Synthesis method of 7-aminoisoquinoline

Abstract

The invention discloses a synthesis method of 7-aminoisoquinoline, and belongs to the technical field of organic synthesis. The target compound 7-aminoisoquinoline is obtained by taking a compound 7-bromoisoquinoline as a raw material under the action of dihydroxy-bis (tetramethylethylidene) diamine copper chloride and ammonia monohydrate. According to the synthesis method, the compound 7-bromoisoquinoline is converted into the compound 7-aminoisoquinoline in one step, the reaction condition is mild, aftertreatment and purification are simple, and the synthesis method is suitable for industrial large-scale production; finally, the compound 7-aminoisoquinoline is prepared through short steps, simple and convenient operation, low cost, relatively mild reaction conditions and ideal yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of 7-aminoisoquinoline. BACKGROUND

[0002] Isoquinoline compounds and their derivatives have a wide range of applications, especially in the fields of medicine, material science, agricultural chemistry and analytical chemistry. Compound 7-aminoisoquinoline is an important isoquinoline compound and also an important molecular building block. As a key intermediate, it is used to synthesize pyridine amide compounds that can inhibit Syk kinase in patent WO2013 / 192046; it is used to synthesize phenylpyridine quaternary ammonium salt derivatives in patent CN119241507A, which have the effect of inhibiting FtsZ and can be used as new FtsZ inhibitors, and also have good antibacterial activity; it is used to synthesize SOX11 inhibitors in patent WO2021 / 257544, which can be used for the treatment of mantle cell lymphoma.

[0003] The conventional synthesis route of compound 7-aminoisoquinoline includes: first, taking 1,2,3,4-tetrahydroisoquinoline as a raw material, and preparing through nitration, high-temperature oxidation and hydrogenation three-step reactions, which is a complicated synthesis route with high risk of reaction conditions. Second, taking 7-bromoisoquinoline as a raw material, and preparing through metal-catalyzed coupling reaction and hydrolysis reaction two-step reactions, which needs to use expensive metal catalysts, has high cost and unsatisfactory yield. Therefore, it is of great significance to develop a new synthesis method of 7-aminoisoquinoline. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a synthesis method of 7-aminoisoquinoline. The synthesis method has the advantages of low cost, short steps, easy operation, relatively mild reaction conditions, low safety hazards, and high yield.

[0005] The technical scheme of the present application is as follows:

[0006] The present application provides a synthesis method of 7-aminoisoquinoline in the first aspect, comprising the following steps:

[0007] Dissolve 7-bromoisoquinoline in an organic solvent I, then add copper catalyst and ammonia source solution in sequence, and stir to obtain a reaction liquid;

[0008] Post-treat the reaction liquid to obtain 7-aminoisoquinoline;

[0009] The ammonia source solution is aqueous ammonia solution.

[0010] Preferably, the organic solvent I is selected from at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0011] Preferably, the mass-volume ratio g / mL of the 7-bromoisoquinoline to the organic solvent I is 1:5-40.

[0012] Preferably, the copper catalyst is chloro-dihydroxy-bistetramethyldiethylene diamine copper; the molar ratio of the 7-bromoisoquinoline to the chloro-dihydroxy-bistetramethyldiethylene diamine copper is 1.0:0.05-1.0.

[0013] Preferably, the mass percentage concentration of the aqueous ammonia solution is 25-28%.

[0014] Preferably, the molar ratio of the 7-bromoisoquinoline to the aqueous ammonia is 1.0:5.0-20.0.

[0015] Preferably, the temperature of the stirring reaction is 80-200℃, and the time is 8-25h.

[0016] Preferably, the specific process of the post-treatment is as follows: the reaction liquid is poured into ice water, stirred, filtered to obtain a filter cake, washed, added into an organic solvent II, stirred after being warmed, filtered, the filtrate is collected, and the crude product is obtained by rotary evaporation, and the 7-aminoisoquinoline is obtained by purification.

[0017] Preferably, the stirring after being warmed refers to stirring for 20-40min after being warmed to 40-60℃.

[0018] Preferably, the organic solvent II is selected from at least one of methanol, ethanol, n-propanol, and isopropanol.

[0019] Preferably, the purification is selected from one or more of beating, column chromatography, recrystallization, and distillation.

[0020] The 7-aminoisoquinoline synthesis method provided by the application has the beneficial technical effects that:

[0021] The 7-aminoisoquinoline synthesis method provided by the application is to use the compound 7-bromoisoquinoline as a raw material, and to obtain the compound under the action of chloro-dihydroxy-bistetramethyldiethylene diamine copper and aqueous ammonia. The synthesis method realizes one-step conversion of the compound 7-bromoisoquinoline into the compound 7-aminoisoquinoline, and has the advantages of relatively low raw material, simple operation, mild reaction condition, simple post-treatment and purification, and process amplification. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 The nuclear magnetic hydrogen spectrum of the 7-aminoisoquinoline prepared for the embodiment 1 of the application. DETAILED DESCRIPTION

[0023] The present invention will now be described in detail with reference to the embodiments.

[0024] Based on the problems in the existing synthesis of 7-aminoisoquinoline, this invention provides a new method for synthesizing 7-aminoisoquinoline.

[0025] The synthesis of 7-aminoisoquinoline in this invention includes the following steps:

[0026] 7-Bromoisoquinoline was dissolved in organic solvent I, and then a copper catalyst and an ammonia source solution were added sequentially. The reaction was stirred to obtain a reaction solution. The reaction solution was post-treated to obtain 7-aminoisoquinoline. The ammonia source solution was an aqueous solution of ammonia monohydrate.

[0027] In some embodiments of the present invention, the synthetic route of the 7-aminoisoquinoline is as follows:

[0028] Understandably, this invention involves a copper-catalyzed aromatic nucleophilic substitution process where Cu(II) complexes, such as copper dihydroxy-bis(tetramethylethylenediamine) chloride, are reduced to active Cu(I) species by ammonia. Cu(I) attacks the C-Br bond in 7-bromoisoquinoline to form an aryl-copper(III) intermediate. Then, ammonia (NH3) provided by ammonia monohydrate solution acts as a nucleophile to attack the aryl-copper(III) intermediate, resulting in ligand exchange and the formation of an ammonium-copper(III) complex. The copper catalyst is then released from the intermediate to obtain 7-aminoisoquinoline, while the regenerated Cu(I) can enter the next catalytic cycle.

[0029] It is understandable that the 7-position of the raw material 7-bromoisoquinoline used in this invention is more prone to substitution due to electronic effects and steric hindrance; the tetramethylethylenediamine (TMEDA) ligand of copper dihydroxy-bis(tetramethylethylenediamine) chloride can stabilize low-valent copper and inhibit the occurrence of side reactions; and the monohydrate ammonia can provide nucleophilic ammonia molecules to avoid heterocyclic decomposition under strong base conditions.

[0030] In some embodiments, the organic solvent I is selected from at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

[0031] In some embodiments, the mass-to-volume ratio (g / mL) of the 7-bromoisoquinoline to the organic solvent I is 1:5 to 40, including but not limited to 1:5, 1:10, 1:20, 1:30, and 1:40.

[0032] In some embodiments, the molar ratio of the 7-bromoisoquinoline to the copper dihydroxy-bis(tetramethylethylenediamine) chloride is 1.0:0.05 to 1.0, including but not limited to 1:0.5, 1:1, 1:0.05, and 1:0.1.

[0033] In some embodiments, the ammonia monohydrate solution is a commercially available product with a mass percentage concentration of 25% to 28%, including but not limited to 25%, 26%, 27%, and 28%. Mass percentage concentration refers to the percentage of the solute in the solution relative to the total mass of the solution.

[0034] In some embodiments, the molar ratio of 7-bromoisoquinoline to the ammonia monohydrate is 1.0:5.0 to 20.0, including but not limited to 1:5, 1:10, 1:15, and 1:20.

[0035] In some embodiments, the stirring reaction is carried out in an autoclave.

[0036] In some embodiments, the temperature of the stirring reaction is 80 to 200°C, including but not limited to 80°C, 100°C, 120°C, 140°C, 160°C, 180°C, and 200°C, and the time is 8 to 25 hours, including but not limited to 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, and 25 hours.

[0037] In some embodiments, the specific process of the post-processing is as follows: the reaction solution is poured into ice water, stirred and filtered, the filter cake is washed and added to organic solvent II, heated and stirred, filtered, the filtrate is collected and evaporated to dryness to obtain crude product, and the crude product is purified to obtain 7-aminoisoquinoline.

[0038] In some embodiments, the heating and stirring refers to heating to 40–60°C and then stirring for 20–40 minutes. The temperature of the heating and stirring includes, but is not limited to, 40°C, 50°C, and 60°C; the time includes, but is not limited to, 20 minutes, 30 minutes, and 40 minutes.

[0039] In some embodiments, the organic solvent II is selected from at least one of methanol, ethanol, n-propanol, and isopropanol.

[0040] In some embodiments, the purification method is selected from one or more of pulping, column chromatography, recrystallization, and distillation.

[0041] The present invention will be further described below through examples and other means.

[0042] Example 1

[0043] A method for synthesizing 7-aminoisoquinoline includes the following steps:

[0044] (1) Compound 1, namely 7-bromoisoquinoline (500.00 g, 2.40 mol, 1.00 eq), was dissolved in dimethyl sulfoxide (8.0 L), and then dihydroxy-bis(tetramethylethylenediamine)copper chloride (111.61 g, 240.32 mmol, 0.10 eq) and ammonia monohydrate (28.00% in water, 3.01 kg, 24.03 mol, 10.00 eq) were added. The mixture was stirred in an autoclave at 130 °C for 12 hours.

[0045] (2) After the reaction is complete, the reaction solution is poured into ice water (10.0L), stirred and filtered. The filter cake is washed three times with water (1.0L×3) and the solid is collected. The solid is added to methanol (5.0L), heated to 50℃ and stirred for 30 minutes, filtered and the filtrate is collected. The filtrate is evaporated to dryness, and ethyl acetate (1.0L) is added and purified to obtain target compound 2, namely 7-aminoisoquinoline (weight 339.10g, purity 98%, yield 96%).

[0046] The 1H NMR spectrum of the obtained compound 2 (7-aminoisoquinoline) is as follows: Figure 1 As shown, the characterization data is as follows:

[0047] 1 H NMR (400MHz, DMSO) δ8.91(s,1H),8.11(d,J=5.0Hz,1H),7.64(d,J=8.8Hz,1H),7.5 2(d,J=5.5Hz,1H),7.18(dd,J=8.7,2.1Hz,1H),6.93(d,J=1.6Hz,1H),5.70(s,2H).

[0048] Example 2-3

[0049] The synthesis methods of Examples 2-3 are basically the same as those of Example 1. The difference is that in step (1) of Examples 2-3, the molar amounts of copper dihydroxy-bis(tetramethylethylenediamine) chloride are 120.16 mmol and 1.92 mol, respectively. The rest remains unchanged. The yield of 7-aminoisoquinoline in Examples 2-3 is shown in Table 1.

[0050] Examples 4-5

[0051] The synthesis methods of Examples 4-5 are basically the same as those of Example 1. The difference is that in step (1) of Examples 4-5, the molar amount of ammonia monohydrate is 12.02 mol and 48.06 mol respectively. The rest remains unchanged. The yield of 7-aminoisoquinoline in Examples 4-5 is shown in Table 1.

[0052] Examples 6-7

[0053] The synthesis methods of Examples 6-7 are basically the same as those of Example 1. The difference is that in step (1) of Examples 6-7, N,N-dimethylformamide and acetonitrile are used to replace dimethyl sulfoxide in Example 1, respectively. The rest remains unchanged. The yield of 7-aminoisoquinoline in Examples 6-7 is shown in Table 1.

[0054] Examples 8-9

[0055] The synthesis methods of Examples 8-9 are basically the same as those of Example 1. The difference is that in step (1) of Examples 8-9, the stirring reaction temperatures are 90℃ and 150℃ respectively, and the rest remains unchanged. The yields of 7-aminoisoquinoline in Examples 8-9 are shown in Table 1.

[0056] Examples 10-11

[0057] The synthesis methods of Examples 10-11 are basically the same as those of Example 1, except that the stirring reaction time in step (1) of Examples 10-11 is 8h and 20h respectively. The rest of the contents remain unchanged. The yield of 7-aminoisoquinoline in Examples 10-11 is shown in Table 1.

[0058] Table 1 Synthesis conditions and 7-aminoisoquinoline yield results for each example.

[0059]

[0060] As shown in Table 1, comparing Examples 1-3, the yields of the target compound 7-aminoisoquinoline were consistently high when the molar ratio of compound 1 to dihydroxy-bis(tetramethylethylenediamine)copper chloride was 1.0:0.05–0.8. Specifically, the product yields were essentially equivalent when the molar ratios of compound 1 to dihydroxy-bis(tetramethylethylenediamine)copper chloride were 1.0:0.1 and 1.0:0.8. The results from Examples 1 and 4-5 indicate that the yields of the target compound 7-aminoisoquinoline were consistently high when the molar ratio of compound 1 to ammonia monohydrate was 1.0:5.0–20.0. Specifically, the product yields were essentially equivalent when the molar ratios of compound 1 to ammonia monohydrate were 1.0:10.0 and 1.0:20.0. In Examples 1 and 6-7, dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile were used as solvents for the reaction, respectively. All reactions proceeded smoothly, and the yields of the target compound 7-aminoisoquinoline were high. The reaction with dimethyl sulfoxide as the solvent yielded the highest result. The results from Examples 1 and 8-9 show that the reaction was optimally performed at 130°C. The results from Examples 1 and 10-11 show that the reaction was optimally performed after 12 hours.

[0061] The present invention also investigated the effect of different raw materials on the reaction, as detailed in Comparative Examples 1-4.

[0062] Comparative Example 1

[0063] The experiment was essentially the same as in Example 1, except that the copper catalyst was changed. In this comparative example, copper dihydroxy-bis(tetramethylethylenediamine)amine chloride was replaced with copper tris(triphenylphosphine)bromide (Cu(PPh3)3Br), 223.57 g, 240.32 mmol, 0.10 eq. The purified product weighed 241.00 g, with a yield of 68% and a purity of 98%.

[0064] Comparative Example 2

[0065] The experiment was essentially the same as in Example 1, except that the copper catalyst was changed. In this comparative example, copper dihydroxy-bis(tetramethylethylenediamine)amine chloride was replaced with cuprous oxide (Cu₂O), 34.39 g, 240.32 mmol, 0.10 eq. The purified product weighed 201.00 g, with a yield of 57% and a purity of 98%.

[0066] Comparative Example 3

[0067] The process is essentially the same as in Example 1, except that the ammonia source has been changed. In this comparative example, the ammonia monohydrate solution has been modified to be a mixture of ammonium chloride (NH4Cl) and potassium phosphate (K3PO4), with a molar ratio of NH4Cl to K3PO4 of 10:3. The ammonia source solution is obtained by adding 1.29 kg of ammonium chloride (NH4Cl) and 1.70 kg of potassium phosphate (K3PO4) to 1.5 L of water. In this case, some heterocyclic compounds will decompose during the synthesis process.

[0068] Comparative Example 4

[0069] The process is essentially the same as in Example 1, except that the ammonia source has been changed. In this comparative example, the ammonia monohydrate solution has been modified to be a mixture of ammonium acetate (NH4OAc) and K3PO4, with a mass ratio of NH4OAc to K3PO4 of 10:3. The ammonia source solution is obtained by adding 1.85 kg of ammonium acetate (NH4OAc) and 1.70 kg of K3PO4 to 2.0 L of water. In this case, partial heterocyclic decomposition will also occur during the synthesis process.

[0070] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 7-aminoisoquinoline, characterized in that, Includes the following steps: 7-Bromoisoquinoline was dissolved in organic solvent I, and then copper catalyst and ammonia source solution were added sequentially. The reaction was stirred to obtain a reaction solution. The reaction solution was post-treated to obtain 7-aminoisoquinoline; The ammonia source solution is an aqueous solution of ammonia monohydrate.

2. The synthesis method according to claim 1, characterized in that, The organic solvent I is selected from at least one of dimethyl sulfoxide, acetonitrile, N,N-dimethylacetamide, and N,N-dimethylformamide.

3. The synthesis method according to claim 1, characterized in that, The mass-to-volume ratio (g / mL) of the 7-bromoisoquinoline to the organic solvent I is 1:5 to 40.

4. The synthesis method according to claim 1, characterized in that, The copper catalyst is copper dihydroxy-bis(tetramethylethylenediamine) chloride; The molar ratio of 7-bromoisoquinoline to copper chloride dihydroxy-bis(tetramethylethylenediamine) is 1.0:0.05-1.

0.

5. The synthesis method according to claim 1, characterized in that, The mass percentage concentration of the ammonia monohydrate aqueous solution is 25-28%.

6. The synthesis method according to claim 1, characterized in that, The molar ratio of 7-bromoisoquinoline to the ammonia monohydrate is 1.0:5.0 to 20.

0.

7. The synthesis method according to claim 1, characterized in that, The stirring reaction is carried out at a temperature of 80–200°C for a duration of 8–25 hours.

8. The synthesis method according to claim 1, characterized in that, The specific post-processing procedure is as follows: the reaction solution is poured into ice water, stirred and filtered, the filter cake is washed and added to organic solvent II, heated and stirred, filtered, the filtrate is collected and evaporated to dryness to obtain crude product, and the crude product is purified to obtain 7-aminoisoquinoline.

9. The synthesis method according to claim 8, characterized in that, The heating and stirring refers to heating to 40-60℃ and then stirring for 20-40 minutes. The organic solvent II is selected from at least one of methanol, ethanol, n-propanol, and isopropanol.

10. The synthesis method according to claim 8, characterized in that, The purification method is selected from one or more of pulping, column chromatography, recrystallization, and distillation.

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