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Synthesizing method of key intermediate for synthesizing lactate dehydrogenase A (LDHA) inhibitor

A lactate dehydrogenase and inhibitor technology, which is applied in the field of synthesis of 6,6-aromatic ring-substituted-2,4-piperidinedione, can solve the problem of being unsuitable for industrial scale-up production, low atom economy and difficult by-products. Separation and other problems, to achieve the effect of atom economy, avoid low temperature reaction, good methodological significance

Active Publication Date: 2019-02-22
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In summary, the preparation of compound 10 has problems such as pyrolysis, difficult separation of by-products, complicated post-treatment, and low amplification yield, which is not suitable for industrial scale-up production.
[0008] For chiral (R)- or (S)-GNE-140, in WO2015140133A1, WO2015142903A2 and ACS Medicinal Chemistry Letters (2016), 7(10), 896-901, the racemate GNE-140 was prepared first, and then manually Single-chiral products are prepared by separation on chiral columns, but there are problems of high resolution cost, long resolution cycle, and low atom economy.

Method used

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  • Synthesizing method of key intermediate for synthesizing lactate dehydrogenase A (LDHA) inhibitor
  • Synthesizing method of key intermediate for synthesizing lactate dehydrogenase A (LDHA) inhibitor
  • Synthesizing method of key intermediate for synthesizing lactate dehydrogenase A (LDHA) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Step (1) Preparation of Compound 2

[0048]

[0049] Compound 3-bromothiophene (228g, 1.4mol) was dissolved in anhydrous tetrahydrofuran (2.3L), and isopropylmagnesium chloride (1L, 1.4mol, 1.4M tetrahydrofuran solution) was added at room temperature, and compound 1 was added after stirring for 2 hours ( 267g, 1.4mol), continue stirring at room temperature. After TLC monitors that the reaction is complete, slowly add saturated ammonium chloride solution (2L) to the reaction solution, and leave it to stand after stirring at room temperature for 20 minutes, separate the organic phase, add ethyl acetate (1L×3) to the aqueous layer for extraction, and combine The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was dispersed in ethyl acetate / petroleum ether mixed solution (200mL / 300mL) and stirred overnight, filtered and dried to obtain yellow solid compound 2 (317g, harvested Rate: 82%, 1 ...

Embodiment 2

[0069] Step (1) Preparation of Compound 2

[0070]

[0071] The compound 3-bromothiophene (366g, 2.2mol) was dissolved in anhydrous tetrahydrofuran (2.9L), and isopropylmagnesium chloride-lithium chloride (1.7L, 2.2mol, 1.3M tetrahydrofuran solution) was added at room temperature, and stirred for 1.5 hours Then compound 1 (210 g, 1.1 mol) was added, and stirring was continued at room temperature. After the completion of the reaction monitored by TLC, the compound 2 (282 g, yield: 93%) was purified as a yellow solid according to the post-treatment method of step (1) of Example 1.

[0072] Step (2) Preparation of Compound 3

[0073]

[0074] Dissolve compound 2 (83g, 0.3mol) in dichloromethane (1.2L), add manganese dioxide (35g, 0.4mol) and stir at room temperature. After TLC monitoring shows that the reaction is complete, according to Example 1 step (2) Purified by the post-processing method to obtain yellow solid compound 3 (68 g, yield: 83%).

[0075] Step (3) Prepar...

Embodiment 3

[0090] Step (1) Preparation of Compound 2

[0091]

[0092] The compound 3-bromothiophene (196g, 1.2mol) was dissolved in anhydrous tetrahydrofuran (2L), and isopropylmagnesium chloride-lithium chloride (923mL, 1.2mol, 1.3M tetrahydrofuran solution) was added at room temperature, stirred for 1.5 hours and then added Compound 1 (153 g, 800 mmol), continued stirring at room temperature. After the completion of the reaction monitored by TLC, the compound 2 (198 g, yield: 90%) was purified as a yellow solid according to the post-treatment method of step (1) of Example 1.

[0093] Step (2) Preparation of Compound 3

[0094]

[0095] Dissolve compound 2 (110g, 0.4mol) in dichloromethane (1.5L), add PCC (112g, 0.5mol) and stir at room temperature. After TLC monitoring shows that the reaction is complete, according to the step (2) of Example 1, The work-up method was purified to obtain compound 3 (85 g, yield: 78%) as a yellow solid.

[0096] Step (3) Preparation of compound ...

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Abstract

The invention relates to a synthesizing method of a key intermediate compound X for synthesizing a lactate dehydrogenase A (LDHA) inhibitor. According to the synthesizing method, a compound IX is prepared through the steps such as addition, oxidization, replacing and acidolysis by adopting a compound I as a raw material; and a the compound X is prepared by the compound IX through a enzyme ring closing, and through the method, the compound X with the single configuration can be prepared, wherein the ee value of the compound X is higher than 99%. A reaction is easy to operate, simple easy and convenient in subsequentto after-treatment, high in total yield, environmentally friendly, low in cost and suitable for industrial production. (Pplease see the specifications for the chemical structuralformulas).

Description

technical field [0001] The present invention relates to a method for synthesizing key intermediates of lactate dehydrogenase A (LDHA) inhibitors, more specifically a synthesis of 6,6-aromatic ring substituted-2,4-piperidinedione Method, the invention belongs to the field of organic synthesis. Background technique [0002] Different from normal cells, most cancer cells mainly rely on glycolysis rather than mitochondrial oxidative phosphorylation to synthesize ATP. Among them, LDHA is an important metabolic enzyme in glycolysis metabolism, which catalyzes the conversion of pyruvate to lactic acid and promotes NADH + to NAD + Transformation, so that pyruvate can not participate in the tricarboxylic acid cycle and oxidative phosphorylation process. LDHA is expressed in a variety of tumors, and the higher the expression level, the lower the patient's survival rate. In a variety of mouse tumor models, knockout of the LDHA gene can inhibit tumor growth, and the inhibitory effect...

Claims

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Application Information

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IPC IPC(8): C07D409/04C07D333/20C07D333/22C07D333/24C07D409/14C07D405/04C07D417/04
CPCC07B2200/07C07D333/20C07D333/22C07D333/24C07D405/04C07D409/04C07D409/14C07D417/04
Inventor 郑保富李朝平周治国高强
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
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