Preparation method of amido-containing 3, 4-dihydroisoquinoline-1 (2H)-ketone derivative

Abstract

The invention provides a preparation method of an acylamino-containing 3, 4-dihydroisoquinoline-1 (2H)-ketone derivative, and belongs to the technical field of heterocyclic compounds. The preparation method comprises the following steps: adding a palladium catalyst, a ligand, alkali, 1, 3, 5-triformic acid phenol ester, a propargylamine derivative and amine into an organic solvent, reacting at 90-110 DEG C for 22-26 hours, and performing post-treatment to obtain the amido-containing 3, 4-dihydroisoquinoline-1 (2H)-ketone derivative. The preparation method is simple and convenient to operate, the initial raw materials are cheap and easy to obtain, the reaction efficiency is high, the substrate compatibility is good, and the amido-containing 3, 4-dihydroisoquinoline-1 (2H)-ketone derivative can be efficiently and rapidly synthesized in one step.

Description

Technical Field

[0001] The present application relates to a method for preparing an amide-containing 3,4-dihydroisoquinoline-1(2H)-one derivative, belonging to the technical field of heterocyclic compounds. Background Art

[0002] 3,4-Dihydroisoquinolin-1(2H)-one derivatives are an important structural skeleton that is widely present in natural products and drug molecules and has multiple biological activities (Chemistry Select. 2020, 5, 8157-8184). For example, Palonosetron is a selective 5-hydroxytryptamine 3 receptor (5-HT3) antagonist, mainly used to prevent acute and delayed vomiting caused by moderate or severe emetogenic chemotherapy. Compound A is a GSK-3 inhibitor. Compound B is an inhibitor of thromboembolic disease.

[0003]

[0004] Carbonylation reaction provides an important method for the direct and efficient synthesis of carbonyl compounds (Chem. Rev. 2019, 119, 2090-2127). However, there are few reports on the synthesis of 3,4-dihydroisoquinolin-1(2H)-one derivatives based on carbonylation reaction, and it is not widely used at present, but it has great application potential and needs to be further studied. Summary of the invention

[0005] In view of this, the present application provides a method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative. The preparation steps are simple, and the obtained product, an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative, can be compatible with multiple functional groups at the same time, has good reaction substrate compatibility, and has good applicability.

[0006] Specifically, the present application is implemented through the following scheme:

[0007] A method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative, characterized in that: a palladium catalyst, a ligand, a base, 1,3,5-tricarboxylic acid phenol ester, a propargylamine derivative and an amine are added to an organic solvent, reacted at 90-110° C. for 22-26 hours, and after ensuring that the reaction is complete, post-processing is performed to obtain an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative.

[0008] The structural formula of the propargylamine derivative is:

[0009]

[0010] The structural formula of the amine is:

[0011] R-NH2

[0012] The structural formula of the amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative is:

[0013]

[0014] R is a substituent selected from C1-C6 alkyl, substituted phenyl or unsubstituted phenyl, wherein the corresponding substituent on the substituted phenyl is selected from C1-C6 alkyl, C1-C6 alkoxy or halogen.

[0015] The reaction equation of the above process is as follows:

[0016]

[0017] The above scheme uses propargylamine derivatives, amines and 1,3,5-tricarboxylic acid phenol ester (TFBen) as starting materials. The in situ generated palladium (0) catalyst oxidatively adds the carbon-iodine bond in the propargylamine derivative to form an aryl palladium (II) intermediate. Subsequently, intramolecular cyclization generates an alkenyl palladium (II) intermediate. Then, the CO gas released by TFBen coordinates with the alkenyl palladium (II) intermediate and migrates to insert to form an acyl palladium (II) intermediate. Finally, the amine nucleophilically attacks the acyl palladium (II) intermediate, and a reductive elimination is performed to obtain an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative.

[0018] Further, as a preference:

[0019] The molar ratio of propargylamine derivative, amine, palladium catalyst, ligand, base and 1,3,5-tricarboxylic acid phenol ester is 1.0:2.0:0.1:0.2:2.0:5.0. In the process of material preparation, the amount of organic solvent used is sufficient to dissolve the raw materials well. Therefore, the amount of organic solvent used corresponding to 0.2 mmol of propargylamine derivative is preferably controlled to be around 2.0 mL.

[0020] The organic solvent is dioxane, and at this time, various raw materials can be converted into products with a higher conversion rate.

[0021] The palladium catalyst is palladium acetate, which has a higher reaction efficiency among many palladium catalysts.

[0022] The ligand is triphenylphosphine.

[0023] When palladium acetate is selected as the palladium catalyst and triphenylphosphine is selected as the ligand, the molar ratio of palladium acetate to triphenylphosphine is 0.1:0.2.

[0024] The base is potassium carbonate.

[0025] The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally the corresponding amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative is obtained by column chromatography purification. The column chromatography purification parameters can be set conventionally.

[0026] The amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative is any one of the following structural formulas:

[0027]

[0028] In the above preparation method, amine, 1,3,5-tricarboxylic acid phenol ester, palladium acetate, triphenylphosphine and potassium carbonate are generally commercially available products and can be easily obtained from the market. The propargylamine derivative can be quickly synthesized from corresponding propargylamine, benzyl bromide, o-iodobenzoic acid and other raw materials.

[0029] Compared with the prior art, the beneficial effects of the present invention are embodied in that: the preparation method is easy to operate and the post-processing is simple; the reaction starting materials are cheap and easy to obtain, the substrate functional group tolerance range is wide, the reaction efficiency is high, and the amide-containing 3,4-dihydroisoquinoline-1(2H)-one derivative is synthesized efficiently and quickly in one step, and the practicability is strong. DETAILED DESCRIPTION

[0030] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application clearer, the technical solutions of this application will be further described in detail below in combination with the specific cases in the embodiments of this application. It should be understood that the specific embodiments described herein are only used to explain this application and are not used to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0031] According to the raw material ratio in Table 1, propargylamine derivative (II), amine, 1,3,5-tricarboxylic acid phenol ester, palladium acetate, triphenylphosphine, potassium carbonate and 2.0 mL of organic solvent were added to a 10 mL Schlenk tube, mixed and stirred evenly, and reacted at 100° C. for 24 hours, as shown in Table 1. After the reaction was complete, it was filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative (I).

[0032] The reaction equation of the above process is as follows:

[0033]

[0034] Table 1: Raw material addition amounts for different implementation schemes

[0035]

[0036]

[0037] Table 2: Comparison of the effects of different implementation plans

[0038]

[0039] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Me is the methyl group, n Pr is n-propyl, n Bu is n-butyl, i Bu is isobutyl, t Bu is tert-butyl, OMe is methoxy, Cy is cyclohexyl, Ph is phenyl, and Bn is benzyl.

[0040] At the same time, the applicant also confirmed the structure of the product prepared by the above reaction, with Examples 1 to 5 as representatives, and the test results are as follows:

[0041] The NMR of the amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative (I-1) prepared in Example 1 is ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0042]

[0043] 1 H NMR (400MHz, CDCl3) δ8.09-8.01(m,1H),7.80-7.73(m,1H),7.51-7.43(m,2H),7.28(t,J=2.1Hz,1H),7.25-7.20(m,9 H),6.06(t,J=6.0Hz,1H),4.76(s,2H),2.89-2.80(m,2H),1.15(q,J=7.3Hz,2H),1.07(s,6H),0.56(t,J=7.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ170.3,165.5,139.5,138.2,138.1,137.3,136.9,131.9,129.0,128.8,128.73,128.66,1 28.6,128.2,127.9,127.8,127.6,127.3,127.1,62.2,45.3,41.6,29.0,22.0,11.3; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 29 H 31 N2O2+ :439.2830; found:439.2836.

[0044] The NMR of the amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative (I-2) prepared in Example 2 is ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0045]

[0046] 1 H NMR (400MHz, CDCl3) δ8.11-8.07(m,1H),7.78-7.73(m,1H),7.51-7.45(m,2H),7.29(d,J=7.0Hz,1H),7.25-7.21(m,9H),5.77(t ,J=6.1Hz,1H),4.81(s,2H),2.92(q,J=6.8Hz,2H),1.16-1.11(m,2H),1.08(s,6H),0.95(q,J=7.5Hz,2H),0.74(t,J=7.2Hz,3H); 13 C NMR (100MHz, CDCl3) δ170.2,165.5,139.6,138.09,138.06,137.2,132.0,129.0,128.9,128.7,128.6,128 .2,128.0,127.9,127.6,127.3,127.1,62.2,45.3,39.7,30.8,28.9,20.0,13.8; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 30 H 33 N2O2 + :453.2537; found:453.2532.

[0047] Example 3 The NMR ( 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0048]

[0049] 1H NMR (400MHz, CDCl3) δ8.64(s,1H),7.80(d,J=7.8Hz,1H),7.72(d,J=7.7Hz,1H),7.40(t,J=7.6Hz,1H),7.28(d,J=4 .7Hz,6H),7.24-7.19(m,2H),7.13(q,J=7.7Hz,5H),6.99(d,J=8.2Hz,2H),4.95(s,2H),2.24(s,3H),1.13(s,6H); 13 C NMR (100MHz, CDCl3) δ168.3,165.4,156.6,139.2,138.1,137.7,137.3,137.2,131.9,131.2,128.9,128.8,128.70,1 28.67,128.2,127.9,127.8,127.44,127.40,127.3,122.5,113.9,62.2,55.5,45.5,29.2; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 33 H 31 N2O2 + :487.2380; found:487.2376.

[0050] The NMR of the amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative (I-4) prepared in Example 4 is ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0051]

[0052] 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),7.81(d,J=7.5Hz,1H),7.76(d,J=7.6Hz,1H),7.42(t,J=7.0Hz,1H),7.34(t,J =7.5Hz,1H),7.27(d,5H),7.26-7.23(m,3H),7.20-7.15(m,4H),6.87(t,J=8.7Hz,2H),4.92(s,2H),1.13(s,6H); 13C NMR (100MHz, CDCl3) δ168.4, 165.4, 159.7 (d, J = 244.1Hz), 139.2, 137.8, 137.5, 137.1, 133.9, 132.1, 129.0, 128.9, 128.8, 128.7, 128.4, 128.1 (d, J = 4.1Hz), 127.42, 127.36, 122.6 (d, J = 7.9Hz), 115.5 (d, J = 22.5Hz), 62.3, 45.5, 29.1; HRMS (ESI-TOF) m / z: [M+H] + Calcd.for C 32 H 28 FN2O2 + :491.2129; found:491.2132.

[0053] The NMR of the amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative (I-5) prepared in Example 5 is ( 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0054]

[0055] 1 H NMR (400MHz, CDCl3) δ7.92(d,J=7.5Hz,1H),7.70(d,J=7.5Hz,1H),7.44-7.30(m,2H),7.25-7.20(m,10H),7.1 9-7.14(m,3H),6.85(d,J=7.2Hz,2H),6.33(t,J=6.1Hz,1H),4.81(s,2H),4.13(d,J=5.7Hz,2H),1.07(s,6H); 13 C NMR (100MHz, CDCl3) δ170.1,165.4,139.5,138.0,137.6,137.5,137.3,137.0,132.0,128.8,128.7,12 8.6,128.2,128.01,127.96,127.43,127.36,127.1,62.2,45.3,44.0,28.9; HRMS(ESI-TOF)m / z:[M+H] + Calcd.for C 33 H 31 N2O2 + :487.2380; found:487.2386.

Claims

1. A method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative, characterized in that: A palladium catalyst, a ligand, a base, 1,3,5-tricarboxylic acid phenol ester, a propargylamine derivative and an amine are added to an organic solvent, reacted at 90 to 110° C. for 22 to 26 hours, and then post-treated to obtain an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative. The structural formula of the propargylamine derivative is: The structural formula of the amine is: R-NH2 The structural formula of the amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative is: R is a substituent selected from C1-C6 alkyl, substituted phenyl or unsubstituted phenyl, wherein the corresponding substituent on the substituted phenyl is selected from C1-C6 alkyl, C1-C6 alkoxy or halogen.

2. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to claim 1, characterized in that: The molar ratio of the propargylamine derivative, the amine, the palladium catalyst, the ligand, the base, and 1,3,5-tricarboxylic acid phenol ester is 1.0:2.0:0.1:0.2:2.0:5.

0.

3. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to claim 1, characterized in that: The organic solvent is dioxane.

4. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to claim 1, characterized in that: The palladium catalyst is palladium acetate.

5. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to claim 1, characterized in that: The ligand is triphenylphosphine.

6. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to claim 1, characterized in that: The base is potassium carbonate.

7. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to claim 1, characterized in that: The post-treatment process is as follows: the reaction product is filtered, the sample is mixed with silica gel, and finally purified by column chromatography to obtain the corresponding amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative.

8. The method for preparing an amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative according to any one of claims 1 to 7, characterized in that: The amide-containing 3,4-dihydroisoquinolin-1(2H)-one derivative is any one of the following structural formulas:

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