JPH08119905A - Production of ethyl benzylpyruvate - Google Patents

Abstract

PURPOSE: To provide a process for producing ethyl benzylpyruvate in one step and high yield. CONSTITUTION: Ethyl benzylpyruvate is produced by reacting 2- bromoethylbenzene with metallic magnesium, reacting the obtained Grignard reagent with diethyl oxalate to obtain a Grignard complex and hydrolyzing the complex. The above reactions are carried out by using t-butyl methyl ether(BME) as a reaction solvent in the reaction of 2-bromoethylbenzene with metallic magnesium and the reaction of the Grignard reagent with diethyl oxalate.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing ethyl benzylpyruvate. More specifically, it relates to a one-step method for producing ethyl benzylpyruvate by Grignard reaction, which is useful as a synthetic intermediate for angiotensin converting enzyme inhibitors and the like in blood pressure lowering agents.

[0002]

2. Description of the Related Art Conventionally, as a method for producing ethyl benzylpyruvate, many multistep production methods have been known. For example, a method based on the addition reaction of an alkyllithium reagent to triethoxyacetonitrile (Tetrahedron Lett., 1981, 1509), a method based on the reaction of ethyl α-oxo-1H-imidazole-1-acetate with a Grignard reagent (J. Org. Chem., 198
1, 46 , 211), a method based on the alcoholysis of acyl cyanides (Tetrahedron Lett., 1980, 3539), and a method based on the acylation of mercaptal anions with ethyl chloroformate (J. Org. Chem., 1963, 28, 96
1), a method based on alkylation by homogeneous reaction of 1,3-dithian-2-carboxylate (J.Org.Chem., 19
72, 37 , 505), 1,3-dithiane-2-carboxylate-based alkylation-based method (Synth
etic Comm., 1981, 11 , 343), a method based on the addition reaction of methyl methylthiomethyl sulfoxide to nitrile (Tetrahedron Lett., 1978, 375), and a method based on the addition reaction of Grignard reagent to diethyl oxalate.
(Synthetic Comm., 1981, 11 , 943).

However, among these, all of the methods (1) to (9) require multi-steps and are disadvantageous in industrial production as compared with the one-step production method. The method of 1 is excellent in that ethyl benzylpyruvate can be produced by a one-step reaction, but the yield is 55%.
Therefore, further improvement is desired.

Therefore, an object of the present invention is to provide a method for producing ethyl benzylpyruvate which is useful as a synthetic intermediate for angiotensin converting enzyme inhibitors and the like in antihypertensive agents in one step in high yield. .

[0005]

Means for Solving the Problems As a result of various investigations by the present inventors to solve such a problem, in the method (1), the Grignard complex once formed is further attacked by the Grignard reagent to produce a by-product. We found that the yield was low due to the occurrence, and we found that there was a point in controlling the excess reaction by this Grignard reagent. As a result of various studies on such control methods, the reaction proceeds when the Grignard reagent and diethyl oxalate are reacted in a solvent in which the product, the Grignard complex, is difficult to dissolve, for example, tert-butyl methyl ether (BME). As the Grignard complex precipitates and moves out of the reaction system, excess reaction can be effectively reduced,
It was discovered that the target ethyl benzylpyruvate could be produced in high yield, and further research was conducted to complete the present invention.

That is, the gist of the present invention is: (1) benzylpyrubin which is obtained by reacting 2-bromoethylbenzene with magnesium metal to obtain a Grignard reagent, then reacting with diethyl oxalate to obtain a Grignard complex, and then performing hydrolysis. In the method for producing ethyl acid salt, as a reaction solvent in the reaction between 2-bromoethylbenzene and magnesium metal and the reaction between Grignard reagent and diethyl oxalate,
a method for producing ethyl benzylpyruvate, characterized in that tert-butyl methyl ether (BME) is used;
(2) As the reaction solvent, a mixed solvent of BME and another inert organic solvent is used, (3) the method described in (1), and as a reaction solvent, 0.3 to 1 relative to the Grignard reagent. BM containing 1 mol of tetrahydrofuran
E solution or a mixed solvent solution of BME and another inert organic solvent is used (1) or (2)
The method described in (4) the inert organic solvent is diethyl ether, diisopropyl ether, dimethoxyethyl ether, tetrahydrofuran, dioxane, 1,3-dioxolane, toluene, benzene, xylene, hexane,
The method according to (2) or (3), which is one or more solvents selected from the group consisting of cyclohexane, pyridine, and triethylamine, and (5) the mixing ratio (volume ratio) of the mixed solvent is BME1. The method according to any one of (2) to (4), wherein the method is 1 or less.
And (6) The method according to any one of (1) to (5), wherein the reaction between the Grignard reagent and diethyl oxalate is carried out under the condition that a Grignard complex as a product is precipitated.

The present invention will be described in detail below. The present invention is an improved method for producing ethyl benzylpyruvate by reacting 2-bromoethylbenzene with metallic magnesium to obtain a Grignard reagent, then reacting with diethyl oxalate to obtain a Grignard complex, and then performing hydrolysis. Is. That is, the conventional method (Synthetic Comm., 1981,
11 , 943), the Grignard complex once formed is further attacked by the Grignard reagent to form a by-product, which lowers the yield.In order to avoid this, the Grignard reaction is performed in an organic solvent in which the Grignard complex is difficult to dissolve. There is the point in doing it. Under such conditions, the Grignard complex formed as a result of the Grignard reaction is successively precipitated, so that the Grignard complex can be transferred to the outside of the reaction system and further attack by the Grignard reagent can be avoided, and thus the yield of the Grignard complex is improved. However, the solvent for the Grignard reaction is also substantially the solvent for preparing the Grignard reagent. This is because the Grignard reaction is a reaction performed by adding a Grignard reagent solution to diethyl oxalate. Therefore, first, the solvent used when preparing the Grignard reagent will be described.

The Grignard reagent used in the present invention can be prepared by reacting metallic magnesium with 2-bromoethylbenzene according to a conventional method. As the reaction solvent, tert-butyl methyl ether (BME) or a mixed solvent of BME and an inert organic solvent is preferably used from the viewpoint that the Grignard reaction is carried out in an organic solvent in which the Grignard complex is difficult to dissolve. Then, from the viewpoint of the initiation reaction and the solubility of the Grignard reagent, it is carried out in BME or a mixed solvent of BME and an inert organic solvent containing about 0.3 to 1.1 mol of tetrahydrofuran in the Grignard reagent to be prepared. Is more preferable.
This is because when the Grignard reagent is solvated with tetrahydrofuran, the solubility in a hydrophobic organic solvent such as ether is remarkably increased, the dispersion in the reaction solvent is improved, and the Grignard reagent synthesis reaction proceeds efficiently. .

Here, the inert organic solvent means a solvent which is not attacked by the Grignard reagent, for example, ethers such as diethyl ether, diisopropyl ether, dimethoxyethyl ether, tetrahydrofuran, dioxane, 1,3-dioxolane, toluene, benzene, xylene, Solvents such as hexane, cyclohexane, pyridine, triethylamine and the like are meant.

The mixing ratio (volume ratio) of BME and the inert organic solvent is usually 1 or less with respect to BME1 of the inert organic solvent. This is because in this range, the same effect as BME can be obtained.

The reaction conditions for reacting 2-bromoethylbenzene with magnesium metal to obtain a Grignard reagent are as follows:
There is no particular difference from the conventional method. All the containers and reagents used in the reaction are kept dry, and the steam is blocked by N ₂ substitution and N ₂ sealing. A reaction vessel such as a four-necked flask is charged with metallic magnesium and dried BME or dry BME containing about 0.5 to 1.1 times mol of tetrahydrofuran as metallic magnesium is charged, and a small amount of I ₂ is added.
Charge. To this, a portion of dry BME containing 2-bromoethylbenzene in an equimolar amount to metallic magnesium is added and stirred at room temperature. After the iodine color disappeared and the initiation reaction was observed, the rest of the dry BME containing 2-bromoethylbenzene was slowly added dropwise, and the mixture was kept warm with stirring for a certain period of time. The temperature at this time is usually 30 to 60 ° C, preferably 50 to 60 ° C. The reaction time, that is, the dropping time and the subsequent heat retention time are usually 1 depending on the amount of the reaction solution, the reaction temperature, etc.
~ 12 hours, preferably 1-3 hours. The reaction solution thus obtained is used as it is for the reaction with diethyl oxalate.

2-Bromoethylbenzene used in the present invention is commercially available from Wako Pure Chemical Industries, Ltd., and metallic magnesium is
Commercial products are available from Wako Pure Chemical Industries, Ltd., and BME are commercially available from Tokyo Kasei.

[0013] The reaction of Grignard reagents with diethyl oxalate is, N ₂ substitution was charged a small amount of first diethyl oxalate neck flask was N ₂ seal, followed by reaction with oxalic acid containing Grignard reagent obtained as described above Diethyl is poured in parallel, and the reaction is usually carried out at −30 to 50 ° C., preferably −15 to 20 ° C. for 1 to 15 hours with stirring. The Grignard complex formed by the reaction gradually precipitates and moves out of the reaction system. Deposition may be difficult depending on the solvent, but in such a case, the reaction temperature is kept low. The Grignard complex thus obtained is then subjected to hydrolysis.

The diethyl oxalate used in the present invention is commercially available from Wako Pure Chemical Industries.

The hydrolysis is carried out as follows. After charging hydrochloric acid water into a N ₂ -substituted and N ₂ -sealed four-necked flask and cooling to 5 to 15 ° C., a reaction solution containing a Grignard complex and concentrated hydrochloric acid water were co-injected at low temperature, and further to 5 to 15 ° C. Incubate for 0.1 to 1 hour. This processing is also almost the same as the conventional method. Thus, the desired product, ethyl benzylpyruvate, is obtained.

In order to isolate the desired ethyl benzylpyruvate, the above reaction solution is separated and the organic solvent layer is separated,
After washing successively with aqueous sodium bicarbonate and aqueous sodium chloride, the solvent is distilled off to obtain ethyl benzylpyruvate. The ethyl benzylpyruvate obtained by the present invention is useful as a synthetic intermediate for angiotensin converting enzyme inhibitors and the like in antihypertensive agents.

[0017]

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

[0018] thermometer four-necked flask 500ml-volume drying may Example 1, a cooling tube conducts rigorous N ₂ substitution mounting was subjected to N ₂ seal the cooling tube top. Then, 0.2 mol (4.84 g) of Mg was charged, and then 0.11 mol (8) of tetrahydrofuran (THF) dried with a molecular sieve.
g) and tert-butyl methyl ether (BME) 8 g
And a little I ₂ . Further, 6 ml of a liquid obtained by mixing 0.2 mol (37.4 g) of 2-bromoethylbenzene with 84 g of BME dried with molecular sieves was added, and the mixture was stirred at room temperature. After the iodine color disappears and the fever is confirmed,
The remaining mixed solution of 2-bromoethylbenzene and BME was added dropwise at 52 to 57 ° C over 1 hour. 55-
Incubate at 60 ℃ for 1 hour and then cool to 20 ℃,
The reaction solution was transferred to a dropping funnel having a volume of ml.

After thoroughly drying, a thermometer, a stirrer, and a cooling pipe were attached, N ₂ was sufficiently replaced, and a 500 ml four-necked flask sealed with N ₂ from the upper part of the cooling pipe was used. Charge 0.036 mol (5.3 g), 1
Cooled to 0 ° C. Then, 0.205 mol (30 g) of diethyl oxalate and a Grignard reagent of 2-bromoethylbenzene were co-injected at 5 to 10 ° C over 80 minutes. After incubating for 15 minutes, raise the temperature to 50 ° C and heat at 50-55 ° C for 30 minutes.
It was kept warm for a minute, then cooled to 30 ° C., and transferred to a 500 ml dropping funnel.

A 1000 ml four-necked flask equipped with a thermometer, a stirrer, and a cooling tube and sealed with N ₂ from the top of the cooling tube was charged with 64 g of 6.7% HCl water and cooled to 10 ° C. Next, the reaction solution containing the Grignard complex and 18
Aqueous HCl solution (14 g) was co-injected at 15 ° C or lower over 15 minutes. After keeping the temperature for 10 minutes, the layers were separated, and the oil layer was mixed with 40 g of water and 0.
It was washed with 40 g of 4% NaHCO ₃ water and 20 g of NaCl water. The mixture was concentrated under reduced pressure at 40 to 50 ° C to obtain 31.1 g of ethyl benzylpyruvate. The yield was 75.4%.

Example 2 A well-dried four-necked flask having a capacity of 500 ml was equipped with a thermometer and a cooling tube to sufficiently perform N ₂ substitution, and N _{2 was} sealed from the upper part of the cooling tube. Then, 0.2 mol (4.84 g) of Mg was charged, and then tert-butyl methyl ether (BME) 16 dried with a molecular sieve was used.
I added a little bit of g and I ₂ . Further, 6 ml of a liquid obtained by mixing 0.2 mol (37.4 g) of 2-bromoethylbenzene with 84 g of BME dried with molecular sieves was added, and the mixture was stirred at room temperature. After the color of iodine disappeared and heat generation was confirmed, the remaining mixed solution of 2-bromoethylbenzene and BME was added dropwise at 52 to 57 ° C over 1 hour. 5 more
Incubate at 5-60 ° C for 1 hour and then cool to 40 ° C.
The reaction solution was transferred to a dropping funnel having a volume of 00 ml.

After thoroughly drying, a thermometer, a stirrer, and a cooling tube were attached, N ₂ was sufficiently replaced, and a 500 ml four-necked flask sealed with N ₂ from the upper part of the cooling tube was used. Charge 0.036 mol (5.3 g), 1
Cooled to 0 ° C. Then, 0.205 mol (30 g) of diethyl oxalate and a Grignard reagent of 2-bromoethylbenzene were co-injected at 5 to 10 ° C over 80 minutes. After incubating for 15 minutes, raise the temperature to 50 ° C and heat at 50-55 ° C for 30 minutes.
It was kept warm for a minute, then cooled to 30 ° C., and transferred to a 500 ml dropping funnel.

A 1000 ml four-necked flask equipped with a thermometer, a stirrer and a cooling tube and sealed with N ₂ from the upper part of the cooling tube was charged with 64 g of 6.7% HCl water and cooled to 10 ° C. Next, the reaction solution containing the Grignard complex and 18
Aqueous HCl solution (14 g) was co-injected at 15 ° C or lower over 15 minutes. After keeping the temperature for 10 minutes, the layers were separated, and the oil layer was mixed with 40 g of water and 0.
It was washed with 40 g of 4% NaHCO ₃ water and 20 g of NaCl water. It concentrated at 40-50 degreeC under reduced pressure, and obtained 28.2g of ethyl benzyl pyruvates. The yield was 68.5%.

The thermometer four-necked flask 500ml-volume drying well Example 3, cooling tube conducts rigorous N ₂ substitution mounting was subjected to N ₂ seal the cooling tube top. Then, 0.2 mol (4.84 g) of Mg was charged, and then tert-butyl methyl ether (BME) 16 dried with a molecular sieve was used.
I added a little bit of g and I ₂ . Further, 6 ml of a liquid obtained by mixing 0.2 mol (37.4 g) of 2-bromoethylbenzene with 84 g of BME dried with molecular sieves was added, and the mixture was stirred at room temperature. After the color of iodine disappeared and heat generation was confirmed, the remaining mixed solution of 2-bromoethylbenzene and BME was added dropwise at 52 to 57 ° C over 1 hour. 5 more
Incubate at 5-60 ° C for 1 hour and then cool to 40 ° C.
The reaction solution was transferred to a dropping funnel having a volume of 00 ml.

After thoroughly drying, a thermometer, a stirrer, and a cooling tube were attached, N ₂ was sufficiently replaced, and a 500 ml four-necked flask sealed with N ₂ from the top of the cooling tube was charged with diisopropyl ether. 15 g and diethyl oxalate 0.
036 mol (5.3 g) was charged and cooled to 10 ° C. Subsequently, 0.205 mol (30 g) of diethyl oxalate and 2- to 5-bromoethylbenzene Grignard reagent were added to 5-1.
Parallel injection was performed at 0 ° C. for 80 minutes. After incubating for 15 minutes, 5
The temperature was raised to 0 ° C., kept at 50 to 55 ° C. for 30 minutes, cooled to 30 ° C., and transferred to a 500 ml dropping funnel.

A 1000 ml four-necked flask equipped with a thermometer, a stirrer and a cooling tube and sealed with N ₂ from the upper side of the cooling tube was charged with 64 g of 6.7% HCl water and cooled to 10 ° C. Next, the reaction solution containing the Grignard complex and 18
Aqueous HCl solution (14 g) was co-injected at 15 ° C or lower over 15 minutes. After keeping the temperature for 10 minutes, the layers were separated, and the oil layer was mixed with 40 g of water and 0.
It was washed with 40 g of 4% NaHCO ₃ water and 20 g of NaCl water. It concentrated under reduced pressure at 40-50 degreeC, and obtained 28.9g of ethyl benzyl pyruvates. The yield was 70.0%.

Examples 4, 5, 6 Instead of the diisopropyl ether of Example 3, 15 g of dimethoxyethyl ether, toluene or hexane was used.
Was carried out in the same manner as in Example 3. The yields at that time were 72%, 73%, or 69%, respectively.

The thermometer four-necked flask 500ml-volume drying may Example 7, a cooling tube conducts rigorous N ₂ substitution mounting was subjected to N ₂ seal the cooling tube top. Then, 0.2 mol (4.84 g) of Mg was charged, and then tert-butyl methyl ether (BME) 16 dried with a molecular sieve was used.
Some g and I ₂ were charged. Further, 6 ml of a liquid prepared by mixing 0.2 mol (37.4 g) of 2-bromoethylbenzene with a mixed liquid of 42 g of BME and 42 g of diisopropyl ether dried with molecular sieves was stirred at room temperature. After the iodine color disappeared and heat generation was confirmed, the remaining mixed solution of 2-bromoethylbenzene, BME, and diisopropyl ether was added dropwise at 52 to 57 ° C over 1 hour. After incubating at 55-60 ℃ for 1 hour, 40 ℃
The reaction solution was transferred to a dropping funnel having a volume of 300 ml.

After thoroughly drying, a thermometer, a stirrer, and a cooling pipe were attached, N ₂ was sufficiently replaced, and a 500 ml four-necked flask sealed with N ₂ from the top of the cooling pipe was placed in diethyl oxalate. 0.036 mol (5.3 g) was charged and cooled to 10 ° C. Then, diethyl oxalate 0.2
The Grignard reagent of 05 mol (30 g) and 2-bromoethylbenzene was co-injected at 5 to 10 ° C over 80 minutes. 1
After keeping the temperature for 5 minutes, the temperature is raised to 50 ° C, the temperature is kept at 50 to 55 ° C for 30 minutes, then cooled to 30 ° C,
It was transferred to a dropping funnel having a capacity of ml.

A 1000 ml four-necked flask equipped with a thermometer, a stirrer and a cooling tube and sealed with N ₂ from the upper side of the cooling tube was charged with 64 g of 6.7% HCl water and cooled to 10 ° C. Next, the reaction solution containing the Grignard complex and 18
Aqueous HCl solution (14 g) was co-injected at 15 ° C or lower over 15 minutes. After keeping the temperature for 10 minutes, the layers were separated, and the oil layer was mixed with 40 g of water and 0.
It was washed with 40 g of 4% NaHCO ₃ water and 20 g of NaCl water. It concentrated under reduced pressure at 40-50 degreeC, and obtained 28.9g of ethyl benzyl pyruvates. The yield was 70.0%.

[0031]

Industrial Applicability According to the production method of the present invention, ethyl benzylpyruvate can be produced in one step and in a high yield.

Claims (6)

[Claims] 1. A method for producing ethyl benzylpyruvate, which comprises reacting 2-bromoethylbenzene with metallic magnesium to obtain a Grignard reagent, then reacting with diethyl oxalate to obtain a Grignard complex, and then performing hydrolysis. A method for producing ethyl benzylpyruvate, which comprises using tert-butyl methyl ether (BME) as a reaction solvent in a reaction between bromoethylbenzene and metallic magnesium and a reaction between a Grignard reagent and diethyl oxalate. 2. The method according to claim 1, wherein a mixed solvent of BME and another inert organic solvent is used as a reaction solvent. 3. The method according to claim 1, wherein a mixed solvent further containing 0.3 to 1.1 mol of tetrahydrofuran based on the Grignard reagent is used as a reaction solvent. 4. The inert organic solvent is diethyl ether,
Diisopropyl ether, dimethoxyethyl ether,
The method according to claim 2 or 3, which is one or more solvents selected from the group consisting of tetrahydrofuran, dioxane, 1,3-dioxolane, toluene, benzene, xylene, hexane, cyclohexane, pyridine and triethylamine. . 5. The mixing ratio (volume ratio) of the mixed solvent is BME.
The method according to any one of claims 2 to 4, wherein the ratio is 1 or less per 1. 6. The method according to claim 1, wherein the reaction between the Grignard reagent and diethyl oxalate is carried out under the condition that the product Grignard complex is precipitated.