KR100371086B1 - Method for High Efficient Epoxidation of Carbon-Carbon Double Bond on the Solid-Phase - Google Patents

Abstract

The present invention relates to a high-efficiency epoxidation method of a carbon-carbon double bond compound linked to a solid support, and more particularly, to a carbon-carbon double bond compound linked to a solid support in the presence of an organic oxidant of meta-chloroperbenzoic acid ( m- cpba). In preparing the epoxide product by the epoxidation reaction, 3-chlorobenzoic acid which is inevitably produced as a by-product using a biphasic solvent in which a low polar organic solvent is mixed with an aqueous solution of an inorganic weak base in an appropriate ratio. High-efficiency epoxidation of carbon-carbon double bond compounds connected to a solid support that leads to the water layer and inhibits side reactions by 3-chlorobenzoic acid to the epoxidation reaction proceeding in the organic layer to effectively obtain the epoxide product of the desired double bond. It is about a method.

Description

Method for High Efficient Epoxidation of Carbon-Carbon Double Bond on the Solid-Phase

The present invention relates to a high-efficiency epoxidation method of a carbon-carbon double bond compound linked to a solid support, and more particularly, to a carbon-carbon double bond compound linked to a solid support in the presence of an organic oxidant of meta-chloroperbenzoic acid ( m- cpba). In preparing the epoxide product by the epoxidation reaction, 3-chlorobenzoic acid which is inevitably produced as a by-product using a biphasic solvent in which a low polar organic solvent is mixed with an aqueous solution of an inorganic weak base in an appropriate ratio. High-efficiency epoxidation of carbon-carbon double bond compounds connected to a solid support that leads to the water layer and inhibits side reactions by 3-chlorobenzoic acid to the epoxidation reaction proceeding in the organic layer to effectively obtain the epoxide product of the desired double bond. It is about a method.

Combinatorial Chemical Synthesis is a new field of research in the development of new materials and new materials. Whereas traditional organic synthesis synthesizes a single compound in a single reaction, combinatorial chemical synthesis is more diverse and numerous. It is a new concept of chemical synthesis that synthesizes compounds at the same time. The introduction of combinatorial chemical synthesis has facilitated the search for new compounds of lead structure and optimization of their structure and function. In addition, since most of the combined chemical synthesis techniques are carried out on a solid support, continuous multistage reactions and automation of reaction processes are possible, and the separation and purification process of the product is very simple. Therefore, high throughput screening (HTS) is achieved. The advantage is that it is possible.

Although the combinatorial chemical synthesis technology is a new synthesis method that overcomes the inefficiency and inefficiency of the existing synthesis technology, there are some reasons why it could not be easily applied to the field of organic synthesis. One of the main causes is that chemical reactions on solid supports often cause unwanted side reactions due to the excessive use of most reaction reagents and, depending on the physical properties of the solid support used, Due to the limitations, the choice of reaction conditions is extremely narrow. In the field of combinatorial chemical synthesis, Merrifield resin and Wang resin are the most widely used solid supports, but these supports have very swelling effects in polar solvents such as alcohol and water. low. Therefore, almost no polar solvent is used as the chemical reaction solvent on the solid support using Merifield resin and Wang resin.

Therefore, in the conventional method of epoxidizing a double bond compound on a solid support, a low polar solvent such as dichloromethane, chloroform and tetrahydrofuran having excellent swelling effect of Merifield resin or royal resin is used as a reaction solvent. In addition, a desired epoxy compound is obtained by using an excess of meta-chloroperbenzoic acid ( m - cpba) which is an organic oxidizing agent.

In general, in carrying out the epoxidation of a double bond compound under m- cpba oxidation conditions, an aliphatic double bond compound is known to not cause side reactions even when an excess of m- cpba is used. Acid-labile double bond compounds are known to produce byproducts when an excess of m- cpba is used.

That is, when the oxidation of the benzylic olefin represented by the following formula (1) in an excess m- cpba conditions as shown in the following reaction formula 1 is generated from m- cpba after the end of the reaction 3-chloro represented by the formula (3) There is a problem that benzoic acid is produced as a target, and then easily reacts with the benzylic position, which lacks the electrons of the epoxy compound represented by Formula 2, to ring-open the epoxy ring, and then a by-product represented by Formula 4 is mainly obtained.

In Scheme 1: X represents CH ₂ , NH or oxygen atom (O); R ₁ and R ₂ represent an aliphatic and phenyl group having a hydrogen atom, a methyl group, an ethyl group, a propyl group, an alkoxy group bonded thereto; Ⓟ represents a solid support in the form of beads and fins as a high polymer of polystyrene-divinyl benzene.

In addition, when epoxidation of a double bond compound is carried out using Merrifield resin or royal resin as a solid support phase, the selection of the reaction solvent acts as an important factor for increasing yield, and the polarity with a large swelling effect is small. It is common to select a reaction solvent.

Accordingly, the present inventors have tried to develop a method for more effectively epoxidation of aliphatic double bond compounds as well as acid labile or aromatic ring adjacent double bond compounds on a solid support and under m- cpba oxidant conditions. . As a result, m- cpba in a dual phase solvent in which an inorganic weak base is dissolved in water, which is a highly polar reaction solvent which is generally avoided in the organic reaction on a solid support, and then mixed with a low polar organic solvent having a good swelling effect at an appropriate ratio. When the oxidation reaction is carried out, 3-chlorobenzoic acid, which is a byproduct, is effectively dissolved into the water layer, thereby inhibiting the ring-opening reactivity of the epoxy compound, which is the oxidation product of the double bond compound, on the solid support in the organic layer, thereby suppressing the double bond epoxide product. The present invention has been completed by knowing that the yield can be increased.

Accordingly, an object of the present invention is to provide a method for efficiently epoxidizing aliphatic or benzylic double bond compounds or acid labile double bond compounds on a solid support.

The present invention provides a method of epoxidizing an aliphatic or benzylic double bond compound or an acid labile double bond compound in the presence of an oxidizing agent,

Epoxidation of a double-bond solvent system consisting of water containing an inorganic weak base and a low polar organic solvent and a double bond compound connected on a solid support in the presence of an organic oxidant of meta-chloroperbenzoic acid ( m- cpba). It features.

Referring to the present invention in more detail as follows.

In the present invention, in order to prevent addition reaction with the epoxy compound produced on the solid support, 3-chlorobenzoic acid generated during the meta-chloroperbenzoic acid ( m- cpba) oxidation reaction, polarity avoiding the use in the organic reaction on the solid support By using a dual phase mixed solvent consisting of water, which is a large solvent, and an organic solvent having a relatively low polarity, and adding an inorganic weak base to the dual phase solvent system to make the water layer basic, the 3-chlorobenzoic acid produced as a by-product is effectively induced into the water layer. There is one specificity of the technology. As a result, the resulting epoxy compound on the solid support is present in the organic layer due to the nature of the resin was able to efficiently remove the addition reaction of 3-chlorobenzoic acid.

That is, the present invention suppresses side reactions in which the resulting epoxide product is ring-opened by optimizing the reaction conditions such as reaction solvent system and base use in epoxidizing the double bond compound on the solid support. . Such an epoxidation method according to the present invention, even if the epoxidation reaction of the benzylic double bond compound and the acid labile double bond compound as well as the aliphatic double bond compound is suppressed to the maximum production of the side reactions to maximize the yield of the target epoxide compound I was able to maximize. In addition, even when a small amount of the organic oxidizing agent of m- cpba can obtain a sufficiently maximized yield, and even if an excessive amount of m- cpba is used, the effect does not cause a great change in the yield.

Referring to the composition of the solvent system and the selection range of the base according to the present invention in detail.

In the present invention, a solvent having a polarity and water having a relatively low polarity is mixed as a solvent, and it is advantageous to use a small amount of water as much as possible. Water is preferably used within 30% by volume relative to the total volume ratio of the organic solvent, preferably using water in the range of about 10% by volume is the most effective reaction. The organic solvent of the present invention can be applied to any low polar organic solvent capable of forming a double phase with water, specifically, dichloromethane, chloroform, carbon tetrachloride, ethyl ether, and the like.

In addition, in the present invention, it is efficient to use an appropriate base to more rapidly dissolve 3-chlorobenzoic acid, which is a by-product of the m- cpba epoxidation reaction, into the water layer. At this time, it is preferable to select an inorganic weak base as a base to be used. The reason is that most inorganic weak bases dissolve well in the water layer, while the solubility in the organic layer is extremely low, so that 3-chlorobenzoic acid is formed as an anion and then induced to exist only in the water layer to attack the epoxy ring on the solid support present in the organic layer. This is because it lowers the probability. Inorganic weak base in the present invention is NaHCO ₃ , Na ₂ HPO ₄ , Na ₂ CO ₃ , K ₂ CO ₃ and the like.

According to the experimental results of the present inventors, in performing the preparation method according to the present invention, an organic base such as triethylamine, diisopropylethylamine, or the like is used instead of the inorganic weak base as the base used in the solvent system, or When only an organic solvent having no water was used even in the presence of an inorganic weak base, no effect of inhibiting the formation of the ring-opening reaction product of the epoxy compound as a by-product was obtained (see Examples 1, 2, and 3).

Under the above reaction conditions, the desired epoxy compound (Formula 2) can be obtained in good yield even when the oxidizing agent m- cpba is used in an excess amount (1.5 to 3.0 equivalents), and an adduct of 3-chlorobenzoic acid as a by-product is obtained. It was confirmed that (Formula 4) was not produced.

In addition, in order to confirm whether the epoxidation reaction product was produced according to the present invention, the compound detached from the solid support after the m- cpba oxidation reaction was purified and then analyzed by NMR and mass spectra.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

Example 1 Using Only an Organic Solvent m- Desorption for cpba epoxidation and formation

Ⅰ-1) Diolefin Resin 1a in Dichloromethane Single Organic Solvent m- cpba oxidation

Meta-chloroperbenzoic acid ( m- cpba; 37.9 mg, 0.22 mmol) was added to a dichloromethane solution (10 ml) of an olefin-introduced resin (Formula 1a; 100.0 mg, 0.11 mmol) at 0 ° C., followed by 2 The mixture was stirred for 12 hours at room temperature. After completion of reaction, the reaction mixture was filtered and saturated NaHCO ₃ aqueous solution, H ₂ O, CH ₂ Cl ₂ , DMF, DMF / H ₂ O, 50% Et ₃ N / CH ₂ Cl ₂ , MeOH and CH ₂ Cl ₂ / MeOH After repeated washings to obtain a light brown solid (Formula 4a; 108.0 mg).

The desired resin in this reaction was an epoxy compound (Formula 2a), but the actually obtained product was a resin represented by Formula 4a in which 3-chlorobenzoic acid was added to the epoxy compound represented by Formula 2a.

I-2) Desorption from Resin 4a for Confirmation of the Addition Reaction of 3-chlorobenzoic Acid

In order to confirm that the resin represented by the formula (4a) was obtained as a result of the reaction under the single organic solvent conditions according to I-1) was carried out as follows.

Trifluoroacetic acid (TFA) was added to the main reaction product obtained in I-1), that is, resin (100.0 mg, 0.11 mmol) to which 3-chlorobenzoic acid represented by Chemical Formula 4a was added, was added to a dichloromethane (5 mL) solution and stirred. , 0.5 ml) was added, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was washed with CH ₂ Cl ₂ and MeOH, the filtrates were combined and concentrated, and then the pH was adjusted to weak base by addition of 10% NaHCO ₃ aqueous solution (5-10 mL). Ethyl acetate (25 mL × 3) was added and extracted. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over MgSO ₄ , and concentrated to give an off-white solid (15.1 mg, 4 step overall yield = 34% from Wang resin) represented by Chemical Formula 5a.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.06 (t, 1H), 7.99 (m, 1H), 7.56 (m, 1H), 7.41 (t, 1H), 6.69 (t, 1H), 6.60 ( m, 1H), 6.55 (m, 1H), 6.05 (d, 1H), 3.94 (d, 1H), 3.38 (br s, 2H), 1.49 (s, 3H), 1.34 (s, 3H); M / S 347.79

To summarize the results of the present embodiment, in carrying out the epoxidation reaction of the benzylic double bond on the solid support, the solid support phase epoxide compound (Formula 2a) under the existing solid support phase oxidation conditions using m- cpba ) Is hardly produced, and it can be seen that a by-product obtained by adding 3-chlorobenzoic acid represented by the formula (4a) to the epoxy ring is obtained.

Ⅰ-3) Addition and Desorption of 4-ethylaniline for Confirmation of Formation of Epoxy Compound on Solid Support

Epoxide resin (100.0 mg, 0.11 mmol) represented by the formula (2a) and Mg (ClO ₄ ) ₂ (49.1 mg, 0.22 mmol) were added to an acetonitrile solution (1 mL) and stirred with 4-ethylaniline (53.2 mg, 0.44 mmol) was added, followed by stirring at 35 ° C. for 12 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate resin was washed repeatedly with CH ₂ Cl ₂ , DMF and MeOH, dried, and then placed in a dichloromethane (5 mL) solution and stirred with trifluoroacetic acid (TFA, 0.5 mL). Was added and reacted at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was washed repeatedly with CH ₂ Cl ₂ and MeOH, the filtrates were combined and concentrated, and then the pH was adjusted with an inorganic weak base by addition of 10% NaHCO ₃ aqueous solution (5-10 mL). Then, ethyl acetate (25 mL × 3) was added and extracted. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over MgSO ₄ , concentrated under reduced pressure, and then chromatographed on silica gel under a mixed solvent of hexane / ethyl acetate (2/1, v / v). The separation was purified by chromatography. As a result, a compound (15.0 mg, 5 step overall yield = 34%) was added to the 3-chlorobenzoic acid represented by the formula (4a) to the epoxy compound.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.06 (t, 1H), 7.99 (m, 1H), 7.56 (m, 1H), 7.41 (t, 1H), 6.69 (t, 1H), 6.60 ( m, 1H), 6.55 (m, 1H), 6.05 (d, 1H), 3.94 (d, 1H), 3.38 (br s, 2H), 1.49 (s, 3H), 1.34 (s, 3H); MS 347.79

In summary, the reaction conditions of Example I-1) indicate that the epoxidation reaction of benzylic double bonds on the solid support is followed by the addition of 3-chlorobenzoic acid after the epoxy compound is produced. It can be estimated.

Example 2 Using only an organic solvent in the presence of a base m- Desorption for cpba epoxidation and formation

Ⅱ-1) NaHCO ₃ In the presence of dichloromethane solution m- cpba oxidation

Dichloromethane solution of _{NaHCO 3 m- cpba (37.9 ㎎,} 0.22 mmol) and put (73.93 ㎎, 0.88 mmol) stirring at 0 ℃ to (10 ㎖) of; (100.0 ㎎, 0.11 mmol Formula 1a) The olefin is introduced into the resin After the addition, the mixture was stirred at the same temperature for 2 hours and at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered and repeatedly washed with a saturated NaHCO ₃ aqueous solution, H ₂ O, CH ₂ Cl ₂ , DMF, DMF / H ₂ O, MeOH and CH ₂ Cl ₂ / MeOH mixed solution to obtain a light brown solid resin. (Formula 4a; 106 mg) was obtained.

The desired resin in this reaction was an epoxy compound (Formula 2a), but the actually obtained product was a resin represented by Formula 4a in which 3-chlorobenzoic acid was added to the epoxy compound represented by Formula 2a.

Even when using triethylamine, diisopropylethylamine, or the like as a base in the reaction, an epoxy compound represented by Formula 2a was not obtained. This addition was a resin represented by the general formula (4a).

II-2) Desorption from Resin 4a for Confirmation of Addition of 3-Chlorobenzoic Acid

In order to confirm that the resin represented by the formula (4a) was obtained as a result of the reaction in the organic solvent conditions in the presence of the base according to II-1).

Trifluoroacetic acid (TFA) was added to the main reaction product obtained in II-1), that is, resin (100 mg, 0.11 mmol) to which 3-chlorobenzoic acid represented by Chemical Formula 4a was added, was added to dichloromethane (5 mL) solution and stirred. , 0.5 ml) was added, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was washed with CH ₂ Cl ₂ and MeOH, the filtrates were combined and concentrated, and then the pH was adjusted to weak base by addition of 10% NaHCO ₃ aqueous solution (5-10 mL). Ethyl acetate (25 mL × 3) was added and extracted. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over MgSO ₄ , and concentrated to give an off-white solid (15.1 mg, 4 step overall yield = 32% from Wang resin) represented by Chemical Formula 5a.

¹ H NMR (200 MHz, CDCl ₃ ): δ 8.06 (t, 1H), 7.99 (m, 1H), 7.56 (m, 1H), 7.41 (t, 1H), 6.69 (t, 1H), 6.60 ( m, 1H), 6.55 (m, 1H), 6.05 (d, 1H), 3.94 (d, 1H), 3.38 (br s, 2H), 1.49 (s, 3H), 1.34 (s, 3H); M / S 347.79

Example 3 In a Biphasic Solvent Using Base-Based Water m- Desorption for cpba epoxidation and formation

Ⅲ-1) NaHCO ₃ In the presence of water and a biphasic solvent with dichloromethane m- cpba epoxidation reaction

Saturated NaHCO ₃ aqueous solution (1 mL) was added to a dichloromethane solution (10 mL) of an olefin-introduced resin (Formula 1a; 100.0 mg, 0.11 mmol), and m- cpba (37.9 mg, 0.22 mmol) was stirred at 0 ° C. After the addition, the mixture was stirred at the same temperature for 2 hours and then stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered and repeatedly washed with a saturated NaHCO ₃ aqueous solution, H ₂ O, CH ₂ Cl ₂ , DMF, DMF / H ₂ O, MeOH and CH ₂ Cl ₂ / MeOH mixed solution to obtain a light brown solid resin. (Formula 2a; 100 mg) was obtained.

Ⅲ-2) NaHCO ₃ In the presence of water and chloroform in a biphasic solvent m -cpba epoxidation reaction

Saturated NaHCO ₃ aqueous solution (2 mL) was added to a chloroform solution (20 mL) of an olefin-introduced resin (Formula 1a; 1.0 g, 1.1 mmol), and m- cpba (379.0 mg, 2.2 mmol) was added while stirring at 0 ° C. Then, the mixture was stirred at the same temperature for 2 hours, and then stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was filtered and repeatedly washed with a saturated NaHCO ₃ aqueous solution, H ₂ O, CH ₂ Cl ₂ , DMF, DMF / H ₂ O, MeOH and CH ₂ Cl ₂ / MeOH mixed solution to obtain a light brown solid resin. (Formula 2a; 1,049.8 mg) was obtained.

Ⅲ-3) Addition and Desorption of 4-ethylaniline for Confirmation of Formation of Epoxy Compound on Solid Support

Epoxide resin (100.0 mg, 0.11 mmol) represented by the formula (2a) and Mg (ClO ₄ ) ₂ (49.1 mg, 0.22 mmol) were added to an acetonitrile solution (1 mL) and stirred with 4-ethylaniline (53.2 mg, 0.44 mmol) was added, followed by stirring at 35 ° C. for 12 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was washed repeatedly with CH ₂ Cl ₂ , DMF, and MeOH to obtain a resin with aniline added to the epoxy compound represented by Formula 6a. The obtained resin 7a was added to a dichloromethane (5 mL) solution, trifluoroacetic acid (TFA, 0.5 mL) was added with stirring, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was washed repeatedly with CH ₂ Cl ₂ and MeOH, the filtrates were combined and concentrated, and then the pH was adjusted with a weak base by addition of 10% NaHCO ₃ aqueous solution (5-10 mL). Ethyl acetate (25 mL × 3) was added and extracted. The organic layer was washed with water (10 mL) and saturated brine (10 mL), dried over MgSO ₄ , concentrated under reduced pressure, and then purified by column chromatography on silica gel under a mixed solvent of hexane / ethyl acetate (2/1, v / v). Separation and purification yielded a pale yellow solid (11.5 mg, 5 step overall yield = 33% from Wang resin) represented by Chemical Formula 7a.

¹ H NMR (200 MHz, CD ₃ OD): δ 7.01 (m, 2H), 6.70 to 6.63 (m, 4H), 4.34 (d, 1H), 3.67 (d, 1H), 2.50 (q, 2H) , 1.44 (s, 3H), 1.27 (s, 3H), 1.19 (t, 3H); M / S 312.95

As a result of this reaction, it was confirmed that an epoxy compound was formed on a solid support by obtaining a product (Formula 7a) in which 4-ethylaniline was added to the epoxy ring. However, little by-product (formula 5a) in which 3-chlorobenzoic acid was added to the epoxy ring was obtained (within 5%). In conclusion, the epoxidation of carbon-carbon double bonds unstable to benzyl and acid on a solid support under the reaction conditions of the present invention can be confirmed to effectively inhibit the addition reaction of 3-chlorobenzoic acid.

Example 4 Change in Yield of Epoxy Compounds According to Water Content in Dual-Phase Solvent Using Base-Based Water

The epoxidation reaction was carried out in the same manner as in Example 3, except that the yield change of the epoxy compound produced when the water content was changed was confirmed. The results are shown in Table 1 below.

Example 5 Change in Yield of Epoxy Compounds According to Base Selection in a Dual-Phase Solvent Using Base-Present Water

The epoxidation reaction was carried out in the same manner as in Example 3, except that the yield change of the epoxy compound produced when the type of the base was changed was confirmed. The results are shown in Table 2 below.

As exemplified in the above examples, the epoxidation reaction using m- cpba of a benzylic double bond compound and an acid labile carbon-carbon double bond compound, which is generally linked to a solid support, is a 3-chlorobenzoic acid which is a by-product of m- cpba. It is difficult to obtain the target epoxy compound on the solid support by attacking the epoxy ring in the benzylic position where the electrons in the carbon position lacking are insufficient. However, when the double phase solvent reaction using water in the presence of the inorganic weak base which is the reaction condition according to the present invention can effectively inhibit the epoxy ring attack of 3-chlorobenzoic acid, which is a by-product of m- cpba, benzylic on the solid support And extremely useful for epoxidation of acid-stable carbon-carbon double bonds.

Therefore, the present invention has improved the applicability of the combined chemical synthesis technology using the organic reaction on the solid support, which makes it easier to search for the lead compound of the new structure and to optimize the structure and function.

Claims (5)

Double - bond solvent system composed of water containing inorganic weak base and low polar organic solvent, and double bond connected to solid support as represented by the following formula (1) in the presence of organic oxidizing agent of meta-chloroperbenzoic acid ( m- cpba) A high efficiency epoxidation method of a carbon-carbon double bond compound connected to a solid support, characterized in that the compound is epoxidized: In Chemical Formula 1, X represents CH ₂ , NH or an oxygen atom (O); R ₁ and R ₂ represent an aliphatic and phenyl group having a hydrogen atom, a methyl group, an ethyl group, a propyl group, an alkoxy group bonded thereto; Ⓟ represents a solid support in the form of beads and fins as a high polymer of polystyrene-divinyl benzene. delete The method of claim 1 wherein the solid support is Merrifield resin or Wang resin. The method of claim 1, wherein the reaction solvent system contains less than 30% by volume of water based on the total amount of the organic solvent. The method of claim 1 wherein the inorganic weak base is selected from NaHCO ₃ , Na ₂ CO ₃ , Na ₂ HPO ₄ and K ₂ CO ₃ high efficiency epoxidation method of a carbon-carbon double bond compound connected to a solid support.