KR100619439B1 - Method for preparing amine derivative introduced with formyl group - Google Patents

Abstract

The present invention is a novel method for preparing an amine derivative having a formyl group in nitrogen, which is useful as an intermediate for synthesizing intermediates or functional polymers of physiologically active substances such as medicines and pesticides, and compounds having primary or secondary amine groups. Which protected nitrogen (N) with a formyl group by reacting with formic acid, bis (trichloromethyl) carbonate, and triphenylphosphine at atmospheric pressure and in mild conditions near room temperature It is a new way of obtaining derivatives.

Formyl groups, formic acid, trichloromethyl (bis), triphenylphosphine, primary amines, secondary amines, formylation

Description

Process for the preparation of N-formylamine derivatives

Many researchers have been working to introduce formyl groups as functional groups that protect the nitrogen of amino acids for the purpose of regulating the reaction progression of acids and amines to facilitate the desired reaction in protein synthesis. Has been progressed by. In addition to protein synthesis, N-formylamine derivatives have been of great interest as intermediates for obtaining isocyanide by introducing formyl groups into primary amines.

The present invention is a method of reacting formic acid (formic acid) directly to a primary amine or a secondary amine in the presence of triphosphene (bis) and triphenylphosphine (amine) of the general formula (II) It is a method of synthesizing N-formylamine derivative of the following general formula (I) by reacting formic acid with formic acid under normal pressure and room temperature.

Wherein R represents a substituted or unsubstituted C1 to C5 alkyl or a substituted or unsubstituted C6 to C12 aryl group, and R 'represents a hydrogen (H) or methyl group or a substituted or unsubstituted C1 to C5 Alkyl or substituted or unsubstituted C6 to C12 aryl group.

Huffman was published in J. Org. Chem. For the synthesis of N-formylamine derivatives in the literature published on page 23, 727, formic acid and acetic anhydride were reacted at around 60 ° C. for 2 hours to obtain acetic formic anhydride as a formyl group introduction reagent. The reagent was reacted with the amine for 60 hours at room temperature to obtain the target compound. Waki et al. J. Org. Chem. For the synthesis of N-formylamine derivatives in the literature published on page 42, 2019, formic acid was dissolved in chloroform, and then the solution was mixed with dicyclohexylcarbodiimide (DCC) solution pre-dissolved in chloroform at low temperature to obtain a reagent for introducing formyl groups. After first preparing, the reagent was reacted with an amine to synthesize a target compound. Yale was published in 1971 in J. Org. Chem. To synthesize N-formylamine derivatives in the literature published on 36, 3238 pages, the target compound was synthesized using phenylformate, a formyl group introduction reagent. Chen et al. Synthesized formic anhydride as a formyl introduction reagent by reacting formic acid with N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride in a document published on Synthesis 709 in 1979. The desired compound was synthesized by reacting with an amine. Gramain et al. Synthesized the target compound by synthesizing diformylacetamide (N, N-diformylacetamide) synthesized in two steps from formamide in a document published on page 264 of Synthesis in 1982 using a formyl introduction reagent. More recently, in 2002, Hill et al., Published in Organic Letter Vol. 4, p. 111, trifluoroethanol (2,2,2-trifluoroethanol) and formic acid were reacted at 80 ° C. for 18 hours, followed by vacuum distillation to give trifluoroethyl. The desired compound was synthesized by synthesizing formate (2,2,2, -trifluoroethyl formate) with a formyl introduction reagent and reacting with an amine.

As such, the conventional techniques known to date are formyl, which is a first step of preparing another reagent capable of introducing a formyl group to introduce a formyl group into a primary or secondary amine, and a two-step reaction of reacting this reagent with an amine. It is composed of a formylation reaction, and the reaction conditions of the process for preparing a reagent for introducing a formyl group have a problem such as a violent condition at a high temperature or a long time, and a reaction condition for using the reagent for introducing a formyl group. In addition, when high temperature conditions or acid-sensitive functional groups are present in the reactants, by-products may occur, resulting in poor yield or difficulty in purifying, and thus, formyl groups may be introduced directly from the primary or secondary amines. The development of new manufacturing processes has long been a demanding task in this area.

The present inventors who have carefully observed these problems of the prior art react directly with formic acid from primary amines or secondary amines, which are well-established techniques in the field requiring the synthesis of N-formylamine derivatives. Efforts have been made to find the reaction conditions for synthesizing the desired N-formylamine derivatives under mild reaction conditions, and as a result, within one hour under mild conditions without the need for the synthesis of another reagent to introduce the formyl group. The present invention has been completed by developing a method for obtaining a target compound in high yield and high purity without generating by-products in a short time.

The present invention provides a novel preparation of N-formylamine derivatives represented by the following general formula (I) having formyl groups in nitrogen useful as intermediates for synthesizing intermediates or functional polymers of bioactive substances such as medicines and pesticides. By way of reacting formic acid directly with primary or secondary amines, amines of the following general formula (II) are present with triphosphene and triphenylphosphine: It is synthesized by reacting with formic acid under normal pressure and room temperature under mild conditions.

Wherein R represents a substituted or unsubstituted C1 to C5 alkyl or a substituted or unsubstituted C6 to C12 aryl group, and R 'represents a hydrogen (H) or methyl group or a substituted or unsubstituted C1 to C5 Alkyl or substituted or unsubstituted C6 to C12 aryl group.

The present invention provides a novel N-method for which the overall synthesis process is simple and reacts under mild conditions near room temperature at atmospheric pressure, and also does not require the synthesis of the formyl group introduction reagents used in the conventional synthesis methods and generates little by-products. It is a synthesis method of -formylamine derivative.

Formic acid (formic acid) used in the present invention is 1 to 5 mole times, preferably 1.0 to 1.2 mole times compared to the amine derivative of the general formula (II) and triphosphene (bis (trichloromethyl) carbonate) is represented by the general formula (II 0.3 to 1 mole times, preferably 0.3 to 0.5 mole times, and triphenylphosphine is 1.0 mole compared to the formamide derivative of Formula (II). The reaction temperature is reacted at 0 to 45 ^o C, preferably 0 to 25 ^o C. As the reaction solvent, all common organic solvents such as chloroform, dichloromethane and toluene can be used. Referring to the reaction sequence constituting the present invention is as follows.

First, formic acid is dissolved in triphenylphosphine and trichloromethyl carbonate in a solvent, dichloromethane, cooled to 0 ^o C in an ice-bath and stirred for 5 minutes. do. Add triethylamine and amine to introduce a formyl group, remove ice-bath and naturally warm to room temperature and stir for 10 minutes to 1 hour, preferably 10 minutes to 30 minutes. This completeness can be confirmed by TLC.

The amine derivatives of general formula (II) used as starting materials in the present invention are mostly commercially available and can be easily synthesized by general known methods. The amine derivative of the general formula (II) to which the method of the present invention can be applied can be any aliphatic primary amine and aliphatic secondary amine, and in the case of aromatic amines, electron withdrawing group which reduces electron density in benzene ring. Amines), as well as amines with electron donating groups that increase electron density in benzene rings, are applicable to all primary and secondary amines. N-formylamine derivatives of general formula (I) are useful derivatives that can be used not only as monomers for the synthesis of protein engineering intermediates or functional polymers, but also as intermediates for medicinal or bioactive substances.

Hereinafter will be described in more detail based on the embodiments using the present invention. However, the present invention is not limited to the methods presented in the embodiments.

Example 1.

In a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of bis (trichloromethyl) carbonate were added to a 30 mL flask. Stirred) and cooled to 0-5 ° C. Into this solution was added 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine, followed by stirring for 20 minutes. Then, a solution of 146.3 mg (2.0 mmole) of butylamine in 1.0 mL of dichloromethane was added. Stirring for 20 minutes produces excess solids and confirms the completion of the reaction by TLC.

After completion of the reaction, the reaction mixture was filtered and the solid obtained by washing with a small amount of dichloromethane was dried to obtain 182 mg of N-butylformamide as a target compound (yield 90.0%).

Example 2.

In a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of bis (trichloromethyl) carbonate were added to 12 mL of dichloromethane under a nitrogen atmosphere. Stirred) and cooled to 0-5 ° C. 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine were added to the solution, followed by stirring for 20 minutes. A solution of 214.3 mg (2.0 mmole) of benzylamine in 2.0 mL of dichloromethane was added thereto. Stirring for 20 minutes produces excess solids and confirms the completion of the reaction by TLC.

After completion of the reaction, the reaction mixture was filtered and the solid obtained by washing with a small amount of dichloromethane was dried to obtain 250 mg of the target compound N-benzylformamide (yield 92.5%).

Example 3.

In a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of bis (trichloromethyl) carbonate were added to a 30 mL flask. Stirred) and cooled to 0-5 ° C. Into this solution, 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine were added and stirred for 20 minutes, followed by a solution of 114.2 mg (2.0 mmole) of allylamine in 1.0 mL of dichloromethane. Stirring for 20 minutes produces excess solids and confirms the completion of the reaction by TLC.

After completion of the reaction, the reaction mixture was filtered, and the solid obtained by washing with a small amount of dichloromethane was dried to obtain 160 mg of N-allylformamide as a target compound (yield 94.0%).

Example 4

In a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of bis (trichloromethyl) carbonate were added to 12 mL of dichloromethane under a nitrogen atmosphere. Stirred) and cooled to 0-5 ° C. Into this solution was added 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine, followed by stirring for 20 minutes, followed by a solution of 246.3 mg (2.0 mmole) of orthomethoxyaniline in 2.0 mL of dichloromethane. After stirring for about 20 minutes, it was confirmed by TLC that the solid was formed in excess and the reaction was completed.

After completion of the reaction, the reaction mixture was filtered and the solid obtained was washed with a small amount of dichloromethane and dried to obtain 290 mg of N- (2-methoxyphenyl) formamide as a target compound (yield 95.9%).

Example 5

In a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of bis (trichloromethyl) carbonate were added to 12 mL of dichloromethane under a nitrogen atmosphere. Stirred) and cooled to 0-5 ° C. Into this solution was added 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine. The solution was stirred for 20 minutes, and 255.2 mg (2.0 mmole) of parachloroaniline was dissolved in 2.0 mL of dichloromethane. Stirring for about 20 minutes can confirm by TLC that excess solids are produced and the reaction is complete.

After completion of the reaction, the reaction mixture was filtered and the solid obtained was washed with a small amount of dichloromethane and dried to obtain 280 mg of N- (4-chlorophenyl) formamide as a target compound (yield 90.0%).

Example 6

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of triphosphene (bis (trichloromethyl) carbonate) were added with 12 mL of dichloromethane and stirred in an ice bath under nitrogen atmosphere. Cool to 0-5 ° C. 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine were added to the solution, stirred for 20 minutes, and 274.4 mg (2.0 mmole) of 4-methoxy-N-methylaniline was dissolved in 3.0 mL of dichloromethane. After the solution was added and stirred for about 20 minutes, it was confirmed by TLC that excess solids were formed and the reaction was completed.

After completion of the reaction, the reaction mixture was filtered and the solid obtained was washed with a small amount of dichloromethane and dried to obtain 310 mg of N- (4-methoxyphenyl) -N-methylformamide as a target compound (yield 93.8%).

Example 7

In a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine and 196 mg (0.66 mmole) of bis (trichloromethyl) carbonate were added to 12 mL of dichloromethane under a nitrogen atmosphere. Stirred) and cooled to 0-5 ° C. 92 mg (2.0 mmole) of formic acid and 607 mg (6.0 mmole) of triethylamine were added to the solution, followed by stirring for 20 minutes. Then, 242.4 mg (2.0 mmole) of dipyridin-2-ylamine was dissolved in 3.0 mL of dichloromethane. After the addition and stirring for about 20 minutes, it was confirmed by TLC that the solid was formed in excess and the reaction was completed.

After completion of the reaction, the reaction mixture was filtered and the solid obtained by washing with a small amount of dichloromethane was dried to obtain 380 mg of N, N-dipyridin-2-ylformamide as a target compound (yield 95.3%).

Example 8-10

A formamide derivative having the following structure was synthesized in the same manner as in Example 1, except that the amine derivative having the following structure was used instead of the butylamine used in Example 1.

The prior art known so far is to form another reagent capable of introducing the formyl group to introduce the formyl group into the primary or secondary amine, followed by the formation of a formylation reaction which reacts the reagent with the amine. It has been implemented in two stages. In addition to the problems that the conventional methods require a process for preparing a reagent for introducing a formyl group and take a long time, the reaction conditions for using the reagent for introducing the formyl group also require high temperature or acid. If sensitive functional groups are present inside the reactants, the development of a new manufacturing process that can introduce formyl groups directly from primary amines or secondary amines due to problems such as by-products and poor yield or difficulty in purification. While it has been demanded as a sought-after task in this field, the present inventors can directly react with formic acid from primary or secondary amines to synthesize desired N-formylamine derivatives under mild reaction conditions near atmospheric pressure and room temperature. By completing the present invention can be obtained a synthetic method excellent in the reliability and reproducibility of the reaction, the present invention When it is applied to industrialization, the reaction step and process time can be drastically reduced compared to the previous methods, and the separation and purification process of the target compound can be easily performed without causing the environmental problem by the by-products, which will greatly contribute to the economic improvement.

Claims (3)

The amine represented by the following general formula (I) characterized by reacting the amine of the following general formula (II) with formic acid in the presence of triphenylphosphine and trichloromethyl (bis) Method for preparing N-formylamine derivative.

Wherein R represents a substituted or unsubstituted C1 to C5 alkyl or a substituted or unsubstituted C6 to C12 aryl group, and R 'represents a hydrogen (H) or methyl group or a substituted or unsubstituted C1 to C5 Alkyl or substituted or unsubstituted C6 to C12 aryl group. A process for the preparation of an N-formylamine derivative of formula (I) from an amine derivative of formula (II) in a compound wherein in claim 1 R or R ′ is part of a compound comprising a carboxylic acid moiety of an amino acid. In claim 1, triphosphene (bis (trichloromethyl) carbonate) is reacted in the presence of triphenylphosphine (triphenylphosphine) using 0.3 to 1.0 molar ratio compared to the amine derivative of Formula (II). Process for the preparation of N-formylamine derivatives of I).