JP2000290231A - Production of 3-acetoxy-2-methylbenzoic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound in a high yield and at a high purity by converting hydroxymethylbenzoic acid into corresponding metal salt followed by addition of acetic anhydride to acetylate the metal salt. SOLUTION: This compound, 3-acetoxy-2-methylbenzoic acid, is obtained by converting 3-hydroxy-2-methylbenzoic acid into the corresponding metal salt followed by addition of acetic anhydride to acetylate the metal salt. The metal salt is e.g. a group Ia, IIa, IIIb, IVa or VIII metal salt, but it is preferably an alkali metal salt such as of lithium, sodium or potassium; an alkaline earth metal salt such as of calcium or magnesium; or a metal salt such as of aluminum or zinc. The amount of the metal salt to be used is preferably 0.5-3.0 equivalent, more preferably 0.8-1.5 equivalent, based on 3-hydroxy-2- methylbenzoic acid. The amount of the acetic anhydride to be used is preferably 0.5-3.0 equivalent, more preferably 0.8-1.5 equivalent, based on 3-hydroxy-2- methylbenzoic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to 3-acetoxy-
The present invention relates to a method for producing 2-methylbenzoic acid.

2. Description of the Related Art 3-Acetoxy-2-methylbenzoic acid (hereinafter referred to as AMBA) is a compound useful as an intermediate of pharmaceuticals such as HIV protease inhibitors. AMB
As a method for producing A, a method is described in which 3-hydroxy-2-methylbenzoic acid (hereinafter referred to as HMBA) is used as a raw material and acetylation is performed with acetic anhydride using sulfuric acid as a catalyst (US Pat.
926 Example 81) and a method of using acetic anhydride using a pyridine catalyst are disclosed (JP-A-11-576).
5). In the former, the yield is as low as 31% and AMBA cannot be produced at low cost. The latter uses pyridines as catalyst. Temperature control is required to suppress generation of impurities, or pyridine salts produced as by-products need to be removed, which is not industrially suitable.

[0002]

DISCLOSURE OF THE INVENTION The present inventors have studied a method of performing acetylation without using a catalyst such as pyridine. As a result of various studies, HMBA was converted into a metal salt and then reacted with acetic anhydride to obtain AMB with high yield and high purity.
A was found to be obtained. It has also been found that acetic acid by-produced with an alkali metal can be easily removed from the system as a metal acetate salt.

[0003]

That is, the present invention is characterized in that 3-hydroxy-2-methylbenzoic acid is converted to a metal salt and then acetylated by adding acetic anhydride. This is a method for producing benzoic acid.

The metal salts which can be used in the present invention belong to groups Ia, IIa, IIIb, IVa and VIII of the periodic table, but are preferably salts of alkali metals such as lithium, sodium and potassium, calcium and magnesium. And the like, and salts of metals such as aluminum and zinc.

[0005] The amount of the metal salt used in the present invention is 0.5 to 3.0 equivalents, preferably 0.1 equivalent, to the raw material HMBA.
It is 8 to 1.5 equivalents, and a HMBA salt can be prepared and used in water or various organic solvents according to a conventional method.

In the present invention, the amount of acetic anhydride to be reacted with the metal salt of 3-hydroxy-2-methylbenzoic acid is 0.5 to 3.0 equivalents, preferably 0.8 to 1.5 equivalents to the amount of the starting material.
Is equivalent.

In the present invention, the reaction can be performed without using an organic solvent. When using an organic solvent, hydrocarbon solvents such as benzene, toluene, xylene, pentane, hexane, heptane, octane, ligroin, and cyclohexane, chloroform, methylene chloride, dichloroethane, trichloroethylene, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene and trichlorobenzene, carboxylic esters such as ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; ketones such as methyl ethyl ketone and methyl isobutyl ketone; ethyl ether, diisopropyl ether and methyl butyl ether , Dioxane, THF, dimethyl cellosolve,
Ethers such as diethyl cellosolve, cellosolve acetate, methyl carbitol acetate and ethyl cellosolve acetate can be used. Alternatively, they can be used as a mixed solvent thereof.

[0008]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

Example 1 174 g of sodium salt of HMBA was charged into a 1-L glass reactor equipped with a stirrer, a reflux condenser, and a thermometer, and 102 g of acetic anhydride was added. After adding 500 ml, precipitated sodium acetate was removed by suction filtration, and toluene was distilled off from the filtrate to obtain 190 g of crystals. When AMBA in the crystals was quantified by HPLC analysis, it contained 185 g (95% yield).

Example 2 171 g of a calcium salt of HMBA was charged into a 1-L glass reactor equipped with a stirrer, a reflux condenser and a thermometer, and 102 g of acetic anhydride was added thereto. After reacting at 70 ° C. for 3 hours, toluene was added. After adding 500 ml, precipitated calcium acetate was removed by suction filtration, and toluene was distilled off from the filtrate to obtain 195 g of crystals. The amount of AMBA in the crystals was determined by HPLC analysis and found to be 175 g (yield 90%).

Example 3 500 ml of toluene and H were placed in a 1 L glass reactor equipped with a stirrer, a reflux condenser and a thermometer.
152 g of MBA is charged, 69 g of sodium carbonate is added, and water produced is recovered azeotropically with toluene. HMB obtained
133 g of acetic anhydride in a toluene suspension of sodium salt A
After reacting at 60 ° C. for 3 hours, water is added to remove by-produced sodium acetate to the aqueous layer. The solution was cooled to 0 ° C., and the precipitated AMBA was filtered off by suction filtration and dried, and then dried.
46 g of AMBA were obtained (75% yield). AM in filtrate
When BA was quantified by HPLC analysis, 39 g of AMBA
There was. When combined with AMBA obtained as crystals, the conversion was 95%.

Example 4 500 ml of toluene and H were placed in a 1-liter glass reactor equipped with a stirrer, a reflux condenser, and a thermometer.
MBA (152 g) is charged, and a 48% aqueous sodium hydroxide solution (92 g) is added, and water is recovered azeotropically with toluene. 112 g of acetic anhydride is added to the obtained toluene suspension of HMBA sodium salt and reacted at 50 ° C. for 3 hours, and then water is added to remove sodium acetate as a by-product to the aqueous layer. Solution at 0 ° C
After cooling to room temperature, the precipitated AMBA was filtered off by suction filtration and dried to obtain 155 g of AMBA (80% yield).

Example 5 500 ml of toluene and H were placed in a 1 L glass reactor equipped with a stirrer, a reflux condenser, and a thermometer.
152 g of MBA is charged and 78 g of potassium hydroxide powder is added to form a potassium salt of HMBA. After 143 g of acetic anhydride was added to the reaction solution and reacted at 30 ° C. for 3 hours, water was added to remove by-produced potassium acetate to the aqueous layer. The solution was cooled to 0 ° C., and the precipitated AMBA was filtered off by suction filtration and dried to obtain 150 g of AMBA (yield 77%).

Example 6 Example 4 was carried out using methyl isobutyl ketone as the solvent instead of toluene. The same operation as in Example 4 was performed to obtain 155 g of AMBA (80% yield).

Example 7 A 1 L glass reactor equipped with a stirrer, a reflux condenser and a thermometer was charged with 500 ml of butyl acetate and 152 g of HMBA, and charged with 152 g of potassium hydrogen carbonate to form a metal salt. After adding 133 g of acetic anhydride to the reaction solution and reacting at 30 ° C. for 3 hours, water is added to remove by-produced potassium acetate to the aqueous layer. The solution was cooled to 0 ° C., and the precipitated AMBA was filtered off by suction filtration and dried to obtain 132 g of AMBA (yield: 68%).

[0016]

According to the method of the present invention, it is possible to easily obtain AMBA which is a compound which is useful as a raw material for pharmaceuticals in a high yield and purity without using a highly toxic catalyst such as pyridine. .

Claims (1)

[Claims] 1. A method for producing 3-acetoxy-2-methylbenzoic acid, which comprises converting 3-hydroxy-2-methylbenzoic acid into a metal salt and reacting the metal salt with acetic anhydride.