A process for the preparation of 3,3-dimethyl-6-nitro-1,3-dihydroindol-2-one

Abstract

The application discloses a preparation method of 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-ketone, relates to the technical field of medicine intermediate synthesis, and comprises the following steps: dissolving 6-amino-3,3-dimethyl-1,3-dihydroindole-2-ketone in a solvent, adding an oxidizing reagent in the presence of a catalyst, and reacting to obtain 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-ketone. The 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-ketone is prepared by one-step method, the reaction operation is simple, the yield is high, the product does not need to be purified by column chromatography, and the method is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically to a method for preparing 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one. Background Technology

[0002] 3,3-Dimethyl-6-nitro-1,3-dihydroindole-2-one (I) is an important intermediate used in the synthesis of Adibendan, a long-acting cardiotonic agent used to treat severe congestive heart failure (J. Med. Chem. 1989, 32, 1481-1491). I can also be used to synthesize AKI-001, a pentacyclic aurora kinase inhibitor, which may be used in cancer treatment research (J. Med. Chem. 2008, 51, 4465-4475). Therefore, 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one (I) has a broad market prospect.

[0003] The existing synthetic processes for 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one (I) are reported as follows:

[0004] Patent CN110950868A reports a method for preparing I from 2-cyanomethylbenzyl nitrile (II). II is methylated to give 2-(2-cyanopropane-2-yl)benzonitrile (III); III undergoes cyclization in the presence of concentrated sulfuric acid to give 4,4-dimethyl-4H-isoquinoline-1,3-dione (IV); IV reacts with fuming nitric acid in the presence of concentrated sulfuric acid to give the nitrated product 4,4-dimethyl-7-nitro-4H-isoquinoline-1,3-dione (V); V reacts with liquid bromine under alkaline conditions to give 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one (I). This process is relatively complex, involving four steps from II to I, with a reported overall yield of 10.4%. Furthermore, it requires the use of concentrated sulfuric acid as a solvent and hazardous reagents such as fuming nitric acid and liquid bromine. Therefore, this method is not suitable for large-scale preparation of I.

[0005]

[0006] Reagents and conditions: a) NaH, MeI, 18.1%; b) 90% H2SO4, 97.3%; c) HNO3, H2SO4, 98.2%; d) NaOH, Br2, 59.9%.

[0007] Therefore, it is of great significance to develop a simple, short, high-yield preparation method for 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one (I). Summary of the Invention

[0008] Therefore, the technical problem to be solved by the present invention is to overcome the problems of the complex preparation method of 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one in the prior art, the need for hazardous reagents, and the unsuitability for large-scale production. Thus, the present invention provides a rapid and efficient method for preparing 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one, which prepares 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one in one step. The reaction operation is simple, the yield is high, the product does not require column chromatography purification, and it is suitable for large-scale production.

[0009] Therefore, the present invention provides a method for preparing 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one, comprising the following steps:

[0010] 6-Amino-3,3-dimethyl-1,3-dihydroindole-2-one was dissolved in a solvent, and an oxidizing agent was added in the presence of a catalyst to react and give 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one.

[0011] The reaction process is as follows:

[0012]

[0013] Preferably, the catalyst is methylrhenium trioxide (MTO).

[0014] Preferably, the molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindol-2-one and methylrhenium trioxide is 1.0:0.01 to 1.0:0.50.

[0015] Preferably, the molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindole-2-one and methylrhenium trioxide is 1.0:0.05 to 1.0:0.10.

[0016] Preferably, the oxidant is hydrogen peroxide (H2O2).

[0017] Preferably, the molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindole-2-one to the oxidant is 1.0:1.0 to 1.0:50.0.

[0018] Preferably, the molar ratio of the 6-amino-3,3-dimethyl-1,3-dihydroindole-2-one to the oxidant is 1.0:8.0 to 1.0:10.0.

[0019] Preferably, the solvent is at least one of trifluoroacetic acid or acetic acid.

[0020] Preferably, the reaction temperature is -78℃ to 150℃.

[0021] Preferably, the reaction temperature is 60℃~100℃.

[0022] The technical solution of this invention has the following advantages:

[0023] This invention provides a method for preparing 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one. The raw material 6-amino-3,3-dimethyl-1,3-dihydroindole-2-one is widely available, and 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one can be obtained rapidly and efficiently in just one step. The preparation method of this invention is simple to operate, has a high yield, and the product does not require column chromatography purification, making it suitable for large-scale production. Attached Figure Description

[0024] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0025] Figure 1 This is the hydrogen spectrum of 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one obtained in Example 1 of this invention. Detailed Implementation

[0026] The following embodiments are provided to better understand the present invention and are not limited to the preferred embodiments described. They do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the protection scope of the present invention.

[0027] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0028] Example 1

[0029]

[0030] 6-Amino-3,3-dimethylindol-2-one (VI) (50.00 g, 0.284 mol, 1.0 equiv.) was added to trifluoroacetic acid (TFA, 500 mL), followed by the sequential addition of methylrhenium trioxide (MTO, 7.08 g, 0.028 mol, 0.10 equiv.) and hydrogen peroxide (30% H2O2, 170 g, 1.42 mol, 5.0 equiv). The mixture was heated to 70 °C and reacted for 10 hours. Hydrogen peroxide (30% H2O2, 170 g, 1.42 mol, 5.0 equiv) was then added, and the reaction continued for another 24 hours. The reaction mixture was cooled to room temperature and poured into 6 liters of ice water. The mixture was filtered, and the filter cake was washed three times with water and dried to obtain 42.30 g of a light brown solid, 3,3-dimethyl-6-nitro-1,3-dihydroindol-2-one, with a yield of 72.3%.

[0031] The proton NMR spectrum of the obtained 3,3-dimethyl-6-nitro-1,3-dihydroindole-2-one is shown below. Figure 1 As shown.

[0032] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 10.75 (s, 1H), 7.90 (dd, J = 8.12, 2.16Hz, 1H), 7.59 (m,, 2H), 1.31 (s, 6H).

[0033] Example 2

[0034] 6-Amino-3,3-dimethylindol-2-one (VI) (10.00 g, 0.057 mol, 1.0 equiv.) was added to trifluoroacetic acid (TFA, 60 mL), followed by the addition of methylrhenium trioxide (MTO, 0.71 g, 2.85 mmol, 0.05 equiv.) and hydrogen peroxide (30% H₂O₂, 68 g, 0.57 mol, 10.0 equiv.). The mixture was heated to 60 °C and reacted for 48 hours. The reaction mixture was cooled to room temperature and poured into 600 mL of ice water. The mixture was filtered, and the filter cake was washed three times with water and dried to obtain 7.43 g of a light brown solid, 3,3-dimethyl-6-nitro-1,3-dihydroindol-2-one, with a yield of 63.5%.

[0035] Example 3

[0036] 6-Amino-3,3-dimethylindol-2-one (VI) (10.00 g, 0.057 mol, 1.0 equiv.) was added to acetic acid (AcOH, 80 mL), followed by the sequential addition of methylrhenium trioxide (MTO, 1.15 g, 4.56 mmol, 0.08 equiv.) and hydrogen peroxide (30% H₂O₂, 55 g, 0.46 mol, 8.0 equiv.). The mixture was heated to 100 °C and reacted for 10 hours. The reaction mixture was cooled to room temperature and poured into 800 mL of ice water. The mixture was filtered, and the filter cake was washed three times with water and dried to obtain 6.28 g of a light brown solid, 3,3-dimethyl-6-nitro-1,3-dihydroindol-2-one, with a yield of 53.4%.

[0037] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A process for the preparation of 3,3-dimethyl-6-nitro-l,3-dihydroindol-2-one, characterized in that, The method comprises the following steps: 6-amino-3,3-dimethyl-1,3-dihydroindol-2-one is dissolved in a solvent, and an oxidant is added in the presence of a catalyst to obtain 3,3-dimethyl-6-nitro-1,3-dihydroindol-2-one; The reaction process is: ； The catalyst is methyltrioxorhenium; The oxidant is hydrogen peroxide; The solvent is at least one of trifluoroacetic acid or acetic acid; The reaction temperature is -78℃ ~ 150℃.

2. A 3,3-dimethyl-6-nitro-l,3-dihydroindol-2-one according to claim 1, characterized in that, The molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindol-2-one to methyltrioxorhenium is 1.0:0.01~1.0:0.

50.

3. A 3,3-dimethyl-6-nitro-l,3-dihydroindol-2-one according to claim 2, characterized in that, The molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindol-2-one to methyltrioxorhenium is 1.0:0.05~1.0:0.

10.

4. A process for the preparation of 3,3-dimethyl-6-nitro-l,3-dihydroindol-2-one according to claim 1, characterized in that, The molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindol-2-one to the oxidant is 1.0:1.0~1.0:50.

0.

5. A process for the preparation of 3,3-dimethyl-6-nitro-l,3-dihydroindol-2-one according to claim 4, characterized in that, The molar ratio of 6-amino-3,3-dimethyl-1,3-dihydroindol-2-one to the oxidant is 1.0:8.0~1.0:10.

0.

6. A process for the preparation of 3,3-dimethyl-6-nitro-l,3-dihydroindol-2-one according to claim 1, characterized in that, The reaction temperature is 60℃~ 100℃.

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