KR100619440B1 - Formamide derivative manufacturing method - 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. The compound is reacted in the presence of formic acid, diphosgene, and triphenylphosphine at normal pressure and under mild conditions near room temperature to obtain an amine derivative which protects nitrogen (N) with a formyl group. It's a new way.

Formyl groups, formic acid, diphosgene, primary amines, secondary amines, formylation, triphenylphosphine

Description

    Process for the preparation of formamide 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 (formamide derivatives) have been of 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 with a primary amine or a secondary amine, and the amine of the following general formula (II) in the presence of diphosgene and triphenylphosphine (formic) acid) is reacted under mild conditions near room temperature and room temperature to synthesize formamide derivatives of the following general formula (I).

Wherein R represents a substituted or unsubstituted alkyl having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and R 'represents a hydrogen (H) or methyl group or a substituted or unsubstituted carbon number 1 to 20 alkyl or substituted or unsubstituted aryl group having 6 to 20 carbon atoms.

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 reagent for introducing a formyl group. 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 mixed at low temperature in a solution of dicyclohexylcarbodiimide (DCC) previously dissolved in chloroform. A reagent to introduce a formyl group was prepared first, and then 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. Reacted with formic anhydride by reacting formic acid with carbodiimide hydrochloride (N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride) in a document published on Synthesis 709 in 1979. The target compound was synthesized by synthesizing with an introduction reagent and reacting it with an amine. Gramain et al. Synthesized a target compound by synthesizing diformylacetamide (N, N-diformylacetamide) 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, 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. In order to synthesize the desired N-formylamine derivatives (formamide derivatives) under the mild reaction conditions of the above, it has been tried to find the reaction conditions that do not require the synthesis of another reagent for introducing the formyl group. The present invention was completed by developing a method for obtaining a target compound in high yield and high purity without generating by-products in a short time within 1 hour.

The present invention is a novel method for preparing a formamide derivative represented by the following 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 in the presence of diphosgene and triphenylphosphine. It is a method of synthesis by reacting under normal pressure and mild conditions near room temperature.

Wherein R represents a substituted or unsubstituted alkyl having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and R 'represents a hydrogen (H) or methyl group or a substituted or unsubstituted carbon number 1 to 20 alkyl or substituted or unsubstituted aryl group having 6 to 20 carbon atoms.

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 used 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 an amine derivative of the general formula (II) 0.5 to 1.2 mole times, preferably 0.5 to mole times, are used. Triphenylphosphine (triphenylphosphine) is used 1 to 1.5 mole times compared to the amine derivative of the general formula (II) 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, triphenylphosphine and diphosgene are dissolved in dichloromethane as a solvent, cooled to 0 ^° C. in an ice bath, and then stirred for 5 minutes. To this, formic acid (triicamine), triethylamine and amine to introduce a formyl group were added, the ice-bath was removed, and the temperature was naturally raised to room temperature, and stirred for 10 minutes to 1 hour, preferably 10 minutes to 30 minutes. Completion of the reaction 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 (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.

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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 5 minutes. A solution of 214.3 mg (2.0 mmole) of benzylamine in 2.0 mL of dichloromethane was added. After 30 minutes of stirring, an excess of solids was produced and the reaction was 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 255 mg of N-benzylformamide as a target compound (yield 94.4%).

Example 2.

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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 5 minutes. Then, 114.2 mg (2.0 mmole) of allylamine was added to 1.0 mL of dichloromethane. After 30 minutes of stirring, an excess of solids was produced and the reaction was 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 160 mg of N-allylformamide as a target compound (yield 94.2%).

Example 3.

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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 mixture was stirred for 5 minutes, and 146.3 mg (2.0 mmole) of butylamine was added to 1.0 mL of dichloromethane. After 30 minutes of stirring, an excess of solids was produced and the reaction was 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 191 mg of N-butylformamide as a target compound (yield 94.4%).

Example 4.

  Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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. After stirring for 5 minutes, a solution of 246.3 mg (2.0 mmole) of o-methoxyaniline in 2.0 mL of dichloromethane was added. After stirring for about 30 minutes, it was confirmed by TLC that excess solids were produced 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 280 mg of N- (2-methoxyphenyl) formamide as a target compound (yield 92.6%).

Example 5.

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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 5 minutes. A solution of 255.2 mg (2.0 mmole) of parachloroaniline in 2.0 mL of dichloromethane was added thereto. After stirring for about 30 minutes, it was confirmed by TLC that excess solids were produced 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 196 mg of N- (4-chlorophenyl) formamide as a target compound (yield 95.1%).

Example 6.

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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, stirred for 5 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 30 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.

Into a 30 mL flask, 524 mg (2.0 mmole) of triphenylphosphine, 198 mg (1.0 mmole) of diphosgene, and 10 mL of dichloromethane were added to a 30 mL flask and stirred in an ice bath. 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 5 minutes, followed by a solution of 242.4 mg (2.0 mmole) of dipyridine-2-ylamine 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-dipyridine-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 benzylamine 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 react directly with formic acid from primary or secondary amines to form N-formylamine derivatives (formamides) under mild reaction conditions near normal pressure and room temperature. By completing the present invention capable of synthesizing derivatives), it is possible to secure a synthesis method excellent in the reliability and reproducibility of the reaction. 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 improving economic efficiency. It is expected to contribute.

Claims (3)

Of the formamide derivative represented by the following general formula (I), characterized by reacting an amine of the general formula (II) with formic acid in the presence of triphenylphosphine and diphosgene Manufacturing method.

Wherein R represents a substituted or unsubstituted alkyl having 1 to 20 carbon atoms or a substituted or unsubstituted aryl group having 6 to 20 carbon atoms, and R 'represents a hydrogen (H) or methyl group or a substituted or unsubstituted carbon number 1 to 20 alkyl or substituted or unsubstituted aryl group having 6 to 20 carbon atoms. 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 amount of diphosgene (diphosgene) of the general formula (I) is characterized in that the reaction in the presence of triphenylphosphine (triphenylphosphine) using 0.5 to 1.0 mole times compared to the amine derivative of the general formula (II) Process for the preparation of formamide derivatives.