A preparation method of 5-ethyl-2-pyrrolecarboxylic acid

Abstract

The present invention discloses a method for preparing 5-ethyl-2-pyrrolecarboxylic acid. The method comprises the steps of: (1) subjecting methyl 4-bromo-2-pyrrolecarboxylate to Friedel-Crafts acylation to obtain a compound having the structure shown in Formula 1; (2) subjecting the compound having the structure shown in Formula 1 to hydrogenation to obtain a compound having the structure shown in Formula 2; and (3) hydrolyzing the compound having the structure shown in Formula 2 to obtain 5-ethyl-2-pyrrolecarboxylic acid having the structure shown in Formula 3.

Description

Technical Field

[0001] The present invention relates to the field of organic chemistry, and particularly to a method for preparing 5-ethyl-2-pyrrolecarboxylic acid. Background Art

[0002] 5-Ethyl-2-pyrrolecarboxylic acid has very important application prospects as a fine chemical raw material and a pharmaceutical intermediate. Patent WO2005026149A1 discloses a method for preparing ethyl 5-ethyl-2-pyrrolecarboxylate. This method uses 2,2,2-trichloro-1-(5-ethyl-1H-pyrrol-2-yl)ethan-1-one as a raw material to react with sodium ethoxide to obtain ethyl 5-ethyl-2-pyrrolecarboxylate. Its raw material 2,2,2-trichloro-1-(5-ethyl-1H-pyrrol-2-yl)ethan-1-one is synthesized according to the preparation method reported in the Journal of the Chemical Society, Perkin transactions I, 1996, 18, 2277–2289, Molins-Pujol, etc. This method prepares 2,2,2-trichloro-1-(5-ethyl-1H-pyrrol-2-yl)ethan-1-one by Friedel-Crafts acylation of 2-ethylpyrrole with trichloroacetyl chloride.

[0003]

[0004] Since the raw material 2-ethylpyrrole is not easily available and expensive, and the Friedel-Crafts reaction will generate regioisomeric impurities of 3-position acylation, purification is troublesome and it is not suitable for industrial production.

[0005] Synthetic Communications, 1989, 19, 763–768, Elder, Todd, etc. reported a method for preparing ethyl 5-ethyl-2-pyrrolecarboxylate. This method uses 2-(2-ethyl-1,3-pentacyclic-2-yl)acetaldehyde as a raw material to perform nucleophilic addition with ethyl 2-(dibenzylamino)acetate under the action of LDA, then hydrogenation to remove benzyl, and finally deprotection and ring closure under acidic conditions to obtain ethyl 5-ethyl-2-pyrrolecarboxylate.

[0006]

[0007] This method has raw materials that are not easily available and expensive, and the low-temperature reaction is difficult to scale up, with a very high cost, and it is also not suitable for industrial production.

[0008] Therefore, there is an urgent need in the art to provide a method for preparing 5-ethyl-2-pyrrolecarboxylic acid suitable for industrial production. Summary of the Invention

[0009] The present invention aims to provide a method for preparing 5-ethyl-2-pyrrolecarboxylic acid.

[0010] Specifically, the present invention provides a method for preparing 5-ethyl-2-pyrrolecarboxylic acid having a structure as shown in Formula 3, and the method comprises the steps of:

[0011] (1) Subjecting methyl 4-bromo-2-pyrrolecarboxylate to Friedel-Crafts acylation to obtain a compound having a structure as shown in Formula 1;

[0012] (2) Subjecting the compound having a structure as shown in Formula 1 to hydrogenation to obtain a compound having a structure as shown in Formula 2;

[0013] (3) Hydrolyzing the compound having a structure as shown in Formula 2 to obtain 5-ethyl-2-pyrrolecarboxylic acid having a structure as shown in Formula 3;

[0014]

[0015] In one or more embodiments, step (1) is carried out at 0 ± 5 °C.

[0016] In one or more embodiments, step (1) is carried out in the presence of a Lewis acid as a catalyst.

[0017] In one or more embodiments, the reaction solvent for step (1) comprises one or more of the following: dichloromethane, 1,2-dichloroethane, chloroform, and ether.

[0018] In one or more embodiments, step (2) is carried out in a solvent containing acetic acid.

[0019] In one or more embodiments, the hydrogenation pressure for step (2) is 101 KPa - 505 KPa.

[0020] In one or more embodiments, the hydrogenation reaction temperature in step (2) is 40 °C - 60 °C.

[0021] In one or more embodiments, the catalyst used for step (2) is selected from palladium on carbon and / or palladium hydroxide on carbon.

[0022] In one or more embodiments, step (3) is hydrolyzed using an alkaline solution.

[0023] In one or more embodiments, step (3) further comprises purifying 5-ethyl-2-pyrrolecarboxylic acid having a structure as shown in Formula 3 by recrystallization. Detailed implementation manners

[0024] After extensive and in-depth research, the inventors found that the target compound 5-ethyl-2-pyrrolecarboxylic acid can be obtained by using a cheap raw material, methyl 4-bromo-2-pyrrolecarboxylate, through Friedel-Crafts acylation, hydrogenation, and hydrolysis. Based on this, the present invention was completed.

[0025] Specifically, a method for preparing 5-ethyl-2-pyrrolecarboxylic acid provided by the present invention includes the steps:

[0026] In the first step, methyl 4-bromo-2-pyrrolecarboxylate undergoes Friedel-Crafts acetylation in the presence of a catalyst to obtain a compound with the structure shown in Formula 1;

[0027] In the second step, the compound with the structure shown in Formula 1 undergoes catalytic hydrogenolysis to obtain a compound with the structure shown in Formula 2;

[0028] In the third step, the compound with the structure shown in Formula 2 is hydrolyzed to obtain 5-ethyl-2-pyrrolecarboxylic acid with the structure shown in Formula 3.

[0029] The above first step can be carried out at about 0 °C. For example, but not limited to, -3 to 2 °C, -4 to 5 °C, -0.5 to 1 °C, 0.5 - 3 °C, -5 to 4 °C, etc.

[0030] The catalyst used in the above first step can be a Lewis acid. In one embodiment of the present invention, the Lewis acid includes but is not limited to boron trifluoride diethyl etherate, aluminum trichloride, zinc dichloride, tin tetrachloride, or a mixture of two or more of them.

[0031] Solvents that can be used in the above first step include but are not limited to dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether, or a mixture thereof.

[0032] In one embodiment of the present invention, in the above first step, methyl 4-bromo-2-pyrrolecarboxylate is catalyzed by boron trifluoride diethyl etherate in dichloromethane and undergoes Friedel-Crafts acetylation to obtain Compound 1.

[0033] In one embodiment of the present invention, in the above first step, methyl 4-bromopyrrole-2-carboxylate and the reaction solvent are mixed at about 0 °C, a Lewis acid catalyst is added, and the mixture is made uniform at about 0 °C (for example, but not limited to, stirring for about 1 hour, etc.) to obtain a reactant containing Compound 1. Further, the reactant containing Compound 1 can be extracted in ice water, and after combining the organic phases, it is washed, dried, and filtered to obtain Compound 1.

[0034] The above first step basically has no side reactions (such as Friedel-Crafts reaction at the 3-position, etc.), and the yield of obtaining Compound 1 is high (for example, more than 90%), and pure product can be obtained without column chromatography.

[0035] The hydrogenation (hydrogenolysis) reaction in the second step above is carried out in a solvent containing acetic acid, and the content of acetic acid is at least 50% v / v% based on the total volume of the solvent containing acetic acid. In one embodiment of the present invention, those that form a mixed solvent with acetic acid include, but are not limited to, methanol, ethanol, or a mixture thereof.

[0036] The hydrogenation pressure in the second step above is above atmospheric pressure, and increasing the pressure will contribute to hydrogenation.

[0037] A higher temperature in the hydrogenation reaction of the second step above is helpful for hydrogenation. For example, but not limited to, 40 - 60 °C; in one embodiment of the present invention, about 50 °C is selected, which can not only complete the reaction but also has mild conditions.

[0038] The catalysts used in the second step above include, but are not limited to, palladium on carbon, palladium hydroxide on carbon, or a mixture thereof.

[0039] In one embodiment of the present invention, in the second step, compound 1 is catalytically hydrogenolyzed with palladium on carbon or a similar catalyst in a mixed solvent containing at least 50 v / v% acetic acid to obtain compound 2; the mixed solvent may also contain methanol, ethanol, or a mixture thereof.

[0040] In one example of the present invention, in the second step, compound 1 and a mixed solvent containing at least 50 v / v% acetic acid are mixed, a catalyst is added in a nitrogen atmosphere, and hydrogenation is carried out for 4 - 7 hours in a hydrogen atmosphere at least at atmospheric pressure and at least about 50 °C to obtain a reactant containing compound 2; further, the reactant containing compound 2 is filtered.

[0041] The third step above is carried out by hydrolysis using an alkaline solution obtained from an alkaline reagent; the alkaline reagent is, for example, but not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; the solvents for forming the alkaline solution include, but are not limited to, water, ethanol, methanol, or a mixture thereof.

[0042] In one embodiment of the present invention, the third step further includes recrystallizing and purifying 5 - ethyl - 2 - pyrrolecarboxylic acid having a structure as shown in formula 3.

[0043] In one embodiment of the present invention, in the third step, compound 2 is hydrolyzed by adding an aqueous solution of an alkaline reagent in an alcohol solvent to obtain a crude product of compound 3, and then recrystallized and purified.

[0044] In one example of the present invention, compound 2 and an alcohol solvent are mixed and then an aqueous solution of an alkaline reagent is added dropwise, and stirred at room temperature for more than 10 hours to obtain a reactant containing compound 3. Further, the alcohol solvent in the reactant containing compound 3 is removed, the aqueous phase is adjusted to a pH of about 3 with an acidic substance (for example, but not limited to an inorganic acid such as hydrochloric acid), extracted, washed, dried, and filtered to obtain a crude product of compound 3, and recrystallized in a reagent to obtain the target compound 3.

[0045] In this text, "room temperature" refers to 10 - 40 °C, for example but not limited to, 20 - 30 °C, 15 - 25 °C, etc.

[0046] In this text, "the compound with the structure shown in Formula 1" and "Compound 1" can be used interchangeably, and "the compound with the structure shown in Formula 2" and "Compound 2" can be used interchangeably. And so on, all refer to the compounds with the structures corresponding to the following numbers.

[0047]

[0048]

[0049] To enable those skilled in the art to understand the features and effects of the present invention, the following provides a general description and definition of the terms and expressions mentioned in the specification and claims. Unless otherwise specified, all technical and scientific terms used herein shall have the ordinary meanings understood by those skilled in the art regarding the present invention. In case of conflicts, the definitions in this specification shall prevail.

[0050] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate values, the relevant values in the specific embodiments have been presented as precisely as possible herein. However, any numerical value inherently and inevitably contains standard deviations due to individual testing methods. Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range. Or, the term "about" represents that the actual value falls within the acceptable standard error of the average value, depending on the consideration of those skilled in the art. Except for experimental examples, or unless otherwise clearly stated, it can be understood that all ranges, quantities, numerical values and percentages (such as those used to describe material amounts, time lengths, temperatures, operating conditions, quantity ratios and others similar) used herein are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximate values and can be changed as needed. At least these numerical parameters should be understood as the values indicated by the significant digits and obtained by applying the general rounding method.

[0051] The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any composition form, as long as there is no contradiction in the combination of these features. All possible combinations should be considered as within the scope described in this specification. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent or similar purpose. Therefore, unless otherwise specifically stated, the disclosed features are only general examples of equivalent or similar features.

[0052] The main advantages of the present invention are as follows: the raw materials used are inexpensive, the reaction conditions are simple, and the target product and intermediates do not require column purification; high-purity target product can be obtained by recrystallization in methyl tert-butyl ether.

[0053] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages, ratios, proportions, or parts are by weight. The units in the weight / volume percentages in the present invention are well-known to those skilled in the art, for example, it refers to the weight (grams) of the solute in 100 milliliters of the solution. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are only for demonstration purposes.

[0054] The synthesis routes of the following embodiments are as follows:

[0055]

[0056] Example 1

[0057] Step 1:

[0058] Add methyl 4-bromopyrrole-2-carboxylate (2600 g, 12.8 mol) and dichloromethane (26 L) to a 50 L reaction kettle, cool to 0 °C in an ice bath, add boron trifluoride diethyl etherate (9040 g, 64 mol), and then dropwise add acetic anhydride (6500 g, 64 mol). After the addition is complete, stir at 0 °C for 1 h. Pour into ice water (26 L), extract with dichloromethane (10 L x 3); combine the organic phases, wash with water (10 L x 2) and saturated brine (10 L), dry over sodium sulfate, and filter. The filtrate is concentrated to dryness to obtain yellow solid compound 1 (2897 g, 11.8 mol, yield 92%).

[0059] 1 H NMR (400 MHz, DMSO-d6) 12.85 (brs, 1H), 6.98 (s, 1H) 3.83 (s, 3H), 2.56 (s, 3H) ppm;

[0060] Step 2:

[0061] Compound 1 (1600 g, 6.5 mol), methanol (16 L) and acetic acid (16 L) were added to a 50 L reactor. The air was replaced with nitrogen, and then 10% Pd / C (containing 55% water, 160 g) was added. Nitrogen was replaced with hydrogen, and the mixture was heated to 50 °C and hydrogenated under a pressure of 101 KPa for 6 hours. After filtration, the filtrate was concentrated by rotary evaporation to obtain Compound 2 (906 g, 5.9 mol, yield 91%).

[0062] 1 H NMR (400 MHz, DMSO-d6) 11.64 (s, 1H), 6.68 (dd, J1 = 2.4 Hz, J2 = 3.6 Hz, 1H), 5.91 (dd, J1 = 2.4 Hz, J2 = 3.6 Hz, 1H), 3.72 (s, 3H), 2.56 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H) ppm;

[0063] Step 3:

[0064] Compound 2 (660 g, 4.3 mol) and ethanol (3.3 L) were added to a three-necked flask, and then 2 M aqueous sodium hydroxide solution (4.3 L) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. Ethanol was removed by rotary evaporation, and the aqueous phase was acidified to pH 3 with 3 N hydrochloric acid and extracted with ethyl acetate (1.5 L x 3). The organic phases were combined, washed with saturated brine (1.5 L), dried over sodium sulfate, and filtered. The filtrate was concentrated by rotary evaporation to obtain a crude product, which was recrystallized from methyl tert-butyl ether to obtain a white solid, the target compound 3 (459 g, 3.3 mmol, 76%).

[0065] 1 H NMR (400 MHz, DMSO-d6) 12.00 (brs, 1H), 11.46 (brs, 1H), 6.62 (dd, J1 = 2.4 Hz, J2 = 3.6 Hz, 1H), 5.87 (dd, J1 = 2.4 Hz, J2 = 3.6 Hz, 1H), 2.55 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H) ppm.

[0066] Example 2

[0067] Compound 1, Compound 2 and the target compound 3 were also obtained respectively, with the remaining conditions being the same as those in Example 1 except that the reaction temperature in Step 1 was changed from 0 °C to about 5 °C.

[0068] Example 3

[0069] Compound 1, Compound 2 and the target compound 3 were also obtained respectively, with the remaining conditions being the same as those in Example 1 except that the temperature of the hydrogenation reaction in Step 2 was 40 °C, the pressure was 505 KP, and the reaction time was 4 hours.

[0070] Example 4

[0071] Except that the temperature of the hydrogenation reaction in step 2 was 60 °C, the pressure was 101 KP, and the reaction time was 4 hours, the other conditions were the same as in Example 1, and Compound 1, Compound 2, and the target compound 3 were also obtained respectively.

[0072] Example 5

[0073] Methyl 4-bromopyrrole-2-carboxylate (5.2 g, 25.6 mmol) and dichloromethane (52 mL) were added to a 100 mL reaction kettle, cooled to 0 °C in an ice bath, boron trifluoride etherate (18.1 g, 128.0 mol) was added, and then acetic anhydride (13.0 g, 128.0 mol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 30 °C and stirred for 1 h. It was poured into ice water (52 mL), and extracted with dichloromethane (50 mL x 3); the organic phases were combined, washed with water (50 mL x 2) and saturated brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to dryness to obtain a crude product, and the crude product was purified by column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain a yellow solid compound 1 (4.5 g, yield 72%).

[0074] At high temperatures, a side reaction of Friedel-Crafts reaction at the 3-position occurred, the reaction became complicated, column chromatography purification was required, and the yield decreased.

[0075] Example 6

[0076] Compound 1 (1.6 g, 6.5 mmol), methanol (32 mL) were added to a 50 mL reaction kettle, the air was replaced with nitrogen, and then 10% Pd / C (containing 55% water, 160 mg) was added. Nitrogen was replaced with hydrogen, heated to 50 °C, and hydrogenated at a pressure of 101 KPa for 16 hours. The reaction was monitored by TLC, and the reaction was not complete.

[0077] The above are only the preferred embodiments of the present invention, and are not intended to limit the scope of the essential technical content of the present invention. The essential technical content of the present invention is broadly defined in the scope of the claims of the application. Any technical entity or method completed by others, if it is exactly the same as that defined in the scope of the claims of the application, or an equivalent change, will be regarded as covered by the scope of that claim.

Claims

1. A preparation method of 5-ethyl-2-pyrrolecarboxylic acid with a structure as shown in Formula 3, characterized in that, The method includes the steps: (1) Subjecting methyl 4-bromo-2-pyrrolecarboxylate to Friedel-Crafts acylation to obtain a compound with the structure shown in Formula 1; (2) Subjecting the compound with the structure shown in Formula 1 to hydrogenation to obtain a compound with the structure shown in Formula 2; (3) Hydrolyzing the compound with the structure shown in Formula 2 to obtain 5-ethyl-2-pyrrolecarboxylic acid with the structure shown in Formula 3; Step (2) is carried out in a solvent containing acetic acid; Based on the total volume of the solvent containing acetic acid, the content of acetic acid is at least 50% v / v%; The hydrogenation pressure in Step (2) is 101 KPa - 505 KPa; In Step (2), the hydrogenation reaction temperature is 40°C - 60°C; The catalyst used in Step (2) is selected from palladium carbon and / or palladium hydroxide on carbon.

2. The preparation method according to claim 1, characterized in that, Step (1) is carried out at 0 ± 5°C.

3. The preparation method according to claim 1, characterized in that, Step (1) is carried out using a Lewis acid as a catalyst.

4. The preparation method according to claim 1, characterized in that, The reaction solvent for Step (1) includes one or more of the following: dichloromethane, 1,2-dichloroethane, chloroform, diethyl ether.

5. The preparation method according to claim 3, characterized in that, The Lewis acid is selected from boron trifluoride diethyl etherate, aluminum trichloride, zinc dichloride, tin tetrachloride, or a mixture of two or more of them.

6. The preparation method according to claim 1, characterized in that, In Step (1), methyl 4-bromo-2-pyrrolecarboxylate is catalyzed with boron trifluoride diethyl etherate in dichloromethane and subjected to Friedel-Crafts acetylation to obtain Compound 1.

7. The preparation method according to claim 1, characterized in that, The solvent that forms a mixed solvent with acetic acid in Step (2) is selected from methanol, ethanol, or a mixture thereof.

8. The preparation method according to claim 1, characterized in that, In Step (3), hydrolysis is carried out using an alkaline solution.

9. The preparation method according to claim 8, characterized in that, In Step (3), hydrolysis is carried out using an alkaline solution obtained from an alkaline reagent, and the alkaline reagent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; and / or, the solvent for forming the alkaline solution is selected from water, ethanol, methanol, or a mixture thereof.

10. The preparation method according to claim 1, characterized in that, Step (3) further includes purifying 5-ethyl-2-pyrrolecarboxylic acid with the structure shown in Formula 3 by recrystallization.

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