KR20050071791A - New process for the preparation of formamide derivatives - Google Patents

Abstract

The present invention is a novel method for preparing formamide derivatives having formyl groups in nitrogen, which are useful as intermediates for synthesizing intermediates or functional polymers of physiologically active substances such as medicines and pesticides, and having primary or secondary amine groups. It is a new method to obtain amine derivatives protecting nitrogen (N) with formyl groups by reacting the compounds under normal pressure and mild conditions in the presence of diphosgene in the presence of formic acid.

Description

New process for the preparation of formamide derivatives

 Many researchers have attempted to introduce formyl groups as functional groups to protect the nitrogen of amino acids for a long time in order to control the reaction direction of acid and amine in order to facilitate the desired reaction in protein synthesis. Has been progressed by. N-formylamine derivatives (formamide derivatives) have also been of interest as intermediates for obtaining isocyanide by introducing formyl groups into primary amines in addition to protein synthesis.

The present invention is a method of reacting formic acid (formic acid) directly with a primary amine or a secondary amine by reacting the amine of the formula (II) with formic acid (formic acid) in the presence of diphosgene in a mild condition near normal pressure, room temperature It is a method of synthesizing the formamide derivative of formula (I).

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. As described in the literature published on page 23, page 727, as a reagent for introducing a formyl group for synthesizing N-formylamine derivatives, acetic formic anhydride was obtained by reacting formic acid and acetic anhydride at around 60 ° C for 2 hours to obtain acetic formic anhydride. And reacted at room temperature for 60 hours to obtain the target compound. In addition, Waki et al., J. Org. Chem. As shown in the literature published on pages 42 and 2019, a formyl group introduction reagent for synthesizing N-formylamine derivatives was first dissolved in formic acid in chloroform, and then the solution was mixed in dicyclohexylcarbodiimide (DCC) solution previously dissolved in chloroform at low temperature. After the preparation, the reagent was reacted with an amine to synthesize a target compound. Yale was published in 1971 in J. Org. Chem. As reported in the literature on Volume 36, page 3238, phenylformate was used as a formyl group introduction reagent to synthesize N-formylamine derivatives. Chen et al. Synthesized formic anhydride, a formyl introduction reagent, by first reacting formic acid with N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride, as shown in the literature published on Synthesis 709 in 1979. The desired compound was synthesized by reacting with an amine. Gramain et al. Synthesized N, N-diformylacetamide, a formyl group introduction reagent, in two stages from formamide in two steps, as described in the literature published on Synthesis 264 in 1982, and then synthesized the target compound using the formyl group introduction reagent. More recently, in 2002, Hill et al. Reported that 2,2,2-trifluoroethanol and formic acid were reacted at 80 ° C for 18 hours, as reported in the literature on Organic Letter 4, 111, followed by vacuum distillation. 2,2, -trifluoroethyl formate was first synthesized, and the target compound was synthesized by reacting this reagent with an amine.

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. It is composed of a reaction, the reaction conditions of the process for preparing a reagent for introducing the formyl group is a problem such as a vigorous condition of a high temperature or takes a long time, the reaction conditions for using the reagent for introducing the formyl group is also high When the temperature condition or acid-sensitive functional groups are present inside the reactant, the by-products are generated to reduce the yield or difficult to purify. Therefore, in order to improve the problems of the conventional two-step synthesis method, It has long been possible to develop new manufacturing processes that can introduce formyl groups directly from secondary amines. The feud has been required to challenge.

In order to improve the problems of the conventional two-step synthesis technology, the present inventors react directly with formic acid (formic acid) from primary amine or secondary amine, which is a well-established technique in the field requiring N-formylamine derivative synthesis, Efforts have been made to find reaction conditions for the synthesis of the desired N-formylamine derivatives (formamide derivatives) under mild reaction conditions near room temperature, and as a result, without the need for the synthesis of another reagent to introduce a formyl group The present invention has been completed by developing a new method for obtaining a target compound in high yield and high purity without generating by-products in a short time within 1 hour under mild conditions.

The present invention is a novel method for preparing a formamide derivative represented by the general formula (I) having a formyl group in nitrogen, which is useful as an intermediate for synthesizing intermediates or functional polymers of bioactive substances such as medicines and pesticides. Formic acid is reacted directly with primary or secondary amines. It is synthesized by reacting amine of formula (II) with formic acid in the presence of diphosgene under mild conditions near atmospheric pressure and room temperature. .

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 diphosgene is 0.5 to 1.2 mole times compared to the amine derivative of the general formula (II) , Preferably from 0.6 to 1.0 mole times, 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 diphosgene 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 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 the benzene ring. Is applicable to all primary and secondary amines, as well as amines with), as well as amines with electron donating groups that increase the electron density in the benzene ring. N-formylamine derivatives (formamide derivatives) of general formula (I) are useful derivatives that can be used not only as monomers capable of synthesizing intermediates of protein engineering or functional polymers, but also as intermediates of pharmaceuticals 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. 396 mg (2.0 mmole) of diphosgene was added to the solution, followed by stirring for 5 minutes. Then, a solution of 146.3 mg (2.0 mmole) of butylamine in 1.0 mL of dichloromethane was added and stirred for about 20 minutes. Can be confirmed by TLC.

After confirming the 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 195 mg of N-butylformamide as a target compound (yield 96.4%).

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. 396 mg (2.0 mmole) of diphosgene was added to the solution, followed by stirring for 5 minutes. A solution of 114.2 mg (2.0 mmole) of allylamine in 1.0 mL of dichloromethane was added thereto, followed by stirring for about 30 minutes. 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 157 mg of N-allylformamide as a target compound (yield 92.4%).

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. 396 mg (2.0 mmole) of diphosgene was added to the solution, followed by stirring for 5 minutes. A solution of 214.3 mg (2.0 mmole) of benzylamine in 2.0 mL of dichloromethane was added thereto, followed by stirring for about 20 minutes. 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. 396 mg (2.0 mmole) of diphosgene 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. Completion 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 290 mg of N- (2-methoxyphenyl) formamide as a target compound (yield 95.9%).

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. 396 mg (2.0 mmole) of diphosgene was added to the solution, followed by stirring for 5 minutes. 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. Completion 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. 396 mg (2.0 mmole) of diphosgene 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, followed by stirring for about 20 minutes. Can be confirmed by TLC.

 5 mL of saturated salt water was added to separate the water layer from the organic layer, and 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)-as a target compound. 315 mg of N-methylformamide was obtained (yield 95.3%).

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. 396 mg (2.0 mmole) of diphosgene was added to the solution and stirred for 5 minutes. A solution of 242.4 mg (2.0 mmole) of dipyridin-2-ylamine in 3.0 mL of dichloromethane was added thereto, followed by stirring for about 20 minutes. This can be confirmed by TLC.

 5 mL of saturated salt water was 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-2- as a target compound. Obtained 391 mg of ylformamide (yield 98.1%).

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.

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. These conventional methods require the addition of a process for preparing a reagent for introducing a formyl group and require a long reaction time. In addition, the reaction conditions for using the reagent for introducing a formyl group also require high temperatures, or When sensitive functional groups are present inside the reactant, by-products are generated, which lowers the yield and makes purification difficult. Therefore, in order to alleviate these problems, development of a new manufacturing process capable of directly incorporating formyl groups into primary or secondary amines has long been a subject of interest in the field. The present inventors have forgotten to formic acid from primary or secondary amines. The present invention enables the synthesis of the desired N-formylamine derivatives (formamide derivatives) under the reaction conditions of the reaction with formic acid directly under normal pressure and room temperature. Was done. When the present invention is applied to industrialization, the reaction step and process time can be drastically reduced compared to the previous methods, and the separation and purification of the target compound can be easily performed without causing environmental problems by by-products, thereby greatly contributing to economic improvement. It seems to be.

Claims (3)

A method for preparing a formamide 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 diphosgene. 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 formamide derivatives of formula (I) from amine derivatives of formula (II) in compounds wherein R or R 'is part of a compound comprising a carboxylic acid portion of an amino acid. The method for preparing the formamide derivative of formula (I) according to claim 1, wherein the diphosgene is used in an amount of 0.5 to 1.2 mole times compared to the amine derivative of formula (II).