阅读说明：本技术 用于制备4-甲氧基吡咯衍生物的中间体的方法 (process for preparing intermediates of 4-methoxy pyrrole derivatives ) 是由 辛政泽 孙正贤 李承哲 于 2018-06-21 设计创作，主要内容包括：本发明涉及4-甲氧基吡咯衍生物的中间体的制备方法。根据本发明的制备方法的优点在于：通过使用廉价的起始原料能够降低生产成本,整体上不需要高温反应；使用廉价且无爆炸性的试剂来代替(三甲基硅烷基)重氮甲烷,并且此外,整体上能够以高产率来制备4-甲氧基吡咯衍生物的中间体。(The present invention relates to a process for the preparation of intermediates for 4-methoxypyrrole derivatives. The preparation method according to the invention has the advantages that: the production cost can be reduced by using cheap starting materials, and high-temperature reaction is not required on the whole; inexpensive and non-explosive reagents are used instead of (trimethylsilyl) diazomethane, and furthermore, intermediates of 4-methoxypyrrole derivatives can be prepared in high yield as a whole.)

1. A method of preparing a compound represented by the following chemical formula 1, the method comprising the steps of:

1) Reacting a compound represented by the following chemical formula 1-1 with ammonium chloride and sodium cyanide or potassium cyanide, followed by reaction with an acid to prepare a compound represented by the following chemical formula 1-2;

2) Protecting a compound represented by the following chemical formula 1-2 with an amino protecting group (P) to prepare a compound represented by the following chemical formula 1-3;

3) reacting a compound represented by the following chemical formula 1-3 with (i) potassium or sodium methylmalonate, (ii) carbonyldiimidazole and (iii) magnesium halide, followed by reaction with an acid, to prepare a compound represented by the following chemical formula 1-4;

4) Reacting a compound represented by the following chemical formula 1-4 with N, N-dimethylformamide dimethyl acetal to prepare a compound represented by the following chemical formula 1-5;

5) Reacting a compound represented by the following chemical formula 1-5 with dimethyl sulfate to prepare a compound represented by the following chemical formula 1-6; and

6) reacting a compound represented by the following chemical formula 1-6 with an acid to prepare a compound represented by the following chemical formula 1,

[ chemical formula 1]

[ chemical formula 1-1]

[ chemical formulas 1-2]

[ chemical formulas 1-3]

[ chemical formulas 1 to 4]

[ chemical formulas 1 to 5]

[ chemical formulas 1 to 6]

2. The method of claim 1, wherein,

in step 1, the molar ratio of the compound represented by chemical formula 1-1 to ammonium chloride is 10:1 to 1: 10; and is

The molar ratio of the compound represented by chemical formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1: 10.

3. The method of claim 1, wherein,

In step 1, the reaction of the compound represented by chemical formula 1-1 with ammonium chloride and sodium cyanide or potassium cyanide is performed at 0 to 40 ℃; and the reaction with the acid is carried out at 80 to 120 ℃.

4. the method of claim 1, wherein,

The acid in step 1 is acetic acid or hydrochloric acid.

5. The method of claim 1, wherein,

The amino protecting group (P) in step 2 is t-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), tosyl or acyl.

6. the method of claim 1, wherein,

The reaction of step 2 is carried out at 10 ℃ to 40 ℃.

7. the method of claim 1, wherein,

The magnesium halide in step 3 is magnesium chloride or magnesium bromide.

8. The method of claim 1, wherein,

in step 3, the molar ratio of the compound represented by chemical formula 1-3 to potassium or sodium methylmalonate is 10:1 to 1: 10;

a molar ratio of the compound represented by chemical formula 1-3 to carbonyldiimidazole is 10:1 to 1: 10; and is

The molar ratio of the compound represented by chemical formula 1-3 to the magnesium halide is 10:1 to 1: 10.

9. the method of claim 1, wherein,

The acid in step 3 is hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid.

10. The method of claim 1, wherein,

In step 3, the reaction between the compound represented by chemical formula 1-3 and (i) potassium or sodium methylmalonate, (ii) carbonyldiimidazole and (iii) magnesium halide is performed at 50 to 100 ℃, and the reaction with acid is performed at 0 to 40 ℃.

11. The method of claim 1, wherein,

In step 4, the molar ratio of the compound represented by chemical formula 1-4 to N, N-dimethylformamide dimethyl acetal is 1:1 to 1: 10.

12. The method of claim 1, wherein,

The reaction of step 4 is carried out at 20 ℃ to 70 ℃.

13. the method of claim 1, wherein,

In step 5, the molar ratio of the compound represented by chemical formula 1-5 to dimethyl sulfate is 10:1 to 1: 10.

14. The method of claim 1, wherein,

The reaction of step 5 is carried out at 20 ℃ to 60 ℃.

15. The method of claim 1, wherein,

In step 6, the molar ratio of the compound represented by chemical formula 1-6 to trifluoroacetic acid is 1:1 to 1: 30.

16. the method of claim 1, wherein,

The reaction of step 6 is carried out at 10 ℃ to 40 ℃.

17. The method of claim 1, wherein,

The acid in step 6 is trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid.

Technical Field

the present invention relates to a process for the preparation of intermediates useful in the preparation of 4-methoxypyrrole derivatives.

Background

Gastrointestinal ulcers, gastritis and reflux esophagitis occur when the balance between aggressive factors (such as gastric acid, helicobacter pylori pepsin, stress, alcohol and tobacco) and defensive factors (such as gastric mucosa, bicarbonate, prostaglandins, degree of blood supply, etc.) is disrupted. Therefore, therapeutic agents for gastrointestinal tract injury such as gastrointestinal ulcer, gastritis and reflux esophagitis are classified into drugs for inhibiting aggressive factors and drugs for enhancing protective factors.

Meanwhile, it has been reported that gastrointestinal ulcers, gastritis, and reflux esophagitis develop ulcers even without an increase in gastric acid secretion. Therefore, as the aggressive factors increase, the decrease of the defensive factors due to the pathological changes of the gastric mucosa is considered to play an important role in the development of gastric ulcer. Therefore, in addition to drugs that inhibit aggressive factors, drugs that enhance defensive factors are also used to treat gastrointestinal ulcers and gastritis. As drugs for enhancing defensive factors, mucosal protective drugs that adhere to ulcer sites to form physicochemical membranes, and drugs that promote synthesis and secretion of mucus are known.

On the other hand, helicobacter pylori (h.pyrori), a bacterium present in the stomach, is known to cause chronic gastritis, gastric ulcer, duodenal ulcer, and the like, and many patients suffering from gastrointestinal tract injury are infected with helicobacter pylori (h.pyrori). Therefore, these patients should take antibiotics such as clarithromycin, amoxicillin, metronidazole, and tetracycline in addition to the antiulcer drug such as a proton pump inhibitor or a gastric pump antagonist. Thus, various side effects have been reported.

Therefore, there is a need to develop an antiulcer drug which inhibits gastric acid secretion (e.g., proton pump inhibitory activity) and enhances protective factors (e.g., increase in mucus secretion) while having a disinfecting activity against helicobacter pylori.

In this regard, korean patent No.10-1613245 discloses that a 4-methoxypyrrole derivative or a pharmaceutically acceptable salt thereof has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and disinfectant activity against helicobacter pylori, and thus is effective for preventing and treating gastrointestinal tract injury due to gastrointestinal ulcer, gastritis, reflux esophagitis, or helicobacter pylori (helicobacter pylori).

In the preparation of the 4-methoxypyrrole derivatives disclosed in the above patents, the following compounds were prepared as intermediates:

According to the description of the above patent, the intermediate was prepared from 2, 4-difluorophenylglycine, and the preparation method included a total of four steps (8-1) to (8-3) of example 8 disclosed in korean patent No. 10-1613245). However, according to the production method of the above patent, the total yield is as low as 9.0%, and a high-temperature reaction is required in the whole, thereby requiring expensive equipment. In particular, (trimethylsilyl) diazomethane is used as a reactant, but this reagent is not only expensive but also explosive and therefore unsuitable for large-scale industrial production.

in view of the above, the present inventors have intensively studied a novel production method capable of producing the above-mentioned intermediate. Thus, the present inventors have found a production method in which a high-temperature reaction is not required as a whole, such as the production method described below, and an inexpensive non-explosive agent is used instead of (trimethylsilyl) diazomethane, and further, the yield is improved as a whole, thereby completing the present invention.

Disclosure of Invention

Technical problem

It is an object of the present invention to provide a process for preparing intermediates which are useful for preparing 4-methoxypyrrole derivatives.

Technical scheme

In order to achieve the above object, the present invention provides a preparation method as shown in the following reaction scheme 1, more specifically, the preparation method comprising the steps of:

1) Reacting a compound represented by the following chemical formula 1-1 with ammonium chloride and sodium cyanide or potassium cyanide, followed by reaction with an acid to prepare a compound represented by the following chemical formula 1-2;

2) Protecting a compound represented by the following chemical formula 1-2 with an amino protecting group (P) to prepare a compound represented by the following chemical formula 1-3;

3) Reacting a compound represented by the following chemical formula 1-3 with (i) potassium or sodium methylmalonate, (ii) carbonyldiimidazole and (iii) magnesium halide, followed by reaction with an acid, to prepare a compound represented by the following chemical formula 1-4;

4) Reacting a compound represented by the following chemical formula 1-4 with N, N-dimethylformamide dimethyl acetal to prepare a compound represented by the following chemical formula 1-5;

5) Reacting a compound represented by the following chemical formula 1-5 with dimethyl sulfate to prepare a compound represented by the following chemical formula 1-6; and

6) The compound represented by the following chemical formula 1 is prepared by reacting a compound represented by the following chemical formula 1-6 with an acid to prepare a compound represented by the following chemical formula 1 via deprotection.

[ reaction scheme 1]

Hereinafter, the present invention will be described in detail for each step.

(step 1)

Step 1, which relates to the synthesis of Strecker amino acids, is a step of preparing amino acids of the compound represented by chemical formula 1-2 from chemical formula 1-1.

The reaction essentially consists of two reactions. First, the first reaction is to react the compound represented by chemical formula 1-1 with ammonium chloride and sodium cyanide or potassium cyanide.

preferably, the molar ratio of the compound represented by chemical formula 1-1 to ammonium chloride is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3. Preferably, the molar ratio of the compound represented by chemical formula 1-1 to sodium cyanide or potassium cyanide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3.

Preferably, in the first reaction, an alcohol having 1 to 4 carbon atoms, and ammonium hydroxide or ammonium carbonate are used as a solvent. More preferably, the alcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol, isopropanol, butanol or tert-butanol.

Preferably, the first reaction is carried out at 0 ℃ to 40 ℃. When the reaction temperature is lower than 0 ℃, there is a problem that the yield is lowered. When the reaction temperature exceeded 40 ℃, the yield no longer increased significantly.

preferably, the first reaction is carried out for 1 to 48 hours. When the reaction time is less than 1 hour, there is a problem that the reaction proceeds insufficiently and thus the yield is lowered. When the reaction time exceeded 48 hours, the yield no longer increased significantly.

On the other hand, after the first reaction is completed, a step of purifying the product may be included, if necessary. Preferably, the purification is carried out by crystallizing the cyanamide compound from the reaction product. As the crystallization solvent, water and an alcohol having 1 to 4 carbon atoms may be used. Preferably, the alcohol having 1 to 4 carbon atoms is methanol, ethanol, propanol, isopropanol, butanol or tert-butanol. Preferably, water is added to the reaction product and cooled to 10 ℃ to 15 ℃. Then, an alcohol having 1 to 4 carbon atoms is added thereto and stirred for 10 minutes to 2 hours.

After the first reaction is completed, a second reaction is performed in which the product of the first reaction is reacted with an acid.

as acids which may be used, mention may be made of acetic acid or hydrochloric acid. Preferably, acetic acid and hydrochloric acid are used together. The acid not only acts as a reactant in the second reaction, but also acts as a solvent. Therefore, it is preferred to use an amount of acid sufficient to dissolve the first product.

preferably, the second reaction is carried out at 80 ℃ to 120 ℃. When the reaction temperature is lower than 80 ℃, there is a problem that the yield is lowered. When the reaction temperature exceeded 120 ℃, the yield no longer increased significantly.

Preferably, the second reaction is carried out for 1 to 10 hours. When the reaction time is less than 1 hour, there is a problem that the reaction proceeds insufficiently and thus the yield is lowered. When the reaction time exceeded 10 hours, the yield no longer increased significantly.

On the other hand, after the second reaction is completed, a step of purifying the product may be further included, if necessary.

(step 2)

Step 2 is a step of protecting the compound represented by chemical formula 1-2 with an amino protecting group (P), which is a step of preparing the compound represented by chemical formula 1-3 by reacting the compound represented by chemical formula 1-2 with a compound capable of introducing an amino protecting group (P).

Preferably, the amino protecting group (P) is t-butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), Tosyl (Tosyl) or Acyl (Acyl). Further, the compound capable of introducing the amino protecting group (P) refers to various compounds used in the art for introducing a protecting group. For example, when the amino protecting group (P) is a tert-butyloxycarbonyl group (Boc), a compound capable of introducing the amino protecting group includes di-tert-butyl dicarbonate.

Preferably, the molar ratio of the compound represented by chemical formula 1-2 to the compound capable of introducing the amino protecting group (P) is 10:1 to 1:10, and more preferably 3:1 to 1: 5.

Preferably, the reaction is carried out in the presence of a base. As the base, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, or cesium carbonate can be used, and sodium hydrogencarbonate is preferably used. Preferably, the molar ratio of the compound represented by chemical formula 1-2 to the base is 1:1 to 1:10, and more preferably 1:1 to 1: 5.

Preferably, as the solvent for the above reaction, water, tetrahydrofuran, dioxane, dichloromethane, butanol, tetrahydrofuran or a mixture thereof may be used. Preferably, water is used together with tetrahydrofuran.

Preferably, the reaction is carried out at 10 ℃ to 40 ℃. When the reaction temperature is less than 10 ℃, there is a problem that the yield is lowered. When the reaction temperature exceeded 40 ℃, the yield no longer increased significantly. More preferably, the reaction is carried out at 20 ℃ to 30 ℃.

preferably, the above reaction is carried out for 1 to 48 hours. When the reaction time is less than 1 hour, there is a problem that the reaction proceeds insufficiently and thus the yield is lowered. When the reaction time exceeded 48 hours, the yield no longer increased significantly. More preferably, the above reaction is carried out for 6 to 24 hours.

on the other hand, after the completion of the reaction, if necessary, a step of purifying the product may be further included.

(step 3)

Step 3 is a reaction of substituting a carboxyl group of the compound represented by chemical formula 1-3, wherein the reaction essentially consists of two reactions.

First, the first reaction is a reaction for preparing a compound of the following formula, which is a magnesium salt of the compound of formulae 1 to 4 to be prepared. The second reaction is a reaction for preparing the compound represented by chemical formula 1-4 by dissociating the magnesium salt of the compound represented by chemical formula 1-4.

The compounds represented by chemical formulas 1 to 4 are difficult to crystallize. Thus, in the present invention, it is prepared by first preparing its magnesium salt, followed by purification by crystallization.

First, the first reaction is a reaction of the compound represented by chemical formula 1-3 with (i) potassium or sodium methylmalonate, (ii) carbonyldiimidazole and (iii) magnesium halide. Preferably, as the magnesium halide, magnesium chloride or magnesium bromide may be used, and magnesium chloride is more preferably used.

Preferably, the molar ratio of the compound represented by chemical formula 1-3 to potassium or sodium methylmalonate is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3. Preferably, the molar ratio of the compound represented by chemical formula 1-3 to carbonyldiimidazole is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3. Preferably, the molar ratio of the compound represented by chemical formula 1-3 to the magnesium halide is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3.

Preferably, the first reaction is carried out in the presence of triethylamine. Preferably, the molar ratio of the compound represented by chemical formula 1-3 to triethylamine is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3.

preferably, acetonitrile or tetrahydrofuran is used as the solvent for the first reaction, and more preferably acetonitrile is used.

Preferably, the first reaction is carried out at 50 ℃ to 100 ℃. When the reaction temperature is less than 50 ℃, there is a problem that the yield is lowered. When the reaction temperature exceeds 100 ℃, a side reaction occurs, which is not preferable.

preferably, the first reaction is carried out for 10 minutes to 10 hours. When the reaction time is less than 10 minutes, there is a problem that the reaction proceeds insufficiently and thus the yield is lowered. When the reaction time exceeds 10 hours, side reactions occur, which is not preferable. More preferably, the above reaction is carried out for 10 minutes to 5 hours.

After the first reaction is completed, a second reaction is performed in which the product of the first reaction is reacted with an acid.

As the acid that can be used, hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid may be mentioned, with hydrochloric acid being preferred.

As the solvent for the second reaction, ethyl acetate, water, dichloromethane or a mixture thereof may be used. Preferably, ethyl acetate is used with water.

The pH of the second reaction is adjusted to 4 to 8 using an acid at 0 ℃ to 40 ℃. When the reaction temperature is lower than 0 ℃ or higher than 40 ℃, there is a problem that the yield is lowered. The pH of the second reaction is preferably adjusted to 6 to 8. When the pH is 8 or higher, the magnesium salt is not completely dissociated, and the yield is reduced.

On the other hand, after the second reaction is completed, a step of purifying the product may be further included, if necessary.

(step 4)

step 4 is a step of preparing a pyrrole derivative from the compound represented by chemical formula 1-4, which is a step of preparing the compound represented by chemical formula 1-5 from the compound represented by chemical formula 1-4 and N, N-dimethylformamide dimethyl acetal.

Preferably, the molar ratio of the compound represented by chemical formula 1-4 to N, N-dimethylformamide dimethyl acetal is 1:1 to 1:10, and more preferably 1:1 to 1: 5.

preferably, toluene or xylene may be used as a solvent for the reaction, and toluene is more preferably used.

Preferably, the reaction is carried out at 20 ℃ to 70 ℃. When the reaction temperature is lower than 20 ℃, there is a problem that the yield is lowered. When the reaction temperature exceeded 70 ℃, the yield was no longer significantly increased.

Preferably, the reaction is carried out for 30 minutes to 12 hours. When the reaction time is less than 30 minutes, there is a problem that the reaction proceeds insufficiently, and thus the yield is lowered. When the reaction time exceeded 12 hours, the yield no longer increased significantly.

On the other hand, since the compounds represented by chemical formulas 1 to 5 as reaction products are chemically unstable, it is preferable to continuously perform the subsequent reaction of step 5 without further purification.

(step 5)

Step 5 is a reaction of substituting a hydroxyl group of the compound represented by chemical formula 1-5 with a methoxy group, which is a step of reacting the compound represented by chemical formula 1-5 with dimethyl sulfate to prepare a compound represented by chemical formula 1-6.

preferably, the molar ratio of the compound represented by chemical formula 1-5 to dimethyl sulfate is 10:1 to 1:10, more preferably 5:1 to 1:5, and most preferably 3:1 to 1: 3.

Further, the reaction is preferably carried out in the presence of a base. As the base, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, potassium butyrate, or cesium carbonate can be used, and potassium carbonate is preferably used. Further, the reaction may be carried out using methyl iodide in the presence of a base. Preferably, the molar ratio of the compound represented by chemical formula 1-5 to the base is 1:1 to 1:5, and more preferably 1:1 to 1: 3.

Preferably, as the solvent for the reaction, an alcohol having 1 to 4 carbon atoms or a ketone having 3 to 6 carbon atoms is used. More preferably, the solvent used for the reaction is methanol, ethanol, propanol, butanol, tert-butanol, acetone, methyl ethyl ketone or isobutyl ketone.

Preferably, the reaction is carried out at 20 ℃ to 60 ℃. When the reaction temperature is lower than 20 ℃, there is a problem that the yield is lowered. When the reaction temperature exceeds 60 ℃, a side reaction occurs, which is not preferable.

Preferably, the reaction is carried out for 1 to 24 hours. If the reaction time is less than 1 hour, there is a problem that the reaction proceeds insufficiently and thus the yield is lowered. When the reaction time exceeds 24 hours, side reactions occur, which is not preferable.

On the other hand, after the completion of the reaction, if necessary, a step of purifying the product may be further included.

(step 6)

Step 6 is a step of removing a protecting group of the compound represented by chemical formula 1-6, which is a step of reacting the compound represented by chemical formula 1-6 with an acid to prepare a compound represented by chemical formula 1.

As acids which can be used, trifluoroacetic acid, hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid may be mentioned, preferably trifluoroacetic acid.

Preferably, the molar ratio of the compound represented by chemical formula 1-6 to the acid is 1:1 to 1:30, and more preferably 1:5 to 1: 20.

Preferably, as a solvent for the reaction, dichloromethane, ethyl acetate, methanol, toluene, diethyl ether, tetrahydrofuran or water may be used, and preferably, dichloromethane is used.

Preferably, the reaction is carried out at 10 ℃ to 40 ℃. If the reaction temperature is less than 10 ℃, there is a problem that the yield is lowered. If the reaction temperature exceeds 40 ℃, side reactions occur, which is not preferable.

Preferably, the reaction is carried out for 1 to 24 hours. When the reaction time is less than 1 hour, there is a problem that the reaction proceeds insufficiently and thus the yield is decreased. When the reaction time exceeded 24 hours, the yield no longer increased significantly.

On the other hand, after the completion of the reaction, if necessary, a step of purifying the product may be further included.

Advantageous effects

As described above, the preparation method according to the present invention is advantageous in that production costs can be reduced by using inexpensive starting materials, a high-temperature reaction is not required as a whole, an inexpensive and non-explosive reagent is used instead of (trimethylsilyl) diazomethane, and furthermore, an intermediate of a 4-methoxypyrrole derivative can be prepared in high yield as a whole.

Detailed Description

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention thereto. On the other hand, in examples and comparative examples, the compound prepared in each step was used in the next step, and hereinafter each step yielded a product in an amount larger than that described in the next step thereof.