KR102125041B1 - Method of synthesis of ferrocene derivatives - Google Patents

Abstract

The present invention is a method of synthesizing 4-ferrocenyl butanoic acid that can improve the performance of a rocket propellant, using sodium borohydride and polymethylhydrosiloxane, and using sodium borohydride and formic acid for safe and economical mass synthesis It relates to a method for producing 4-ferrocenyl butanoic acid that can be applied commercially.

Description

Method of synthesis of ferrocene derivatives {Method of synthesis of ferrocene derivatives}

The present invention is a method for producing a ferrocene (ferrocene) derivative, and more specifically, using sodium borohydride and polymethylhydrosiloxane as a method of synthesizing 4-ferrocenyl butanoic acid that can improve the performance of a rocket propellant, and It relates to a method for preparing 4-ferrocenyl butanoic acid more safely and economically using sodium borohydride and formic acid.

For the development of a superior performance rocket propellant, the development of a binder and a combustion additive is an important factor. In order to increase the combustion speed of the rocket propellant, transition metal compounds such as Fe and Cr have been mainly used. In general, ferrocene (ferrocene) compounds are known as very probable combustion catalysts because they have a large combustion rate increase effect and a low burning rate pressure exponent compared to iron oxides such as iron(III) oxide.

However, the existing materials have an unintended mobility to move toward the surrounding insulating material, and the amount added is gradually decreased over time, resulting in an uneven combustion, which causes stability problems.

In order to improve this problem, it is possible to replace the alkyl group having a high molecular weight or bind to a binder through Friedel-Crafts alkylation to ferrocene or cause more stable and even combustion. Among them, 3-(feroocenoyl)propionic acid is used to produce 4-ferrocenyl butanol using lithium aluminum hydride (LiAlH ₄ ), or there is a bypass reaction through esterification due to the risk of lithium aluminum hydride. However, this method is dangerous, very expensive, and requires great care in handling. The inventors of the present invention have developed 4-ferrocenyl butanol manufacturing method technology to improve this (Domestic Registration No. 10-1853565, No. 10-1853566)

However, in the case of 4-ferrocenyl butanol, the removal product is formed as a side reaction when applying to the nucleophilic substitution reaction to the binder copolymer used for the rocket propellant as a combustion accelerator, which is difficult in the commercialization step.

Accordingly, the inventors of the present invention have confirmed that 4-ferrocenyl butanoic acid can be used as a new ferrocene derivative applicable to the commercialization stage, and that a method of production that can be safely and efficiently applied to mass synthesis processes Want to provide.

Zn amalgam, which is mainly used in connection with the conventional method of producing 4-ferrocenyl butanoic acid, has a disadvantage of using Hg and Zn alloys. Zn amalgam alloys containing mercury are difficult to manufacture and handle, and toxic mercury byproducts can be produced, making it difficult to apply to mass production processes.(J. Am. Chem. Soc., 1957, 79, 3420 -3424; Dalton Trans., 2017, 46, 10847; Appl. Organometal.Chem. 2016, 30, 524-530; Adv. Synth. Catal. 2015, 357, 3453-3457)

Therefore, the problem to be solved by the present invention is to improve the performance of a rocket propellant, and to apply a new ferrocene (ferrocene) derivative, 4-ferrocenyl butanoic acid, which can be applied to the commercialization stage, safely and efficiently in a mass synthesis process. Provides a new manufacturing method that can be done.

In order to solve the above problems, the present invention, (tetrahydro-5-oxo-2-furanyl)-ferrosine ((tetrahydro-5-oxo-2) represented by the following formula [2] according to the following [Scheme A] -Furanyl)-ferrocene is reacted with formic acid and water to provide a method for producing 4-ferrocenyl butanoic acid represented by the following formula [3].

[Scheme A]

In addition, the above formula [2] is reacted with sodium borohydride by reacting 3-ferrocenyl propionic acid represented by the following formula [1] according to the following [Reaction Scheme B] with sodium borohydride. [2] is characterized by manufacturing.

[Scheme B]

According to an embodiment of the present invention, [Scheme A] may be a Pd/C (carbon-supported palladium) reaction is performed under a catalyst.

According to an embodiment of the present invention, the formula [2] in [Scheme A] may be reacted with formic acid and water in a solution state.

According to an embodiment of the present invention, the formula [1] in [Scheme B] may be reacted with sodium borohydride in a solution state.

In addition, the present invention provides a method for producing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid) represented by the following formula [3], including the following steps according to the following [Scheme C].

(Iv) reacting a solution containing 3-ferrocenyl propionic acid represented by the following formula [1] with sodium borohydride,

(Ii) removing the solvent after the reaction and reacting with formic acid and water.

[Scheme C]

According to one embodiment of the present invention, the step (ii) may be that the reaction is performed under Pd/C (carbon-supported palladium) catalyst.

In addition, the present invention is a solution of (tetrahydro-5-oxo-2-furanyl)-ferrosine represented by the following formula [2] according to the following [Scheme D], potassium fluoride (KF) solution, chlorobenzene and poly It provides a method for preparing 4-ferrocenyl butanoic acid represented by the following formula [3] by reacting with methylhydrosiloxane (PMHS).

[Scheme D]

On the other hand, the formula [2] is to prepare the following formula [2] by reacting 3-ferrocenyl propionic acid represented by the following formula [1] with sodium borohydride according to the following reaction scheme B It is characterized by.

[Scheme E]

According to an embodiment of the present invention, [Scheme D] may be that the reaction is performed under a palladium acetate (Pd(OAc) ₂ ) catalyst.

According to an embodiment of the present invention, the formula [2] in [Reaction Scheme D] may be reacted with a potassium fluoride solution, chlorobenzene and polymethylhydrosiloxane in a solution state.

According to an embodiment of the present invention, in [Scheme E], the formula [1] may be reacted with sodium borohydride in a solution state.

According to the present invention, the synthesis reaction of 4-ferrocenyl butanoic acid is stable because it is synthesized using sodium borohydride, a reducing agent that is mild and has excellent reaction stability, and is easy to handle. It has excellent process efficiency and can synthesize 4-ferrocenyl butanoic acid in large quantities to achieve commercialization. In addition, 4-ferrocenyl butanoic acid can be useful in the synthesis of ferrocenyl-podophyllotoxin conjugates, which are biologically active.

1 is (tetrahydro-5-oxo-2-furanyl)-ferrosine ((tetrahydro-5-oxo-2-furanyl)-ferrocene represented by [Formula 2] prepared according to an embodiment of the present invention ) ¹ H NMR spectrum.
2 is (tetrahydro-5-oxo-2-furanyl)-ferrosine ((tetrahydro-5-oxo-2-furanyl)-ferrocene represented by [Formula 2] prepared according to an embodiment of the present invention ) ¹³ C NMR spectrum.
3 is a ¹ H NMR spectrum of 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid) represented by [Formula 3] prepared according to an embodiment of the present invention.
4 is a ¹³ C NMR spectrum of 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid) represented by [Formula 3] prepared according to an embodiment of the present invention.
5 is a synthetic reaction diagram of 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid) according to an embodiment of the present invention.
6 is a synthetic reaction diagram of 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid) according to an embodiment of the present invention.
7 is a synthetic reaction diagram of 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid) according to an embodiment of the present invention.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Synthesis Example 1: Preparation of 4-ferrocenyl butanoic acid

[Scheme 1]

(1) [Formula 2] Preparation of (tetrahydro-5-oxo-2-furanyl)-ferrocene

(Tetrahydro-5-oxo-2-furanyl)-ferrocene represented by [Chemical Formula 2] was prepared in the following manner according to [Scheme 1].

1.43 g of (3-Ferrocenoyl propionic acid) was added to 20 mL of ethanol and stirred, and 0.996 g of sodium borohydride (NaBH ₄ ) in ethanol with 3-ferrocenoyl propionic acid dissolved in 0°C ice bath for 10 minutes. It was added slowly, and when the generation of hydrogen gas was completed, the ice bath was removed. The mixture was stirred at 60° C. for 5 hours to measure TLC, and when the reaction was confirmed as a result of TLC measurement, conc. The pH was adjusted to 1 with HCl, ethanol was removed by evaporation, and 20 mL of methanol was added to evaporate. After removing the methanol by evaporation, it was sufficiently dissolved in 50 mL of methylene chloride, and then 20 mL of a brine solution was added to prepare a mixed solution. 50 mL of methylene chloride was added from the mixed solution using a separatory funnel and extracted until no product remained in the water layer (50 mL × 3 times). MgSO ₄ was added to the extracted methylene chloride solution to remove moisture, followed by filtration under reduced pressure and removal of methylene chloride by evaporation. Dissolve the orange solid product in 1 mL of methylene chloride, apply it on silica pad, and pour it with a mixture of hexane and ethyl acetate (2:1, v/v) until the orange band descends, and evaporate the organic solvent of the obtained solution. After removal, vacuum drying followed to obtain 1.32 g (yield 98%) of the target compound that is orange in color ((tetrahydro-5-oxo-2-furanyl)-ferrocene).

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.340-5.304 (m, 1H), 4.226-4.185 (m, 9H), 2.677-2.502 (m, 3H), 2.290-2.189 (m, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ176.906, 85.451, 79.217, 68.703, 68.641, 67.378, 66.184, 29.271, 29.020

(2) [Formula 3] Preparation of 4-ferrocenyl butanoic acid

According to [Scheme 1], 4-ferrocenyl butanoic acid represented by [Chemical Formula 3] was prepared in the following manner.

0.053 g of Pd/C was added to the reaction flask, 1 mL of water was added, and 5 mL of ethanol and 0.27 g of (tetrahydro-5-oxo-2-furanyl)-ferrocene were added to the Pd/C solution, followed by stirring. 1 mL of formic acid was added and stirred at 80° C. for 4 hours, and the reaction was checked by TLC. After the reaction was completed, the organic solvent was evaporated after filtering to remove Pd/C. After the mixture was sufficiently dissolved in 50 mL of methylene chloride, a mixed solution was prepared by adding 10 mL of brine solution. At this time, after checking whether the pH was 1, if not, it was adjusted with HCl. Using a separatory funnel, 50 mL of methylene chloride was added to the mixed solution and extraction was performed until no product remained in the water layer (50 mL × 5 times). MgSO ₄ was added to the extracted methylene chloride solution to remove moisture, followed by filtration under reduced pressure and removal of methylene chloride by evaporation. After dissolving the orange solid product in 1 mL of methylene chloride and applying it on silica pad, hexane and ethyl acetate (4: 1, v/v) mixed solution flows until the orange band is lowered, and the organic solvent of the obtained solution is evaporated. After removal, 0.24 g (yield 89%) of a target compound that was orange after vacuum drying (4-ferrocenyl butanoic acid) was obtained.

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.044 (s, 1H), 4.121-4.049 (m, 9H), 2.322-2.227 (m, 4H), 1.732-1.701 (m, 2H)

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ174.854, 88.653, 68.739, 68.153, 67.337, 33.866, 28.750, 26.145.

Synthesis Example 2: Preparation of 4-ferrocenyl butanoic acid

[Scheme 2]

According to [Scheme 2], 4-ferrocenyl butanoic acid represented by [Chemical Formula 3] was prepared as follows.

After adding 1.43 g of 3-Ferrocenoyl propionic acid to 20 mL of ethanol and stirring, 0.996 g of sodium borohydride (NaBH ₄ ) in ethanol dissolved with 3-ferrocenoyl propionic acid in 0°C ice bath was slowly added for 10 minutes. When the addition, hydrogen gas generation was completed, the ice bath was removed, and the mixture was stirred at 60° C. for 5 hours, and TLC was measured. When the completion of the reaction was confirmed as a result of TLC measurement, ethanol was removed by evaporation, and the mixture from which the solvent was removed was dissolved in 20 mL of formic acid. The mixture of Pd/C and 1 mL of water was added to the formic acid mixture, stirred at 60° C. for 4 hours, and the reaction was checked by TLC. After the reaction was completed, the organic solvent was evaporated after filtering to remove Pd/C. After the mixture was sufficiently dissolved in 100 mL of methylene chloride, 20 mL of the brine solution was added to prepare a mixed solution, and the process of adding and extracting 100 mL of methylene chloride from the mixed solution using a separatory funnel did not leave any product in the water layer. Extracted until (50 mL × 5 times). MgSO ₄ was added to the extracted methylene chloride solution to remove moisture, followed by filtration under reduced pressure and removal of methylene chloride by evaporation. After dissolving the orange solid product in 2 mL of methylene chloride and applying it on silica pad, hexane and ethyl acetate (4:1, v/v) mixed solution flows until the orange bands descend, and the organic solvent of the obtained solution is evaporated. After removal, vacuum drying followed to obtain 1.22 g (yield 90%) of 4-ferrocenyl butanoic acid, which is the target compound that exhibits an orange color.

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.044 (s, 1H), 4.121-4.049 (m, 9H), 2.322-2.227 (m, 4H), 1.732-1.701 (m, 2H)

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ174.854, 88.653, 68.739, 68.153, 67.337, 33.866, 28.750, 26.145.

Synthesis Example 3: Preparation of 4-ferrocenyl butanoic acid

[Scheme 3]

(1) [Formula 2] Preparation of (tetrahydro-5-oxo-2-furanyl)-ferrocene

(Tetrahydro-5-oxo-2-furanyl)-ferrocene represented by [Chemical Formula 2] was prepared in the following manner according to [Scheme 3].

After adding 1.43 g of 3-Ferrocenoyl propionic acid to 20 mL of ethanol and stirring, 0 C. In the ice bath, 0.996 g of sodium borohydride (NaBH ₄ ) was slowly added to ethanol dissolved with 3-ferrocenoyl propionic acid for 10 minutes, and when the generation of hydrogen gas was completed, the ice bath was removed and the mixture was removed. TLC was measured while stirring at ℃ for 5 hours. When the reaction was confirmed as a result of TLC measurement, conc. The pH was adjusted to 1 with HCl, ethanol was removed by evaporation, and 20 mL of methanol was added to evaporate. After removing the methanol by evaporation, it was sufficiently dissolved in 50 mL of methylene chloride, and then 20 mL of a brine solution was added to prepare a mixed solution. 50 mL of methylene chloride was added from the mixed solution using a separatory funnel and extracted until no product remained in the water layer (50 mL × 3 times). MgSO ₄ was added to the extracted methylene chloride solution to remove moisture, followed by filtration under reduced pressure and removal of methylene chloride by evaporation. After dissolving the orange solid product in 1 mL of methylene chloride and applying it onto the silica pad, hexane and ethyl acetate (2:1, v/v) mixed solution flowed until the orange band descended, and the organic solvent of the obtained solution was evaporated and removed. After vacuum drying, 1.32 g (yield 98%) of the target compound ((tetrahydro-5-oxo-2-furanyl)-ferrocene), which was orange in color, was obtained.

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.340-5.304 (m, 1H), 4.226-4.185 (m, 9H), 2.677-2.502 (m, 3H), 2.290-2.189 (m, 1H).

¹³ C NMR (100 MHz, CDCl ₃ ): δ176.906, 85.451, 79.217, 68.703, 68.641, 67.378, 66.184, 29.271, 29.020

(2) [Formula 3] Preparation of 4-ferrocenyl butanoic acid

According to [Scheme 3], 4-ferrocenyl butanoic acid represented by [Chemical Formula 3] was prepared in the following manner.

0.27 g of (tetrahydro-5-oxo-2-furanyl)-ferrocene was dissolved in 5 mL of THF, and Pd(OAc) ₂ was dissolved in THF in which (Tetrahydro-5-oxo-2-furanyl)-ferrocene was dissolved. After adding 0.0112 g, 0.116 g of 2 M KF solution and 0.01 mL of chlorobenzene are sequentially added, and 0.09 mL of PMHS is slowly added, and the mixture is reacted at room temperature for 1 hour. After the reaction is completed, 10 mL of diehtyl ether is added to the reaction mixture, and when the layer is separated, the ether layer is extracted from the mixed solution using a separatory funnel (10 mL ether × 3 times). MgSO ₄ was added to the extracted ether solution to remove moisture, followed by filtration under reduced pressure and ether removal by evaporation. The obtained orange solid product was separated by column chromatography to prepare 0.24 g (yield 88%) of 4-ferrocenyl butanoic acid as a reaction product.

¹ H NMR (400MHz, DMSO-d ₆ ): δ 12.044 (s, 1H), 4.121-4.049 (m, 9H), 2.322-2.227 (m, 4H), 1.732-1.701 (m, 2H)

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ174.854, 88.653, 68.739, 68.153, 67.337, 33.866, 28.750, 26.145.

Since the specific parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that this specific technique is only a preferred embodiment, whereby the scope of the present invention is not limited. will be. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (12)

(Tetrahydro-5-oxo-2-furanyl)-ferrosine ((tetrahydro-5-oxo-) represented by the following formula [2] according to the following [Scheme A] under Pd/C (carbon-supported palladium) catalyst Method of preparing 4-ferrocenyl butanoic acid represented by the following formula [3] by reacting 2-furanyl)-ferrocene with formic acid and water:
[Scheme A]

. delete According to claim 1,
The formula [2] is a method for preparing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid), characterized in that it reacts with formic acid and water in solution. According to claim 1,
In the above formula [2], 3-ferrocenyl propionic acid represented by the following formula [1] according to [Scheme B] is reacted with sodium borohydride to form the following formula [2] Method for producing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid), characterized in that to prepare:
[Scheme B]

The method of claim 4,
The formula [1] is a method for producing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid), characterized in that it reacts with sodium borohydride in solution. Method for preparing 4-ferrocenyl butanoic acid represented by the following formula [3], including the following steps according to the following [Reaction Scheme C]:
(Iv) reacting a solution containing 3-ferrocenyl propionic acid represented by the following formula [1] with sodium borohydride,
(Ii) removing the solvent after the reaction, and reacting with formic acid and water under a Pd/C (carbon-supported palladium) catalyst,
[Scheme C]

. delete Potassium fluoride (KF) solution of (tetrahydro-5-oxo-2-furanyl)-ferrosine represented by the following formula [2] according to the following [Scheme D] under palladium acetate (Pd(OAc) ₂ ) catalyst, Method for preparing 4-ferrocenyl butanoic acid represented by the following formula [3] by reacting with chlorobenzene and polymethylhydrosiloxane (PMHS):
[Scheme D]

. delete The method of claim 8,
The formula [2] is a method for producing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid), characterized in that it reacts with a potassium fluoride solution, chlorobenzene and polymethylhydrosiloxane in solution. The method of claim 8,
The formula [2] is characterized by preparing the following formula [2] by reacting 3-ferrocenyl propionic acid represented by the following formula [1] with sodium borohydride according to the following reaction scheme E Method for preparing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid):
[Reaction Scheme E]

. The method of claim 11,
The formula [1] is a method for producing 4-ferrocenyl butanoic acid (4-ferrocenyl butanoic acid), characterized in that it reacts with sodium borohydride in solution.

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