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Synthesis method of methyl 4-formyl-3-hydroxybenzoate

A technology for the synthesis of methyl hydroxybenzoate and its method, which is applied in the field of synthesis of methyl 4-formyl-3-hydroxybenzoate, and can solve the problems of difficult scale-up production of compounds, high cost of raw materials and catalysts, expensive palladium catalysts, etc. , to achieve the effect of good application prospects, good economic benefits, and simple routes

Inactive Publication Date: 2019-11-05
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although this route improves route 1 and solves the problem of selectivity, it has the following disadvantages: 1) the cost of raw materials is high; 2) it needs to use expensive palladium catalyst; 3) the reaction of the second step needs to use Ozone, requiring specialized equipment and instrumentation
[0010] It can be seen that the synthesis method of methyl 4-formyl-3-hydroxybenzoate in the prior art, due to the high cost of raw materials and catalysts, purification methods and other reasons make this compound difficult to scale up production

Method used

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  • Synthesis method of methyl 4-formyl-3-hydroxybenzoate
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  • Synthesis method of methyl 4-formyl-3-hydroxybenzoate

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Experimental program
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Effect test

Embodiment 1

[0040]

[0041] Under the protection of an inert gas, compound 1 (methyl 3-hydroxybenzoate) (300g, 1.97mol, 1eq) was added to acetonitrile (4.5L), and when the temperature was lowered to 0°C, slowly added in batches at this temperature 3 equivalents of anhydrous magnesium chloride (564g, 5.92mol, 3eq); after completion, continue to add triethylamine (995g, 9.85mol, 5eq) in batches to the reaction solution at this temperature; Paraformaldehyde (354g, 11.8mol, 6eq) was added in batches to the reaction solution, and after the addition was completed, the temperature was raised to 80°C, and the reaction was completed for 12 hours to obtain a reaction solution.

[0042] The reaction solution was lowered to room temperature, ethyl acetate (3 L) was added, and stirred for 0.5 hours. The reaction solution was poured into 3M aqueous hydrochloric acid (4 L), and the layers were separated. After layering, extract twice with ethyl acetate (1L*2), combine the organic phases, wash with w...

Embodiment 2

[0044] Under the protection of an inert gas, compound 1 (methyl 3-hydroxybenzoate) (152.0g, 1.0mol, 1eq) was added to acetonitrile (2.5L), and when the temperature was lowered to 0°C, slowly batchwise Add 3 equivalents of anhydrous zinc chloride (408.9g, 3.0mol, 3eq); after completion, continue to add triethylamine (506g, 5.0mol, 5eq) in batches to the reaction solution at this temperature; At this temperature, paraformaldehyde (180 g, 6.0 mol, 6 eq) was added in batches to the reaction solution. After the addition, the temperature was raised to 80° C., and the reaction was completed for 12 hours to obtain a reaction solution.

[0045] The reaction solution was lowered to room temperature, ethyl acetate (1.5 L) was added, and stirred for 0.5 hours. The reaction solution was poured into 3M aqueous hydrochloric acid (2L), and the layers were separated. After layering, extract twice with ethyl acetate (1L*2), combine the organic phases, wash with water, spin dry, beat with EA, a...

Embodiment 3

[0047] Under the protection of an inert gas, compound 1 (methyl 3-hydroxybenzoate) (152.0g, 1.0mol, 1eq) was added to acetonitrile (2.5L), and when the temperature was lowered to 0°C, slowly batchwise Add 3 equivalents of anhydrous magnesium chloride (285.6g, 3.0mol, 3eq); After completion, add paraformaldehyde (180g, 6.0mol, 6eq) in batches to the reaction solution at this temperature, raise the temperature to 80°C after the addition, and react for 12 hours to complete to obtain the reaction solution.

[0048] The reaction solution was lowered to room temperature, ethyl acetate (1.5 L) was added, and stirred for 0.5 hours. The reaction solution was poured into 3M aqueous hydrochloric acid (2L), and the layers were separated. After layering, extract twice with ethyl acetate (1L*2), combine the organic phases, wash with water, spin dry, beat with EA, and filter to obtain 135g of the product (yield: 75%, purity 97%).

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Abstract

The invention discloses a synthesis method of methyl 4-formyl-3-hydroxybenzoate. The method includes the following step that methyl 3-hydroxybenzoate as a raw materials reacts with paraformaldehyde under the action of Lewis acid and an organic base to obtain the methyl 4-formyl-3-hydroxybenzoate. The method solves the problems of poor selectivity, expensive raw materials, complex steps and harsh reaction conditions in the prior art and has the advantages that raw materials for reaction are cheap, conditions are mild, purification is simple, the product purity is high and the method is more suitable for scale-up production.

Description

technical field [0001] The invention relates to the technical field of synthesis of organic chemical intermediates, in particular to a method for synthesizing methyl 4-formyl-3-hydroxybenzoate. Background technique [0002] Methyl 4-formyl-3-hydroxybenzoate is an extremely important pharmaceutical intermediate with broad application prospects. The intermediate and its derivatives have been reported to be used to construct many active molecules of pharmaceutical drugs. Such as the preparation of GluN2C-selective potentiators, folate receptor-targeted indoquinoline compounds, S1P 1 Receptor Antagonist, Phosphodiesterase 4 Inhibitor, PI3K Inhibitor, Mammalian Histone Deacetylase Inhibitor, JAD Inhibitor, Protease-Activated Receptor 4 (PAR4) Inhibitor, Muscarinic Receptor Antagonist , NK2 receptor antagonists, renin inhibitors, etc. [0003] At present, regarding the synthetic route of methyl 4-formyl-3-hydroxybenzoate, the following synthetic routes are generally adopted in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/343C07C67/58C07C69/84
CPCC07C67/343C07C67/58C07C69/84
Inventor 米涛冉涂强
Owner 上海毕得医药科技股份有限公司
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