Synthesis method for 2- methoxyl-4-amino-5-ethylsulfonylbenzoic acid

Abstract

The invention relates to a synthesis method for 2-methoxyl-4-amino-5-ethylsulfonylbenzoic acid which is an important immediate for antipsychotics Amisulpride. The method uses 2-methoxyl-4-methyl anthranilate as raw material, and carries out amino protection, sulphurization, deamination protection, chloridization, reduction, thylization, esterolysis and crystallization, and then the 2-methoxyl-4-amine-5-ethylsulfonylbenzoic acid is prepared. The method uses common reagents with easy obtainment as reaction mediums, the reaction condition is high, and the prepared product has the advantages of high purity and high yield, and is suitable for industrialization production.

Description

technical field

[0001] The invention relates to a method for synthesizing an important intermediate 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid of the antipsychotic drug amisulpride. It belongs to the field of medical technology. Background technique

[0002] 2-Methoxy-4-amino-5-ethylsulfonylbenzoic acid is an important intermediate in the synthesis of the antipsychotic drug amisulpride. Depending on the initial raw materials used in the synthesis or the different reaction pathways, the currently reported synthesis methods are:

[0003]

[0004] line 1

[0005]

[0006] line 2

[0007]

[0008] line 3

[0009] Each of the above methods has advantages and disadvantages. In line 1, this method is simple to operate, the product can be obtained in two steps, the reaction cycle is short, the conditions are mild, and the operation is simple. Its disadvantage is that the reaction raw materials are too expensive and the yield in the second step is low. The solvents...

Examples

Embodiment 1

[0015] Embodiment 1: Synthesis of 2-methoxy-4-acetamido-5-sulfonylbenzoic acid methyl ester

[0016] Add 50g of 2-methoxy-4-aminobenzoic acid methyl ester, 72.5g of acetic anhydride, and 105g of acetic acid into a 250ml three-necked flask, control the temperature at 20-30 degrees, quickly add 24.5g of concentrated sulfuric acid dropwise, and heat up after the dropwise addition After reacting for 1 h, the temperature was lowered and filtered to obtain 60 g of white product.

Embodiment 2

[0017] Example 2: Synthesis of 2-methoxy-4-amino-5-sulfonylbenzoic acid methyl ester

[0018] Add 60 g of the product obtained in Example 1 to a 500 three-necked flask, 600 g of methanol and react at 20-25 degrees for 12 hours, and filter 47 g of the dried product.

Embodiment 3

[0019] Example 3: Synthesis of 2-methoxy-4-amino-5-chlorosulfonylbenzoic acid methyl ester

[0020] Add 47g of the product obtained in Example 2, 50g of phosphorus pentachloride, and 78g of acetonitrile into a 500ml three-necked flask, heat up to 84 degrees, and reflux for 1 hour. After the reaction is complete, the reaction solution is poured into a mixed solution of ethyl acetate and water. , static layering, the ethyl acetate solution of the target product was obtained, dried and filtered over anhydrous magnesium sulfate.

technical field

[0001] The invention relates to a method for synthesizing an important intermediate 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid of the antipsychotic drug amisulpride. It belongs to the field of medical technology. Background technique

[0002] 2-Methoxy-4-amino-5-ethylsulfonylbenzoic acid is an important intermediate in the synthesis of the antipsychotic drug amisulpride. Depending on the initial raw materials used in the synthesis or the different reaction pathways, the currently reported synthesis methods are:

[0003]

[0004] line 1

[0005]

[0006] line 2

[0007]

[0008] line 3

[0009] Each of the above methods has advantages and disadvantages. In line 1, this method is simple to operate, the product can be obtained in two steps, the reaction cycle is short, the conditions are mild, and the operation is simple. Its disadvantage is that the reaction raw materials are too expensive and the yield in the second step is low. The solvents...

Examples

Embodiment 1

[0015] Embodiment 1: Synthesis of 2-methoxy-4-acetamido-5-sulfonylbenzoic acid methyl ester

[0016] Add 50g of 2-methoxy-4-aminobenzoic acid methyl ester, 72.5g of acetic anhydride, and 105g of acetic acid into a 250ml three-necked flask, control the temperature at 20-30 degrees, quickly add 24.5g of concentrated sulfuric acid dropwise, and heat up after the dropwise addition After reacting for 1 h, the temperature was lowered and filtered to obtain 60 g of white product.

Embodiment 2

[0017] Example 2: Synthesis of 2-methoxy-4-amino-5-sulfonylbenzoic acid methyl ester

[0018] Add 60 g of the product obtained in Example 1 to a 500 three-necked flask, 600 g of methanol and react at 20-25 degrees for 12 hours, and filter 47 g of the dried product.

Embodiment 3

[0019] Example 3: Synthesis of 2-methoxy-4-amino-5-chlorosulfonylbenzoic acid methyl ester

[0020] Add 47g of the product obtained in Example 2, 50g of phosphorus pentachloride, and 78g of acetonitrile into a 500ml three-necked flask, heat up to 84 degrees, and reflux for 1 hour. After the reaction is complete, the reaction solution is poured into a mixed solution of ethyl acetate and water. , static layering, the ethyl acetate solution of the target product was obtained, dried and filtered over anhydrous magnesium sulfate.

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