JP2002167358A - CRYSTAL OF 4'-METHYLBIPHENYL-2-CARBOXYLIC t-BUTYL ESTER AND ITS PRODUCING METHOD - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple method for industrially producing high purity crystal of 4'-methylbiphenyl-2-carboxylic t-butyl ester. SOLUTION: The crystal of 4'-methylbiphenyl-2-carboxylic t-butyl ester shows the peak of heat absorption at 53-55 deg.C and the amount of heat absorption (δH) of 83-85 J/g when measured by a differential scanning calorimeter. The method for producing the above crystal of 4'-methylbiphenyl-2-carboxylic t-butyl ester is characterized by crystallizing 4'-methylbiphenyl-2-carboxylic t-butyl ester in the presence of isopropanol and water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a crystal of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester and a method for producing the same. More specifically, 4'-methylbiphenyl-2 useful as an intermediate for producing a hypotensive agent
-Crystalline t-butyl ester crystals and a method for producing the same.

[0002]

2. Description of the Related Art 4'-Methylbiphenyl-2-carboxylic acid t-butyl ester has a low melting point of about 50.degree.
It is a compound that is difficult to obtain as high-purity crystals. For example, when 4'-methylbiphenyl-2-carboxylic acid t-butyl ester is produced by the method described in Step 2 on page 51 of JP-A-5-506443, 4'-methylbiphenyl-2-carboxylic acid t It takes a long time to concentrate the ether extract of -butyl ester under vacuum to obtain the solid, and it is difficult to remove the solid, which is disadvantageous in industrial production. In addition, since 4'-methylbiphenyl-2-carboxylic acid t-butyl ester has high solubility in an organic solvent, it has a drawback that it is difficult to purify by crystallizing using an organic solvent.

Therefore, conventionally, 4'-
The development of a method for industrially obtaining methyl biphenyl-2-carboxylic acid t-butyl ester crystals has been awaited.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and is intended to provide a simple method and a high purity 4′-methylbiphenyl-2-carboxylic acid t-type.
An object of the present invention is to provide a method capable of industrially producing butyl ester crystals.

[0005]

That is, the gist of the present invention is as follows.
(1) 4′-Methylbiphenyl-2 having an endothermic peak at a temperature of 53 to 55 ° C. as measured by a differential scanning calorimeter (hereinafter referred to as DSC) and having an endothermic amount (δH) of 83 to 85 J / g. -Crystals of carboxylic acid t-butyl ester and (2) 4′- in the presence of isopropanol and water
Methylbiphenyl-2-carboxylic acid t-butyl ester exhibits an endothermic peak at a temperature of 53 to 54 ° C as measured by DSC, which is characterized by crystallizing, and an endothermic amount (δ
The present invention relates to a method for producing crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester having H) of 83 to 85 J / g.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester of the present invention were prepared by DSC
Shows a sharp endothermic peak at a temperature of 53 to 55 ° C., and an endothermic amount (δH) of 83 to 85 J / g.
And big. Therefore, the crystals of the 4'-methylbiphenyl-2-carboxylic acid t-butyl ester of the present invention can be prepared, for example, by preparing 4'-methyl prepared by the method described in Step 2 on page 51 of JP-A-5-506443. [Temperature at which endothermic peak appears when measured by DSC: 50.85] in comparison with t-butyl biphenyl-2-carboxylate.
° C, endothermic amount (δH): 67.71 J / g] and high purity, so that it can be suitably used as a production intermediate of a hypotensive agent.

Further, according to the production method of the present invention, crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester having a large average particle diameter (average particle diameter: 900 to 15)
00 μm). Therefore, the melting point of the crystals of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester is as low as about 50 ° C., but since the average particle diameter is large, the time required for drying can be reduced. Therefore, there is an advantage that the melting and the like can be avoided.

In the present invention, as a starting compound,
Crude crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester or oily 4'-methylbiphenyl-
2-Carboxylic acid t-butyl ester can be used.

[0009] Oily 4'-methylbiphenyl-2-carboxylic acid t-butyl ester can be obtained, for example, by reacting 4'-methylbiphenyl-2-carboxylic acid with 2-methylpropene.

The reaction between 4'-methylbiphenyl-2-carboxylic acid and 2-methylpropene can be carried out, for example, in an organic solvent such as toluene. The reaction temperature may usually be about 0 to 40 ° C.

During the reaction, a phosphorus halide such as phosphorus oxychloride and a small amount of water are added to the reaction system to promote the reaction. It is desirable to add the phosphorus halide in a ratio of 0.05 to 1 mol, preferably 0.15 to 0.4 mol, per 1 mol of 4'-methylbiphenyl-2-carboxylic acid.

After completion of the reaction, the obtained reaction solution is added to an aqueous solution of an alkali such as sodium hydroxide, for example, in order to prevent hydrolysis of the produced 4'-methylbiphenyl-2-carboxylic acid t-butyl ester. It is preferable to adjust the pH to 8 or more. The reaction solution is separated into two layers, an aqueous layer and an organic layer, of which the organic layer is taken out.

Since unreacted 2-methylpropene remains in the organic layer, the unreacted 2-methylpropene is removed from the organic layer by heating. At this time, an alkali metal carbonate such as potassium carbonate is added to the organic layer as a stabilizer,
It is preferable to heat to a temperature of 95 to 110 ° C. to degas 2-methylpropene.

The organic layer is preferably concentrated for crystallization by a method such as distillation under reduced pressure. The temperature at which the organic layer is concentrated is 12 from the viewpoint of the stability of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester.
The temperature is desirably 0 ° C or lower, preferably 100 ° C or lower, and is desirably 50 ° C or higher, preferably 53 ° C or higher from the viewpoint of improving the concentration rate.

Analysis by high performance liquid chromatography (hereinafter referred to as HPLC) revealed that the residual amount of the organic solvent was 5%.
In the case where the amount of the organic solvent is not less than 10% by weight, isopropanol is added to the organic layer, and the amount of the organic solvent remaining in the organic layer is reduced by removing the organic solvent from the organic layer under reduced pressure in the same manner as described above. It is preferable to concentrate the organic layer so as to be less than 5% by weight. The amount of isopropanol used in this concentration operation is not particularly limited as long as the amount of the organic solvent can be distilled off, and is usually per 100 parts by weight of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester. , 130 to 200 parts by weight, preferably 150 to 18 parts by weight
It is desirably 0 parts by weight.

After these operations, the obtained concentrate is dissolved in isopropanol, and a crystallization operation is performed. The amount of isopropanol is from 150 to 250 parts by weight, preferably from 170 to 230 parts by weight, per 100 parts by weight of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester, from the viewpoint of crystallization and improvement in yield. Is preferred.

[0017] It is preferable to add decolorizing carbon to the isopropanol solution of the obtained concentrate for decolorization. The amount of decolorizing carbon is usually per 100 parts by weight of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester,
It is preferably about 4 to 8 parts by weight. The temperature of the concentrated solution of isopropanol during decolorization is 40 to 80 ° C,
Preferably it is 50-70 degreeC. Thereafter, in order to separate decolorized carbon, it is preferable to filter the isopropanol solution of the concentrate.

The resulting 4'-methylbiphenyl-2-carboxylic acid t-butyl ester is prepared by adjusting the temperature of the concentrated solution of the isopropanol solution to preferably 15 to 21 ° C, more preferably 17 to 19 ° C. Crystallization can be achieved by adding seed crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester to promote crystallization. The amount of the seed crystal was 4'-methylbiphenyl-2.
-Per 100 parts by weight of carboxylic acid t-butyl ester,
It may be about 0.04 to 0.05 parts by weight.

After seeds are added to the concentrated solution of isopropanol, the concentrated solution of isopropanol is preferably cooled to a temperature of 15 to 25 ° C., more preferably 16 to 24 ° C., in order to sufficiently grow crystals. It is preferable to ripen for 4 hours.

Thereafter, in order to adjust the crystal form, it is preferable to adjust the temperature of the isopropanol solution of the concentrated solution to 11 to 15 ° C. In this case, the cooling rate is 10 ° C./hour or less, preferably 1 to 2 from the viewpoint of adjusting the crystal form.
C./hour is desirable.

Next, water is added dropwise to an isopropanol solution of this concentrated liquid. The water temperature is 5-20 ° C, preferably 10
It is desirable that the temperature be 15 ° C. to improve the yield by growing crystals. The amount of water added is 40 to 60 parts by weight, preferably 4 to 100 parts by weight of isopropanol.
The amount is preferably 5 to 55 parts by weight from the viewpoint of crystallization. In addition, the dropping time of water is usually 1 hour or more, preferably 2 to 3 hours, from the viewpoint of crystal growth.

After the dropwise addition of water, the concentrated solution of isopropanol is cooled to 10 ° C. or less for ripening of the crystals.
Preferably, it is desirable to cool to 0-5 ° C. The cooling rate at the time of cooling is 10 ° C./hour or less, preferably 1 to
Desirably, it is 2 ° C./hour. The aging is usually performed for 2 hours or more, preferably 3 to 4 hours.

After cooling, the crude crystals can be recovered by filtration. The recovered crude crystals are preferably washed with a mixed solvent of isopropanol and water. In this case, isopropanol / water (volume ratio) is 1.8 / 1 to 2.2.
/ 1, preferably 1.9 / 1 to 2.1 / 1. The amount of the mixed solvent for washing is usually 4′-
It is desirably 80 to 150 parts by weight, preferably 100 to 120 parts by weight, per 100 parts by weight of t-butyl methylbiphenyl-2-carboxylate.

The liquid temperature of the mixed solvent is preferably 10 ° C. or less, more preferably 0 to 5 ° C., in order to prevent the loss of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester.

After washing, the obtained wet 4'-methylbiphenyl-2-carboxylic acid t-butyl ester is dried.
The drying temperature is desirably 40 ° C or lower, preferably 30 to 40 ° C. The drying is preferably performed under reduced pressure. In this case, the degree of pressure reduction is usually 0.01 to 3
It is preferably kPa. The drying time is not particularly limited, but usually may be about 5 to 10 hours. In addition,
Thereafter, if necessary, drying under reduced pressure may be performed at 30 to 40 ° C.

The thus obtained crystal of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester of the present invention exhibits an endothermic peak at a temperature of 53 to 55 ° C. as measured by DSC, and an endothermic amount (δH). Has 83 to 85 J / g. In addition, the 4'-methylbiphenyl-
The average particle size of the 2-carboxylic acid t-butyl ester is 9
It is 00 to 1000 μm.

Accordingly, the crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester of the present invention have the advantages of high purity, large crystal grains, and favorable for drying.

[0028]

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

Example 1 354 kg of toluene was placed in a reaction vessel, and 48.7 g of 4'-methylbiphenyl-2-carboxylic acid was added thereto.
g was added, and 89.2 kg of 2-methylpropene was blown into the obtained mixture under vigorous stirring at a temperature of -10 to 0 ° C. 24.38 kg of phosphorus oxychloride was introduced, and 10 to 2
At 5 ° C., 1.43 kg of water was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at a temperature of 20 to 25 ° C. for 1 hour,
Checking by LC confirmed that 4'-methylbiphenyl-2-carboxylic acid t-butyl ester was obtained.

Thereafter, the obtained reaction solution was cooled to 0 to 5 ° C., and added to 636 kg of a 5% aqueous sodium hydroxide solution by 20 to 20 kg.
It was added dropwise at 30 ° C. The reaction vessel was washed with 50.6 kg of toluene, and the obtained washing liquid was added to the 5% aqueous sodium hydroxide solution. After confirming that the pH of the aqueous layer was 8 or more, liquid separation was performed.

Of the separated solution, 11 kg of potassium carbonate was added to the organic layer, and the mixture was heated to 100 to 105 ° C. to degas 2-methylpropene. 153.8 water at 75-80 ° C
kg was added and the mixture was stirred for 30 minutes, and separated. 80 ~
The mixture was concentrated at a temperature of 90 ° C. under a reduced pressure of 1.33 to 5.33 kPa. The amount of the distillate was 395 kg.

When analyzed by HPLC, the residual amount of toluene was 5% or more.
g was added and concentrated under the same conditions. The residual amount of toluene was less than 1% by weight. 251.4 kg of isopropanol and 10.12 kg of decolorizing carbon were added, and the resulting solution was added to 50 to 7
After stirring at 0 ° C. for 30 minutes, the mixture was filtered, and isopropanol 7
The decolorized carbon was washed with 2.6 kg.

The filtrate obtained above and the washing solution are combined, and 1
After cooling to 5 to 20 ° C, crystallization was started by adding seed crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester (84 g), and the mixture was aged at 15 to 20 ° C for 3 hours. 11-1
Cool at a cooling rate of 10 ° C./hour or less to 5 ° C.
213.7 kg of cold water of about 10 ° C. at 15 ° C. was added dropwise over 3 hours to promote crystallization. The mixture was cooled at a cooling rate of 10 ° C./hour or less to 0 to 5 ° C. and aged for 3 hours to complete crystallization.

The obtained wet 4'-methylbiphenyl-2-
The carboxylic acid t-butyl ester is filtered, then
127.9 kg of isopropanol cooled to 5 ° C. and water 8
The mixture was washed with a mixed solvent of 4.4 kg.

The container used for drying is cooled in advance to 10 to 15 ° C., and wet 4′-methylbiphenyl-2
223.8 kg of carboxylic acid t-butyl ester is placed in this drying vessel, dried at a reduced pressure of 0.10 to 1.33 kPa for 6 hours, and then dried at the same reduced pressure at a temperature of 30 to 40 ° C. to obtain 4′-methyl 199.45 kg of biphenyl-2-carboxylic acid t-butyl ester was obtained (yield: 93.5%,
HPLC purity: 98.8%, melting point: 51.5-52.1
° C, bulk density: 0.605 g / cm ³ ).

The particle size distribution of the crystals of the obtained 4′-methylbiphenyl-2-carboxylic acid t-butyl ester was measured by a sieving method. Table 1 shows the results.

[0037]

[Table 1]

The obtained 4'-methylbiphenyl-
The average particle size of the crystals of 2-carboxylic acid t-butyl ester was measured by a micrograph when sieved. As a result, the average particle size was 1400 μm.

Next, the obtained 4'-methylbiphenyl-
The differential thermal analysis of the crystals of 2-carboxylic acid t-butyl ester was measured using DSC under the following conditions. The results are shown in FIG. 1 and below.

[Measurement conditions of DSC] Measuring device: manufactured by PerkinElmer, trade name: DS
C6 Heating rate: 10 ° C / min using aluminum cell

[Results of DSC Measurement] Endothermic peak: 53.996 ° C. Area: 419.473 mJ Endothermic amount (δH): 83.895 J / g

From the above results, it can be seen that the obtained crystal of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester has high purity from the data of HPLC purity and thermal analysis.

The obtained 4'-methylbiphenyl-
FIG. 2 shows a micrograph (magnification: 50 times) of a crystal of 2-carboxylic acid t-butyl ester.

From the results shown in FIG. 2, the obtained 4′-
It can be seen that the crystals of methyl biphenyl-2-carboxylic acid t-butyl ester have a large particle size and are excellent in handleability.

Comparative Example 1 4'-Methylbiphenyl-2 obtained in Example 1
Part of the toluene solution of carboxylic acid t-butyl ester was concentrated by a vacuum pump until almost all of the toluene was removed, but did not crystallize. When seed crystals were inoculated into the obtained concentrated liquid, crystals precipitated out of the entire flask, and it was difficult to remove the crystals from the flask.

[0046]

According to the present invention, high purity 4'-methylbiphenyl-2-carboxylic acid tert-carboxylic acid can be obtained by a simple method.
Butyl ester crystals can be produced industrially.

[Brief description of the drawings]

FIG. 1 is a diagram showing the results of differential thermal analysis of crystals of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester obtained in Example 1.

FIG. 2 is a micrograph of crystals of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester obtained in Example 1.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Hideto Miyamoto 3-21-21 Utajima, Nishiyodogawa-ku, Osaka City Within Sumitomo Fine Chem Co., Ltd. No. 21 Sumika Finechem Co., Ltd. F-term (reference) 4H006 AA02 AD15 BB14 BB31 BC33 BC51 BJ50 BT32

Claims (7)

[Claims] 1. When measured by a differential scanning calorimeter, 53 to
It exhibits an endothermic peak at a temperature of 55 ° C. and has an endotherm (δH) of 8
Crystals of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester having 3-85 J / g. 2. The crystal of t-butyl 4'-methylbiphenyl-2-carboxylate according to claim 1, wherein the average particle diameter is 900 to 1500 μm. 3. A temperature of from 53 to 55 ° C. as measured by a differential scanning calorimeter, characterized by crystallizing 4′-methylbiphenyl-2-carboxylic acid t-butyl ester in the presence of isopropanol and water. A method for producing a crystal of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester having an endothermic peak and having an endothermic amount (? H) of 83 to 85 J / g. 4. A solution of 4'-methylbiphenyl-2-carboxylic acid t-butyl ester in isopropanol,
Water is added to the obtained solution, and crystallization is started at a temperature of 15 to 25 ° C. with stirring, and water is added dropwise with stirring while adjusting the solution temperature to 10 to 20 ° C. The production method according to claim 3, wherein 5. The amount of isopropanol is from 130 to 200 parts by weight per 100 parts by weight of 4′-methylbiphenyl-2-carboxylic acid t-butyl ester.
The manufacturing method as described. 6. The method according to claim 4, wherein the temperature of the water to be dropped is 10 to 20 ° C. 7. A volume ratio of isopropanol / water of 1.8.
The production method according to any one of claims 3 to 6, wherein the ratio is from 1/1 to 2.2 / 1.