JP2000026369A - Production of 3-acetoxy-2-methylbenzoyl chloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce 3-acetoxy-2-methylbenzoyl chloride as a crystal in high yield by using 3-acetoxy-2-methylbenzoic acid as a raw material. SOLUTION: This method for chlorinating 3-acetoxy-2-methylbenzoic acid with thionyl chloride comprises the chlorination reaction in an aliphatic hydrocarbon solvent in the presence of pyridines or dimethylformamide. The objective 3-acetoxy-2-methylbenzoyl chloride can be produced as a high purity crystal in high yield because the solubility of the 3-acetoxy-2-methylbenzoyl chloride in the aliphatic hydrocarbon solvent is small.

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 chloride. More specifically, the present invention relates to a method for producing 3-acetoxy-2-methylbenzoic acid chloride as crystals using 3-acetoxy-2-methylbenzoic acid as a raw material in high yield.

[0002]

2. Description of the Related Art 3-Acetoxy-2-methylbenzoic acid chloride (hereinafter referred to as AMBC) is disclosed in U.S. Pat.
As described in the specification of US Pat. No. 4,926, the compound is useful as an intermediate of a pharmaceutical such as a human immunodeficiency virus protease inhibitor.

As a method for producing AMBC, 3-acetoxy-2-methylbenzoic acid (hereinafter referred to as AMBA) is used as a starting material, and dimethylformamide (hereinafter referred to as DMF) is used in a methyl-t-butyl ether (hereinafter referred to as MTBE) solvent. A method of chlorinating with thionyl chloride (SOCl ₂ ) as a catalyst (WO 98/09951) is known.

[0004]

The above-mentioned WO 98/099
The method disclosed in No. 51 is not economically advantageous because MTBE as a solvent is expensive. In this patent, in order to obtain AMBC as a crystal, MTBE is used.
Is concentrated and replaced with toluene, and then toluene is further concentrated and finally recrystallized with heptane.
Not only is the yield of C as low as 82.3%, but there are drawbacks in that many types of solvents are used and the operation is complicated.

When chlorinating a carboxylic acid, benzene is generally used without solvent or without reacting with the carboxylic acid.
Inert solvents such as aromatic hydrocarbons such as toluene and halogenated hydrocarbons such as methylene chloride and chloroform are often used. However, in the case of a solvent such as an aromatic hydrocarbon or a halogenated hydrocarbon, it is difficult to obtain AMBC as a crystal in a high yield because the generated AMBC has high solubility.

On the other hand, since aliphatic hydrocarbons such as hexane and heptane have low solubility of AMBC, it is easy to obtain AMBC as crystals in high yield, but AMBA which is a raw material used for chlorination reaction is used. It was thought that the chlorination reaction did not proceed because the solubility of was too low.

An object of the present invention is to provide a method for producing 3-acetoxy-2-methylbenzoic acid chloride which can solve the above-mentioned disadvantages of the prior art and can produce AMBC as a high-purity crystal in high yield using AMBA as a raw material. To provide.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned drawbacks. As a result, even when an aliphatic hydrocarbon such as hexane or heptane is used as a solvent, pyridines or DMF can be used. It was determined that the carboxylic acid chlorination reaction proceeds in the presence of a catalyst, and the present invention has been completed.

The method for producing AMBC according to the present invention comprises the steps of:
Is characterized by a chlorination reaction in an aliphatic hydrocarbon solvent in the presence of pyridines or DMF. Thus, when chlorinating AMBA with thionyl chloride, the chlorination reaction in the presence of pyridines or DMF in an aliphatic hydrocarbon solvent allows the solubility of AMBC to be produced in the aliphatic hydrocarbon solvent to be increased. Because of its small size, AMBC can be produced as high-purity crystals in high yield.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION AMBA used as a starting material in the present invention is, for example, reduction of 3-nitro-O-toluic acid to give 3-amino-2-methylbenzoic acid,
3-hydroxy-2 obtained by diazotization and hydrolysis of this
-Can be prepared by acetylating methylbenzoic acid. However, the AMBA used in the present invention is not limited to the one obtained by the above-mentioned production method, and any one obtained by any of the production methods can be used.

The solvent used in the present invention is an aliphatic hydrocarbon such as hexane and heptane. The amount of the aliphatic hydrocarbon solvent used is not particularly limited as long as it can be handled when AMBA and the solvent are charged, and is not particularly limited, but is usually 0.5 to 10 times the weight of AMBA as a raw material.

The catalyst used in the present invention is a pyridine such as pyridine, picoline, lutidine or the like, or DMF, preferably pyridine or DMF. The amount of the catalyst used is 0.000 to 1 mol of AMBA as a raw material.
001 to 0.1 mol, preferably 0.00001 to 0.1 mol.
The range is 01 mole. Addition of more than 0.1 mol does not affect the chlorination reaction, but using more than the required amount is not economical. Also, if it is less than 0.000001 mol,
The chlorination reaction requires a long time, which is not preferable.

The amount of thionyl chloride used as a chlorinating agent in the present invention is 1.0 to 2.0 mol, preferably 1.0 to 1.5 mol, per mol of AMBA as a raw material.
Is a mole. If the amount is less than 1.0 mol per 1 mol of AMBA, the conversion rate of AMBA decreases, and the quality of the obtained AMBC deteriorates. Also, even if it is added in excess of 2.0 mol,
Although it does not affect the chlorination reaction, use beyond necessity is not only economical, but also hinders operations such as removal of excess in a later step and filtration.

In the present invention, the chlorination reaction temperature is 2
It is in the range of 5 to 70C, preferably 30 to 60C. When the reaction temperature exceeds 70 ° C., not only the amount of thionyl chloride becomes insufficient due to the evaporation of thionyl chloride, but also the resulting A
MBC quality is degraded. If the temperature is lower than 25 ° C., the chlorination reaction requires a long time, which is not preferable.

[0015] The chlorination reaction in the present invention is usually carried out by AM
The reaction is carried out by dropping thionyl chloride in a solution containing BA, a solvent and a catalyst. The dropping time of thionyl chloride is determined according to the charged capacity, the reaction temperature, the ability to remove hydrogen chloride and sulfur dioxide generated by the reaction, and the like, and is usually about 0.5 to 24 hours. After completion of the dropwise addition of thionyl chloride, the mixture is stirred at the same temperature for 0.5 to 10 hours to complete the chlorination reaction.

When the chlorination reaction is completed, it is preferable to reduce the pressure of the reaction system and distill and remove excess thionyl chloride, generated hydrogen chloride and sulfur dioxide. that time,
If the solvent distills off, replenish the required amount of solvent.

After the completion of the chlorination reaction or after distilling off excess thionyl chloride, hydrogen chloride formed by the reaction and sulfur dioxide, the reaction mixture is cooled to 10 ° C. or lower, and the solubility of AMBC in aliphatic hydrocarbons is reduced. Is small, AMBC precipitates as crystals. AM deposited
BC crystals are separated by means such as centrifugation and filtration under reduced pressure. The separated AMBC can be recovered as high-purity crystals by drying under reduced pressure.

The hue of the recovered AMBC is A
Depending on the hue of the MBA, white AMBC can be obtained using white AMBA, but similarly colored AMBC can be obtained using colored AMBA. Therefore, when colored AMBA is used as a raw material and white AMBC is required, after completion of the chlorination reaction or after distilling off excess thionyl chloride, generated hydrogen chloride and sulfur dioxide, the reaction solution Activated carbon may be added to decolorize, or AMBC separated and recovered may be dissolved again in hexane, heptane or the like and decolorized with activated carbon.

[0019]

EXAMPLES Example 1 100 m capacity equipped with a stirrer, reflux condenser and thermometer
In a 1 l glass flask, 99.2% pure, light brown A
MBA 19.4 g (0.1 mol) and heptane 19.4 g
And 0.008 g (0.0001 mol) of pyridine were heated to 50 ° C. while stirring. Then, using a dropping funnel, 13.1 g (0.11 mol) of thionyl chloride was added dropwise over 1 hour while maintaining the reaction temperature at 50 ° C., and a chlorination reaction was performed with stirring at the same temperature for 3 hours. . After the completion of the chlorination reaction, the reaction solution was cooled to 5 ° C., and the precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 19.7 g of light brown AMBC crystals. This AMBC
As a result of analyzing the crystals by an area percentage method using a high performance liquid chromatograph, 98.9% of AMBC and 0.2% of AMBA were analyzed.
7%, and the AMBC yield was 91.7% mol. Table 1 shows the results.

Example 2 0.005 g (0.00006 mol) of pyridine was added.
The reaction solution was cooled to 5 ° C., and the precipitated crystals were separated by filtration by suction filtration, dried under reduced pressure, and dried under reduced pressure to obtain 19.7 g of light brown AMBC crystals. I got The AMBC crystal was analyzed by area percentage method using a high performance liquid chromatograph.
MBC 97.4%, AMBA 1.6%, AMBC
The yield was 90.4 mol%. Table 1 shows the results.

Example 3 A chlorination reaction was carried out under the same conditions as in Example 1 except that the amount of pyridine added was 0.04 g (0.0005 mol) and the amount of thionyl chloride added was 14.3 g (0.12 mol). The reaction solution was cooled to 5 ° C., and the precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 18.5 of light brown AMBC crystals.
g was obtained. As a result of analyzing the AMBC crystal by an area percentage method using a high performance liquid chromatograph, it was found that AMBC 9
8.1%, AMBA 1.6%, AMBC yield is
85.4 mol%. Table 1 shows the results.

Example 4 A chlorination reaction was carried out under the same conditions as in Example 1 except that the amount of pyridine added was 0.4 g (0.005 mol) and the amount of thionyl chloride added was 14.3 g (0.12 mol). The reaction solution was cooled to 5 ° C., and the precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 19.3 g of light brown AMBC crystals. The AMBC crystal was analyzed by an area percentage method using a high performance liquid chromatograph.
0% and AMBA 2.1%, and the AMBC yield was 8%.
It was 8.1 mol%. Table 1 shows the results.

Example 5 A chlorination reaction was carried out under the same conditions as in Example 1 except that the amount of pyridine added was 0.005 g (0.00006 mol) and the reaction temperature was 40 ° C., and the reaction solution was cooled to 5 ° C. The precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 18.0 g of light brown AMBC crystals. This AMBC
The crystals were analyzed by an area percentage method using a high performance liquid chromatograph. As a result, 99.6% of AMBC and 0% of AMBA were analyzed.
And the AMBC yield was 84.4 mol%. Table 1 shows the results.

Example 6 Except that the amount of pyridine added was 0.04 g (0.0005 mol), the amount of thionyl chloride added was 14.3 g (0.12 mol), and the catalyst was DMF 0.073 g (0.001 mol). A chlorination reaction was carried out under the same conditions as in Example 1. The reaction solution was cooled to 5 ° C., and the precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 18.8 g of light brown AMBC crystals. The AMBC crystals were analyzed by area percentage method using a high performance liquid chromatograph.
3%, AMBA 3.3%, AMBC yield 8
It was 5.2 mol%. Table 1 shows the results.

Example 7 The chlorination reaction was carried out under the same conditions as in Example 1 except that 19.4 g of hexane was used instead of heptane as a solvent. The reaction solution was cooled to 5 ° C. Separated by filtration and dried under reduced pressure to give light brown AMBC crystals.
3 g were obtained. As a result of analyzing the AMBC crystal by an area percentage method using a high performance liquid chromatograph, the AMBC crystal was analyzed.
99.1%, AMBA 0.3%, and the AMBC yield was 94.8 mol%. Table 1 shows the results.

[0026]

[Table 1]

As shown in Table 1, in each of Examples 1 to 7, AMBC crystals having a purity of 96% or more could be obtained in a high yield of 84 mol% or more.

Example 8 A capacity of 100 m equipped with a stirrer, a reflux condenser and a thermometer
In a 1 l glass flask, 99.2% pure, light brown A
19.4 g (0.1 mol) of MBA and 19.4 g of hexane
And 0.008 g (0.0001 mol) of pyridine were heated to 50 ° C. while stirring. Next, 14.3 g (0.12 mol) of thionyl chloride was added dropwise using a dropping funnel over 1 hour while maintaining the reaction temperature at 50 ° C., and the chlorination reaction was performed while maintaining the same temperature and stirring for 3 hours. . After the completion of the chlorination reaction, the pressure of the reaction system was reduced, and excess thionyl chloride, hydrogen chloride and sulfur dioxide were distilled off together with hexane and removed. Next, 19.4 g of hexane and 0.78 g of activated carbon (trade name: Carbofin-20 manufactured by Takeda Pharmaceutical Co., Ltd.) were added, and the mixture was stirred at 50 ° C. for 0.5 hour, and then the activated carbon was filtered off. The filtrate was cooled to 5 ° C., and the precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 19.7 g of white AMBC crystals. This AMB
As a result of analyzing the C crystal by an area percentage method using a high performance liquid chromatograph, 97.7% of AMBC, AMBA
It was 1.6% and the AMBC yield was 90.6 mol%.

Comparative Example 1 A capacity of 100 m equipped with a stirrer, a reflux condenser and a thermometer
In a 1 l glass flask, 99.2% pure, light brown A
19.4 g (0.1 mol) of MBA and methylene chloride 19.
4 g and pyridine 0.008 g (0.0001 mol)
And heated to 40 ° C. with stirring. Then, using a dropping funnel, 13.1 g (0.11 mol) of thionyl chloride was used.
Was added dropwise over 1 hour while maintaining the reaction temperature at 40 ° C., and the chlorination reaction was carried out while maintaining the same temperature and stirring for 3 hours. After completion of the chlorination reaction, the reaction solution was cooled to 2 ° C., and the precipitated crystals were separated by filtration by suction filtration and dried under reduced pressure to obtain 8.3 g of light brown AMBC crystals. This AMBC
The crystals were analyzed by an area percentage method using a high performance liquid chromatograph. As a result, 99.6% of AMBC and 0.2% of AMBA were analyzed.
3%, and the AMBC yield was 38.9 mol%. Table 2 shows the results.

Comparative Example 2 A chlorination reaction was performed under the same conditions as in Comparative Example 1 except that toluene was used instead of methylene chloride and the reaction temperature was changed to 50 ° C., and the reaction solution was cooled to 2 ° C. to precipitate. The crystals are separated by suction filtration and dried under reduced pressure to give a light brown AMB.
12.3 g of C crystal was obtained. As a result of analyzing the AMBC crystal by an area percentage method using a high performance liquid chromatograph, it was found that AMBC was 99.2% and AMBA was 0.4%.
The MBC yield was 57.4 mol%. Table 2 shows the results.

[0031]

[Table 2]

As shown in Table 2, in Comparative Examples 1 and 2, the AMBC crystal purity was as high as 99% or more.
The AMBC yield was less than 60 mol%,
The yield is significantly lower than the MBC yield of 84 mol% or more.

[0033]

According to the method for producing AMBC of the present invention, AMB
When chlorinating A with thionyl chloride, the chlorination reaction is carried out in an aliphatic hydrocarbon solvent in the presence of a pyridine or DMF catalyst, so that the solubility of AMBC formed in the aliphatic hydrocarbon solvent is low, so that AMBC
Can be obtained with high purity and high yield.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Yoshikatsu Kusunoki, Inventor 3 Hikari, Kashima-shi, Ibaraki Pref.

Claims (1)

[Claims] 1. A process for chlorinating 3-acetoxy-2-methylbenzoic acid with thionyl chloride, wherein the chlorination reaction is carried out in an aliphatic hydrocarbon solvent in the presence of pyridines or dimethylformamide. A method for producing acetoxy-2-methylbenzoic acid chloride.