KR19980076014A - Synthesis method of hydridein derivative using solution phase and solid phase reaction - Google Patents

Abstract

The present invention relates to a method for synthesizing the hydridein derivative of the general formula (I) using a solution phase (solid phase) and a solid phase reaction, reacting the reactants such as amino acid derivatives, aldehyde compounds, isocyanate compounds or the like According to the method of the present invention which is subjected to a solid phase reaction and then cyclized, a high-purity hydridein compound can be prepared in a high yield without using a strong acid and requiring no post-treatment process such as chromatography and recrystallization at a relatively low reaction temperature in a short time. Can be.

[Formula 1]

(Wherein R ¹ , R ² and R ³ are as defined in the specification).

Description

Synthesis method of hydridein derivative using solution phase and solid phase reaction

The present invention utilizes solution phase reaction or solid phase reaction to economically and effectively hydantoin without the use of strong acid and without the need for post-treatment such as chromatography more quickly at low reaction temperature. It relates to a method for synthesizing derivatives.

Heidinto and its derivatives, known as fibrinogen receptor antagonists and effective herbicides, have been produced in solution by several methods (Tomoshige Kobayashi et al.,Bull. Chem. Soc. Jpn.,67, 3082 (1994); Hans Ulrich Stilz et al.,J. Med. Chem., 39, 2118 (1996); Tilmann W. Brandstetter et al.,Tetrahedron Lett., 36, 2149 (1995); Japanese Patent JK P02-19363).

Scheme 1 below shows a method for preparing hydridein compound (4) in a conventional solution (Tomoshige Kobayashi et al., Bull. Chem. Soc. Jpn. , 67, 3082 (1994)). Compound (4) can be obtained by refluxing compound (3), which is an intermediate, in the reaction scheme of DBU and benzene in this scheme, which is difficult to remove DBU having a high breaking point, and chromatography for separation of the target compound produced. The disadvantage is that post processing is required.

Scheme 1

In recent years, several researchers have published methods for preparing hydridein using solid phases (SH DeWitt et al., Proc. Natl. Acad. Sci. USA, 90, 6909 (1993); BA Dressman et al., Tetrahedron Lett., 37, 937 (1996).

Scheme 2 is a method for synthesizing hydridein in solid phase, first published in 1993 (S. H. DeWitt et al.,Proc. Natl. Acad. Sci. USA,90, 6909 (1993)), in this method, there is a problem in that a strong acid such as 6M HCl is used to prepare the hydridein derivative compound (8) and the reaction temperature must be raised to a high temperature of 90 ° C.

Scheme 2

Reaction Scheme 3 is also one of the methods for synthesizing hydridein using a solid phase, and this method also has the disadvantage that a high reaction temperature of up to 90 ° C. and a long reaction time of 48 hours are required for the preparation of the target compound (13) (BA Dressman et al. , Tetrahedron Lett ., 37, 937 (1996)).

Scheme 3

Accordingly, the present inventors continue to study the disadvantages of the conventional method of preparing hedentoin derivatives such as the use of strong acid, high reaction temperature, and long reaction time, and to more effectively prepare the hedentoin derivative. After the reaction, the product is reacted with an isocyanate compound in a benzene solvent, and the product is cyclyzed with diisopropylamine to prepare a hydridein compound in solution in a short time without the need for a strong acid or high temperature. The product obtained by reacting the Wang resin was sequentially reacted with an aldehyde derivative and an isocyanate compound and then cyclized with diisopropylamine to prepare a high-purity hydridein compound having a high yield without requiring an additional purification step in a solid phase. I know It came to completion of this invention.

It is an object of the present invention to provide a method for producing more economically and effectively a hydridein derivative compound having herbicidal activity.

In order to achieve the above object, Oh this reducing the aldehyde derivative compound has the amino acid derivative compound having an R ¹ group R ² in the invention folk (reductive amination) reaction, the isocyanate compound and the reaction with R ³ in the solvent of benzene groups of the product And then, it provides a method for producing a hydridein derivative of the general formula (1) using a solution phase reaction comprising the step of cyclization.

Formula 1

In the above formula,

R ¹ is an alkyl, aryl, or hydroxy aryl group substituted with alkyl or sulfur,

R ² represents branched alkyl, or in each occurrence substituted or unsubstituted aryl or heteroaryl,

R ³ represents lower alkyl, cycloalkyl, or in each case aryl, heteroaryl, unsubstituted or substituted with alkoxy.

As used herein, the term lower alkyl used to define a substituent of the compound of Formula 1 means straight or branched chain alkyl having 1 to 8 carbon atoms including methyl, ethyl, isopropyl, isobutyl, t-butyl, octyl.

The term cycloalkyl means cyclic alkyl of 6 to 8 carbon atoms including cyclohexyl.

The term aryl means a 6-membered monocyclic aromatic group or a 10-membered bicyclic aromatic group, which groups may be optionally substituted by lower alkyl, lower alkoxy or halogen.

In the present invention, the amino acid derivative compound having R ¹ group is also reacted with Wang resin, the product is subjected to reductive amination reaction with an aldehyde derivative compound having R ² group, and the product is reacted with an isocyanate compound having R ³ group, toluene, DMF or It provides a method for preparing the hydridein derivative of Formula 1 using a solid phase reaction comprising the step of reacting in a toluene / DMF mixture (1: 1 v / v) solvent, and then cyclizing.

Hereinafter, the present invention will be described in detail.

Detailed description of the synthesis process of the compound of Formula 1 in the solution phase according to the present invention is as shown in Scheme 4 below.

Scheme 4

Scheme 4 relates to the case of preparing a compound of Formula 1 wherein R ¹ is a benzyl group, R ² is a methoxyphenyl group, and R ³ is an ethoxyphenyl group, according to which phenylalanine methyl ester (14) and 4- Reductive amination reaction of methoxybenzaldehyde (15) gives compound (16). Compound (18) is prepared by reacting the resulting compound (16) with 4-ethoxyphenylisocyanate (17) in benzene solvent for 1 hour. When the produced compound (18) is cyclized using diisopropylamine, the hydridein compound (19) as a target compound can be obtained.

Benzene, toluene, DMF, etc. may be used as the reaction solvent in the solution phase synthesis process, and benzene is preferable.

The reaction temperature of the solution phase reaction according to the invention is in the room temperature (25 ° C.) range, and the reaction time is within 1 hour.

Heidetoin compound of Formula 1 may also be prepared using a solid phase reaction as shown in Scheme 5 below.

Scheme 5

According to Scheme 5, 3.5 equivalents of the amino acid derivative (20) protected with FMOC (9-proenylmethoxycarbonyl) group and 1 equivalent of Wang resin (21) were 3.5 equivalents of diisopropylcarbodiimide (DIC). ) And 0.1 equivalent of 4-dimethylaminopyridine (DMAP) under a DMF solvent for 1 day, followed by reaction, and then used in excess of diisopropylcarbodiimide (DIC), amino acid and DMF solvent to filter out the compound (22). ). The yield was 95% at this time (load level of the initial resin was 0.85 mmol / g and after the reaction was 0.81 mmol / g). The resulting compound (22) can be reacted in the presence of 20% piperidine and DMF solvent for 1 hour to obtain compound (23) from which the FMOC protecting group has been removed. A Kaiser test is carried out to confirm the completion of the reaction and the color of the resin will turn dark blue when the FMOC protecting group is completely removed. Because this test is very sensitive and accurate, it is widely used in organic synthesis using solid phase (E. Kaiser et al., Anal. Biochem ., 595 (1970); VK Sarin et al., Anal. Biochem. , 147 (1981). )). Compound (23) from which the FMOC protecting group has been removed is subjected to amination reaction with an aromatic aldehyde having a R ² group to obtain compound (24). At this stage, Kaiser test is performed once again to confirm the completion of the reaction that the resin color does not change. The resultant compound (24) is reacted with isocyanate having 3.5 equivalents of R ³ groups in a DMF and toluene solvent while stirring for 5 hours to give a carbamate compound (25) adhering to the resin. The desired compound of formula (1) can be prepared by cyclizing the obtained compound (25) at room temperature with diisopropylamine. The final compound of Formula 1 can be obtained in high yield by filtering off the diisopropylamine used in excess.

In the preparation of the hydridein compound in the solution phase and the solid phase according to the present invention, reagents that can be used in the final step of the cyclization reaction include diisopropylamine, triethylamine, pyrrolidine, piperidine, and the like. Diisopropylamine is particularly preferred because its low boiling point allows the solvent to be easily removed at low temperatures.

In the solution phase synthesis method according to the present invention, no strong acid is used, no high reaction temperature is required, and the desired compound can be obtained in a short time. Since the hydridein derivative prepared by the solid phase synthesis method is obtained with very high purity, chromatography and recrystallization are performed. It is economical because no post-treatment process such as fire is necessary.

Representative hydridein derivatives that can be prepared in the present invention include the following compounds.

1) (s) -5-benzyl-3- (4-ethoxy-phenyl) -1- (4-methoxy-benzyl) -imidazolidine-2,4-dione

2) (s) -5-benzyl-1- (4-dimethylamine-benzyl) -3- (4-methylsulfanyl-phenyl) -imidazolidine-2,4-dione

3) (s) -5-benzyl-3-ethyl-1-naphthalen-2-ylmethyl-imidazolidine-2,4-dione

4) (s) -1-benzo [1,3] dioxol-5-ylmethyl-5-benzyl-3-ethyl-imidazolidine-2,4-dione

In addition, examples of various compounds that can be prepared by the method of the present invention are shown in Table 1 below.

TABLE 1

R ¹ R ² R ³

Combining the substituents of Table 1 can be obtained in various (number 400 cases) of the compound of formula (1) of the present invention.

Hereinafter, the present invention will be described in more detail based on the following examples. However, these Examples are only for illustrating the present invention, the present invention is not limited to these.

The following examples are all using a solid phase and proceeded to the process of Scheme 5.

Example 1 Preparation of (s) -5-benzyl-3- (4-ethoxy-phenyl) -1- (4-methoxy-benzyl) -imidazolidine-2,4-dione

3.5 equivalents of phenylalanine and 1 equivalent of Wang resin, protected with FMOC groups, were stirred for one day in the presence of 3.5 equivalents of diisopropylcarbodiimide (DIC) and 0.1 equivalent of 4-dimethylaminopyridine (DMAP), followed by excess. The diisopropyl carbodiimide (DIC), phenylalanine, 4-dimethylaminopyridine (DMAP), and DMF solvent used were filtered. The resultant compound was reacted for 1 hour in the presence of 20% piperidine and DMF solvent to obtain a compound from which the FMOC protecting group was removed. At this time, a Kaiser Test was performed to change the color of the resin to a dark blue color. This confirmed that the reaction was completed. Then, 3.5 equivalent of 4-methoxybenzaldehyde was reacted with DMA solvent in 1% acetic acid for 5 hours, 5 equivalents of NaBH ₃ CN was added, and the reaction was continued for 1 day. The excess of 4-methoxybenzaldehyde, DMA solvent, acetic acid, NaBH ₃ CN was filtered and subjected to a Kaiser test to confirm the completion of the reaction through the color does not change. The resulting compound was stirred for 5 hours under 3.5 equivalents of 4-ethoxyphenylisocyanate, DMF / toluene (1: 1 v / v) mixed solvent, and then filtered to complete cyclization reaction with diisopropylamine. Diisopropylamine was removed to afford the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.29 (m, 3H), 7.15 (m, 4H), 6.96-6.85 (m, 6H), 5.15 (d, 1H, J = 14.9 Hz), 4.15 (m, 2H), 3.96 (m, 2H), 3.80 (s, 3H), 3.22 (m, 2H), 1.40 (t, 3H, J = 6.9 Hz).

Mass (FAB, m / e): 431 (M ⁺ + 1).

Example 2 Preparation of (s) -5-benzyl-1- (4-dimethylamine-benzyl) -3- (4-methylsulfanyl-phenyl) -imidazolidine-2,4-dione

3.5 equivalents of phenylalanine and 1 equivalent of Wang resin, protected with FMOC groups, were stirred for one day in the presence of 3.5 equivalents of diisopropylcarbodiimide (DIC) and 0.1 equivalent of 4-dimethylaminopyridine (DMAP), followed by excess. The diisopropyl carbodiimide (DIC), phenylalanine, 4-dimethylaminopyridine (DMAP), and DMF solvent used were filtered. The resultant compound was reacted for 1 hour in the presence of 20% piperidine and DMF solvent to obtain a compound from which the FMOC protecting group was removed. At this time, a Kaiser Test was performed to change the color of the resin to a dark blue color. This confirmed that the reaction was completed. Then, 3.5 equivalent of 4-dimethylaminoaldehyde was reacted with DMA solvent in 1% acetic acid for 5 hours, 5 equivalents of NaBH ₃ CN was added, and the reaction was continued for 1 day. After the excess 4-dimethylaminoaldehyde, DMA solvent, acetic acid, NaBH ₃ CN was filtered to perform a Kaiser test to confirm the completion of the reaction through the color does not change. The resulting compound was stirred for 5 hours under 3.5 equivalent of 4-methylsulfanylphenyl isocyanate, DMF / toluene (1: 1 v / v) mixed solvent, and then filtered to complete cyclization reaction with diisopropylamine. . Diisopropylamine was removed to afford the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.30-7.17 (m, 7H), 7.10 (d, 2H, J = 8.3 Hz), 6.68 (d, 2H, J = 8.8 Hz), 5.14 (d, 1H, J = 14.6 Hz), 4.15 (m, 1H), 3.98 (d, 1H, J = 14.6 Hz), 3.21 (m, 2H), 2.95 (s, 6H), 2.45 (s, 3H).

Mass (FAB, m / e): 446 (M ⁺ +1).

Example 3 Preparation of (s) -5-benzyl-3-ethyl-1-naphthalen-2-ylmethyl-imidazolidine-2,4-dione

3.5 equivalents of phenylalanine and 1 equivalent of Wang resin, protected with FMOC groups, were stirred for one day in the presence of 3.5 equivalents of diisopropylcarbodiimide (DIC) and 0.1 equivalent of 4-dimethylaminopyridine (DMAP), followed by excess. The diisopropyl carbodiimide (DIC), phenylalanine, 4-dimethylaminopyridine (DMAP), and DMF solvent used were filtered. The resultant compound was reacted for 1 hour in the presence of 20% piperidine and DMF solvent to obtain a compound from which the FMOC protecting group was removed. At this time, a Kaiser Test was performed to change the color of the resin to a dark blue color. This confirmed that the reaction was completed. Then, 3.5 equivalent of 2-naphthaldehyde was reacted with DMA solvent in 1% acetic acid for 5 hours, 5 equivalents of NaBH ₃ CN was added, and the reaction was continued for 1 day. After the excess 2-naphthaldehyde, DMA solvent, acetic acid, NaBH ₃ CN was filtered to perform a Kaiser test to confirm the completion of the reaction through the color does not change. The resulting compound was stirred for 5 hours under 3.5 equivalents of ethyl isocyanate, DMF / toluene (1: 1 v / v) mixed solvent, and then filtered to complete cyclization reaction with diisopropylamine. Diisopropylamine was removed to afford the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.78 (m, 3H), 7.46 (m, 3H), 7.26 (m, 5H), 7.13 (m, 1H), 5.10 (d, 1H, J = 15.1 Hz) , 3.50 (m, 2H), 3.32 (m, 1H), 3.25 (m, 2H), 3.10 (m, 1H), 0.95 (t, 3H, J = 6.8 Hz).

Mass (FAB, m / e): 343 (M ⁺ +1).

Example 4 Preparation of (s) -1-benzo [1,3] dioxol-5-ylmethyl-5-benzyl-3-ethyl-imidazolidine-2,4-dione

3.5 equivalents of phenylalanine and 1 equivalent of Wang resin, protected with FMOC groups, were stirred for one day in the presence of 3.5 equivalents of diisopropylcarbodiimide (DIC) and 0.1 equivalent of 4-dimethylaminopyridine (DMAP), followed by excess. The diisopropyl carbodiimide (DIC), phenylalanine, 4-dimethylaminopyridine (DMAP), and DMF solvent used were filtered. The resultant compound was reacted for 1 hour in the presence of 20% piperidine and DMF solvent to obtain a compound from which the FMOC protecting group was removed. At this time, a Kaiser Test was performed to change the color of the resin to a dark blue color. This confirmed that the reaction was completed. Thereafter, 3.5 equivalents of pipenonal was reacted with DMA solvent in 1% acetic acid for 5 hours, 5 equivalents of NaBH ₃ CN was added, and the reaction was continued for 1 day. Excess pipenol, DMA solvent, acetic acid, NaBH ₃ CN filtered in excess of the Kaiser test was carried out to confirm the completion of the reaction through the color does not change. The resulting compound was stirred for 5 hours under 3.5 equivalents of ethyl isocyanate, DMF / toluene (1: 1 v / v) mixed solvent, and then filtered to complete cyclization reaction with diisopropylamine. Diisopropylamine was removed to afford the title compound.

¹ H NMR (CDCl ₃ , ppm): δ 7.28 (m, 3H), 7.13 (m, 2H), 6.72 (m, 1H), 6.66 (m, 2H), 5.95 (s, 2H), 5.02 (d , 1H, J = 15.1 Hz), 3.50 (m, 2H), 3.32 (m, 1H), 3.25 (m, 2H), 3.10 (m, 1H), 0.95 (t, 3H, J = 6.8 Hz).

Mass (FAB, m / e): 353 (M ⁺ +1).

As described above, the method for synthesizing the solution phase hydridein of the present invention by reacting an amino acid derivative with an aldehyde compound and then reacting the product with an isocyanate compound in a solvent and cyclizing the hydridein compound in solution phase in a short time without requiring high temperature According to the solid phase synthesis method in which an amino acid derivative and Wang resin are reacted, and a product is sequentially reacted with an aldehyde derivative and an isocyanate compound, and then cyclized, a high purity without the need for post-treatment such as chromatography and recrystallization is required. Heidetoin compounds are produced in high yield. Therefore, the solution-phase or solid-phase hydridein synthesis method of the present invention is a very economical and effective method for producing hydridein.

Claims (5)

R was ^first group of amino acid derivatives R aldehyde derivative compound and a reductive amination reaction and having ^two groups, the isocyanate compound and the reaction with a group R ³ of the product in a solvent, to including the step of cyclization Hayden hydantoin derivative of the general formula (I) Method for using the solution phase reaction of. Formula 1 In the above formula, R ¹ is an alkyl, aryl, or hydroxy aryl group substituted with alkyl or sulfur, R ² represents branched alkyl, or in each occurrence substituted or unsubstituted aryl or heteroaryl, R ³ represents lower alkyl, cycloalkyl, or in each case aryl, heteroaryl, unsubstituted or substituted with alkoxy. The process according to claim 1, wherein benzene, toluene or DMF is used as the solvent. The method of claim 1, wherein the reaction is performed within 1 hour at room temperature (25 ° C.). Reacting the amino acid derivative compound having the R ¹ group with a Wang resin, reacting the product with an aldehyde derivative compound having the R ² group, and reacting the product with an isocyanate compound having the R ³ group, followed by cyclization. Manufacturing method using a solid phase reaction of the hydridein derivative of the formula (1) comprising. The process according to claim 1 or 4, wherein the cyclization reaction is carried out using diisopropylamine, triethylamine, pyrrolidine or piperidine.