JPH0820567A - Production of o-benzoylbenzamides - Google Patents

Abstract

PURPOSE:To readily obtain the subject compounds useful as a raw material for medicines in high yield and purity by reacting an o-benzoylbenzoic acid with thionyl chloride and then reacting the resultant compound with ammonia gas. CONSTITUTION:This method for producing o-benzoylbenzamides of formula II (R1 to R4 are each H, alkyl, alkoxy or halogen) is to react a compound of formula I with thionyl chloride in an organic solvent (e.g. toluene) at -20 to +100 deg.C, further introducing ammonia gas in the absence of water into the reactional system and reacting the resultant compound therewith at -20 to +60 deg.C under reduced pressure. Thereby, the formation of both an acid chloride from the acid with the thionyl chloride and acid amide from the acid chloride with the ammonia can be carried out in the same bath. The organic solvent is used in a volume of 1-50 times (vol./wt.) based on the compounds of formula I and the thionyl chloride is used at 0.9-2.0 molar ratio to the compounds of formula I. Dimethylformamide is preferably used as a catalyst in reacting the thionyl chloride therewith.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing o-benzoylbenzoic acid amides.

[0002]

2. Description of the Related Art o-Benzoylbenzoic acid amides are important intermediates as raw materials for medicines. As a method for producing o-benzoylbenzoic acid amides, 1) a method of thermally decomposing an ammonium salt of o-benzoylbenzoic acid 2) J. C. S. , 1948, 292-295; in chloroform, O-benzoylbenzoic acid is reacted with thionyl chloride to form an acid chloride, chloroform and thionyl chloride are distilled off, and benzene is further added,
Distill to remove traces of thionyl chloride. Furthermore, 0
There is a method of adding ammonia water at -5 ° C to obtain an amide. However, there are problems that the reaction temperature is high, the raw materials are dangerous, there is a problem in safety, etc., and it is difficult to call it an industrial method.

[0003]

As described above, the conventional synthetic method requires a complicated operation and cannot be manufactured industrially at low cost, and thus an inexpensive manufacturing method has been desired.

[0004]

The method 1) of the conventional method for producing an acid amide described above is a method that can be easily performed in a laboratory, but in the case of industrial production, a special production apparatus is used. It is necessary and the reaction is not easy to control. The method 2) uses a solvent that is dangerous to the human body, such as chloroform and benzene, so it is not industrial as it is. As a result of detailed examination of the method 2), the present inventor has found that the acid chloride formation of an acid with thionyl chloride and the acid amidation formation of ammonia can be easily produced in the same bath, and the present invention has been completed.

That is, the present invention is as follows: (1) Reaction of o-benzoylbenzoic acid with thionyl chloride in an organic solvent, and further ammonia gas
A method for producing o-benzoylbenzoic acid amides, which is characterized by introducing into a reaction system (2) o-benzoylbenzoic acid is a compound represented by the following formula (1),

Embedded image (In the formula, R _{1 to} R ₄ represent a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom, and R _{1 to} R ₄ may be the same or different.) O-benzoylbenzoic acid amide The method for producing o-benzoylbenzoic acid amides according to the above item (1), wherein the compound is a compound represented by the following formula (2):

[Chemical 4] (In the formula, R _{1 to} R ₄ represent a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom, and R _{1 to} R ₄ may be the same or different.) (3) Thionyl chloride The reaction temperature is -20
The method for producing o-benzoylbenzoic acid amides according to the above (1) or (2), which is -100 ° C (4) The temperature at which ammonia gas is reacted is -20 to 6
Method for producing o-benzoylbenzoic acid amide according to the above (1), (2) or (3), which is 0 ° C. (5) The organic solvent is selected from toluene, xylene, chlorobenzene and dichlorobenzene. The above-mentioned items (1), (2), which are one kind or a mixture of two or more kinds,
(3) or the manufacturing method of o-benzoyl benzoic acid amide as described in (4) (6) The preceding paragraph (1), which introduces ammonia gas under reduced pressure,
(2), (3), (4) or (5) The method for producing o-benzoylbenzoic acid amides according to (5) (7) The temperature at which thionyl chloride is reacted is 0 to 8
The above-mentioned (1), (2), (3), (4), which is 0 ° C.,
(5) or a method for producing o-benzoylbenzoic acid amides according to (6) (8) In the case of reacting thionyl chloride, the catalytic amount of dimethylformamide is added (1), (2),
O- according to (3), (4), (5), (6) or (7)
Method for producing benzoylbenzoic acid amide (9) The temperature at which thionyl chloride is reacted is 20 to 20.
The above (1), (2), (3), (4), which is 50 ° C.,
(5), (6), (7) or (8) The method for producing o-benzoylbenzoic acid amides according to (8) The temperature at which ammonia gas is reacted is 0 to 30.
The above (1), (2), (3), (4)
O- according to (5), (6), (7), (8) or (9)
Method for producing benzoylbenzoic acid amides (11) The above-mentioned (1), (2), which is a solvent in which water is not present in the organic solvent when reacting with ammonia gas.
(3), (4), (5), (6), (7), (8),
(9) A method for producing o-benzoylbenzoic acid amides according to (10) (12) In the formula (1), any of R _{1 to} R ₄ is a hydrogen atom, (1), (2), ( 3), (4),
(5), (6), (7), (8), (9), (10) or (11) The method for producing o-benzoylbenzoic acid amides according to (13) The temperature for reacting ammonia gas is 0-15
The above (1), (2), (3), (4)
(5), (6), (7), (8), (9), (10),
(11) A method for producing o-benzoylbenzoic acid amides according to (12), (14) The above-mentioned item (1), wherein the organic solvent is toluene.
(2), (3), (4), (5), (6), (7),
(8), (9), (10), (11), (12) or (13) The method for producing o-benzoylbenzoic acid amides according to (15) (15) Reaction of o-benzoylbenzoic acids with thionyl chloride Ammonia gas is reacted without separating the obtained acid chloride from the reaction solvent, and the above (1), (2), (3), (4), (5),
(6), (7), (8), (9), (10), (1
1), (12), (13) or (14) The method for producing o-benzoylbenzoic acid amides according to

The present invention will be described in detail below. O-Benzoylbenzoic acids are added to the organic solvent, and water is separated while refluxing the solvent as needed. If the o-benzoylbenzoic acid is sufficiently anhydrous, this operation is not necessary.
Sufficiently anhydrous means that the water content is 0.5% or less. Keeping the temperature within a certain range, add thionyl chloride slowly. If the temperature is low and the reaction rate is slow, a catalytic amount of dimethylformamide is added. After the reaction is complete,
Excessive thionyl chloride and dimethylformamide are distilled off under reduced pressure. At this time, before blowing in ammonia,
The acid chloride formed may or may not be separated from the reaction solvent, but it is preferable not to separate it. Then, the temperature is kept within a certain range, and ammonia gas is blown in. After the reaction is completed, the reaction mixture is filtered under reduced pressure and sufficient washing water is added to remove ammonia, ammonia chloride, and ammonia salts of o-benzoylbenzoic acids. Or, wash it with water to some extent, transfer the cake to a beaker, add a large amount of water,
Stir well, filter again under reduced pressure, and wash with water. Alternatively, the reaction solution is depressurized and heated, most of the solvent is distilled off, water is then added, and the remaining organic solvent is distilled off to obtain a highly pure o-
Benzoylbenzoic acid amides are obtained. Further, an aqueous suspension of the reaction product is filtered under reduced pressure, washed with sufficient water, and dried under reduced pressure to obtain high-purity o-benzoylbenzoic acid amides.

Specific examples of the o-benzoylbenzoic acids of the formula (1) used in the present invention include 2- (4'-chlorobenzoyl) benzoic acid, 2- (4'-bromobenzoyl) benzoic acid and 2- (4'-Fluorobenzoyl) benzoic acid, 2- (4'-methylbenzoyl) benzoic acid, 2-
(4'-Methoxybenzoyl) benzoic acid, 3-chloro-
2- (4'-chlorobenzoyl) benzoic acid, 4-chloro-2- (4'-chlorobenzoyl) benzoic acid, 5-chloro-2- (4'-chlorobenzoyl) benzoic acid, 6-chloro-2- (4'-chlorobenzoyl) benzoic acid, 4,
Examples thereof include 5-dichloro-2- (4'-chlorobenzoyl) benzoic acid and o-benzoylbenzoic acid. Above all o
-Benzoylbenzoic acid is preferred.

As the organic solvent, toluene, xylene,
Examples thereof include chlorobenzene and dichlorobenzene. Of these, toluene is preferable. The amount used is 1 to 50 (volume / weight) times, preferably 1 to 10 (volume / weight) times, and particularly preferably 2 to o-benzoylbenzoic acids.
7 (volume / weight) times. When it exceeds 50 times, the production efficiency is deteriorated, and when it is less than 1 time, acid chloride is precipitated. The temperature for reacting thionyl chloride is -20 to 100 ° C.
And preferably 0 to 80 ° C., particularly preferably 2
It is 0 to 50 ° C. When the temperature exceeds 100 ° C, the production of by-products is activated. If it is lower than -20 ° C, the reaction rate is slow. The amount of thionyl chloride used is not particularly limited, but is preferably 0.9 to 2.0 mol ratio with respect to o-benzoylbenzoic acid. When the reaction temperature is below 50 ° C., it is preferred to use dimethylformamide as catalyst. The amount used is not particularly limited, but with respect to o-benzoylbenzoic acids,
0.1 to 20% by weight is preferable. The lower the reaction temperature, the higher the amount used. The reaction time for reacting thionyl chloride is 0.5 to 20 hours, preferably 1 to 10 hours. After the reaction with thionyl chloride, if excess thionyl chloride is present, it may be removed under reduced pressure by distillation under reduced pressure. Similarly, dimethylformamide may be removed from the reaction system by distillation under reduced pressure.

When reacting with ammonia gas, the temperature is -20 to 60 ° C, preferably 0 to 30 ° C, particularly preferably 0 to 15 ° C. When it exceeds 60 ° C, the concentration of ammonia dissolved in the reaction solution becomes low and the reaction rate becomes low. When the temperature is lower than -20 ° C, o-benzoylbenzoyl chlorides are precipitated and the reaction rate becomes slow. Since the reaction rate is defined by the flow rate of ammonia, the reaction time is 0.5 to 20 hours, preferably 0.5 to 10 hours,
Particularly preferably, the ammonia flow rate is adjusted so as to be 1 to 5 hours. If the amount of o-benzoylbenzoyl chloride as a raw material decreases, the reaction rate becomes extremely slow. HPL
The reaction is completed when the area percentage of C (high performance liquid chromatography) is 1% or less of o-benzoylbenzoic acid chlorides. HPLC analysis conditions: INERTSIL ODS-2 4.6 mm × 15 cm Acetonitrile / 0.3% phosphoric acid = 50/50 (VOL
/ VOL) 0.8 ml / min 35 ° C. The reaction system in which ammonia gas is introduced is under reduced pressure and normal pressure.
Although any pressure such as under pressure is possible, a reduced pressure system is preferable from the viewpoint of controlling the reaction rate and saving the amount of ammonia used. The pressure is reduced to 20 to 100 mmHg, and the flow rate is controlled using the reaction temperature as a guide. Return to normal pressure to complete the reaction. When introducing ammonia, it is preferable that water is not present in the reaction system, so ammonia gas is used.

[0010]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. In HPLC analysis,% is area%.

Example 1 A 500 cc four-necked flask equipped with a stirrer and a thermometer was used.
70 g of o-benzoylbenzoic acid, 210 cc of toluene
And heated to 40 ° C, thionyl chloride 40.5g
Was added dropwise over 15 minutes. The temperature dropped to 35 ° C.
Dimethylformamide 0.6 cc was added. Then, the reaction was completed by holding at 25 to 40 ° C. for 3 hours. HPLC analysis: raw material 0.36%, acid chloride 9
9.3%. Further, the temperature was maintained at 40 to 50 ° C., and nitrogen was bubbled through the reaction solution for 2 hours. Then, toluene, thionyl chloride and dimethylformamide were distilled at 40 to 50 ° C. under reduced pressure with an aspirator. When 115 cc of a toluene solution containing thionyl chloride and dimethylformamide was distilled off, 225 cc of new toluene was added and the mixture was cooled to 5 ° C or lower. Check the degree of vacuum at 25 mmHg and seal the container. Ammonia gas was introduced while maintaining the temperature below 7 ° C. After 2.5 hours, the reaction system returned to normal pressure, so the introduction of ammonia was stopped. After 4.0 hours H
According to PLC analysis, the starting acid chloride was 1.0% and the acid amide was 98.0%, so the temperature was returned to room temperature, and the reaction solution was filtered under reduced pressure. The reaction flask was washed with 150 cc of toluene. Toluene was thoroughly removed from the filter cake and water was added to 200
It was washed with 0 cc. Transfer cake to 1 liter beaker and water
800 cc was added, and the mixture was stirred at room temperature for 2 hours. Further, it was filtered under reduced pressure. It was washed with 1000 cc of water. It was dried under reduced pressure with a desiccator. Yield of o-benzoylbenzoic acid amide
66.5 g, yield 95.5%, melting point 164-165
° C, HPLC purity 99.5%

Example 2 A 1-liter four-necked flask equipped with a stirrer and a thermometer was charged with 2-
(4′-Fluorobenzoyl) benzoic acid (100 g) and toluene (420 cc) were added, the mixture was heated to 30 ° C., and thionyl chloride (60.0 g) was added dropwise over 15 minutes. Further, 10 g of dimethylformamide was added. Then 2
The reaction was completed when kept at 0 to 30 ° C. for 4 hours. HP
LC analysis: raw material 0.36%, acid chloride 99.3%.
Then, toluene, thionyl chloride and dimethylformamide were distilled at 40 to 50 ° C. under reduced pressure with an aspirator. When a toluene solution containing thionyl chloride and dimethylformamide was distilled off by 270 cc,
270 cc of fresh toluene was added and cooled to 5 ° C or lower. Check the degree of vacuum at 25 mmHg and seal the container. Ammonia gas was introduced while maintaining the temperature below 7 ° C. After 2.5 hours, the reaction system returned to normal pressure, so the introduction of ammonia was stopped. After 4.0 hours, HPLC analysis revealed that the starting acid chloride was 1.0% and the acid amide was 98.0%, so the temperature was returned to room temperature, and the reaction solution was filtered under reduced pressure. The reaction flask was washed with 200 cc of toluene. Toluene is thoroughly removed from the filter cake. Transfer the cake to a 1 liter beaker and add water 8
00 cc was added, Perex SS-H (trade name, surfactant, manufactured by Kao Corporation) was added a little, and the mixture was stirred at room temperature for 2 hours. Further, it was filtered under reduced pressure. It was washed with 1000 cc of water. It was dried under reduced pressure with a desiccator. Yield of 2- (4′-fluorobenzoyl) benzoic acid amide 91.5 g, yield 92%, melting point 177-178 ° C., HPLC purity
99.5%

Example 3 A 1-liter 4-necked flask equipped with a stirrer and a thermometer was charged with 2-
(4'-Bromobenzoyl) benzoic acid 100g and toluene 420cc were added, it heated at 30 degreeC, and thionyl chloride 48.4g was dripped over 15 minutes. Further, 10 g of dimethylformamide was added. Then 20 ~
The reaction was completed when kept at 30 ° C. for 4 hours. HPLC
Analysis: 0.36% raw material, 99.3% acid chloride. Then, toluene, thionyl chloride and dimethylformamide were distilled at 40 to 50 ° C. under reduced pressure with an aspirator. When 270 cc of a toluene solution containing thionyl chloride and dimethylformamide was distilled off, the reduced pressure was returned to normal pressure, 270 cc of fresh toluene was added, and the mixture was cooled to 5 ° C or lower. Ammonia gas was introduced while maintaining the temperature below 7 ° C. After 2.5 hours, the reaction system returned to normal pressure, so the introduction of ammonia was stopped. HPLC after 4.0 hours
Analysis showed that the starting material acid chloride was 1.0%, and the acid amide was 9
Since it became 8.0%, while maintaining the temperature at 40 to 50 ° C., a toluene solution containing thionyl chloride and dimethylformamide was distilled off by about 300 cc, and then 300 cc of water was added,
Further, toluene was distilled off under reduced pressure. Then, the pressure was returned to normal pressure, and the precipitated acid amide was filtered under reduced pressure and washed with water. It was dried in a vacuum desiccator at room temperature. Yield of 2- (4′-bromobenzoyl) benzoic acid amide 89.6 g, yield
90%, melting point 213-215 ° C, HPLC purity 99.
4%.

Example 4 In a 500 cc four-necked flask equipped with a stirrer and a thermometer,
70 g of o-benzoylbenzoic acid and 210 cc of o-dichlorobenzene were added, the mixture was heated to 40 ° C., and 40.5 g of thionyl chloride was added dropwise over 15 minutes. The temperature is 35 ° C
Was going down. Dimethylformamide 0.6 cc was added. After that, if kept at 25 to 40 ° C for 3 hours,
The reaction is complete. HPLC analysis: starting material 0.36%, acid chloride 99.3%. Furthermore, by maintaining at 40 to 50 ° C, 2
Nitrogen was bubbled through the reaction for hours. After that, decompression with an aspirator, at 40 to 50 ° C., o-dichlorobenzene,
Thionyl chloride and dimethylformamide were distilled. When 115 cc of an o-dichlorobenzene solution containing thionyl chloride and dimethylformamide was distilled off, 225 cc of new o-dichlorobenzene was added, and 5
It was cooled to below ℃. Check the degree of vacuum at 25 mmHg and seal the container. Ammonia gas was introduced while maintaining the temperature below 7 ° C. After 2.5 hours, the reaction system returned to normal pressure, so the introduction of ammonia was stopped. HPLC after 4.0 hours
Analysis showed that the starting material acid chloride was 1.0%, and the acid amide was 9
Since the content became 8.0%, the temperature was returned to room temperature, and the mixture was filtered under reduced pressure.
The reaction flask was washed with 150 cc of o-dichlorobenzene. The o-dichlorobenzene was sufficiently removed from the filter cake and washed with 2000 cc of water. The cake was transferred to a 1-liter beaker, 800 cc of water was added, and the mixture was stirred at room temperature for 2 hours. Further, it was filtered under reduced pressure. It was washed with 1000 cc of water.
It was dried under reduced pressure with a desiccator. Yield of o-benzoylbenzoic acid amide 66.5 g, yield 95.5%, melting point 1
64-165 ° C, HPLC purity 99.5%

[0015]

According to the method of the present invention, o-benzoylbenzoic acid amides can be obtained with high yield, high purity and simple operation.
Can be manufactured.

Claims (15)

[Claims] 1. A method for producing o-benzoylbenzoic acid amides, which comprises reacting o-benzoylbenzoic acids with thionyl chloride in an organic solvent, and further introducing ammonia gas into the reaction system. 2. An o-benzoylbenzoic acid compound is a compound represented by the following formula (1): (In the formula, R _{1 to} R ₄ represent a hydrogen atom, an alkyl group, an alkoxy group, or a halogen atom, and R _{1 to} R ₄ may be the same or different.) O-benzoylbenzoic acid amide The method for producing o-benzoylbenzoic acid amides according to claim 1, wherein the compounds are compounds represented by the following formula (2). Embedded image (In the formula, R _{1 to} R ₄ represent a hydrogen atom, an alkyl group, an alkoxy group or a halogen atom, and R _{1 to} R ₄ may be the same or different.) 3. The temperature at which thionyl chloride is reacted is
The method for producing o-benzoylbenzoic acid amides according to claim 1 or 2, which is -20 to 100 ° C. 4. The temperature for reacting ammonia gas is -2.
The method for producing o-benzoylbenzoic acid amides according to claim 1, 2 or 3, which is 0 to 60 ° C. 5. The o-benzoyl according to claim 1, 2, 3 or 4, wherein the organic solvent is one kind selected from toluene, xylene, chlorobenzene and dichlorobenzene, or a mixture of two or more kinds. Method for producing benzoic acid amides. 6. The method for producing o-benzoylbenzoic acid amides according to claim 1, 2, 3, 4 or 5, wherein ammonia gas is introduced under reduced pressure. 7. The temperature at which thionyl chloride is reacted is
It is 0-80 degreeC, The manufacturing method of o-benzoyl benzoic acid amides of Claim 1, 2, 3, 4, 5 or 6. 8. When reacting with thionyl chloride,
A dimethylformamide is added in a catalytic amount.
The method for producing o-benzoylbenzoic acid amides according to 3, 4, 5, 6 or 7. 9. The temperature at which thionyl chloride is reacted is
It is 20-50 degreeC, Claims 1, 2, 3, 4, 5, 6, 7.
Or the method for producing o-benzoylbenzoic acid amides according to item 8. 10. The temperature for reacting ammonia gas is 0.
-30 degreeC, Claims 1, 2, 3, 4, 5, 6, 7, 8
Or the method for producing o-benzoylbenzoic acid amides according to 9 above. 11. A solvent in which water does not exist in the organic solvent used when reacting with ammonia gas.
The method for producing o-benzoylbenzoic acid amides according to 4, 5, 6, 7, 8, 9 or 10. 12. In the formula (1), R _{1 to} R ₄ are all hydrogen atoms, 1, 2, 3, 4, 5, 6,
7. A method for producing o-benzoylbenzoic acid amides according to 7, 8, 9, 10 or 11. 13. The temperature for reacting ammonia gas is 0.
~ 15 ℃, 1, 2, 3, 4, 5, 6, 7,
The method for producing o-benzoylbenzoic acid amides according to 8, 9, 10, 11 or 12. 14. The organic solvent is toluene as claimed in claim 1,
The method for producing o-benzoylbenzoic acid amides according to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13. 15. An ammonia gas is reacted without separating the acid chloride obtained by reacting o-benzoylbenzoic acid with thionyl chloride from the reaction solvent. , 6, 7, 8, 9,
The method for producing o-benzoylbenzoic acid amides according to 10, 11, 12, 13 or 14.