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Preparation method of key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of 5-ht4 receptor agonist

A technology of hydroxybenzoic acid and amino, which is applied in organic chemistry, bulk chemical production, etc., can solve problems such as difficult purification, complicated operation, and low yield of synthesis process, so as to improve market competitiveness, optimize preparation process, and process heavy good effect

Active Publication Date: 2021-08-06
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The process is complicated to operate, the raw material is expensive, there are more reaction sites, and more by-products are generated. When repeated in the gram scale of the laboratory, the external standard yield is only 24%. When the kilogram scale is scaled up, the external standard yield Only 22%
On the whole, the yield of the existing synthesis process is low, it is difficult to purify, and the economic benefits are not good

Method used

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  • Preparation method of key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of 5-ht4 receptor agonist
  • Preparation method of key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of 5-ht4 receptor agonist
  • Preparation method of key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of 5-ht4 receptor agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The first step: the synthesis of 4-amino-3,5-dibromo-2-hydroxybenzoic acid

[0038] Dissolve p-amino-o-hydroxybenzoic acid (146.3g, 0.956mol, 1.0eq) in dichloroethane (4.0L), add NBS (373.8g, 2.1mol, 2.2eq) under stirring, and heat to 80-85 ℃, after 4 hours, the central control, HPLC showed that the raw material was completely consumed, the temperature was lowered to below 35 ℃, and the solvent was evaporated under reduced pressure. Pour the system into 2.0L ice water, stir vigorously for half an hour, filter, wash twice with water to obtain the crude product, beat the crude product with ethanol twice, drain, and recrystallize the filter cake with ethyl acetate to obtain 4-amino-3,5-dibromo - 274.5 g of 2-hydroxybenzoic acid, purity 99%, yield: 93.0%. m / z=311.7[MH] detected by mass spectrometry + , and the solid was determined to be 4-amino-3,5-dibromo-2-hydroxybenzoic acid.

[0039] The second step: Synthesis of 2-trimethylsilyl-4-amino-5-bromobenzofuran-7-carboxyli...

Embodiment 2

[0045] Step 1: Synthesis of 4-amino-3,5-dichloro-2-hydroxybenzoic acid

[0046] Dissolve p-amino-o-hydroxybenzoic acid (146.3g, 0.956mol, 1eq) in dioxane (4.0L), add NCS (333.8g, 2.5mol, 2.6eq) under stirring, and heat to 80-85°C , after 4 hours of central control, HPLC showed that the raw materials were completely consumed, the temperature was lowered to below 35°C, and the solvent was evaporated under reduced pressure. The system was poured into 2.0L ice water, stirred vigorously for half an hour, filtered, washed twice with water to obtain the crude product, the crude product was beaten with ethanol twice, drained, and the filter cake was recrystallized with ethyl acetate to obtain 4-amino-3,5-dichloro -2-Hydroxybenzoic acid 198.5g, purity 99%, yield: 94%. Mass spectrometry m / z=222.2[MH] + , and the solid was determined to be 4-amino-3,5-dichloro-2-hydroxybenzoic acid.

[0047] The second step: the synthesis of 2-triethylsilyl-4-amino-5-chlorobenzofuran-7-carboxylic acid...

Embodiment 3

[0053] The first step: the synthesis of methyl 4-acetamido-3,5-dichloro-2-hydroxybenzoate

[0054] Dissolve methyl p-acetamido-o-hydroxybenzoate (200g, 0.956mol, 1.0eq) in acetonitrile (4.0L), add dichlorohydantoin (376.3g, 1.91mol, 2.0eq) under stirring, and heat to 80 -85°C, central control after 4 hours, HPLC showed that the raw materials were completely consumed, the temperature was lowered to below 35°C, and the solvent was evaporated under reduced pressure. The system was poured into 2.0L ice water, stirred vigorously for half an hour, filtered, washed twice with water to obtain the crude product, the crude product was beaten twice with ethanol, drained, and the filter cake was recrystallized with ethyl acetate to obtain 4-acetylamino-3,5-di Chloro-2-hydroxybenzoic acid methyl ester 243.6g, purity 99%, yield: 92%. Mass spectrometry m / z=278.1[MH] + , identified as methyl 4-acetamido-3,5-dichloro-2-hydroxybenzoate.

[0055] The second step: Synthesis of methyl 2-trimeth...

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Abstract

The preparation method of the key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of 5-HT4 receptor agonist. The invention discloses a preparation method of 4-amino-5-halogenated benzofuran-7-carboxylic acid, which belongs to the field of organic synthesis. Using para-protected amino-o-hydroxybenzoic acid / ester, halogenated reagent, and triethylethynyl silicon as main raw materials, 4-amino-5-halogenated benzofuran-7-carboxylic acid is obtained through three-step reaction. The process is simple and easy to operate, the reaction steps are short, the intermediates are easy to separate, the total yield is more than 51%, the raw materials are cheap and easy to obtain, and the production cost is greatly reduced. The synthesis method has obvious competitive advantages.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of 4-amino-5-halobenzofuran-7-carboxylic acid. Background technique [0002] The 5-HT4 receptor is one of the seven subtypes of the 5-hydroxytryptamine receptor. Studies have found that the receptor agonist is effective in the treatment of Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, Huntington's disease , Parkinson's disease, and several other psychiatric conditions (Curr. Top. Med. Chem., 2010, 10, 527-553). At the same time, the receptor agonist improves memory in different behavioral experiments in rodents (Naunyn-Schmiedeberg`s Archives of PharmacoLogy, 2003, 367:621-628), and plays a role in regulating synaptic plasticity and determining stored synaptic information. Specific properties also play a key role (CerebralCortex, 2005, 15, 1037-1043). [0003] However, there are no drugs on the market ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/79
CPCC07D307/79Y02P20/55
Inventor 孙鹏边奕澄田贝贝李超石磊吴保平张欣李涛
Owner SHANGHAI ZAIQI BIO TECH
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