KR100647890B1 - Process for preparing serine alkyl ester derivatives - Google Patents

Abstract

The present invention relates to a method for preparing a serine alkyl ester derivative, and more particularly, a serine alkyl ester derivative represented by the following Chemical Formula 1 by carrying out a hydroxymethylation reaction of glycine aldimine derivative and paraformaldehyde in the presence of a specific metal base. It relates to a method of manufacturing.

In Formula 1, Ar represents an aromatic group, R represents a hydrocarbon group of 1 to 12 carbohydrates.

Glycine alkyl ester, aldimine reaction, paraformaldehyde, aldol reaction, hydroxymethylation, serine alkyl ester derivative

Description

Process for preparing serine alkyl ester derivatives

The present invention relates to a method for preparing a serine alkyl ester derivative, and more particularly, a serine alkyl ester derivative represented by the following Chemical Formula 1 by carrying out a hydroxymethylation reaction of glycine aldimine derivative and paraformaldehyde in the presence of a specific metal base. It relates to a method of manufacturing.

[Formula 1]

In Formula 1, Ar represents an aromatic group, R represents a hydrocarbon group of 1 to 12 carbohydrates.

It is thought that amino acids can be easily obtained by hydrolyzing the protein, but since it is not easy to recover and recover only amino acids from the hydrolyzate, it is not useful as a method for producing commercial amino acids.

A typical organic synthesis method of amino acids is the Strecker reaction using aldehyde and cyanide as the main raw materials. According to the striker reaction shown in Scheme 1, amino acids of racemates can be easily obtained by reacting the reactants of aldehyde, cyanide and ammonia in a chemical method.

However, in the Stacker reaction according to Scheme 1, a highly toxic chemical is used as a reactant, which is an environmental problem. Therefore, after completion of the reaction, a high-purification process is required so that there is almost no residual amount of cyanide in the amino acid product. There is a disadvantage to be done. Nevertheless, the reason why the stacker reaction is used as a typical manufacturing method is that the manufacturing method is relatively easy and the yield is high.

DL-serine or alkyl esters thereof are also known to be synthesized from glycolaldehyde by the Strecker reaction according to Scheme 1 (US Pat. No. 5,030,750). However, not only is the production method of the glycol aldehyde used as a reaction raw material difficult, but also the yield is very low since the glycol aldehyde is obtained by partial oxidation of ethylene glycol. In addition, since cyanide is used as a reactant, there is a disadvantage in that the cyanide is completely removed.

As a method of making the reaction raw material easier, a method of producing chlorinated vinyl acetate and treating sodium acetate with a Strecker synthesis method is known (German Patent No. 2,252,843), but it is still necessary to use cyanide soda. There is a problem.

Various amino acids were prepared using N-acetylaminodiethylmalonate as a method without using cyanide [BS Furniss, AJ Hannaford, PWG Smith, AR Tarchell, Vogel's Textbook of Practical Organic Chemistry , 5th Ed. 755-756, 1988]. However, harsh conditions are required because the production of raw materials is difficult and the decarbonation process is required in the aftertreatment process.

As a method of easily synthesizing amino acids, a method of using glycine aldimine or glycine ketimine as a raw material has also been introduced [L. Ghosez, JP Antoine, E. Deffense, M. Navarro, V. Libert., Tetra. Lett. 23 , 4355-4358, 1982; CM Casparski, MJ Miller, Tetrahedron , 47 , 5367-5378]. Although glycine ketimine is mainly used as a raw material because glycine ketimine is more stable than glycine aldehyde, there is a disadvantage in that the preparation method of glycine ketimine is not easy. For example, glycine ketimine is prepared through the Grignard reaction using R ¹ R ² NH as a raw material, and thus, there are many disadvantages for commercial use. On the contrary, since glycine aldimine is synthesized by the dehydration reaction of aldehyde and amine, the reactivity is very good, and it is very useful for industrial application because it can be obtained in a sufficiently high yield even with slight heating even during manufacture.

Methods for preparing glycine aldimine derivatives are known in the literature [Martin J. O'Donnell, Robin L. Polt, J. Org. Chem. 1982, 47 , 2663-2666; D. Ferroud, JP Genet, R. Kiolle, Tetrahedron Lett. 27 , 23-26, 1986], and the preparation method thereof is also relatively simple, as shown in the following Scheme 2, and can be easily prepared by a known method.

Although it is known that alkyl aldehydes can proceed in a relatively mild reaction in glycidaldehyde and aldehydes, there has been no successful synthesis of serine alkyl esters using formaldehyde as a raw material.

Aldol reaction between glycinedimine and aldehyde is carried out in a two-phase in which both the aqueous layer and the organic layer are present. Therefore, sodium hydroxide or potassium hydroxide is usually added as a phase transfer catalyst to enhance reactivity. In addition, a high optically active material can be obtained by selectively using an optically active phase transfer catalyst. It is also possible to synthesize a serine alkyl ester derivative by performing an aldol reaction with glycine aldimine in two-phase conditions using formaldehyde as an aldehyde compound, but in aqueous base solution, the reactant is decomposed or the product is unstable with the base medium. Since there is a problem of converting to a product, a technique for synthesizing a serine alkyl ester by an aldol reaction between glycinedimine and paraformaldehyde has not been developed yet.

On the other hand, when an Aldol reaction with various aldehyde derivatives is carried out in the presence of a base using Ni (II) -glycine complex as an organometallic compound as a reaction material, it is known that the reaction proceeds relatively well, and that formaldehyde also proceeds well. [YN Belokon, Tetrahedron: Asymmetry 12 , 481-485, 2001]. However, this method has a drawback that the process of preparing the Ni (II) -glycine complex used as a reaction raw material serves as the most important reaction step, and the decomposition of the complex compound is difficult in a later step. In addition, since glycine ketimine must be prepared, it is difficult to apply industrially due to the problem of regenerating raw materials and preparing nickel complex compounds again.

The inventors of the present invention have tried to develop a method for easily synthesizing a serine alkyl ester derivative using a raw material that is relatively easy to manufacture while excluding the use of harmful substances such as cyanide. As a result, the glycine aldimine derivative is very reactive and can be easily reacted with a variety of electrophiles, complete the present invention by knowing that it can sufficiently control the reactivity with paraformaldehyde if only the optimal base is selected and used It became.

None of the literature published to date has successfully performed the hydroxymethylation reaction of glycinealdehyde with paraformaldehyde.                         

Accordingly, an object of the present invention is to provide a method for producing a serine alkyl ester derivative in high yield by hydroxymethylation with paraformaldehyde using glycine aldehyde as a raw material.

The present invention in the presence of a metal base represented by MH, MR 'or M-OR' (wherein M is an alkali metal of Li, Na or K, R 'is a hydrocarbon group having 1 to 20 carbon atoms), Characterized by a method of preparing a serine alkyl ester derivative represented by the following formula (1) by performing a hydroxymethylation reaction of the glycine aldimine derivative and the paraformaldehyde.

[Formula 2]

[Formula 1]

In Formula 1 or 2, Ar is an aromatic group, R is a hydrocarbon group having 1 to 12 carbon atoms.

Referring to the present invention in more detail as follows.

The present invention relates to a method for successfully carrying out the hydroxymethylation reaction of glycine aldimine derivatives represented by Formula 2 with paraformaldehyde due to the selection of specific metal bases.

Bases commonly used in the field of organic synthesis include organic bases such as diazabicyclundecene (DBU), or inorganic bases such as metal hydroxides. According to the experimental results of the present inventors, when a conventional organic base such as diazabicyclundecene (DBU) or a metal hydroxide such as NaOH is applied to the preparation method of the present invention, the reaction does not proceed and is used as a reactant. The glycine aldimine derivative represented by the formula (1) was decomposed.

However, when using a metal base represented by MH, MR 'or M-OR' (wherein M is an alkali metal of Li, Na or K, and R 'is a hydrocarbon group having 1 to 20 carbon atoms), It was confirmed that the hydroxymethylation reaction was performed smoothly. Therefore, the selection of the base catalyst is very important in carrying out the hydroxymethylation reaction according to the present invention. The metal base selected by the present invention may be used within the range of about 0.01 to 10 g per mole of glycine aldimine derivative represented by Chemical Formula 1, and when the reaction conditions are optimized, the amount of the metal base catalyst used is 0.05 to 1 g. It can be significantly lowered to about / mol and can greatly suppress side reactions.

The metal base catalyst selected and used by the present invention can be easily decomposed by moisture. Therefore, it is important to carry out the preparation method according to the present invention under anhydrous conditions, and when the reaction is carried out in a state where the reactant or solvent is sufficiently dried so that moisture is not present, a satisfactory reaction yield is achieved even with the use of a very small amount of catalyst. You can get it.

Referring to the catalysis mechanism according to the present invention, first, the metal base catalyst activates hydrogen at the methylene (CH ₂ ) position of the glycinediamine derivative to combine with paraformaldehyde to produce a ROM-like product similar to the catalyst. The material acts as a catalyst. However, as the reaction proceeds, the ROM-type product may show a tendency to decompose as the ROH form decomposes. Therefore, if a higher production yield is expected, the metal base catalyst is continuously added in small amounts during the reaction to improve reactivity. It is desirable to maintain.

As the reaction solvent, it is more preferable to use an aprotic organic solvent having no hydrogen bonding properties such as tetrahydrofuran, dioxane, ethyl acetate, dichloromethane, acetonitrile.

The reaction temperature is carried out in the range of -78 to 50 ° C, more preferably in the range of -10 to 25 ° C.

In the case of the glycine aldimine derivative represented by Formula 2 used as a reactant, the aromatic group (Ar) is an aromatic group having 1 to 3 benzene rings, and more preferably, when an electron acceptor substituent such as halogen is present in the benzene ring The reactivity may be better, and the inventors have confirmed that the compound substituted by halogen at the C-2 and C-4 positions of the benzene ring has sufficient reactivity. In the case of the glycine aldimine derivative, the hydrocarbon group (R) may be a hydrocarbon group having 1 to 20 carbon atoms, more preferably a hydrocarbon group having 1 to 12 carbon atoms, and functional groups such as methyl group, ethyl group, and butyl group are significantly different in the reaction. There is no.

All reagents used in the preparation method of the present invention were used in GR grade and used without any special purification. In the case of reusable solvent, in order to remove as much water as possible, dehydration with anhydrous magnesium sulfate or azeotropic distillation was used.

The nuclear magnetic resonance (NMR) instrument used for the analysis of the reactants used a Varian 300 MHz, high-efficiency liquid chromatography (HPLC) using Hitachi, Inc. HPLC conditions are as follows.

[HPLC Analysis Conditions]

HPLC column: CAPCELL PAK C18 (4.6 φ × 250 mm)

Developing solvent: acetonitrile aqueous solution

Solvent flow rate: 0.5 mL / min

Detector: UV 200-254 nm

Sample volume: 10 μl (0.2% solution)

Chart Speed: 0.25 cm / min

Preparation Example 1

29 g of 4-chlorobenzaldehyde, 29 g of glycineethyl ester hydrochloride, 21 g of triethylamine, and 300 mL of dichloromethane were added to a 500 mL flask to reflux for 8 hours, and then cooled to room temperature. 200 mL of water was added thereto, stirred for 30 minutes, and the layers were separated to recover a dichloromethane solution, and the solvent was distilled off to dehydrate.

45.2 g (100% yield); ¹ H NMR (CDCl ₃ ) δ 8.23 (s, 1H, HC = N), 7.71 (d, 2H), 7.38 (d, 2H), 4.37 (s, 2H), 4.23 (q, 2H), 1.23 (t , 3H)

Preparation Example 2

29 g of 4-chlorobenzaldehyde, 29 g of glycineethyl ester hydrochloride, 21 g of triethylamine, and 300 mL of ethyl acetate were added to a 500 mL flask, and the mixture was refluxed for 4 hours and then cooled to room temperature. 200 mL of water was added thereto, stirred for 30 minutes, and the layers were separated. The ethyl acetate solution was recovered, and the solvent was distilled off.

45.2 g (100% yield); ¹ H NMR (CDCl ₃ ) δ 8.23 (s, 1H, HC = N), 7.71 (d, 2H), 7.38 (d, 2H), 4.37 (s, 2H), 4.23 (q, 2H), 1.23 (t , 3H)

Example 1

45.2 g of the compound synthesized in Preparation Example 1, 6.4 g of 95% paraformaldehyde, and 300 mL of dioxane were added to a 500 mL flask, and the flask was immersed in an ice water container and stirred until the contents were sufficiently cooled. 0.1 g of 60% NaH coated with oil was split in over 2 hours. After completion of the reaction, the conversion was measured by LC analysis. The result was 98%. The solvent was concentrated to give 51.6 g of product. The obtained product was present as an oxazole-type isomer, so that NMR analysis was not easy, and hydrolysis was performed. 120 mL of 6N HCl was added to the reaction product, stirred for 30 minutes at room temperature, and the layers were separated to recover 29 g of 4-chlorobenzaldehyde. NMR analysis of the material recovered in the aqueous layer confirmed that it was serine ethyl ester. Water in the aqueous layer was concentrated to give 36.5 g of the product. NMR measurement using NaOD and D ₂ O to analyze the purity was confirmed to have a purity of 92% and the yield was 95%.

¹ H NMR (D ₂ O) δ 4.1 (q, 2H), 4.0 (t, 1H), 3.8 (m 2H), 1.1 (t, 3H)

Example 2

45.2 g of the compound synthesized in Preparation Example 2, 6.4 g of 95% paraformaldehyde, and 200 mL of ethyl acetate were added to a 500 mL flask, and the flask was immersed in an ice water container and stirred until the contents were sufficiently cooled. 0.1 g of 60% NaH coated with oil was split in over 2 hours. After the reaction, the conversion was measured by LC analysis. As a result, it was 97.8%. 120 mL of 6N HCl was added to the reaction product, which was stirred for 30 minutes at room temperature, followed by layer separation to recover 4-chlorobenzaldehyde. Serine ethyl ester was recovered as an aqueous layer. The same NMR results as in Example 3 were obtained, and the reaction yield was 94.8%.

Examples 3 to 5

The same method as in Example 1, except that the solvent was changed. The results are summarized in Table 1 below.

division menstruum Conversion rate Reaction yield Example 1 Dioxane 98% 95% Example 2 Ethyl acetate 97.8% 94.8% Example 3 Tetrahydrofuran 97.3% 92.5% Example 4 Dichloromethane 96.8% 91.5% Example 5 Acetonitrile 96.8% 92.2%

Examples 6 and 7

The same method as in Example 1 except that the metal base was changed. The results are summarized in Table 2 below.

division Metal base usage Conversion rate Reaction yield Example 6 NaOCH ₃ 0.5 g 94.3% 88.5% Example 7 n-BuLi (1.7M) 1 mL 92.8% 87.5%

Examples 8-11

The same procedure as in Example 1 was carried out except that the aromatic group (Ar) and the alkyl group (R) of the glycine aldimine derivative used as the reactant were changed. The results are summarized in Table 3 below.

division Aromatic group (Ar) Alkyl group (R) Conversion rate Reaction yield Example 8 C ₆ H ₅ C ₂ H ₅ 94.3% 90.3% Example 9 2,4-Cl ₂ C ₆ H ₃ C ₂ H ₅ 95.8% 91.5% Example 10 2-ClC ₆ H ₄ C ₂ H ₅ 96.5% 92.3% Example 11 4-ClC ₆ H ₄ CH ₃ 97.8% 94.8%

Comparative Example 1

45.2 g of the compound synthesized in Preparation Example 1, 6.4 g of paraformaldehyde, 1 g of DBU, and 300 mL of dioxane were added thereto, and the resultant was stirred for 8 hours at room temperature, followed by NMR analysis. Thus, 4-chlorobenzaldehyde and glycine ethyl ester were completely dissolved. Decomposed

Comparative Example 2

45.2 g of the compound synthesized in Preparation Example 1, 6.4 g of paraformaldehyde, 1 mL of 20% NaOH, and 300 mL of dioxane were added thereto, and the mixture was stirred at room temperature for 8 hours, and then subjected to NMR analysis. The result was completely decomposed with chlorobenzaldehyde and glycine ethyl ester.

The present invention is characterized in that it is possible to perform the hydroxymethylation reaction, which has not been performed by the conventional method using a phase transfer catalyst, and has the advantages of an environmentally friendly process. Conventional chemical synthesis of representative amino acids is applied to the Strecker (Strecker) synthesis method using cyanic soda that is environmentally problematic due to its high toxicity, but in the present invention, high yield of serine alkyl ester without using any cyanide There is an advantage to obtain a derivative.

Therefore, the present invention can easily synthesize serine alkyl ester derivatives, and furthermore, it can be an industrially very useful method for preparing DL-serine by chemical synthesis.

Claims (9)

Glycine represented by the following formula (2) in the presence of a metal base represented by MH, MR 'or M-OR' (wherein M is an alkali metal of Li, Na or K, and R 'is a hydrocarbon group having 1 to 20 carbon atoms) Method for producing a serine alkyl ester derivative represented by the following formula (1), characterized in that by performing a hydroxymethylation reaction of the aldimine derivative and paraformaldehyde: [Formula 2]

[Formula 1]

In Formula 1 or 2, Ar is an aromatic group, R is a hydrocarbon group having 1 to 12 carbon atoms. The method of claim 1, wherein the metal base catalyst is used in an amount of 0.01 to 10 g per mole of glycine aldimine derivative. The method of claim 2, wherein the metal base catalyst is used in an amount of 0.05 to 1 g per mole of glycine aldimine derivative. The method of claim 1, wherein the reaction temperature is in the range of -78 to 50 ℃. The method of claim 4, wherein the reaction temperature is in the range of -10 to 25 ℃. The method according to claim 1, wherein the solvent of the reaction is an aprotic solvent selected from dioxane, dichloromethane, tetrahydrofuran, acetonitrile and ethyl acetate. The method according to claim 1, wherein Ar of the glycine aldimine derivative is an aromatic group having 1 to 3 benzene rings, and R is a hydrocarbon group having 1 to 20 carbon atoms. The method according to claim 1, wherein Ar of the glycine aldimine derivative is an aromatic group having 1 to 3 benzene rings substituted with halogen, and R is a hydrocarbon group having 1 to 12 carbon atoms. The method of claim 1, wherein the reaction is performed under anhydrous conditions.