Synthetic method for primary amides from dioxazolones in copper catalysis

Abstract

The present invention relates to a method for synthesizing a novel primary amide using dioxazolone as a starting material and adding a copper salt catalyst, and more specifically, to a method for producing an environmentally friendly primary amide derivative with a short reaction time, low reaction temperature, and the generation of harmless carbon dioxide as a byproduct. The present invention provides an efficient method that enables the safety of compounds and low-cost synthesis even in large-scale reactions. Furthermore, it suppresses the use of highly corrosive ammonia, which was required in the conventional synthesis of primary amides, while simultaneously providing more environmentally friendly synthesis conditions through a water-added co-solvent system. Furthermore, the organic synthesis method of primary amides according to the present invention can be widely applied to the synthesis of pharmaceutical intermediates, natural products, and low-molecular-weight new drug candidate compounds.

Description

Technology Field

[0001] The present invention relates to a method for synthesizing a novel primary amide using dioxazolone as a starting material and adding a copper salt catalyst, and more specifically, to a method for producing an environmentally friendly primary amide derivative with a short reaction time, low reaction temperature, and the generation of harmless carbon dioxide as a byproduct. Background Technology

[0003] Amides are organic compounds in which nitrogen is linked to a carbonyl group. Traditionally, in the condensation reaction between an amine and a carboxylic acid, there is a method involving highly reactive acid chlorides using SOCl2 or (COCl)2. However, this reaction has the disadvantage of using highly toxic SOCl2 or (COCl)2, and because highly corrosive hydrochloric acid gas is produced as a reaction byproduct, an excess amount of base must be added to neutralize it.

[0004] In addition, the most widely used amide synthesis method to date involves the use of active reagents such as EDC-HCl and BTOH-H2O. However, this method also suffers from very low atomic economy and poor stability of the reagents used, leading to safety-related issues during commercialization. Furthermore, since the byproducts generated in this reaction account for a significant portion of the total, there are difficulties in the reaction process for their removal.

[0006] Therefore, there is a growing demand for an eco-friendly and sustainable amide synthesis method that can solve problems such as the use of the aforementioned toxic reagents, the generation of excessive byproducts, and the difficulty of the process for separating them. The problem to be solved

[0008] The present invention aims to provide an environmentally friendly, novel method for producing primary amide derivatives that can solve the problems associated with the synthesis methods of the prior art by utilizing the decarbonogenic reduction reaction of dioxazolone in the presence of a copper catalyst and a silane. means of solving the problem

[0010] The first aspect of the present invention provides a method for synthesizing various primary amides in an ethanol, acetone, or acetone / water cosolvent system using a starting material, dioxazolone which is one of the hydroxyl derivatives, a copper salt catalyst, a ligand containing a nitrogen atom, and an additive capable of providing a hydride.

[0011] More specifically, the invention relates to a method for preparing a primary amide compound of Formula 2 using a dioxazolone represented by Formula 1.

[0012] [Chemical Formula 1]

[0013]

[0015] [Chemical Formula 2]

[0016]

[0018] In the above Chemical Formulas 1 and 2:

[0019] R 1 C3-C 11 alkyl group of, C6-C 10 It is an aryl group, or a C5-C8 heteroaryl group.

[0020] Meanwhile, the above C6-C 10 The aryl group is substituted with or not substituted with NO2, OMe, tBu, OSiR2, Br, Cl, F, O, Cl, Br, or F, and

[0021] The above R is hydrogen, C3-C 11 The alkyl group of, or C6-C 10 It is Arilgi of, and

[0022] The above C3-C 11The alkyl group may be an alkyl group that includes or does not include N or O, or may include a phenyl group or a naphthyl group that is substituted with or not substituted with Cl.

[0024] In one embodiment of the present invention, a copper salt catalyst may be used, preferably Cu(I)X and Cu(II)O2. X may be selected from Cl, Br, I, OAc, etc.

[0026] In one embodiment of the present invention, a ligand capable of providing a nitrogen atom is used, and preferably, pyridine may be used.

[0028] In one embodiment of the present invention, the invention may be carried out in a suitable solvent, preferably in ethanol, acetone, or an acetone / water cosolvent. Effects of the invention

[0030] The present invention provides an efficient method that enables the safety of compounds and low-cost synthesis even in large-scale reactions. Furthermore, it suppresses the use of highly corrosive ammonia, which was required in the conventional synthesis of primary amides, while simultaneously providing more environmentally friendly synthesis conditions through a water-added co-solvent system.

[0031] Furthermore, the organic synthesis method of primary amides according to the present invention can be widely applied to the synthesis of pharmaceutical intermediates, natural products, and low-molecular-weight new drug candidate compounds. Specific details for implementing the invention

[0033] Hereinafter, embodiments and examples of the present invention are described in detail so that those skilled in the art can easily implement the present invention.

[0034] However, the present invention may be implemented in various different forms and is not limited to the embodiments and examples described herein. Furthermore, in order to clearly explain the present invention, parts unrelated to the description have been omitted from the drawings.

[0035] Throughout this specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. Throughout this specification, terms of degree such as "about," "substantially," etc., are used to mean at or near the stated value when inherent manufacturing and material tolerances are presented in the stated meaning, and are used to prevent unscrupulous infringers from unfairly exploiting the disclosure in which precise or absolute values ​​are mentioned to aid in understanding the invention. Throughout this specification, terms of degree such as "step of" or "step of" do not mean "step for."

[0036] Throughout this specification, the description "A and / or B" means "A or B, or A and B".

[0038] The first aspect of the present invention provides a method for synthesizing various primary amides in an ethanol, acetone, or acetone / water cosolvent system using a starting material, dioxazolone which is one of the hydroxyl derivatives, a copper salt catalyst, a ligand containing a nitrogen atom, and an additive capable of providing a hydride.

[0039] More specifically, the invention relates to a method for preparing a primary amide compound of Formula 2 using a dioxazolone represented by Formula 1.

[0040] [Chemical Formula 1]

[0041]

[0043] [Chemical Formula 2]

[0044]

[0046] In the above Chemical Formulas 1 and 2:

[0047] R 1 C3-C 11alkyl group of, C6-C 10 It is an aryl group, or a C5-C8 heteroaryl group.

[0049] Meanwhile, the above C6-C 10 The aryl group is substituted with or not substituted with NO2, OMe, tBu, OSiR2, Br, Cl, F, O, Cl, Br, or F, and

[0050] The above R is hydrogen, C3-C 11 The alkyl group of, or C6-C 10 It is Arilgi of, and

[0051] The above C3-C 11 The alkyl group may be an alkyl group that includes or does not include N or O, or may include a phenyl group or a naphthyl group that is substituted with or not substituted with Cl.

[0053] In the manufacturing method of the present invention, a copper salt catalyst is used, preferably Cu(I)X and Cu(II)O2. X can be selected from Cl, Br, I, OAc, etc.

[0055] In the manufacturing method of the present invention, a ligand capable of providing a nitrogen atom is used, and preferably, pyridine can be used.

[0057] The manufacturing method of the present invention can be carried out in a suitable solvent, preferably in ethanol, acetone, or an acetone / water cosolvent.

[0059] The present invention will be explained in more detail below through embodiments, but the scope of the present invention is not limited by these embodiments.

[0061] [Example]

[0062] A primary amide was prepared using dioxazolone as a starting material through the following reaction.

[0063]

[0065] [Table 1]

[0066]

[0067] As can be seen from the above manufacturing example, when using the manufacturing method of the present invention, the desired primary amide could be produced with a yield of up to 98%.

[0069] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single unit may be implemented in a distributed manner, and components described as distributed may likewise be implemented in a combined form.

[0071] The scope of the present invention is defined by the claims set forth below rather than by the detailed description above, and all modifications or variations derived from the meaning and scope of the claims and equivalent concepts thereof should be interpreted as being included within the scope of the present invention.

Claims

Claim 1 A method for preparing a primary amide represented by Chemical Formula 2, characterized by reacting a dioxazolone represented by Chemical Formula 1 below with 20 mol% of a CuCl copper salt catalyst in the presence of 0.6 equivalents of pyridine and 2 equivalents of Ph2SiH2: [Chemical Formula 1] [Chemical Formula 2] In the above Chemical Formulas 1 and 2:R 1 C3-C 11 alkyl group of, C6-C 10 It is an aryl group of, or a C5-C8 heteroaryl group, and the above C6-C 10 The aryl group is an aryl group substituted with or unsubstituted with NO2, OMe, tBu, OSiR2, O, Cl, Br, or F, and R is hydrogen, C3-C 11 The alkyl group of, or C6-C 10 It is an aryl group of, and the above R is C3-C 11 In the case of an alkyl group, the above C3-C 11 The alkyl group is an alkyl group that may or may not contain N or O, or an alkyl group that includes a phenyl group or a naphthyl group that is substituted with or not substituted with Cl. Claim 2 delete Claim 3 delete Claim 4 A method for producing a primary amide according to claim 1, characterized by being carried out in ethanol, acetone, or an acetone / water cosolvent. Claim 5 A method for producing a primary amide according to claim 1, wherein the primary amide is one of the following compounds: .

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