KR100424845B1 - Method for preparing lactone compounds using polystyrene resin - Google Patents

Abstract

PURPOSE: A method for preparing lactone compounds using polystyrene resin is provided, thereby easily cutting the covalent bond between the resin and organic compound without using strong acid or base, and maintaining the stereochemical structure of homoserine lactone during the cutting process of polystyrene resin. CONSTITUTION: The method for preparing lactone compounds using polystyrene resin comprises reacting a compound of formula (II) with cyanogen bromide(BrCN) in a mixed solvent of water and organic solvent in the presence of acid, wherein R is chemically substitutable groups, such as alkyl, substituted alkyl, alkenyl, substituted alkenyl, allyl, substituted allyl, phenyl, substituted phenyl, hetero and substituted hetero; the organic solvent is selected from chloroform, dichloromethane and dichloroethane; the acid is selected from acetic acid, trifluoroacetic acid and hydrochloric acid.

Description

Method for producing a novel lactone compound using a polystyrene resin.

The present invention relates to an organic synthesis method for producing a novel lactone compound using a polystyrene resin. More specifically, the present invention relates to a method for preparing a novel lactone compound by using a mixed solvent of an organic solvent and water as a solvent through a reaction in a solid phase using a polystyrene resin and treating with cyanogen bromide in the presence of an acid. .

The lactone compound of the present invention is represented by the following general formula (I), which is prepared from the following general formula (II).

구조는 아미노메틸 폴리스티렌 수지를 나타낸다.In the formula, R represents all chemically substitutable groups, for example, alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, hetero, substituted hetero and the like. In the formula (II)

The structure represents an aminomethyl polystyrene resin.

Conventionally, a number of studies have been made in recent years due to the advantage that the organic synthesis method in the solid phase using a resin does not require a purification process such as column chromatography and the advantage that it is easy to build a combinatorial library (Angew. Chem. Int Ed. Engl. 1996, 35, 2288-2337: Tetrahedron 1995, 51, 8135-8137). However, the process of cleaving covalent bonds between the resin and the organic compound in order to obtain the target compound after the reaction in the solid phase not only requires strong conditions such as strong acids and strong bases, but also maintains the stereochemical structure in the process of cutting the polystyrene resin. There was a problem that it is difficult to be.

Therefore, the present invention achieves the present invention by easily cutting the covalent bond between the resin and the organic compound without using the strong acid, strong base required in the process of cutting the covalent bond between the resin and the organic compound to obtain the target compound after the reaction in the solid phase. It was. Still another object of the present invention is to provide a method for synthesizing homoserine lactone in which the stereochemical structure is maintained in the process of cutting polystyrene resin.

Hereinafter, the specific configuration and operation of the present invention will be described in detail.

1 shows a lactone compound used in the present invention.

The present invention provides a process for preparing a new lactone compound, wherein the protecting group is removed from compound (IV) condensed with aminomethyl polystyrene resin and N-Fmoc-L-methionine and then condensed with a suitable carboxylic acid and the condensate (II) Is treated with cyanogen bromide (BrCN) in the presence of an organic solvent and an acid.

The first condensation reaction can be carried out in a conventional manner, it is common to use diisopropyl carbodiimide, 1-hydroxybenzotriazole as the condensation reagent in anhydrous dimethylpoamide solvent. In order to prepare the desired compound (I), the condensation compound (II) is treated with cyanogen bromide (BrCN) in the presence of an acid. At this time, acetic acid, trifluoroacetic acid, hydrochloric acid, etc. may be used as the selected acid, and chloroform, dichloromethane, dichloroethane, etc. may be used as the organic solvent, and it is preferable to use it as a mixed solvent with water. In the present invention all reactions are carried out at or below room temperature.

The manufacturing process of the lactone compounds of the present invention is represented as follows.

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Representative examples of the carboxylic acid (VI) used in the present invention are as follows.

n-butane ooxide (VI-a)

Malonic acid monoethyl ester (VI-b)

(Cyclopentyl) acetic acid (VI-c)

N-carbobenzyloxy-L-valine (VI-d)

N-carbenzyloxy-L-phenylalanine (VI-e)

N-p-tolucialfonyl-L-phenylalanine (VI-f)

3,4-methylenedioxyphenylpropionic acid (VI-g)

p-methoxyphenylacetic acid (VI-h)

4-biphenylcarboxylate (VI-i)

Hereinafter, the concrete configuration and operation of the present invention will be described in detail with reference to Examples.

Example 1.Preparation of Resin (IV) with Methionine

4 g (0.9 mmol) of aminomethylpolystyrene resin, 3.36 g (9 mmol) of N-Fmoc-L-methionine, 1.4 ml (9 mmol) of diisopropylcarbodiimide, 1.2 g (9 mmol) of 1-hydroxybenzotriazole And 1.14 ml (9 mmol) of N-ethyl morpholine were added to 50 ml of anhydrous dimethylpoamide, and the mixture was stirred at room temperature for 2 days. The resin was filtered and washed with dimethylformamide (10 ml x 2), methanol (10 ml x 2) and chloroform (10 ml x 2) to obtain 4.36 g of methionine-bound resin.

Structural formula (IV) of this compound is as follows.

The compound was analyzed using IR as follows.

IR (KBr) 3403, 3024, 2918, 1718, 1670, 1601 cm ^-1

Example 2 Preparation of Resin (V) with Protective Group Removed

4.36 g of Compound (IV) obtained in Example 1 was added to 30 ml of a 20% piperidine dimethine poamide solution, stirred at room temperature for 6 hours, and then the resin was filtered, and then dimethylpoamide (10 ml x 2) and methanol ( 10 ml x 2) and chloroform (10 ml x 2) were washed to obtain 4.24 g of a resin from which the protecting group was removed. Structural formula (V) of this compound is as follows.

The compound was analyzed using IR as follows.

IR (KBr) 3382, 2917, 1664, 1600, 1492 cm ^-1

Example 3 Preparation of N- (Butane Oy) Homoserine Lactone (I)

302 mg (0.27 mmol) of the resin obtained in Example 2, 0.062 ml (0.68 mmol) of n-butanioic acid (IV-a), 0.107 ml (0.68 mmol) of diisopropylcarbodiimide, 92 mg of 1-hydroxybenzotriazole (0.68 mmol) and 0.086 ml (0.68 mmol) of N-ethylmorpholine were added to 5 ml of anhydrous dimethylpoamide and stirred for 2 days at room temperature. The reaction solution was filtered off and the resulting resin compound (II) was washed with dimethylformamide (10ml x 2), methanol (10ml x 2) and chloroform (10ml x 2). The resin obtained above was added to a solution of 5 ml of chloroform and 2 ml of water, followed by 430 mg (4.06 mmol) of cyanogen bromide followed by two drops of 99% trifluoroacetic acid. After stirring for 2 days at room temperature, the mixture was filtered and the chloroform solution was collected in the filtrate, and concentrated under reduced pressure to obtain 23 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3310, 2918, 1774, 1647 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ6.088 (br s, 1H), 4.59 (ddd, J = 11.7, 8.6, 5.8 Hz, 1H), 4.50 ( ddd, J = 9.1, 9.1, 1.2 Hz, 1H), 4.32 (ddd, J = 11.4, 9.3, 5.8 Hz, 1H), 2.90 (dddd, J = 12.6, 8.6, 5.9, 1.2 Hz, 1H), 2.27 ( td, J = 7.4, 1.6 Hz, 2H), 2.16 (dddd, J = 11.5, 11.5, 12.5, 8.8 Hz, 1H), 1.77 (sextet, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz , 3H)

Example 4. Preparation of N- (malonic ethyl ester) homoserine lactone (I)

80 mg (0.47 mmol) of malonic acid monoethyl ester (VI-b) was treated in the same manner as in Example 3 to obtain 18 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3319, 2922, 1737, 1697 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ7.75 (br s, 1H), 4.60 (ddd, J = 11.7, 8.8, 6.5 Hz, 1H), 4.48 ( ddd, J = 9.0, 9.0, 1.2 Hz, 1H), 4.29 (ddd, J = 11.1, 9.3, 6.0 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.38 (s, 2H), 2.81 (dddd, J = 12.5, 8.7, 6.0, 1.3 Hz, 1H), 2.20 (dddd, J = 11.2, 11.2, 12.5, 8.9 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H)

Example 5 Preparation of N- (Cyclopentylacetyl) Yeastserine Lactone (I)

64 mg (0.47 mmol) of (cyclopentyl) acetic acid (VI-c) were treated in the same manner as in Example 3 to obtain 19 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3306, 3035, 1777, 1642 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ 5.94 (br s, 1H), 4.53 (ddd, J = 11.8, 8.8, 5.8 Hz, 1H), 4.47 ( ddd, J = 9.1, 9.1, 1.1 Hz, 1H), 4.28 (ddd, J = 11.4, 9.4, 5.9 Hz, 1H), 2.88 (dddd, J = 12.7, 8.6, 6.0, 1.3 Hz, 1H), 2.26- 2.25 (m, 2H), 2.12 (dddd, J = 11.5, 11.5, 12.5, 8.8 Hz, 1H), 1.89-1.81 (m, 2H), 1.65-1.57 (m, 3H), 1.21-1.13 (m, 4H )

Example 6 Preparation of N- (Cabobenzyloxy-L-valine) Homoserine Lactone (I)

126 mg (0.5 mmol) of N-carbobenzyloxy-L-valine (VI-d) was treated in the same manner as in Example 3 to obtain 29 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3288, 2922, 1776, 1689 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ7.38-7.30 (m, 5H), 6.80 (br d, J = 5.4 Hz, 1H), 5.46 (br d , J = 8.3 Hz, 1H, 5.13 (s, 1H), 4.60-4.54 (m, 1H), 4.47 (t, J = 9.0 Hz, 1H), 4.32-4.25 (m, 1H), 4.09 (m, 1H), 2.78-2.75 (m, 1H), 2.22-2.25 (m, 2H), 1.84 (m, 1H), 1.03, 0.98 (2d, J = 6.8 Hz, 6H)

Example 7 Preparation of N- (Carbenzyloxy-L-phenylalanine) Homoserine Lactone (I)

270 mg (0.9 mmol) of N-carbobenzyloxy-L-phenylalanine (VI-e) was treated in the same manner as in Example 3 to obtain 44 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3297, 2919, 1777, 1691 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ7.35-7.18 (m, 10H), 6.40 (br s, 1H), 5.25 (br s, 1H), 5.09 (s, 3H), 4.43 (m, 2H), 4.39 (ddd, J = 11.3, 8.7, 6.0 Hz, 1H), 4.24 (ddd, J = 10.8, 9.3, 6.0 Hz, 1H), 3.11 (m, 2H ), 2.74 (m, 1 H), 2.09 (m, 1 H)

Example 8 Preparation of N- (p-toluenesulfonyl-L-phenylalanine) homoserine lactone (I)

217 mg (0.68 mmol) of N-p-toluenesulfonyl-L-phenylalanine (VI-f) was treated in the same manner as in Example 3 to obtain the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3288, 2916, 1773, 1654 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ 7.47 (m, 2H), 7.15-7.08 (m, 5H), 6.97 (br d, J = 6.4 Hz, 1H), 6.98 (m, 2H), 5.00 (d, J = 7.2 Hz, 1H), 4.40 (ddd, J = 9.3, 9.3, 1.8 Hz, 1H), 4.28 (ddd, J = 11.0, 8.9, 6.3 Hz , 1H), 4.19 (ddd, J = 10.2, 9.2, 6.4 Hz, 1H), 3.87 (td, J = 7.0, 5.8 Hz, 1H), 2.95-2.83 (m, 2H), 2.59 (dddd, J = 12.7 , 8.7, 6.3, 1.9 Hz, 1H), 2.35 (s, 3H), 2.13 (dddd, J = 10.8, 10.8, 12.7, 9.1 Hz, 1H)

Example 9 Preparation of N- (3,4-methylenedioxyphenylpropionyl) homoserine lactone (I)

102 mg (0.53 mmol) of 3,4-methylenedioxyphenylpropionic acid (VI-g) were treated in the same manner as in Example 3 to obtain 28 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3308, 2923, 1775, 1637 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ6.74-6.64 (m, 3H), 6.01 (br s, 1H), 5.93 (s, 2H), 4.52 ( ddd, J = 11.6, 8.5, 5.8 Hz, 1H), 4.46 (ddd, J = 9.1, 9.1, 1.2 Hz, 1H), 4.27 (ddd, J = 11.3, 9.3, 5.8 Hz, 1H), 2.90 (t, J = 7.4 Hz, 2H), 2.84 (dddd, J = 12.5, 8.5, 5.8, 1.2 Hz, 1H), 2.51 (m, 2H), 2.06 (dddd, J = 11.5, 11.5, 12.6, 8.9 Hz, 1H)

Example 10 Preparation of N- (4-methoxyphenylacetyl) homoserine lactone (I)

113 mg (0.68 mmol) of p-methoxyphenylacetic acid (VI-h) were treated in the same manner as in Example 3 to obtain 29 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3291, 2918, 1773, 1652 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ7.12 (d, J = 7.5 Hz, 2H), 6.82 (d, J = 9.4 Hz, 2H), 5.87 ( br s, 1H), 4.44 (ddd, J = 11.6, 8.7, 6.1 Hz, 1H), 4.36 (ddd, J = 9.0, 9.0, 1.0 Hz, 1H), 4.18 (ddd, J = 11.2, 9.3, 5.9 Hz , 1H), 3.74 (s, 3H), 3.50 (s, 2H), 2.72 (dddd, J = 12.5, 8.6, 5.9, 1.2Hz, 1H), 2.01 (dddd, J = 11.3, 11.3, 12.5, 8.9Hz , 1H)

Example 11 Preparation of N- (4-biphenylcarbonyl) homoserine lactone (I)

194 mg (0.98 mmol) of 4-biphenylcarboxylate (VI-i) was treated in the same manner as in Example 3 to obtain 58 mg of the target compound. The structural formula of this compound is as follows.

The compound was analyzed using IR and ¹ H NMR. The results are as follows.

IR (KBr) 3058, 2917, 1657, 1641 cm ^-1 : ¹ H NMR (CDCl ₃ ) δ 7.89 (m, 2H), 7.69-7.61 (m, 4H), 7.49-7.38 (m, 3H), 6.78 (br d, J = 4.7 Hz, 1H), 4.77 (ddd, J = 11.6, 8.5, 5.5 Hz, 1H), 4.55 (ddd, J = 9.0, 9.0, 1.0 Hz, 1H), 4.38 (ddd, J = 11.3, 9.3, 5.8 Hz, 1H), 3.01 (dddd, J = 12.5, 8.6, 5.8, 1.2 Hz, 1H), 2.29 (dddd, J = 11.4, 11.4, 12.5, 8.8 Hz, 1H)

As described above, the present invention can easily cut the process of cleaving covalent bonds between the resin and the organic compound without using conditions such as strong acid and strong base, and maintain the stereochemical structure in the process of cutting the polystyrene resin. Since homoserine lactone can be prepared, there is an effect of providing a novel organic synthesis method. In addition, the lactone compound of the present invention can be used as pharmaceuticals such as immunosuppressants, anticancer agents, and also useful as synthetic intermediates, which is a very useful invention in the pharmaceutical industry.

Claims (5)

A process for producing a lactone compound represented by the following general formula (I) by treating a compound of the following general formula (II) with cyanogen bromide (BrCN) in the presence of an acid in a mixed solvent of an organic solvent and water.

In the formula, R means all chemically substitutable groups. For example alkyl, substituted alkyl, alkenyl, substituted alkenyl, allyl, substituted allyl, phenyl, substituted phenyl, hetero, substituted hetero and the like. In the above formula (II)

By structure is meant aminomethyl polystyrene resins. The method of claim 1, wherein the organic solvent is selected from chloroform, dichloromethane, dichloroethane. The method of claim 1 wherein the acid is selected from acetic acid, trifluoroacetic acid, hydrochloric acid. The intermediate compound of the following general formula (V) which removed the protecting group from the resin to which methionine was bound.

The compound according to claim 4, wherein the intermediate compound is n-butanioic acid, malonic acid monoethylester, (cyclopentyl) acetic acid, N-carbenzyloxy-L-valine, N-carbenzyloxy-L-phenylalanine , N-toluenesulfonyl-L-phenylalanine, 3,4-methylene dioxyphenylpropionate, P-methoxy phenylacetic acid, 4-biphenylcarboxylate .

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