hz,1H),8.01(d,J=6.2Hz,1H),7.73(dt,J=0.8,8.2Hz,1H),7 .65(ddd,J=1.6,7.0,8.2Hz,1H),7.53(ddd,J=1.2,7.0,8.2Hz,1H),7.21(dd,J=0.8,5.9Hz,1H),4.15(s,3H).

[0045] 13 C NMR (125MHz, CDCl3) δ160.9,139.6,137.8,130.4,126.5,126.0,124.1,119.8,114.9,53.6.

[0046] Example 2

[0047] 1-Allyloxyisoquinoline, yield 86%.

[0048] 1H NMR (500MHz, CDCl3) δ8.32 (dd, J=1.2, 8.2Hz, 1H), 8.00 (d, J=5.9Hz, 1H), 7.73 (d,J=8.2Hz,1H),7.66(ddd,J=1.2,6.6,8.2Hz,1H),7.54(ddd,J=1.6,6.9,8.3 Hz,1H),7.22(d,J=5.5Hz,1H),6.23(tdd,J=5.4,10.6,17.2Hz,1H),5.51(qd, J=1.6,17.3Hz,1H),5.32(qd,J=1.4,10.5Hz,1H),5.07(td,J=1.6,5.5Hz,2H).

[0049] 13 C NMR (125MHz, CDCl3) δ160.1,139.6,137.9,133.5,130.4,126.5,125.7,124.1,119.7,117.1,115.0,66.7.

[0050] Example 3

[0051] 1-Trifluoroethoxyisoquinoline, yield 84%.

[0052] 1 H NMR (500MHz, CDCl3) δ8.30(ddd,J=0.8,2.0,8.6Hz,1H),7.98(d,J=5.9Hz,1H),7.78(d,J=8.2Hz,1H),7.71(ddd ,J=1.2,6.6,8.2Hz,1H),7.60(ddd,J=1.2,6.9,8.3Hz,1H),7.32(dd,J=0.8,5.9Hz,1H),4.97(q,J=8.6Hz,2H).

[0053] 13 C NMR (125MHz, CDCl3) δ158.7,139.3,138.4,131.2,128.3,127.5,126.5,125.5,124.2,122.8.

[0054] Example 4

[0055] 1-Methoxy-6-methylisoquinoline, yield 84%.

[0056] 1H NMR (500MHz, CDCl3) δ8.18(d,J=7.5Hz,1H),8.09(d,J=7.4Hz,1H),7.28–7.19(m,2H),7.03(dd,J=7.5,1.1Hz,1H),4.06(s,3H),2.50(s,3H).

[0057] 13 C NMR (125MHz, CDCl3) δ158.1,143.6,138.0,137.7,128.6,126.2,125.8,120.5,117.3,54.4,21.7.

[0058] Example 5

[0059] 1,5-Dimethoxyisoquinoline, yield 87%.

[0060] 1 H NMR (500MHz, CDCl3) δ8.17(d,J=7.3Hz,1H),7.39(d,J=1.4Hz,1H),7.27(dd,J=7.5,1.4Hz ,1H),7.19(dd,J=7.5,1.4Hz,1H),6.94(dd,J=7.5,1.5Hz,1H),4.06(s,3H),3.81(s,3H).

[0061] 13 C NMR (125MHz, CDCl3) δ159.6,156.2,139.3,132.1,127.9,121.0,119.8,115.6,110.2,56.1,54.4.

[0062] Example 6

[0063] 5-Chloro-1-methoxyisoquinoline, yield 81%.

[0064] 1 H NMR (500MHz, CDCl3) δ8.36 (d, J=7.5Hz, 1H), 8.15 (dd, J=7.5, 1.4Hz, 1H), 7.50 (d ,J=7.5Hz,1H),7.41(dd,J=7.5,1.4Hz,1H),7.31(t,J=7.5Hz,1H),4.06(s,3H).

[0065] 13C NMR (125MHz, CDCl3) δ156.2,144.5,138.4,133.5,128.7,127.8,124.0,119.8,112.8,54.4.

[0066] Example 7

[0067] The specific operation steps are as follows: benzonitrile (0.5mmol), methanol (10mmol), vinylene carbonate (1.5mmol), Cp*Co(CO)I2 (5mol%), copper acetate (20mol%), and low eutectic solvent betaine / hexafluoroisopropanol (5mL) are added to a clean and dry 25mL round-bottom flask in sequence, and the resulting mixed solution is heated at 110°C for 12h. After the reaction is completed, the reaction solution is cooled to room temperature, and the reactants are extracted with ethyl acetate. The yield of the product is analyzed by nuclear magnetic resonance. Then, new benzonitrile (0.5mmol), methanol (10mmol), and vinylene carbonate (1.5mmol) are added to the raffinate in sequence, and the reaction system is heated at 110°C for 12h. After the reaction is completed, the reactants are extracted with ethyl acetate, and the yield of the product is analyzed by nuclear magnetic resonance. Repeat 5 times in sequence.

[0068] Cycle times 1 2 3 4 5 6 Yield 92％ 91％ 90％ 88％ 86％ 85％

[0069] The 1-alkoxyisoquinoline compound with unsubstituted 3 and 4 positions synthesized by the present invention can introduce new functional groups at the 3 and 4 positions by other organic reaction means, thereby realizing the construction of a series of 1-alkoxyisoquinoline compounds to meet the product diversity, such as the following embodiments:

[0070] Example 8

[0071] The chlorination functionalization reaction of the 4-position of 1-methoxyisoquinoline compound is as follows:

[0072]

[0073] The specific operation steps are as follows: 1-methoxyisoquinoline (0.4 mmol), iodoacetylbenzene (0.6 mmol), ethyl chloroformate (2 mmol), and dichloroethane (2 mL) are added in sequence into a 10 mL round-bottom flask, and the resulting mixed solution is heated at 50° C. for reaction for 6 h. After the reaction is completed, the reaction solution is cooled to room temperature, the reactant is extracted with ethyl acetate, and petroleum ether (PE) / ethyl acetate (EA) is used as an eluent, and column chromatography purification is performed using silica gel (200 300 mesh sieve).

[0074] 4-Chloro-1-methoxyisoquinoline, yield 85%.

[0075] 1H NMR(500MHz, CDCl3)δ8.25(dd,J=7.5,1.4Hz,1H),8.08(s,1H),8.02(dd,J=7.5,1 .4Hz,1H),7.62(td,J=7.5,1.5Hz,1H),7.47(td,J=7.5,1.4Hz,1H),4.06(s,3H).

[0076] 13 C NMR (125MHz, CDCl3) δ156.5,142.9,131.1,129.7,126.6,126.0,124.3,123.9,123.3,54.4.

[0077] Example 9

[0078] The amination reaction of the 3-position of 1-methoxyisoquinoline compound is as follows:

[0079]

[0080] The specific operation steps are as follows: 1-methoxyisoquinoline (0.4 mmol), benzotriazole (0.8 mmol), copper acetate (0.04 mmol), Selectfluor (0.6 mmol), potassium carbonate (0.8 mmol), and nitromethane (3 mL) are added in sequence into a 10 mL round-bottom flask, and the resulting mixed solution is heated at 120° C. for 12 h. After the reaction is completed, the reaction solution is cooled to room temperature, the reactant is extracted with ethyl acetate, and petroleum ether (PE) / ethyl acetate (EA) is used as an eluent, and column chromatography purification is performed using silica gel (200 300 mesh sieve).

[0081] 3-(1-Benzotriazole)-1-methoxyisoquinoline, yield 78%.

[0082] 1 H NMR (500MHz, CDCl3) δ8.27(dd,J=7.5,1.2Hz,1H),7.97(ddd,J=10.5,9.6,2.6Hz,3H),7.64–7.52(m,2H),7.51–7.34(m,3H),4.06(s,3H).

[0083] 13 C NMR (125MHz, CDCl3) δ152.0,144.5,142.8,137.8,134.3,130.5,129.3,128.2,126.4,126.3,124.8,118.2,116.6,115.3,106.1,54.4.

[0084] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A green synthesis method of a 1-alkoxyisoquinoline compound, characterized in that: A benzonitrile compound and an alcohol are used as starting materials for the reaction, and a low eutectic is used as a solvent to undergo an addition reaction, and then an intramolecular CH activation / cyclization reaction is carried out with vinylene carbonate under the action of a cobalt catalyst and an additive to prepare a 1-alkoxyisoquinoline compound; The reaction route is as follows: Among them, R 1 is a substituent at any position of the benzene ring, and R 1 One selected from hydrogen, methyl, methoxy, halogen, cyano, ester, trifluoromethyl, and nitro; and there is no substituent at positions 3 and 4 of 1-alkoxyisoquinoline; The deep eutectic solvent is any one of choline chloride and glycerol, betaine and hexafluoroisopropanol; in The molar ratio of choline chloride to glycerol in the choline chloride and glycerol deep eutectic solvent is 1:1-3; The molar ratio of choline chloride to hexafluoroisopropanol in the betaine and hexafluoroisopropanol deep eutectic solvent is 1:1-3; The cobalt catalyst is any one of cobalt acetate, Cp*Co(CO)I2 or [CoCp*(CH3CN)3](SbF6)2; The additive is any one of copper acetate, copper oxide, silver acetate and silver carbonate; The intramolecular CH activation / cyclization reaction conditions are: reacting at 90-120° C. for 12-24 hours; The molar ratio of the benzonitrile compound: alcohol: vinylene carbonate is 1:10-20:3-5; The dosage of the additive is 10-30 mol% of benzonitrile.

2. A green synthesis method of a 1-alkoxyisoquinoline compound as claimed in claim 1, characterized in that: The substituent R in the alcohol 2 It is one of a C1-C4 straight chain or branched chain alkyl group, a trifluoroethyl group, and an allyl group.

3. A green synthesis method of a 1-alkoxyisoquinoline compound as claimed in claim 1 or 2, characterized in that: The amount of the cobalt catalyst used is 2.5-10 mol% of benzonitrile.

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