JPH11322676A - Production of 4'-methyl-2-biphenylcarboxylic acid tert-butyl ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To easily obtain the subject compound useful as an intermediate for the production of hypotensive medicines in a high yield and in a high quality without using a dangerous solvent and needing a complicated operation by reacting methylbiphenylcarboxylic acid with butanol in the presence of an acid catalyst and a dehydrating agent. SOLUTION: This method for producing 4'-methyl-2-biphenylcarboxylic acid tert-butyl ester comprises reacting (A) 4'-methyl-2-biphenylcarboxylic acid with (B) tert-butanol in the presence of (C) an acid catalyst, preferably concentrated sulfuric acid, and (D) a dehydrating agent, preferably anhydrous magnesium sulfate, preferably at 15-35 deg.C usually for about 5-24 hr. The components B, C and D are preferably used in amounts of 5-7 moles, 1.0-1.1 moles and 4-5 moles, respectively, per mole of the component A. A solvent such as toluene may be used in the method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to 4'-methyl-2-.
The present invention relates to a method for producing tert-butyl biphenylcarboxylate. More specifically, 4'-methyl-2-biphenylcarboxylic acid ter useful as an intermediate for producing a hypotensive agent
The present invention relates to a method for producing t-butyl.

[0002]

2. Description of the Related Art Conventionally, a method for producing tert-butyl 4'-methyl-2-biphenylcarboxylate includes (A)
p-Methylphenylzinc chloride and 2-tert-butoxycarbonyliodobenzene were converted to NiCl ₂ (Ph
[Phenyl group, the same applies hereinafter] Production method for reacting in the presence of ₃ P) ₂ catalyst (JP-A-6-1790), and (B) 4′-methyl-2-biphenylcarboxylic acid and isobutene in anhydrous ether Is known in the presence of a concentrated sulfuric acid catalyst (Japanese Unexamined Patent Publication No. 5-506443).

[0003] However, the method (A) includes a raw material.
Preparation of the compound p-methylphenylzinc chloride
It is necessary to carry out at extremely low temperature of -78 ° C
For the preparation of p-methylphenylzinc chloride
Including the disadvantage of requiring operation, 2-tert-
Butoxycarbonyl iodobenzene or NiCl_Two(Ph
_ThreeP)_TwoSuch as the need for relatively expensive reagents
There is a point.

[0004] Since ether is used in the above method (B), a method which does not use a highly dangerous solvent such as ether is desired.

[0005] Therefore, in recent years, there is a long-awaited need to establish a method for producing tert-butyl 4'-methyl-2-biphenylcarboxylate easily and in a high yield in an industrially advantageous manner.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and does not require complicated operations, does not use a dangerous solvent, is easy, and has a high yield. An object is to provide a method capable of producing tert-butyl 4'-methyl-2-biphenylcarboxylate with high quality.

[0007]

The present inventors have conducted intensive studies in view of the above-mentioned prior art, and as a result, have found that the starting material of the present invention has 4'-methyl- having a bulky substituent at the ortho-position of the benzene ring. Despite being 2-biphenylcarboxylic acid, when tert-butanol, an acid catalyst and a dehydrating agent are used, tert-butyl 4′-methyl-2-biphenylcarboxylate can be obtained in extremely high yield and high quality. I found a completely new fact that it can be obtained. The present invention has been completed based on such findings.

[0008] That is, the gist of the present invention is to provide 4'-methyl-2.
-Biphenylcarboxylic acid and tert-butanol,
4'-methyl-2-biphenylcarboxylic acid tert characterized by reacting in the presence of an acid catalyst and a dehydrating agent
A process for producing butyl.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The starting compound 4'-methyl-2-biphenylcarboxylic acid used in the present invention is 4'-methyl-2-biphenylcarboxylic acid.
-Methyl-2-cyanobiphenyl can be easily produced by alkaline hydrolysis.

The amount of tert-butanol used is 4'-
From the viewpoint of reactivity, it is desirably at least 2 mol, preferably at least 5 mol, and preferably at most 10 mol, preferably at most 7 mol, from the viewpoint of reactivity, relative to 1 mol of methyl-2-biphenylcarboxylic acid. Desirably.

As the acid catalyst, sulfuric acid is preferred from the viewpoint of reactivity and economy. In addition, sulfuric acid is usually 96 to
Preference is given to concentrated sulfuric acid having a concentration of 98% by weight.

The amount of the acid catalyst used is 4'-methyl-2
0.8 mol or more, preferably 1.0 mol or more, from the viewpoint of reactivity, and 1.2 mol or less, preferably 1 mol, from the viewpoint of economy, relative to 1 mol of biphenylcarboxylic acid. 0.1 mol or less.

As the dehydrating agent, for example, anhydrous magnesium sulfate, anhydrous calcium chloride and the like can be mentioned. Among these, anhydrous magnesium sulfate is preferred from the viewpoint of reactivity.

The amount of the dehydrating agent used is 4'-methyl-2
-2 mol or more, preferably 4 mol or more, from the viewpoint of reactivity, and 6 mol or less, preferably 5 mol or less from the viewpoint of economy, per 1 mol of biphenylcarboxylic acid. desirable.

Examples of the solvent used for the reaction in the present invention include hydrocarbon solvents such as cyclohexane and toluene, and halogen solvents such as dichloromethane and dichloroethane. It is generally preferable to adjust the amount of the solvent to be used so that 4'-methyl-2-biphenylcarboxylic acid is about 2 to 20 parts by weight based on 100 parts by weight of the solvent.

When 4'-methyl-2-biphenylcarboxylic acid is reacted with tert-butanol, when magnesium sulfate is used as a dehydrating agent, magnesium sulfate releases water of crystallization at about 48 ° C. In order to lose the dehydration ability, it is usually preferably in the range of 0 to 45 ° C, preferably 15 to 35 ° C. The atmosphere may be air or an inert gas such as nitrogen gas.

The reaction time cannot be unconditionally determined because it varies depending on conditions such as the reaction temperature. However, the reaction time may be such that the reaction is completed, and is usually about 5 to 24 hours. The completion of the reaction can be confirmed using, for example, high performance liquid chromatography (HPLC).

The reaction product thus obtained is, for example, poured into an alkaline water such as sodium bicarbonate, extracted with an organic solvent such as toluene, and then concentrated and distilled to remove the organic solvent. Can be released.

4'-Methyl-2- obtained by the present invention
Tert-butyl biphenylcarboxylate can be suitably used as an intermediate for the production of pharmaceuticals.

[0020]

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

Example 1 To a 100 ml flask equipped with a thermometer, 40 ml of toluene, 4.81 g (40 mmol) of anhydrous magnesium sulfate, and 0.55 ml (10 mmol) of concentrated sulfuric acid were added, followed by vigorous stirring. To this was added 2.12 g (10 mmol) of 4'-methyl-2-biphenylcarboxylic acid,
Then 4.78 ml (50 mmol) of tert-butanol were added. The resulting mixture was stirred at room temperature for 19 hours. After confirming the disappearance of the peak of 4'-methyl-2-biphenylcarboxylic acid by HPLC, the reaction solution was poured into 75 ml of a saturated aqueous sodium hydrogen carbonate solution, stirred sufficiently, allowed to stand, and separated. The upper toluene layer was taken, washed with water, dried over anhydrous magnesium sulfate, and concentrated and distilled off with a rotary evaporator to obtain 2.56 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals. (Yield: 94.6% based on 4'-methyl-2-biphenylcarboxylic acid, HPLC purity: 99.9%).

The compound obtained is 4'-methyl-2
It was confirmed that tert-butyl biphenylcarboxylate had the following physical properties.

(1) Melting point: 51 to 53 ° C. (2) IR (neat) ν (cm ⁻¹ ): 2976, 29
28, 1708, 1478, 1446, 1368, 13
02, 1250, 1174, 1128, 848, 82
0,760 (3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.
08 to 7.74 (m, 8H), 2.34 (s, 3H),
1.27 (s, 9H)

Example 2 A 100 ml flask equipped with a thermometer was charged with 40 ml of dichloroethane and 4.81 g of anhydrous magnesium sulfate.
(40 mmol) and 0.55 ml (10 mmol) of concentrated sulfuric acid were added and stirred vigorously. 4'-methyl-
2.12 g (10 mmol) of 2-biphenylcarboxylic acid
And then 4.78 ml of tert-butanol
(50 mmol) was added. The resulting mixture was stirred at room temperature for 19 hours. 4'-Methyl-2- by HPLC
After confirming the disappearance of the biphenylcarboxylic acid peak, the reaction solution was poured into 75 ml of a saturated aqueous sodium hydrogencarbonate solution, stirred sufficiently, allowed to stand still, and separated. The lower dichloroethane layer was taken, washed with water, dried over anhydrous magnesium sulfate, and concentrated and distilled off with a rotary evaporator to obtain 2.31 g of tert-butyl 4'-methyl-2-biphenylcarboxylate as crystals. (Yield: 4'-methyl-2
-86.1% of biphenylcarboxylic acid, HPLC
Purity: 99.9%).

The compound obtained is 4'-methyl-2
It was confirmed that tert-butyl biphenylcarboxylate had the following physical properties.

(1) Melting point: 51 to 53 ° C. (2) IR (neat) ν (cm ⁻¹ ): 2976, 29
28, 1708, 1478, 1446, 1368, 13
02, 1250, 1174, 1128, 848, 82
0,760 (3) ¹ H-NMR (CDCl ₃ ) δ (ppm): 7.
08 to 7.74 (m, 8H), 2.34 (s, 3H),
1.27 (s, 9H)

From the above results, according to the methods of Examples 1 and 2, 4'-methyl-2-biphenylcarboxylic acid t
It turns out that ert-butyl can be obtained simply, with high yield, and with high quality.

[0028]

According to the present invention, 4'-methyl-2 can be prepared without complicated operations and without using dangerous solvents.
The effect is that tert-butyl-biphenylcarboxylate can be conveniently and industrially produced with high yield and high quality.

Claims (3)

[Claims] 1. A method comprising reacting 4'-methyl-2-biphenylcarboxylic acid with tert-butanol in the presence of an acid catalyst and a dehydrating agent.
-A method for producing tert-butyl biphenylcarboxylate. 2. The method for producing tert-butyl 4'-methyl-2-biphenylcarboxylate according to claim 1, wherein the acid catalyst is concentrated sulfuric acid. 3. The method for producing tert-butyl 4′-methyl-2-biphenylcarboxylate according to claim 1, wherein the dehydrating agent is anhydrous magnesium sulfate.