JPS6155503B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 3,4,5-trimethoxybenzamidopyridine.

(Prior art) 3,4,5-trimethoxybenzamide pyridine has three isomers, α, β, and γ, and all of these are useful as 3,4,5-trimethoxybenzamide pyridine as a pharmaceutical agent, such as an ulcer treatment agent. Methoxybenzamide piperidine, N-aminobenzoyl-3,4,5-trimethoxybenzamide piperidine
Publication No. 28436; “Basic and Clinical” 12 , 3422
(1978); see J.med.chem., 14 , 357 (1971))
It is a synthetic intermediate such as. 3,4,5-trimethoxybenzamidopyridine has conventionally been prepared by combining halogenated 3,4,5-trimethoxybenzoyl with the corresponding aminopyridine in the presence of an excess of organic or inorganic base in an organic solvent such as benzene. It was produced by reacting (OH
Hankovsky, H.Hideg, J.med.chem., 9 , 151
(1966); T. Irikura, K. Kasuga, J. med.chem.
, 14, 357 (1971)). However, when using this method, 3,4,5-trimethoxybenzoic acid is first converted into a halogenated 3,4,5-trimethoxybenzoyl compound using a suitable halogenating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, etc. Because of the need to do so, it is not only complicated to operate, but also poses problems in terms of pollution control, so there are many difficulties in industrial implementation.

On the other hand, for amide synthesis from 3,4,5-trimethoxybenzoic acid and an amine, a heterocyclic secondary amine such as morpholine, piperidine or pyrrolidine is synthesized with a tertiary amine such as pyridine in a solvent such as benzene or toluene. There are only examples of synthesis of corresponding acid amides by the action of thionyl chloride or phosphorus trichloride in the presence or absence of (see British Patent No. 872,350 (1961)).

Phosphorus oxychloride is thionyl chloride, phosphorus trichloride,
Unlike halogenating agents such as phosphorus pentachloride, it does not normally react with free carboxylic acids, but is said to react only with alkali salts of carboxylic acids to form acid chlorides (Jikken Chemistry Course, Vol. 19) , 459 pages, Maruzen,
(see 1959). In this connection, German patent no.
No. 642519 (1937) and West German Patent No. 1245958
(1967), both using a significant excess of phosphorus oxychloride over the carboxylic acid and the presence of equimolar alkali halides or catalytic amounts of primary and or secondary amines or the corresponding acid amides. It is shown below that carboxylic acid chlorides can be prepared by high temperature and long reaction times.

(Problems to be Solved) The present inventors have proposed a method for producing, without using acid halides, which are problematic in terms of production, handling, and pollution, as described above.
3,4,5-trimethoxybenzoic acid, the synthesis method of which is well known (e.g. CSMarvel et al., Org.
Syn.Coll., Vol.I, p.537) from 3, 4, 5-
We believed that it would be very convenient if trimethoxybenzamide pyridine could be produced in one step, and as a result of extensive research, we arrived at the present invention.

(Structure of the present invention) The present invention comprises 3,4,5-trimethoxybenzoic acid,
3. characterized in that phosphorus oxychloride and aminopyridine are reacted in the presence of a pyridine base.
This is a method for producing 4,5-trimethoxybenzamide pyridine.

The details of the present invention will be explained in detail below.

(Molar ratio of reactants) In a preferred embodiment of the present invention, 3.
For 1 mole of 4,5-trimethoxybenzoic acid,
About 0.5-0.55 moles of phosphorus oxychloride and about 1 mole of aminopyridine are reacted in the presence of about 1-1.1 moles of pyridine base.

(Pyridine base) In the present invention, a pyridine base is used to participate in the reaction, but if other bases such as tertiary amines such as triethylamine and N/N-dimethylaniline are used, the desired amide pyridine can be produced with high quality and It is a surprising fact that it cannot be synthesized in high yield (see Reference Examples below).

Preferred pyridine bases that can be used include pyridine itself as well as α-, β-, and γ-picolines. In addition, lutidines, collidines, etc. are also used, but these have limited solubility in water or are poorly soluble, and are therefore disadvantageous compared to the lower homologs mentioned above. Furthermore, aminopyridine itself is unfavorable from the viewpoints of operation, post-treatment, product quality, etc. These pyridine bases can be used alone or as a mixture of two or more. The required amount is at least 1 mol per 1 mol of 3,4,5-trimethoxybenzoic acid, but especially when 6 to 7 mol is used also as a solvent, since the pyridine base is water-soluble, Since there is no need to distill off the solvent when removing the produced amide, which will be described later, this process is very convenient in actual operation. When the amount of pyridine base is small, it is advantageous to use an inert solvent to facilitate stirring and reaction.

(Inert Solvent) As described above, in the present invention, an inert solvent can be used to facilitate stirring and reaction. Examples of inert solvents include chloroform, methylchloroform, trichloroethylene,
These include benzene and toluene. The amount of inert solvent used is not particularly important, and it is sufficient to use the amount to facilitate stirring and reaction.

(Addition order of reagents) When carrying out the method of the present invention, after mixing all the reagents except phosphorus oxychloride, phosphorus oxychloride is added dropwise while cooling while suppressing excessive heat generation, and then stirring and The reaction may be carried out by heating, but also by mixing the reagents except for aminopyridine as above,
Then, aminopyridine can be added and reacted. Alternatively, 3,4,5-trimethoxybenzoic acid and phosphorus oxychloride may be mixed and reacted by heating, then pyridine base is added and then aminopyridine is added and reacted; It is also possible to adopt a method in which -trimethoxybenzoic acid and phosphorus oxychloride are mixed, heated and reacted, and then a solution of aminopyridine in pyridine base is added dropwise and reacted. However, in any case, it is desirable that the aminopyridine be added at the same time as the pyridine base, or after that.

(Reaction temperature and time) In order to avoid product decomposition and side reactions, the reaction temperature at which the method of the present invention is carried out is below the reflux temperature of the reaction system, usually 40 to 100°C, more preferably 60 to 100°C.
A range of 80℃ is recommended. The reaction time varies depending on conditions such as the reaction temperature and the presence or absence of an inert solvent, but usually takes about 20 minutes to 5 hours.

(Recovery of product) To recover the desired product from the reaction solution, the reaction solution should be left as is if no inert solvent was present, or the solvent should first be depressurized if the reaction was carried out in the presence of an inert solvent. After distilling off, the reactant is poured into a large amount of water, and the pH is adjusted with an alkali to precipitate the first crystal. After separating this, the mother liquor is concentrated to obtain the second crystal, and these are combined. It is convenient to subject it to a suitable purification method if desired. Alternatively, the reactants can be poured into a large amount of water as described above,
After adjusting the pH, it may be immediately concentrated, and then the precipitated crystals may be taken out and treated in the same manner. Here PH
The alkali used for the preparation needs to be a weak alkali, and usually an alkali bicarbonate, such as sodium bicarbonate, potassium bicarbonate, or ammonium bicarbonate, is preferred because it is less likely to cause decomposition of the product. These alkali bicarbonates can be added in solid form or in aqueous solution. The pH range to be adjusted is about 6 to 10, more preferably about 7 to 9.

(Effects of the Invention) As described above, the present invention does not use acid halides, so it does not cause pollution problems and the operation is simplified. Furthermore, in the conventional method using phosphorus oxychloride, it was necessary to use it in a considerable excess relative to the carboxylic acid, but in the present invention, phosphorus oxychloride is used in a smaller molar proportion than the carboxylic acid to achieve high concentrations under mild conditions. Since high quality 3,4,5-trimethoxybenzamidopyridine can be produced in high yield, its industrial value is extremely large.

(Embodiments of the Invention) Next, embodiments of the present invention will be described with reference to Examples, but the present invention is not limited in any way by the Examples below.

Example 1 3,4,5-trimethoxybenzoic acid 8.5 was added using a 200 ml four-necked colben equipped with a thermometer, reflux condenser, calcium chloride tube, addition funnel and stirrer.
(0.04 mol) was dissolved in 50 ml of chloroform and 10.5 g (0.133 mol) of pyridine, and 3.4 g (0.022 mol) of phosphorus oxychloride was added dropwise at 30 to 40°C over 10 minutes. Then stirred at 60-70℃ for 1 hour and then heated to 50℃.
A solution of 3.8 g (0.04 mol) of 3-aminopyridine dissolved in 20 ml of chloroform was added dropwise, and the mixture was heated under reflux for 40 minutes. After the reaction was completed, the mixture was cooled to 50°C, 40 ml of water was added, and the solvent was evaporated under reduced pressure. The crystalline residue obtained was suspended in 150 ml of water, neutralized with sodium bicarbonate to pH 8, cooled, and the precipitated crystals were separated, washed with water, and dried to give crude 3-(3.4・
9.5 g of the first crystal of 5-trimethoxybenzamido)pyridine was obtained. After the liquid was evaporated to dryness under reduced pressure, 50 ml of water was added, and after cooling, it was separated, washed with water, and dried.
0.1 g of bank crystal was obtained. In addition, 1.1 g of unreacted 3,4,5-trimethoxybenzoic acid was recovered by acidifying the liquid of the second crystal with hydrochloric acid (the identification of this
(using infrared absorption spectra by KBr tablet method). The obtained crude 3-(3,4,5-trimethoxybenzamido)pyridine was 9.6 g in total, and the yield was 95.5% based on the consumed 3,4,5-trimethoxybenzoic acid. The obtained crude product was recrystallized from methanol, and the product exhibited the following physical properties.

Melting point 159.6℃ (Literature value 158-160℃, T. Irikura etal, J.
med.chem., 14 , 357 (1971)) Elemental analysis values Calculated values: C 62.50%, H 5.59% Measured values: C 62.43%, H 5.63% Example 2 In Example 1, the amount of pyridine was changed to 3.5 g (0.044 Carry out the reaction in the same manner except that the amount is reduced to 7.0g (mol).
Crude 3-(3.4.5-trimethoxybenzamido)pyridine was obtained. Almost no second crystals were obtained from the liquid, and 2.9 g of unreacted 3,4,5-trimethoxybenzoic acid was recovered. The yield of crude product was 92.0% based on the consumed 3,4,5-trimethoxybenzoic acid. The crude product was identified using an infrared absorption spectrum using the KBr tablet method, and it was confirmed that it was exactly the same as that obtained in Example 1.

Example 3 3,4,5-trimethoxybenzoic acid 8.5g
(0.04 mol) in 50 ml of benzene and α-picoline
Phosphorus oxychloride dissolved in 12.4g (0.133mol)
3.4 g (0.022 mol) was added dropwise at 30 to 40°C over 10 minutes, stirred at about 70°C for 1 hour, cooled to 50°C, and then 3.8 g (0.04 mol) of 3-aminopyridine was added as a solid for 30 minutes. and further reacted at 75 to 80°C for 40 minutes. After the reaction was completed, the temperature was cooled to 50°C, 40 ml of water was added, and the solvent was distilled off under reduced pressure. The resulting crystalline residue was treated in the same manner as in Example 2 to obtain 9.4 g of crude 3-
(3,4,5-trimethoxybenzamide)pyridine was obtained. 1.1 g of unreacted 3,4,5-trimethoxybenzoic acid was recovered from the liquid. The yield of crude product was 93.5% based on the consumed 3,4,5-trimethoxybenzoic acid. Infrared absorption spectra using the KBr tablet method were used to identify the crude products and recovered raw materials.

Example 4 8.5 g of 3,4,5-trimethoxybenzoic acid
(0.04 mol) in 50 ml of chloroform and pyridine
Dissolved in 21 g (0.265 mol), phosphorus oxychloride 3.4
g (0.022 mol) was added dropwise at 30 to 40°C for 10 minutes.
The mixture was then stirred at 70°C for 1 hour and cooled to 50°C. Next, 5g of 3.8g (0.04mol) of 3-aminopyridine
(0.063 mol) dissolved in pyridine was added dropwise, heated under reflux at 75°C for 50 minutes, and then cooled to 50°C. 40 ml of water was added to this, the solvent was distilled off under reduced pressure, and the resulting crystalline residue was treated in the same manner as in Example 2 to obtain 8.9 g of crude 3-(3,4,5-trimethoxybenzamido)pyridine. Obtained. In addition, 1.3 g of unreacted 3,4,5-trimethoxybenzoic acid was extracted from the liquid.
was recovered. The yield of crude product considering the recovered raw materials was 91.0%. Infrared absorption spectra using the KBr tablet method were used to identify the crude product and recovered raw materials.

Example 5 8.5 g of 3,4,5-trimethoxybenzoic acid
(0.04 mol) was dissolved in 16.8 g (0.212 mol) of pyridine, and 3.4 g (0.022 mol) of phosphorus oxychloride was dissolved in 30~
The mixture was added dropwise at 40°C for 10 minutes, stirred at 70°C for 1 hour, and cooled to 50°C. Then 3-aminopyridine
A solution of 3.8 g (0.04 mol) dissolved in 4 g (0.051 mol) of pyridine was added dropwise, and the mixture was reacted at 75 to 80°C for 40 minutes. After the reaction is complete, cool to 50℃ and add 150ml of water.
was added, the reaction was neutralized with sodium bicarbonate, and
Adjust the pH to 8, cool, separate the precipitated crystals, wash with water,
After drying, 9.5 g of the first crystal of crude 3-(3,4,5-trimethoxybenzamido)pyridine was obtained. The liquid was further concentrated, cooled and treated in the same way to obtain the second crystal 1.6
I got g. Total amount of crude product 11.1g, yield 96.1
%. Note that even when the liquid of the second crystal was made acidic with hydrochloric acid, unreacted 3,4,5-trimethoxybenzoic acid was not recovered. Infrared absorption spectra using the KBr tablet method were used to identify the product.

Example 6 The reaction was carried out in the same manner as in Example 5 except that 3-aminopyridine in Example 5 was replaced with 4-aminopyridine. After neutralizing the reaction solution with sodium bicarbonate to a pH of 8, it was immediately concentrated under reduced pressure to a total volume of about 40 ml, and after cooling, the precipitated crystals were separated, washed with water, and dried.
10.9 g of crude 4-(3.4.5-trimethoxybenzamido)pyridine was obtained. Yield 94.4%. Note that the raw material 3,4,5-trimethoxybenzoic acid was not recovered from the liquid. When the crude product obtained here was recrystallized from methanol, a purified product exhibiting the following physical properties was obtained.

Melting point 168.2℃ (Literature value 166-168.5℃, T.Irikura, etal.J.
med.chem., 14 , 357 (1971)) Elemental analysis values Calculated values C 62.50%, H 5.59% Measured values C 62.42%, H 5.56% Example 7 Converting 4-aminopyridine of Example 6 to 2-aminopyridine Crude 2-(3,4,5-trimethoxybenzamide) was prepared in exactly the same manner as in Example 6 except for
10.7 g of pyridine was obtained. Yield 92.7%. The raw material 3,4,5-trimethoxybenzoic acid was not recovered from the liquid. The physical properties of a purified product obtained by recrystallizing the crude product obtained here from methanol were as follows.

Melting point 57.2℃ (literature value 55-57℃, OOHankovsky etal.J.
med.chem., 9 , 151 (1966)) Elemental analysis values Calculated values C 62.50%, H 5.59% Measured values C 62.54%, H 5.55% Example 8 In Example 2, 4.1 g of β-picoline was used instead of pyridine ( Using 0.044 mol), the reaction and post-treatment were carried out in the same manner as in Example 2 to obtain crude 3-(3.
4,5-trimethoxybenzamide)pyridine
8.5 g of unreacted 3,4,5-trimethoxybenzoic acid and 1.7 g of unreacted 3,4,5-trimethoxybenzoic acid were obtained. The yield of crude product was 92.0 based on the consumed 3,4,5-trimethoxybenzoic acid.
It was %. In addition, for identification of crude products and recovered raw materials,
Infrared absorption spectra using the KBr tablet method were used.

Example 9 4.2 g of 3,4,5-trimethoxybenzoic acid
(0.02 mol) was dissolved in 25 ml of chloroform and added to the solution at 30-40°C for 5 minutes. Then 64
Stir and reflux at ℃ for 1.5 hours, cool to 30℃, add a solution of 1.8 g (0.022 mol) of pyridine diluted with 5 ml of chloroform, and after 5 minutes raise the temperature of the reaction solution to 50℃ and add 1.9 g of 3-aminopyridine. (0.02 mol) to 10
A solution in ml of chloroform was added dropwise. Then, after heating under reflux for 4 hours, it was cooled to 50°C and diluted with water at 20°C.
ml, the solvent was distilled off under reduced pressure, and the resulting crystalline residue was suspended in 150 ml of water, brought to pH 8 with sodium bicarbonate, cooled, separated, washed with water, and dried.
4.2 g of crude 3-(3.4.5-trimethoxybenzamido)pyridine was obtained. Additionally, 0.8 g of unreacted 3,4,5-trimethoxybenzoic acid was recovered from the liquid. The yield of crude product depends on the consumed raw material 3.
It was 90.9% based on 4,5-trimethoxybenzoic acid. In addition, for identification of crude products and recovered raw materials,
Infrared absorption spectra using the KBr tablet method were used.

Example 10 4.2 g of 3,4,5-trimethoxybenzoic acid
(0.02 mol), 1.9 g (0.02 mol) of 3-aminopyridine was dissolved in 10.5 g (0.133 mol) of pyridine,
1.7 g (0.011 mol) of phosphorus oxychloride at 30-40℃
The mixture was stirred at 75-80°C for 2.5 hours, cooled to 50°C, 20ml of water was added, and the solvent was distilled off under reduced pressure. The resulting crystalline residue was dissolved in water.
Suspend in 100ml and neutralize with sodium bicarbonate to pH
8, cooled, separated, washed with water, dried and coarsened to 3-
5.3 g of (3,4,5-trimethoxybenzamide)pyridine was obtained. Yield 92.9%. No unreacted 3,4,5-trimethoxybenzoic acid was recovered from the liquid. The crude product was identified using an infrared absorption spectrum using the KBr tablet method.

Example 11 4.2 g of 3,4,5-trimethoxybenzoic acid
(0.02 mol), 1.9 g (0.02 mol) of 3-aminopyridine in 25 ml of chloroform and 1.8 g of pyridine.
(0.022 mol) dissolved in 1.7 g of phosphorus oxychloride
(0.011 mol) was added dropwise over 10 minutes at 30 to 40°C, followed by stirring and refluxing at 65°C for 4 hours. After cooling to 50°C, 20 ml of water was added, and the same procedure as in Example 10 was carried out to obtain 4.5 g of crude 3-(3,4,5-trimethoxybenzamido)pyridine. 0.6 g of unreacted 3,4,5-trimethoxybenzoic acid was recovered from the liquid. The yield of crude product is 3,4,5
-92.0% relative to trimethoxybenzoic acid. In addition, KBr was used for identification of crude products and recovered raw materials.
Infrared absorption spectra using the tablet method were used.

The following reference examples show the case where no pyridine base is used (reference example 1) and the case where N.
This shows that pure, high-quality 3,4,5-trimethoxybenzamidopyridine cannot be obtained in high yield when using N-dimethylaniline (Reference Example 2) or triethylamine (Reference Example 3). It is.

Example 12 3,4,5-trimethoxybenzoic acid 8.5g
After adding 13.6 g (0.088 mol) of phosphorus oxychloride to (0.04 mol), the mixture was stirred at 60°C for 1 hour and cooled to 40°C. Then, 10.5 g (0.133 mol) of pyridine was added dropwise while cooling, and then 3-aminopyridine was added.
A solution of 3.8 g (0.04 mol) dissolved in 10.5 g (0.133 mol) of pyridine was added dropwise at 30°C to 40°C, and then heated to 75°C.
The reaction was carried out at ~80°C for 40 minutes.

After the reaction was completed, the mixture was cooled to 50°C and gradually added to 150ml of water. Then neutralize with sodium bicarbonate to pH 8.
The precipitated crystals were separated by filtration, washed with water, and dried to obtain 9.0 g of crude 3-(3,4,5-trimethoxybenzamido)pyridine. Yield: 78.3% Infrared absorption spectrum using KBr tablet method was used to identify the product.

Reference example 1 3,4,5-trimethoxybenzoic acid 8.5g
(0.04 mol) was dissolved in 50 ml of chloroform, 3.4 g (0.022 mol) of phosphorus oxychloride was added dropwise at 30 to 40°C over 5 minutes, then heated under reflux at 64°C for 1 hour, cooled to 50°C, and 3- Aminopyridine 3.8g
A solution of (0.04 mol) dissolved in 20 ml of chloroform was added dropwise, and the mixture was further heated under reflux for 4 hours. After the reaction
The mixture was cooled to 50° C., 40 ml of water was added, and the solvent was distilled off under reduced pressure to obtain a crystalline residue, which was treated in the same manner as in Example 2 to obtain 6.8 g of a crude product. This product was determined from the infrared absorption spectrum obtained by the KBr tablet method.
3-(3,4,5-trimethoxybenzamide)
It turned out to be a mixture of pyridine and other unknown compounds. When the liquid from the crude product was acidified with hydrochloric acid, 1.6 g of unreacted 3,4,5-trimethoxybenzoic acid was recovered (as confirmed by infrared absorption spectrum using the KBr tablet method).

Reference Example 2 In Example 2, 5.4 g (0.044 mol) of N.N-dimethylaniline was used instead of pyridine, and the reaction treatment was carried out in the same manner as in Example 2, except that the crude product was
8.9g was obtained. The infrared absorption spectrum of this product by the KBr tablet method was similar to that of the crude product obtained in Reference Example 1, indicating that it was a similar mixture although the composition ratio was quite different. In addition, unreacted 3,4,5-trimethoxybenzoic acid was extracted from the liquid.
0.6 g was recovered (confirmed by infrared absorption spectrum using KBr tablet method).

Reference Example 3 In Example 1, 13.4 g (0.132 mol) of triethylamine was used instead of pyridine, and the reaction treatment was carried out in the same manner as in Example 1 to obtain crude 3-(3.4.5-
6.1 g of trimethoxybenzamido)pyridine was obtained. Yield 52.8%. The infrared absorption spectrum of this product by the KBr tablet method almost matched that obtained in Example 1, but since the reaction solution containing the product was colored and turned into a tar, the separated crude product was also severely colored. Even with decolorization and recrystallization with a methanol solution, a sufficient decolorization effect could not be obtained, and the recrystallization yield was as low as 56.7%.

Claims (1)

[Claims] 1. 3.4.5 characterized in that 3.4.5-trimethoxybenzoic acid, phosphorus oxychloride and aminopyridine are reacted in the presence of a pyridine base.
- A method for producing trimethoxybenzamide pyridine. 2 1 mole of 3,4,5-trimethoxybenzoic acid is reacted with about 0.5 to 0.55 mole of phosphorus oxychloride and about 1 mole of aminopyridine in the presence of at least about 1 mole of pyridine base. The manufacturing method according to scope 1.