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Preparation method of Plk (Polo-like kinase) inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-formic acid

A technology of kinase inhibitor and methyl nitrobenzoate, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of low total yield, complex process, cumbersome operation, etc., and achieve the goals of reducing reaction steps, high product yield and reducing cost Effect

Active Publication Date: 2014-03-26
湖南欧亚药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The synthetic route is relatively long, and the multi-step reaction needs to be purified by silica gel column chromatography, which is cumbersome and unfavorable for industrial operation. One step of Claisen rearrangement requires 190°C High temperature conditions, while the ozonation ring closure step needs to be at a low temperature of -78°C, the reaction conditions are harsh, the process is complicated, the total yield is low, and the cost is high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] A preparation method of Plk kinase inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid, comprising the following steps:

[0051] (1) Synthesis of methyl 3-hydroxy-4-nitrobenzoate

[0052]Add 3-hydroxy-4-nitrobenzoic acid (25.0g, 0.137mol) and methanol (400mL) into a 1L reaction flask, stir to dissolve, add concentrated sulfuric acid (3mL), heat and reflux for 5 hours, after the reaction is complete, drop to At room temperature, add saturated sodium bicarbonate solution dropwise to adjust to neutrality, concentrate to dryness by rotary evaporation under reduced pressure, add ethyl acetate (500mL) to dissolve, wash with saturated brine (2x300mL), dry over anhydrous sodium sulfate, filter, and decompress the filtrate Concentrate to dryness by rotary evaporation to obtain yellow solid, methyl 3-hydroxy-4-nitrobenzoate (26.8g), yield 99.6%, melting point 86~88°C;

[0053] The reaction equation is as follows:

[0054]

[0055] (2) Synthesis of met...

Embodiment 2

[0073] A preparation method of Plk kinase inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid, comprising the following steps:

[0074] (1) Synthesis of methyl 3-hydroxy-4-nitrobenzoate

[0075] Operating process and the ratio of charging capacity are with the step (1) of embodiment 1, and reaction equation is as follows:

[0076]

[0077] (2) Synthesis of 3-(2,2-dimethoxyethoxy)-4-nitrobenzoic acid methyl ester

[0078] The operation process is the same as the step (2) of Example 1, the acetal used is 2-bromoacetaldehyde dimethyl acetal, the alkali is sodium hydride, the solvent is DMA, the reaction temperature is 120 ° C, and the reaction time is 15 hours to obtain 3- (2,2-dimethoxyethoxy)-4-nitrobenzoic acid methyl ester, yield 88.5%, reaction equation is as follows:

[0079]

[0080] (3) Synthesis of methyl 7-nitrobenzofuran-4-carboxylate

[0081] Operation process is with the step (3) of embodiment 1, and the raw material that uses is 3-(2...

Embodiment 3

[0091] A preparation method of Plk kinase inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid, comprising the following steps:

[0092] (1) Synthesis of methyl 3-hydroxy-4-nitrobenzoate

[0093] Operation process and charging capacity are with the step (1) of embodiment 1, and reaction equation is as follows:

[0094]

[0095] (2) Synthesis of 3-(2-oxyethoxy)-4-nitrobenzoic acid methyl ester

[0096] The operation process is the same as step (2) of Example 1, using 2-chloroacetaldehyde aqueous solution, the alkali is potassium hydroxide, the solvent is DMF, the reaction temperature is 135 ° C, and the reaction time is 16 hours to obtain 3-(2-oxoethane Oxygen)-4-nitrobenzoic acid methyl ester, yield 83.8%, reaction equation is as follows:

[0097]

[0098] (3) Synthesis of methyl 7-nitrobenzofuran-4-carboxylate

[0099] Operation process is with the step (3) of embodiment 1, and the raw material that uses is 3-(2-oxyethoxy group)-4-nitrobenzoic ...

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PUM

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Abstract

The invention discloses a preparation method of Plk (Polo-like kinase) inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-formic acid (I), which comprises the following steps: by using 3-hydroxy-4-nitrobenzoic acid as a starting material, firstly esterifying, then condensing the starting material with 2-halogeno acetaldehyde or 2-halogeno acetal under the effect of an alkali acid-binding agent to realize alkylation of hydroxyl, then performing Friedel-Crafts reaction under the catalysis of protonic acid or Lewis acid, performing cyclization to obtain 7-nitrobenzofuran-4-methyl formate, and finally performing catalytic and hydride reduction and hydrolysis to obtain high-yield 7-amino-2,3-dihydrobenzofuran-4-formic acid (I). According to the invention, the synthetic route is simplified and optimized, the reaction processes are reduced, the technology is simplified, the cost is lowered and the production yield is high, and the 7-amino-2,3-dihydrobenzofuran-4-formic acid can be produced in large scale to meet the usage requirements, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of a Plk kinase inhibitor drug intermediate 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid. Background technique [0002] Polo-like kinase (Plk) is a class of serine / threonine protein kinases with highly conserved structure and function, and they are involved in the precise regulation of different stages of the cell cycle. There are many members of the Plks family, including Plk1, Plk2 (also known as Snk), Plk3 (also known as Fnk or Prk) and Plk4 (also known as Sak), which play a crucial role in the regulation of each phase of the cell cycle. important role. Plk1 is highly expressed in a variety of tumors, such as breast cancer, ovarian cancer, colon cancer, pancreatic cancer, lung cancer, endometrial cancer, brain tumor, skin cancer, head and neck cancer, esophageal cancer, gastric cancer, prostate cancer, etc. Expression, its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 林开朝莫国宁薛海鹏闵雄
Owner 湖南欧亚药业有限公司
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