JP2573982B2 - Method for producing 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate useful as an acidic anti-inflammatory agent.

[Problems to be solved by conventional technologies and inventions]

As the aromatic substituted alkanecarboxylic acid which is an acidic anti-inflammatory agent, flurbiprofen, ibuprofen, indomethacin, sulindac, diclofenac and the like are commercially available, and are used as anti-inflammatory, analgesic and antipyretic agents.

An ester derivative having a double ester structure, which is a derivative of the acidic anti-inflammatory agent, has a reduced side effect such as a gastric ulcer-forming effect or an effect on the central nervous system, and has an enhanced drug efficacy as compared with the acidic anti-inflammatory agent. Applicants have found that they are far superior.
Nos. 8 and 60-28957).

The double ester structure is, for example, a compound represented by the general formula (IV): (Wherein, Ar represents an aryl group or a substituted aryl group, and R represents a hydrogen atom or a methyl group). One of the hydroxyl groups of 1,1-dihydroxyethylidene is an acidic anti-inflammatory agent. This is an acylal structure in which a certain aromatic-substituted alkanecarboxylic acid is bonded to the other hydroxyl group with acetic acid.

In the technical field of acidic anti-inflammatory agents, research is continuing to provide ester derivatives having a double ester structure, which are useful anti-inflammatory agents. More specifically, a method for producing an ester derivative of flurbiprofen having a double ester structure (see JP-A-59-15238), a method for producing an ester derivative of indomethacin and diclofenac (see JP-A-60-2)
No. 8957 and U.S. Pat. No. 4,603,217), and a method for producing an ester derivative of sulindac (see British Patent No. 1,345,628).
In these conventional production methods, the general formula (V): (Wherein X represents a chlorine atom, bromine atom or iodine atom) by reacting 1-haloethyl acetate represented by the general formula (IV) with an acidic anti-inflammatory agent. Manufactures ester derivatives.

However, the 1-haloethyl acetate is not commercially available as an industrial raw material, and must be produced by a Blankeylet reaction using acid chloride and acetaldehyde or by addition of hydrogen chloride to a vinyl ester derivative, and thus can be easily produced. Not something. This is because when the 1-haloethyl acetate is produced by the Blanc-Kelley reaction, the acetaldehyde used as the reagent is highly reactive, and the reaction is a rapid and rapid exothermic reaction. This is because it is difficult to obtain a low yield and many by-products are mixed. In addition, when manufacturing by adding hydrogen chloride to vinyl ester derivatives, special reaction equipment is required because of the use of corrosive hydrogen chloride. This is because attention must be paid to prevent exposure of harmful gases to members.

Thus, in order to obtain the desired double ester derivative by the conventional method, it is necessary to produce 1-haloethyl acetate, which has a disadvantage that the production cost is increased.

Further, in the method for producing a double ester derivative by the present inventors described in Japanese Patent Application No. 61-300704, which is different from these, flurbiprofen and vinyl acetate are liable to undergo a polymerization reaction in the system. Therefore, there is a disadvantage that it is difficult to control the reaction.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve the problems of the prior art, and as a result, in the presence of an acid catalyst such as sulfonic acid or Lewis acid, 1,1-ethylidene diacetate which is easily available and easy to handle. The present invention has been found to be able to easily produce 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate in one step in a high yield by performing a transesterification reaction with flurbiprofen. Was completed.

That is, the present invention provides a compound of the formula (I): 1,1-ethylidene diacetate represented by the formula (I)
I): 2- (2-fluoro-4-biphenylyl) represented by
Transesterification with propionic acid in the presence of an acid catalyst gives a compound of formula (III): And a method for producing 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate represented by the formula:

〔Example〕

In the present invention, 1,1-ethylidene diacetate and 2-
Transesterification with (2-fluoro-4-biphenylyl) propionic acid (hereinafter referred to as flurbiprofen) is carried out in the presence of an acid catalyst.

The above-mentioned 1,1-ethylidene diacetate and flurbiprofen are both preferable in that commercially available ones are easily available.

The ratio of the use of flurbiprofen and 1,1-ethylidene diacetate is essentially 1: 1 in molar ratio, but in order to improve the yield with respect to flurbiprofen, 1,1 -It is preferred to use an excess of ethylidene diacetate, molar ratio 1: 1.1 to 1:10, even 1: 1.5 to 1: 3
Is preferable. In particular, a ratio of around 1: 2 is preferred from the viewpoint of facilitating post-reaction treatment and purification.

The acid catalyst used in the present invention can be used without particular limitation as long as it is an acid catalyst that can be used as a catalyst for a transesterification reaction. Specific examples of such an acid catalyst include, for example, p
Sulfonic acids such as toluenesulfonic acid, d-camphorsulfonic acid, methanesulfonic acid, etc., boron trifluoride (including those forming an ether complex), zinc chloride,
Examples include, but are not limited to, Lewis acids such as stannous chloride. Among these acid catalysts, methanesulfonic acid and boron trifluoride etherate complex hardly cause side reactions such as ester hydrolysis and ester exchange other than the main reaction, and significantly promote the ester exchange reaction to achieve high yield. It is particularly preferable because it gives a rate.

The amount of the acid catalyst used depends on the type of the acid catalyst used, but is usually 1 to 20 mol% based on flurbiprofen.
It is preferred to use. When the amount of the acid catalyst used is less than 1 mol% with respect to flurbiprofen, the progress of the reaction slows down. When the amount is more than 20 mol%, the hydrolysis reaction of the target substance and the transesterification reaction other than the main reaction And other side reactions tend to proceed, and the yield tends to decrease.

The temperature at the time of the transesterification is not particularly limited, but is preferably 0 to 120 ° C, more preferably 0 to 80 ° C. If the temperature is lower than 0 ° C., flurbiprofen as a raw material is precipitated, the reaction system becomes non-uniform, and the progress of the transesterification reaction tends to be slow.If it is higher than 120 ° C., severe reaction conditions occur. A transesterification reaction other than the hydrolysis reaction and the main reaction tends to predominate and tends to proceed.

The reaction time varies depending on the reaction temperature, the type of raw material and acid catalyst, and the amount used, but is generally about 0.5 to 30 hours.

In the present invention, a solvent may or may not be used, but when not used, it is preferable to use 1,1-ethylidene diacetate in excess to double as a solvent. On the other hand, when a solvent is used, the type and amount of the solvent are not particularly limited, and do not react with 1,1-ethylidene diacetate, flurbiprofen, a catalyst, etc., and are not reacted with 1,1-ethylidene diacetate, Any solvent can be used as long as it has good compatibility with biprofen and the like. Specific examples of such solvents include, for example, toluene, benzene, ether,
A non-polar solvent such as chloroform is preferred in terms of high solubility of flurbiprofen.

When a solvent is used, the amount used is usually about 5 to 20 times the weight of the total of flurbiprofen and 1,1-ethylidene diacetate.

By the above method, 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate, which is the object of the present invention, is produced.

The thus obtained 1-acetoxyethyl 2-
(2-Fluoro-4-biphenylyl) propionate is finally purified and isolated by a method such as column chromatography on silica gel or thin-film molecular distillation, and a purified product is obtained in a high yield of about 90 to 60%. .

The obtained 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate contains all optical isomers and mixtures thereof.

Next, the method of 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 Preparation of 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate Flurbiprofen (0.244 g, 1 mmol) was dissolved in benzene (6 ml), and 1,1-ethylidene diacetate (0.292) was added to the solution. g (2 mmol) was added. Then, 24 mg (0.1 mmol) of p-toluenesulfonic acid was added thereto, and
Stirred for hours.

After completion of the reaction, 20 ml of n-hexane was added to the reaction mixture,
Unreacted flurbiprofen was removed by washing with 20 ml of 10% potassium carbonate and then with 20 ml of saturated saline. After the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a brown oil. Thereafter, the oil was purified by silica gel column chromatography to obtain 0.23 g of a colorless and transparent oil.

The yield based on flurbiprofen was 70%.

Elemental analysis of the obtained colorless and transparent oil, ¹ H-NM
As a result of R spectrum analysis, mass spectrum analysis, IR spectrum analysis, refractive index, and ultraviolet absorption spectrum analysis, it was confirmed that the substance was 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate.

 The analysis results of the obtained oil are shown below.

Elemental analysis: C ₁₉ H ₁₉ FO ₄ (molecular weight: 330) Calculated (%): C 69.09 H 5.76 Actual (%): C 69.16 H 5.89 ¹ H-NMR spectrum analysis (in CCl ₄ ; internal standard: TMS) ) (Pp
m) δ 6.90-7.43 (m, 8H, aromatic H) Mass spectrum analysis (20 eV, direct) m / e 330 (M ⁺ ) m / e 43 [COCH ₃ ] ⁺ IR spectrum analysis (NaCl plate, neat) (cm ^-1 ) 3060-2875 (aromatic, alkyl, νC-H) 1770 (νC = O ester) 1630 (aromatic νC = C ) Refractive index ▲ n ^24.5 _D ▼ = 1.5353 Ultraviolet absorption spectrum (ethanol solution, 25 ° C.) λmax = 247 nm Example 2 11.5 mg of d-10-camphorsulfonic acid as an acid catalyst
(0.05 mmol) and stirred at 80 ° C. for 25 hours,
The reaction was carried out in the same manner as in Example 1. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 1 to obtain 0.21 g of an oily compound. The yield based on flurbiprofen was 65%. The instrumental analysis values of the obtained compound were consistent with those of the compound obtained in Example 1.

Example 3 0.01 ml (0.16 mmol) of metal sulfonic acid as an acid catalyst
The reaction was carried out in the same manner as in Example 1 except that the mixture was stirred at 40 ° C. for 5 hours. After completion of the reaction, treatment and purification were carried out in the same manner as in Example 1 to obtain 0.26 g of an oily compound. The yield based on flurbiprofen was 80%. The instrumental analysis values of the obtained compound were consistent with those of the compound obtained in Example 1.

Example 4 As an acid catalyst, boron trifluoride etherate (BF ₃ Et ₂
O) The reaction was carried out in the same manner as in Example 1 except that 28 μl (0.1 mmol) of the mixture was stirred at 40 ° C. for 25 hours. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 1 to obtain an oily compound in 0.1 ml.
27g. 82% yield based on flurbiprofen
Met. The instrumental analysis values of the obtained compound were consistent with those of the compound obtained in Example 1.

Example 5 Stannous chloride (SnCl ₂ .H ₂ O) 20.7 mg as an acid catalyst
(0.01 mmol), and the reaction was carried out in the same manner as in Example 1 except that the mixture was stirred at 80 ° C. for 5 hours. After completion of the reaction, treatment and purification were carried out in the same manner as in Example 1 to obtain 0.13 g of an oily compound.
The yield based on flurbiprofen was 40%.
The instrumental analysis values of the obtained compound were consistent with those of the compound obtained in Example 1.

Example 6 13.6 mg (0.1 mmol) of zinc chloride (ZnCl ₂ ) as an acid catalyst
The reaction was carried out in the same manner as in Example 1 except that the mixture was stirred at 80 ° C. for 5 hours. After completion of the reaction, treatment and purification were carried out in the same manner as in Example 1 to obtain 0.07 g of an oily compound. The yield based on flurbiprofen was 20%. The instrumental analysis values of the obtained compound were consistent with those of the compound obtained in Example 1.

〔The invention's effect〕

According to the method of the present invention, using an easily available raw material,
1-acetoxyethyl 2-
(2-Fluoro-4-biphenylyl) propionate can be obtained. Therefore, the manufacturing cost can be kept low.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07C 67/10 9546-4H C07C 67/10 // C07B 61/00 300 C07B 61/00 300

Claims (3)

(57) [Claims] (1) Formula (I): 1,1-ethylidene diacetate represented by the formula (II): 2- (2-fluoro-4-biphenylyl) represented by
Transesterification with propionic acid in the presence of an acid catalyst gives a compound of formula (III): A method for producing 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate represented by the formula: 2. The 1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) according to claim 1, wherein the acid catalyst is a Lewis acid selected from the group consisting of boron trifluoride, zinc chloride and stannous chloride. ) A method for producing propionate. 3. The 1-acetoxyethyl 2- (2-fluoro-acid) according to claim 1, wherein the acid catalyst is a sulfonic acid selected from the group consisting of p-toluenesulfonic acid, d-camphorsulfonic acid and methanesulfonic acid. 4-biphenylyl)
A method for producing propionate.