KR100527624B1 - Process for the preparation of N-formylamine derivatives - 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. It is a new method to obtain an amine derivative which protects nitrogen (N) with formyl group by reacting with formic acid in the presence of bis (trichloromethyl) carbonate under normal pressure and room temperature.

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 directly with a primary amine or a secondary amine. The amine of formula (II) is mild in the presence of bis (trichloromethyl) carbonate in the presence of formic acid and atmospheric pressure, near room temperature. It is a method of synthesizing the N-formylamine derivative of the following general formula (I) by making it react on conditions.

Wherein R represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl group, and R 'represents hydrogen (H) or methyl or substituted or unsubstituted alkyl or substituted or unsubstituted 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 about 60 ° C. for 2 hours to obtain acetic formic anhydride as a formyl introduction reagent, and then the reagent was reacted with amine at room temperature. The reaction was carried out for a time 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. Was synthesized. Gramain et al. Synthesized the target compound by synthesizing N, N-diformylacetamide, which was synthesized in two steps from formamide, in a document published on Synthesis 264 in 1982 using a formyl introduction reagent. More recently, in 2002, Hill et al., Published in Organic Letter Vol. 4, p. 111, 2,2,2-trifluoroethanol and formic acid were reacted at 80 ° C for 18 hours, followed by vacuum distillation to give 2,2,2, -trifluoroethyl. The formate was synthesized with a formyl introduction reagent to react with the amine to synthesize the desired compound.

As such, the conventional technique known to date is formylation, 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. Although the reaction conditions of the process for preparing the reagent for introducing the formyl group are high, it is a violent condition or takes a long time, and the reaction conditions for using the reagent for the introduction of the formyl group are also high temperature. A new manufacturing process that can introduce formyl groups directly from primary or secondary amines due to problems such as by-products and poor yield or difficulty in purification when conditions or acid-sensitive functional groups are present inside the reactants. Has long been a required 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. Formic acid is reacted directly with primary or secondary amines.The amines of the following general formula (II) are reacted with formic acid and atmospheric pressure in the presence of bis (trichloromethyl) carbonate. It is a method of synthesis by reacting under conditions.

Wherein R represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl group, and R 'represents hydrogen (H) or methyl or substituted or unsubstituted alkyl or substituted or unsubstituted 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 bis (trichloromethyl) carbonate is a formamide derivative of the general formula (II) In comparison, 0.5 to 1 mole times, preferably 0.5 to 0.6 mole times, and 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 dichloromethane, a solvent, cooled to 0 ^o C in an ice bath, and then bis (trichloromethyl) carbonate is added to the solution and stirred for 5 minutes. An amine to introduce a formyl group was added thereto, the ice-bath was removed, and the temperature was naturally raised to room temperature, followed by stirring for 10 minutes to 1 hour, preferably 10 minutes to 30 minutes, and the reaction was 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, 92 mg (2.0 mmole) of formic acid and 10 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution, followed by stirring for 5 minutes. A solution of 146.3 mg (2.0 mmole) of butylamine in 1.0 mL of dichloromethane was added and stirred for about 15 minutes. The reaction was completed and can be confirmed 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 190 mg of N-butylformamide as a target compound (yield 93.9%).

Example 2.

In a 30 mL flask, 92 mg (2.0 mmole) of formic acid and 10 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution and stirred for 5 minutes. A solution of 114.2 mg (2.0 mmole) of allylamine in 1.0 mL of dichloromethane was added and stirred for about 30 minutes. The reaction was completed and can be confirmed 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 150 mg of N-allylformamide as a target compound (yield 88.1%).

Example 3.

In a 30 mL flask, 92 mg (2.0 mmole) of formic acid and 12 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution and stirred for 5 minutes. A solution of 214.3 mg (2.0 mmole) of benzylamine dissolved in 2.0 mL of dichloromethane was added and stirred for about 20 minutes. The reaction was completed and can be confirmed 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 260 mg of N-benzylformamide as a target compound (yield 96.2%).

Example 4

  In a 30 mL flask, 92 mg (2.0 mmole) of formic acid and 12 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution and stirred for 5 minutes. Then, a solution of 246.3 mg (2.0 mmole) of o-methoxyaniline in 2.0 mL of dichloromethane was added and stirred for about 20 minutes. The produced and completed reaction can be confirmed 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 297 mg of N- (2-methoxyphenyl) formamide as a target compound (yield 98.2%).

Example 5

In a 30 mL flask, 92 mg (2.0 mmole) of formic acid and 12 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution and stirred for 5 minutes. Then, a solution of 255.2 mg (2.0 mmole) of p-chloroaniline in 2.0 mL of dichloromethane was added and stirred for about 20 minutes. The produced and completed reaction can be confirmed by TLC.

 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 296 mg of N- (4-chlorophenyl) formamide as a target compound (yield 95.1%).

Example 6

In a 30 mL flask, 92 mg (2.0 mmole) of formic acid and 15 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution and stirred for 5 minutes. A solution of 274.4 mg (2.0 mmole) of 4-methoxy-N-methylaniline in 3.0 mL of dichloromethane was added thereto and stirred for about 20 minutes. If the reaction is complete can be confirmed by TLC.

5 mL of saturated salts were added to separate the water layer from the organic layer, and then the organic layer was washed with 4 mL of 3% NaHCO ₃ aqueous solution, dried over anhydrous MgSO ₄ , and the organic solvent was distilled off to obtain N- (4-methoxyphenyl). ) 310 mg of N-methylformamide was obtained (yield 93.8%).

Example 7

In a 30 mL flask, 92 mg (2.0 mmole) of formic acid and 15 mL of dichloromethane were added to a 30 mL flask, and the mixture was stirred in an ice-bath and cooled to 0 to 5 ° C. 297 mg (1.0 mmole) of bis (trichloromethyl) carbonate was added to the solution and stirred for 5 minutes. Then, a solution of 242.4 mg (2.0 mmole) of dipyridin-2-ylamine in 3.0 mL of dichloromethane was added and stirred for about 20 minutes. This completion can be confirmed by TLC.

5 mL of saturated salts were added to separate the water layer from the organic layer, and then the organic layer was washed with 4 mL of 3% NaHCO ₃ aqueous solution, dried over anhydrous MgSO ₄ , and the organic solvent was distilled off to obtain N, N-dipyridin- as a target compound. 389 mg of 2-ylformamide were obtained (yield 97.6%).

Example 8-10

N-formylamine derivatives having the following structure were synthesized in the same manner as in Example 1, except that the amine derivative having the following structure instead of the butylamine used in Example 1 was used.

Conventional techniques known to date are carried out in two stages of a formylation reaction in which a reagent that can introduce a formyl group is introduced first to introduce a formyl group into the primary or secondary amine and then reacted with the amine. Has come. 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)

A method for preparing an N-formylamine derivative represented by the following general formula (I), wherein the amine of the general formula (II) is reacted with formic acid in the presence of bis (trichloromethyl) carbonate. Wherein R represents substituted or unsubstituted alkyl or substituted or unsubstituted aryl group, and R 'represents hydrogen (H) or methyl or substituted or unsubstituted alkyl or substituted or unsubstituted 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. The method for producing an N-formylamine derivative of the general formula (I) according to claim 1, wherein the bis (trichloromethyl) carbonate is used in an amount of 0.5 to 1.0 mole times compared to the amine derivative of the general formula (II).