WO2016153094A1 - Novel method for preparing 3-alkoxy thiophene derivative - Google Patents

Abstract

The present invention provides a novel method for preparing a 3-alkoxy thiophene derivative. The present invention has an advantage in that the 3-alkoxy thiophene derivative can be mass-produced at high efficiency.

Description

Novel Method for Preparing 3-alkoxythiophene Derivatives

The present invention relates to a novel method for preparing 3-alkoxythiophene derivatives, and more particularly, to a method for effectively mass-producing 3-alkoxythiophene derivatives.

3-alkoxythiophenes of formula I are important intermediates in the synthesis of prostaglandins and are known to be difficult to synthesize. 3-alkoxythiophene is also an important block in the manufacture of pharmaceuticals.

[Formula I]

(R: alkyl)

Thus, various synthetic methods for preparing a 3-alkoxythiophene derivative have been studied (Synthetic Metals 2014, 188, 156-160; New J. Chem. 2010, 34, 2558-2563, etc.). Known synthetic methods have a low yield, high impurity or high cost.

[Preceding technical literature]

[Non-Patent Documents]

(Non-Patent Document 1) Synthetic Metals 2014, 188, 156-160

(Non-Patent Document 2) New J. Chem. 2010, 34, 2558-2563

(Non-Patent Document 3) J. Med. Chem., 1997, 40 (25), 4053-4068

(Non-Patent Document 4) J. Het. Chem. 2003, 40 (1), 1-23

(Non-Patent Document 5) Bioorg. Med. Chem. Lett. 2001, 11 (11), 1407-1410

(Non-Patent Document 6) J. Med. Chem., 2003, 46 (23), 4910-4925

One problem to be solved by the present invention is to provide a method for effectively preparing a 3-alkoxythiophene derivative.

In addition, another problem to be solved by the present invention is to provide a 3-alkoxythiophene derivative prepared by the production method of the present invention.

Problems to be solved by the present invention are not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The present invention comprises the steps of (A) reacting a compound of Formula 2 with a compound of Formula 3 to obtain a reactant, and then hydrolyzing the reactant to prepare a compound of Formula 4; (B) preparing a compound of formula 5 by monoalkylation reaction of the compound of formula 4 in the presence of a solvent; And (C) decarboxylation of the prepared compound of Formula 5 by heating to a temperature of 80 ° C to 300 ° C without a solvent, wherein the 3-alkoxythiophene derivative of Formula 1 to provide.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

Wherein R ₁ and R ₂ are each independently alkyl and X is halogen. Preferably, R ₁ and R ₂ are each C ₁ -C ₄ alkyl, more preferably methyl. Also, preferably, X may be bromine.

The reactant of step (A) may be a compound of formula 2-1.

[Formula 2-1]

Wherein R ₁ and R ₂ are each independently alkyl. Preferably, R ₁ and R ₂ are each C ₁ -C ₄ alkyl, more preferably R ₁ and R ₂ may be each methyl.

Step (A) may include (A-1) reacting the compound of Formula 2 with the compound of Formula 3 in the presence of a solvent and a base to obtain the reactant; And (A-2) hydrolyzing the reactant produced in step (A-1) with a base in an aqueous solution to prepare the compound of Chemical Formula 4.

Step (A-1) is a contact step of contacting the solvent (A-1a) with the compound of Formula 2 at 15 to 30 degrees Celsius to obtain a contact; (A-1b) a first addition step of obtaining an additive by adding a base to the contact obtained in the contacting step of (A-1a) at 15 ° C to 30 ° C; (A-1c) a first stirring step of obtaining the first stirring by stirring the additive of the addition step of (A-1b) at 35 degrees Celsius to 45 degrees; (A-1d) a second addition step of obtaining an additive by adding the compound of Formula 3 to the first stirring material; (A-1e) a secondary stirring step of obtaining the secondary agitated by stirring the additive of the secondary addition step of (A-1d) at 80 degrees Celsius to 100 degrees Celsius; And (A-1f) extracting the secondary stirring product of step (A-1e) with a nonpolar solvent to obtain an extract, and concentrating the extract to obtain a concentrate.

The solvent of step (A-1) may be at least one nonpolar solvent selected from dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and dimethyl sulfoxide.

The base of step (A-1) may be at least one selected from K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH.

The nonpolar solvent of step (A-1f) may be at least one selected from dimethylformamide, dichloromethane, benzene, toluene, tetramethane, ethyl ether, isopropyl ether and dimethyl sulfoxide.

The step (A-2) is (A-2a) an addition step of obtaining an additive by adding a base in an aqueous solution to the reaction of the step (A-1) at 15 degrees Celsius to 30 degrees Celsius; (A-2b) agitation step of obtaining the agitated by stirring the additive of the addition step of (A-2a) at 70 to 90 degrees Celsius; And (A-2c) may include the step of adding an acid to the stirring of the stirring step (A-2b).

The base of step (A-2) may be at least one selected from K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH.

The step (A-2c) may be a step of adding the acid to pH 1 after lowering the temperature of the stirred product of the stirring step (A-2b) to -10 degrees to 0 degrees Celsius.

The acid of step (A-2c) may be hydrochloric acid, nitric acid, sulfuric acid or acetic acid.

Step (B) comprises the steps of contacting (Ba) a solvent to obtain a contact by contacting the compound of Formula 4 at 0 to 10 degrees Celsius; (Bb) a dropping step of adding dropwise addition of sulfuric acid to the contact of step (Ba) at 0 ° C to 10 ° C; (Bc) the stirring step of stirring the dropwise addition of the step (Bb) at 10 to 30 degrees Celsius for 2 to 6 hours to obtain a stirred product; And (Bd) may comprise a purification step of purifying the agitated.

The solvent of step (Ba) may be one or more polar solvents selected from methanol, isopropyl alcohol and butanol.

The purification step of the step (Bd) may include a filtration step, an extraction step, a concentration step and a drying step.

The purification step may be carried out with one or more nonpolar solvents selected from dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and dimethyl sulfoxide.

Step (C) may be performed at 160 to 240 degrees Celsius.

Step (C) may be carried out for 6 to 48 hours.

The compound of Formula 2 may be commercially available or prepared.

When the compound of Formula 2 is prepared, the preparation method includes the steps of: (a) contacting the solvent with metal sodium at -10 to 5 degrees Celsius to obtain a contact; (b) a first dropping step of adding a compound of formula 6 to the contact of step (a) at -10 ° C to 10 ° C to obtain a first dropper; (c) a second dropping step of dropping the compound of formula 7 to the first dropping product produced in step (b) at -10 ° C to 10 ° C to obtain a second dropping product; (d) agitation step of obtaining a final agitation by stirring the secondary dropping product produced in step (c) at 15 degrees Celsius to 30 degrees Celsius; (e) adding an acid to the final stirring to obtain an additive; And (f) may further comprise the step of preparing a compound of Formula 2 comprising a purification step of extracting and concentrating the additive obtained in step (e).

[Formula 6]

[Formula 7]

In which R ₂ is alkyl. Preferably R ₂ is C ₁ -C ₄ alkyl, more preferably methyl.

The step (e) may be an acidification step to pH 2 with an acid.

Extraction of step (f) may be carried out with one or more nonpolar solvents selected from dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and dimethyl sulfoxide.

The present invention also provides a 3-alkoxythiophene derivative of the formula (1) prepared by the production method of the present invention.

According to the present invention, 3-alkoxythiophene derivatives can be mass produced at high efficiency.

1 is a flowchart illustrating an embodiment of a ball invention.

Advantages and features of the present invention, and a method of achieving them will be apparent from the following detailed description with reference to the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms, and only the present embodiments are intended to complete the disclosure of the present invention, and the general knowledge in the art to which the present invention pertains. It is provided merely to fully convey the scope of the invention to those skilled in the art, and the present invention is defined only by the scope of the claims.

Like reference numerals refer to like elements throughout. In addition, "and / or" includes each and all combinations of one or more of the components mentioned.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In this specification, the singular also includes the plural unless specifically stated otherwise in the phrase. As used herein, “comprises” and / or “comprising” refers to the presence of one or more other components, steps, operations and / or elements. Or does not exclude additions.

The present invention provides a method for preparing the compound of formula (1).

[Formula 1]

In Formula 1, R ₁ is alkyl, preferably C ₁ to C ₄ alkyl, more preferably methyl. The compound of formula 1 is a 3-alkoxythiophene derivative and is an important intermediate in prostaglandin synthesis and is known to act as an important block in the manufacture of pharmaceuticals as an intermediate that is difficult to synthesize (J. Med. Chem., 1997, 40). (25), pp 4053-4068; J. Het. Chem. 2003, 40 (1) 1-23; Bioorg. Med. Chem. Lett. 2001, 11 (11), 1407-1410; J. Med. Chem. , 2003, 46 (23), pp 4910-4925. Et al.). Therefore, in Formula 1, R ₁ is alkyl, preferably C ₁ to C ₄ alkyl, more preferably methyl, 3-alkoxythiophene derivatives can be used for prostaglandin synthesis, pharmaceutical preparation It can be used for.

Hereinafter, with reference to the drawings and the reaction scheme, an embodiment of a novel method for producing a 3-alkoxythiophene derivative according to the present invention will be described in more detail.

As shown in FIG. 1, an embodiment of the present invention includes (A) preparing a compound of Formula 4, (B) preparing a compound of Formula 5, and (C) a decarboxylation step.

Step (A) is a step of preparing a compound of Formula 4 by reacting a compound of Formula 2 with a compound of Formula 3 to obtain a reactant, and then hydrolyzing the reactant.

[Formula 2]

[Formula 3]

[Formula 4]

Wherein R ₁ and R ₂ are each independently alkyl, preferably C ₁ to C ₄ alkyl, and more preferably methyl. In the above formula, X is halogen, preferably bromine. The compound name of the compound of Formula 2 is alkyl 3-hydroxythiophene-2-carboxylate.

In addition, step (B) is a step of preparing a compound of Formula 5 by monoalkylation reaction of the compound of Formula 4 prepared in the presence of a solvent.

[Formula 5]

Wherein R ₁ is alkyl, preferably C ₁ to C ₄ alkyl, more preferably methyl.

In addition, step (C) is a step of decarboxylation by heating the compound of Formula 5 prepared to a temperature of 80 to 300 degrees Celsius without a solvent.

The compound of formula 2 may be one produced or marketed by the following scheme 1 as a starting material of the present method. This is an embodiment according to the present invention, and the present invention is not limited thereto. The compound of Chemical Formula 2 according to the present invention may be prepared by other production methods known in the art, and commercially available ones may be purchased and used.

[Scheme 1]

Specifically, after (a) contacting step, (b) first dropping step, (c) second dropping step, (d) stirring step, (e) addition step, and (f) purification step, alkyl of Formula 2 3-hydroxythiophene-2-carboxylate can be prepared.

(a) The contacting step may be a step of contacting the solvent with the sodium metal at -10 to 5 degrees Celsius to obtain a contact. The solvent is not limited thereto as long as it is a polar solvent, but may be, for example, methanol, isopropyl alcohol, and / or butanol, and the like. The contact may preferably be contact at -4 degrees Celsius to 4 degrees Celsius.

(b) The first dropping step is to dissolve the compound of Formula 6 in the same solvent as the solvent of the contacting step (a) dropwise at -10 to 10 degrees Celsius to the contact of the contacting step to obtain a first dropping product It may be a step. The dropwise addition may be preferably dropwise at -4 degrees Celsius to 4 degrees Celsius.

(c) the second dropping step is a second dropping product by dissolving the compound of formula 7 in the same kind of solvent as the solvent of the contacting step and (b) dropping the dropping product in the first dropping step at -10 to 10 degrees Celsius It may be a step of obtaining. The dropwise addition may be preferably dropwise at -4 degrees Celsius to 4 degrees Celsius.

(d) The stirring step may be a step of obtaining the final stirring by stirring the resulting secondary dropping product at 15 degrees Celsius to 30 degrees after the end of the second dropping step. At this time, the compound of Formula 2 is produced. The final agitated product is in a state containing no starting material. (d) The stirring of the stirring step may be carried out for 1.5 hours to 4 hours, preferably 1.5 hours to 2 hours. The agitation may preferably be agitation at 18 degrees to 26 degrees Celsius.

(e) The addition step is to obtain an additive by adding an acid (acid) to such a final stirring, it may be an acidification step. As an example, the addition step may be a step of concentrating the final agitated acid and then acidifying the acid to pH 2 with an acid. The acid (aicd) according to the present invention is not limited to this as long as it is a material that can adjust the pH, for example, may be hydrochloric acid, nitric acid, sulfuric acid and / or acetic acid and the like.

After the addition step through a purification step, it is possible to purify the compound of formula (2). The purification step may be a step of extracting and concentrating the additive, specifically, an extraction step of extracting the additive with a solvent to obtain an extract; And concentrating the extract of the extracting step to obtain a concentrate. Through such a purification step, a compound of formula 2 having higher purity may be prepared.

In one embodiment, the extraction step may be a step of obtaining an extract by extracting the additive with a solvent. Specifically, the additive may be extracted with a solvent to obtain a solvent layer, and the solvent layer may be washed with water. The solvent is not limited to this as long as it is a nonpolar solvent, but may be, for example, dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and / or dimethyl sulfoxide and the like. In addition, the concentration step may be a step of removing the water contained in the extract by using anhydrous MgSO ₄ and the like, by removing the solvent by a rotary concentrator, etc., to obtain a concentrate by concentration.

By the above method, the compound of Chemical Formula 2 may be prepared up to 200 to 500 g at a time.

Using the compound of Formula 2 as a starting material, the compound of Formula 1 may be prepared according to the synthesis route of Scheme 2.

Scheme 2

Hereinafter, the synthesis conditions and procedures will be described in detail for each step.

[Step (A)]

After reacting the compound of Formula 2 with the compound of Formula 3 to obtain a reactant, the reactant is hydrolyzed to prepare a compound of Formula 4.

In this case, the reactant may be a compound of Formula 2-1.

[Formula 2-1]

Wherein R ₁ and R ₂ are each independently alkyl, preferably R ₁ and R ₂ are each C ₁ -C ₄ alkyl, more preferably, R ₁ and R ₂ are each methyl Can be. The compound name of the compound of Formula 2-1 is alkyl 3- (2-alkoxy-2-oxoethoxy) thiophene-2-carboxylate.

Step (A) comprises the steps of (A-1) reacting a compound of Formula 2 with a compound of Formula 3 in the presence of a solvent and a base to obtain a reactant; And (A-2) hydrolyzing the reactant produced in step (A-1) with a base in an aqueous solution to prepare a compound of Formula 4. The base in the aqueous solution state is the base is dispersed or dissolved in water, since the base in the aqueous solution state containing water, hydrolysis of the reactant may proceed.

In addition, the step (A-1) as a specific example according to the present invention is the contact step (A-1a), the first addition step (A-1b), the first stirring step (A-1c), the second addition step ( A-1d), a second stirring step (A-1e) and a purification step (A-1f) may be included.

The contacting step may be a step of contacting the solvent with the compound of Formula 2 at 15 degrees to 30 degrees Celsius, preferably at 18 degrees to 25 degrees Celsius to obtain a contact. The solvent is not limited to this as long as it is a nonpolar solvent, but may be, for example, dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and / or dimethyl sulfoxide and the like.

The primary addition step may be a step of obtaining an additive by adding a base to the contact obtained in the contacting step at 15 degrees to 30 degrees Celsius, preferably 18 degrees to 25 degrees Celsius. The base is not limited thereto, but may be, for example, K ₂ CO ₃ , Na ₂ CO ₃ , KOH and / or NaOH, and the like.

In the first stirring step, the additive obtained in the first adding step may be stirred at 35 degrees to 45 degrees Celsius, preferably 38 degrees to 42 degrees Celsius, to obtain a first stirring substance. Stirring of the first stirring step may be carried out for 20 to 50 minutes.

After the completion of the first stirring step, the second addition step may be a step of obtaining the additive by adding the compound of Formula 3 to the first stirring.

The second stirring step is a step of obtaining a secondary stirring material as a final stirring material after stirring at 80 degrees to 100 degrees Celsius, preferably 88 degrees to 93 degrees Celsius after the completion of the second addition step, the starting material Compound of Formula 2-1 is generated from the compound of. After completion of stirring, water is added to obtain a white solid. Stirring of the second stirring step may be carried out for 1.5 to 4 hours. Preferably it may be carried out for 1.5 hours to 2 hours.

This final agitator can be purified to a compound of formula 2-1 through a purification step. The purification step is to extract the final stirred with a solvent to obtain an extract; And concentrating the extract of the extracting step to obtain a concentrate. Through such a purification step, a more pure compound of formula 2-1 may be prepared.

The extraction step is a step of obtaining an extract by extracting the stirring with a solvent. Specifically, the solvent may be extracted by extracting a stirring substance with a solvent, and the solvent layer may be washed with water. The solvent is not limited to this as long as it is a nonpolar solvent, but may be, for example, dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and / or dimethyl sulfoxide and the like. The concentration step is a step of obtaining a concentrate by removing the water contained in the extract using anhydrous MgSO ₄ and the like, by removing the solvent with a rotary concentrator or the like.

In addition, as an embodiment of the present invention, the step (A-2) may include an addition step (A-2a), a stirring step (A-2b), and an acid addition step (A-2c).

The addition step may be a step of obtaining an additive by adding a base in an aqueous solution state at 15 degrees to 30 degrees Celsius, preferably 18 degrees to 25 degrees Celsius, to the reactant of step (A-1). The base is not limited thereto, but may be, for example, NaOH, Na ₂ CO ₃ , KOH and / or K ₂ CO ₃ , and the like.

The stirring step may be a step of obtaining the stirring by stirring the additive of the addition step at 70 degrees to 90 degrees Celsius, preferably 75 to 80 degrees Celsius. Stirring of the stirring step can be carried out for 30 minutes to 2 hours.

The acid addition step may be a step of acidifying by adding acid to the agitate. For example, the acid addition step may be a step of lowering the temperature of the stirring water to -10 degrees Celsius to 0 degrees, and then adding the acid to pH 1. Such acid (aicd) is not limited to this as long as it is a material that can adjust the pH, for example, may be hydrochloric acid, nitric acid, sulfuric acid and / or acetic acid and the like.

By this method, the compound of formula 4 can be prepared in large quantities up to 500 g-5000 g at a time.

[Step (B)]

Step (B) is a monoalkylation reaction of the compound of formula 4 in the presence of a solvent to prepare a compound of formula 5. For example, the compound of Formula 5 may be prepared from the compound of Formula 4 through the contacting step Ba, the dropping step Bb, the stirring step Bc, and the purification step Bd.

The contacting step may be a step of contacting the solvent with the compound of formula 4 at 0 to 10 degrees Celsius, preferably at 0 to 5 degrees Celsius to obtain a contact. The solvent is not limited thereto as long as it is a polar solvent, but may be, for example, methanol, isopropyl alcohol, and / or butanol, and the like.

The dropping step may be a step of adding dropwise sulfuric acid (H ₂ SO ₄ ) to the contact of the contacting step at 0 to 10 degrees Celsius, preferably 4 to 8 degrees Celsius.

The stirring step may be a step of stirring the dropping product of the dropping step at 10 degrees to 30 degrees Celsius for 2 hours to 6 hours, preferably 2 hours to 3 hours. This step is to obtain a final agitator to the compound of formula 5 is produced from the compound of formula (4) starting material.

The purification step may comprise a filtration step of filtering the stirred material, an extraction step, a concentration step and a drying step. Through such a purification step, a more pure compound of formula 5 may be prepared.

Specifically, in the filtration step it is possible to obtain a filtrate by filtering the stirring. In detail, the agitated material is filtered by filter paper, a filtrate is obtained, and the filtered solid can be wash | cleaned with water, etc.

The washed water may be subjected to an extraction step of extracting with a solvent. The solvent is not limited to this as long as it is a nonpolar solvent, but may be, for example, dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and / or dimethyl sulfoxide and the like.

In the concentration step, by removing the solvent with a rotary concentrator, it can be concentrated to obtain a concentrate.

In addition, the filtrate and the concentrate of the filtration step may be subjected to a drying step of drying together.

By this method, the compound of Formula 5 can be prepared in large quantities up to 500 g-5000 g at a time.

[Step (C)]

Step (C) is a step of decarboxylation of the compound of Formula 5 by heating up to a temperature of 80 to 300 degrees Celsius without a solvent.

In one embodiment, the step (C) may be a compound of formula 6 from the compound of formula 5 through a heating step.

In the heating step, only the compound of Formula 5 may be heated for 80 hours to 300 degrees Celsius, preferably 160 degrees to 240 degrees Celsius without a specific solvent, and may be performed for 6 hours to 48 hours. However, the present invention is not limited thereto. This step is to obtain a final product, the compound of formula 6 is produced from the compound of formula (5).

By this method, compounds of formula 6 can be prepared in large quantities up to 500 g-5000 g at a time.

Accordingly, it is possible to provide a 3-alkoxythiophene derivative of Formula 1 which is an embodiment of the present invention produced by one embodiment of the present invention.

Hereinafter, a first embodiment to a fourth embodiment which are specific steps of each step included in the manufacturing method of an embodiment of the present invention. Among them, the first embodiment shows in detail an example of preparing the starting material of the second embodiment. Through such embodiments, one embodiment of the preparation method of the present invention and the 3-alkoxythiophene derivative of Formula 1, which is one embodiment of the present invention thus prepared, will be described in more detail.

<Example 1> Preparation of methyl 3-hydroxythiophene-2-carboxylate

The first embodiment is described in more detail with reference to Scheme 1-1.

Scheme 1-1

A 250 ml two-necked flask is equipped with a thermometer and a dropping funnel and cooled with ice water (minus 10 degrees to 0 degrees Celsius). Into the flask, add 30 ml of anhydrous methanol and 0.8 g of chopped metal sodium, and cut off with nitrogen.

When the internal temperature is 0 degrees Celsius, 2.4 g of methyl 2-mercaptoacetate (Sigma-Aldrich, USA) is slowly added dropwise to a funnel with a solution dissolved in 20 ml of methanol.

After completion of the dropwise addition, 3.5 g of ethyl 2-chloroacrylate (Sigma-Aldrich Co., USA) was slowly added dropwise into a funnel of a dissolved solution in 20 ml of methanol.

After completion of the dropwise addition, the cooling water is withdrawn and stirred at room temperature (18-26 degrees Celsius) for 2 hours. At this time a yellow solid is formed.

Methanol in the agitate is concentrated by volatilization and acidified to pH 2 with 4N hydrochloric acid. The acidified reactant was diluted with dichloromethane and extracted three times with 30 ml each. The organic solvent layer was collected and washed three times with water. The organic solvent layer is separated, anhydrous magnesium sulfate is added and left to dry for about 20 minutes. Thereafter, the anhydrous magnesium sulfate solid was filtered off and concentrated by removing the organic solvent from the residue with a rotary concentrator. As a result, a yellow oil was obtained. The oil obtained in this manner is columned with a hexane and ethyl acetate mixture (hexane: ethyl acetate = 20: 1) to give pale yellow crystals. Yield 68%.

Second Embodiment Preparation of 3- (carboxymethoxy) thiophene-2-carboxylic acid

A second embodiment is described in more detail with reference to Scheme 2-A.

Scheme 2-A

A 250 ml three-necked flask is equipped with a thermometer and a cooler. 1.38 g of methyl 3-hydroxythiophene-2-carboxylate is added to the flask at room temperature (18-25 ° C.) and dissolved in 20 ml of dimethylformamide.

1.2 g of K ₂ CO ₃ was added to the melt and stirred for 10 minutes at room temperature (18-25 degrees Celsius). Solid K ₂ CO ₃ remains upon stirring.

Install the oil bath and stir for 30 minutes at 40 degrees Celsius. Then, 1.4 g of methyl 2-bromoacetate is added at once, and the reaction temperature is raised to 90 degrees Celsius and stirred. After about 2 hours of reaction, water was added to the flask to give a white solid.

Confirm that the reaction proceeded completely by TLC, extract 50 ml each time with dichloromethane, and collect the organic solvent layer. The organic solvent layer is washed again three times with 50 ml of water. The organic solvent layer is separated, anhydrous magnesium sulfate is added and left to dry for about 20 minutes. Thereafter, the anhydrous magnesium sulfate solid was filtered off and concentrated by removing the organic solvent from the residue with a rotary concentrator.

As a result, 2.3 g of methyl 3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylate was obtained. The yield was 87%, NMR data are as follows.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.92 (s, 3H), 6.78 (d, 1H), 7.28 (d, 1H)

Subsequently, 2.3 g of methyl 3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylate was added to a 250 ml flask at room temperature (18-25 degrees Celsius), 40 ml of 1 M NaOH solution was raised to 90 degrees Celsius. Stir at reflux for 1 hour. The reaction solution is cooled with ice water (minus 10 degrees to 0 degrees Celsius) and acidified to pH = 1 with hydrochloric acid.

As a result, 3- (carboxymethoxy) thiophene-2-carboxylic acid is obtained as a white solid. The yield was 93%, NMR data are as follows.

¹ H-NMR (400 MHz, DMSO) δ 4.75 (s, 2H), 6.90 (d, 1H), 7.67 (d, 1H)

Example 3 Preparation of 3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylic acid

A third embodiment is described in more detail with reference to Scheme 2-B.

Scheme 2-B

A 2000 ml three-necked flask was equipped with a stirrer, thermometer and dropping funnel and cooled with ice water. To the flask is added 1500 ml methanol and 100 g of 3- (carboxymethoxy) thiophene-2-carboxylic acid. At this time, the temperature is maintained at 4 degrees Celsius.

37.5 ml of sulfuric acid is added to the dropping funnel and slowly added dropwise. At this time, the dropping temperature is maintained at 4-8 degrees Celsius.

After dropping, the ice-cooled water is removed and stirred at room temperature (15 to 25 degrees Celsius). After about 3 hours, TLC checks whether the starting material 3- (carboxymethoxy) thiophene-2-carboxylic acid has completely reacted.

TLC confirms that the reaction proceeded completely and filters with filter paper.

The filtered solid is washed five times with about 20-30 ml of water and dried in infrared for one day.

The filtrate is placed in a 2000 ml flask, the solvent is concentrated, filtered, and the solid is washed five times with about 100 ml of water and dried in infrared for 1 day.

The washed water layers are collected, extracted with dichloromethane, concentrated, and the solid is washed five times with about 100 ml of water and dried in infrared for 1 day.

The dried solids are collected and weighed. As a result, about 97 g of a brown solid was obtained. The yield was 90%, NMR data are as follows.

¹ H-NMR (400 MHz, DMSO) δ 3.65 (s, 3H), 4.88 (s, 2H), 6.93 (d, 1H), 7.68 (d, 1H)

<Example 4> Preparation of methyl 2- (thiophene-3-yloxy) acetate

A fourth embodiment is described in more detail with reference to Scheme 2-C.

Scheme 2-C

244 g of 3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylic acid are placed in a 2000 ml three-necked flask, equipped with a stirrer, thermometer, cooler and oil bath, and heated to reach 230 degrees Celsius.

Between about 180-200 degrees Celsius, the solids begin to turn into liquid, and gas is produced between 210-230 degrees Celsius.

The reaction temperature rose to 230 degrees Celsius and then dropped back to 165-168 degrees Celsius.

After about 6 hours, TLC checks whether the starting material, 3- (2-methoxy-2-oxoethoxy) thiophene-2-carboxylic acid, is completely reacted.

If the result shows that starting material remains, stir for about 3 hours more.

After confirming that the reaction proceeded completely by TLC, the oil bath was removed, cooled slowly, and the product was collected.

As a result, 177 g of a brown liquid was obtained. The yield was 91%, NMR data are as follows.

¹ H-NMR (400MHz, CDCl ₃ ) δ 3.73 (s, 3H), 4.53 (s, 2H), 6.21 (s, 1H), 6.77 (d, 1H), 7.13 (d, 1H)

Since the 3-alkoxythiophene derivative can be produced in large quantities with high efficiency by the present invention, the present invention has industrial applicability.

Claims (20)

1. (A) reacting a compound of Formula 2 with a compound of Formula 3 to obtain a reactant, and then hydrolyzing the reactant to prepare a compound of Formula 4;

   (B) preparing a compound of formula 5 by monoalkylation reaction of the compound of formula 4 in the presence of a solvent; And

   (C) decarboxylation of the prepared compound of formula 5 by heating to a temperature of 80 to 300 degrees Celsius without solvent;

   To prepare a 3-alkoxythiophene derivative of the formula

   [Formula 1]

   

   [Formula 2]

   

   [Formula 3]

   

   [Formula 4]

   

   [Formula 5]

   

   Wherein R ₁ and R ₂ are each independently alkyl and X is halogen.
2. The method of claim 1, wherein R ₁ and R ₂ are each C ₁ -C ₄ alkyl.
3. The method of claim 1, wherein R ₁ and R ₂ are each methyl.
4. The method of claim 1, wherein X is bromine.
5. The method of claim 1,

   The reactant of step (A) is a compound of formula 2-1:

   [Formula 2-1]

   

   Wherein R ₁ and R ₂ are each independently alkyl.
6. The method of claim 1,

   Step (A) is

   (A-1) reacting the compound of Formula 2 with the compound of Formula 3 in the presence of a solvent and a base to obtain the reactant; And

   (A-2) A process for producing a compound of Formula 4 by hydrolyzing the reactant produced in step (A-1) with a base in an aqueous solution state.
7. The method of claim 6, wherein step (A-1)

   (A-1a) contacting the solvent to obtain a contact by contacting the compound of Chemical Formula 2 at 15 ° C. to 30 ° C .;

   (A-1b) a first addition step of obtaining an additive by adding a base to the contact obtained in the contacting step of (A-1a) at 15 ° C to 30 ° C;

   (A-1c) a first stirring step of obtaining the first stirring by stirring the additive of the addition step of (A-1b) at 35 degrees Celsius to 45 degrees;

   (A-1d) a second addition step of obtaining an additive by adding the compound of Formula 3 to the first stirring material;

   (A-1e) a secondary stirring step of obtaining the secondary agitated by stirring the additive of the secondary addition step of (A-1d) at 80 degrees Celsius to 100 degrees Celsius; And

   (A-1f) A method of producing a method comprising the step of extracting the secondary stirring product of step (A-1e) with a nonpolar solvent to obtain an extract and concentrating the extract to obtain a concentrate.
8. The method of claim 6,

   The solvent of step (A-1) is characterized in that at least one nonpolar solvent (nonpolar solvent) selected from dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and dimethyl sulfoxide Way.
9. The method of claim 6, wherein the base of step (A-1) is at least one selected from K ₂ CO ₃ , Na ₂ CO ₃ , KOH, and NaOH.
10. The method of claim 6, wherein step (A-2)

    (A-2a) an addition step of obtaining an additive by adding a base in an aqueous solution state at 15 ° C. to 30 ° C. to the reaction product of step (A-1);

    (A-2b) agitation step of obtaining the agitated by stirring the additive of the addition step of (A-2a) at 70 to 90 degrees Celsius; And

    (A-2c) A method of preparing a method comprising adding an acid to the stirred product of the stirring step (A-2b).
11. The method according to claim 10, wherein the step (A-2c) is a step of adding the acid to pH 1 after lowering the temperature of the stirred product of the stirring step (A-2b) to -10 degrees to 0 degrees Celsius.
12. The process according to claim 10 or 11, wherein the acid of step (A-2c) is hydrochloric acid, nitric acid, sulfuric acid or acetic acid.
13. The method of claim 1, wherein step (B)

    (Ba) contacting the solvent to obtain a contact by contacting the compound of Formula 4 at 0 ° C to 10 ° C;

    (Bb) a dropping step of adding dropwise addition of sulfuric acid to the contact of step (Ba) at 0 ° C to 10 ° C;

    (Bc) the stirring step of stirring the dropwise addition of the step (Bb) at 10 to 30 degrees Celsius for 2 to 6 hours to obtain a stirred product; And

    (Bd) a manufacturing method comprising a purification step of purifying the stirred material.
14. The method of claim 13, wherein the solvent of step (Ba) is at least one polar solvent selected from methanol, isopropyl alcohol and butanol.
15. The method of claim 13,

    Purification step of the step (Bd) comprises a filtration step, an extraction step, a concentration step and a drying step.
16. The method of claim 1, wherein step (C) is performed at 160 degrees to 240 degrees Celsius.
17. The method of claim 1, wherein step (C) is performed for 6 hours to 48 hours.
18. The method of claim 1,

    (a) contacting the solvent with metal sodium at -10 to 5 degrees Celsius to obtain a contact;

    (b) a first dropping step of adding a compound of formula 6 to the contact of step (a) at -10 ° C to 10 ° C to obtain a first dropper;

    (c) a second dropping step of dropping the compound of formula 7 to the first dropping product produced in step (b) at -10 ° C to 10 ° C to obtain a second dropping product;

    (d) agitation step of obtaining a final agitation by stirring the secondary dropping product produced in step (c) at 15 degrees Celsius to 30 degrees Celsius;

    (e) adding an acid to the final stirring to obtain an additive; And

    (f) a preparation method further comprising the step of preparing the compound of formula 2, including a purification step of extracting and concentrating the additive obtained in step (e):

    [Formula 6]

    

    [Formula 7]

    

    In which R ₂ is alkyl.
19. The method of claim 18, wherein the extraction of step (f) is carried out with at least one apolar solvent selected from dimethylformamide, dichloromethane, benzene, toluene, methane tetrachloride, ethyl ether, isopropyl ether and dimethyl sulfoxide. Manufacturing method.
20. The 3-alkoxythiophene derivative of Chemical Formula 1 produced by the method of claim 1.

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