JPH06743B2 - Method for producing indoline-2-carboxylic acid - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing indoline-2-carboxylic acids. More specifically, the general formula I (Wherein X represents a halogen atom, Y represents a hydroxyl group, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl oxy group, or an amide residue). 2-halogenophenylalanine, 2
-Halogenophenylalanine ester or 2-halogenophenylalanine amide, in the presence of amine, using a copper-based catalyst for ring closure, the general formula II (Wherein Y is the same as above)
-A method for producing carboxylic acids.

Indoline-2-carboxylic acid compounds are important compounds as raw materials for various medicines. For example, optically active (S)
-Indoline-2-carboxylic acid is angiotensin I
(S) -1-[(S) -3-Mercapto-2-oxopropyl] -indoline-2-carboxylic acid useful as a converting enzyme inhibitor Structural formula Can be used for [Journal of Medicinal
Chemistry (J. Med. Chem.), 26, 394 (198)
3)].

(Conventional Technology and Problems) As a method for producing indoline-2-carboxylic acid, N
-Method of reducing acetylindole-2-carboxylic acid or its methyl ester using a platinum oxide catalyst at room temperature under normal pressure [Journal of Chemistry, Vol. 87, pp. 760-762 (19
66)] or a method of reducing indole-2-carboxamide with phosphonium iodide and hydriodic acid [Australian Journal of Chemistry (Aust.
J. Chem.), 20, 1935 (1967)] and the like are known. However, since all of these methods use expensive indole-2-carboxylic acid as a starting material, it is difficult to say that these methods are industrially advantageous for obtaining indoline-2-carboxylic acids, and a method for inexpensive production is desired. ing.

(Means and Actions for Solving Problems) Under the circumstances, the present inventors have conducted industrial production from the compound represented by the above formula I into the indoline-2-carboxylic acid represented by the formula II. The present invention has been completed by finding an advantageous new method.

That is, it has been found that 2-halogenophenylalanine, 2-halogenophenylalanine ester or 2-halogenophenylalanine amide is extremely efficiently ring-closed and converted into indoline-2-carboxylic acid by using a copper catalyst in the presence of amine. It is a thing.

The present invention will be described in detail below.

Formula I used in the present invention In the 2-halogenophenylalanine represented by, X is a halogen atom and is fluorine, chlorine, bromine or iodine. Y is a hydroxyl group or an unsubstituted alkoxy group having 1 to 10 carbon atoms such as a hydroxyl group, a methoxy group, an ethoxy group, a propoxy group, a butyloxy group, a hexyloxy group, an isopropoxy group, an isobutoxy group or a hydrogen atom on the carbon chain of the hydroxyl group. , A substituted alkoxy group having 1 to 10 carbon atoms substituted with an alkoxy group or the like, or a methylamide residue, an ethylamide residue, a propylamide residue, a butylamide residue in which one or two hydrogen atoms of an amide residue are replaced, It is an amide residue such as a diethylamide residue, a diisopropylamide residue, a dibutylamide residue or a monoethanolamide residue.

Specific examples of the 2-halogenophenylalanines include, for example, 2-chlorophenylalanine, 2-chlorophenylalanine ethyl ester, 2-chlorophenylalanine ethylene glycol ester, 2-chlorophenylalanine amyl ester, 2-chlorophenylalanine butylamide and 2-chlorophenylalanine. Phenylalanine monoethanolamide, 2-bromophenylalanine isopropyl ester, 2-bromophenylalanine glycerose ester, 2-bromophenylalanine hexyl ester, 2-bromophenylalanine diethylamide, 2
-Bromophenylalanine dibutylamide and the like.

2-Halogenophenylalanine can be easily produced by, for example, inducing 2-halogenobenzaldehyde into a hydantoin or azlactone form and subjecting it to reductive ring opening according to a known phenylalanine synthesis method, and further conversion to 2-halogenophenylalanine. It is easily performed by a conventional method.

Examples of the amine used in the method of the present invention include butylamine, hexylamine, heptylamine, octylamine, diethylamine, triethylamine, dibutylamine, tripropylamine, tributylamine, ethylenediamine, monoethanolamine, diethanolamine, benzylamine, pyridine, piperidine. , Morpholine, 4-N, N-dimethylaminopyridine,
Examples include diisopropylethylamine. Among these amines, it is preferable to use an amine having a boiling point of 100 ° C. or higher in order to carry out the reaction at atmospheric pressure. When the starting material I is 2-halogenophenylalanine or 2-halogenophenylalanine ester, when a primary amine is used, I is converted into an amide of the primary amine at the same time as the ring-closing reaction, and the indole-2-amine of the primary amine used. Carboxamide is formed. Therefore, when it is desired to obtain indoline-2-carboxylic acid or indoline-2-carboxylic acid ester, it is necessary to use a secondary amine or a tertiary amine.

Further, the copper-based catalyst used in the method of the present invention may be one that supplies copper ions to the reaction system, for example, metallic copper, copper chloride, copper bromide, copper iodide, cuprous oxide, copper oxide, hydroxide. Examples thereof include inorganic copper compounds such as copper and copper sulfate, and organic copper compounds such as copper oxalate and copper acetate.

In the method of the present invention, the amine is used in a 1-fold molar amount or more, and preferably in a 2- to 10-fold molar amount with respect to 2-halogenophenylanilines. The copper catalyst is used in the range of 1 to 20% by weight, preferably 2 to 10% by weight, based on the 2-halogenophenylanilines.

The ring-closing reaction is preferably performed by heating, and the temperature is preferably 100 to 200 ° C., although it varies depending on the boiling point of the amine used. The reaction time is preferably 2 to 8 hours. Also, since the indoline-2-carboxylic acid that is generated is easily oxidized,
The reaction is preferably carried out in an inert gas stream such as nitrogen, helium or argon.

In the method of the present invention, after completion of the reaction, the indoline-2-carboxylic acid can be obtained by treating the reaction mixture with an ordinary method such as filtration, solvent extraction, water washing, or column chromatography. If necessary, high-purity indoline-2-carboxylic acid can be obtained by further treatment such as distillation or recrystallization.

(Examples) Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 1 Synthesis of indoline-2-carboxylic acid a) Synthesis of 2-chlorophenylalanine o-chlorobenzaldehyde 74 in a 1 l eggplant flask.
g and acetylglycine 42.1 g were added, and acetic anhydride 9
Add 2 g and 22 g of sodium acetate, attach the cooling tube, and
The mixture was heated at 50 ° C. under reflux for 1.5 hours. Although it solidifies when left to cool,
It was crushed and washed with 300 ml of cold water. After suction dehydration, the product was washed with 120 ml of ether and dried in a vacuum, and 65.2 g of azlactone of α-acetaminocinnamic acid as a yellow powder (yield 8
2%) was obtained.

Then, 50 g of the azlactone, 30 g of red phosphorus, and 300 ml of acetic anhydride were added to a 1-liter flask, and 200 ml of 57% hydroiodic acid was added dropwise with stirring. After completion of dropping, a cooling tube was attached, the temperature was raised to 140 ° C., and the mixture was heated under reflux for 3 hours.
After allowing to cool, the reaction solution was dried under reduced pressure, and 500 ml of water and ether 2 were added.
00 ml was added and stirred well to separate the aqueous layer. 20 water layers
A white precipitate was obtained by concentrating under reduced pressure to 0 ml and adjusting the pH to 6 with concentrated aqueous ammonia. The precipitate was collected by filtration, washed with 50 ml of cold water, and dried in vacuum to obtain 37.5 g (yield 83%) of 2-chlorophenylalanine.

b) Synthesis of indoline-2-carboxylic acid 20 g of diethanolamine was placed in a 100 ml flask equipped with a condenser, a stirrer and a dropping funnel, and 1.0 g of anhydrous cupric chloride was gradually added while blowing nitrogen. . Then, the temperature was raised to 100 ° C., and 10 g of 2-chlorophenylalanine was gradually added while blowing nitrogen,
The temperature was raised to 0 ° C., and the mixture was heated under reflux for 4 hours. After the reaction, the mixture was allowed to cool, extracted with 200 ml of ethyl acetate, 50 ml of water was added to the ethyl acetate layer to adjust to pH 5, and the mixture was washed twice (100 ml in total). The ethyl acetate layer was dehydrated with anhydrous sodium sulfate, and then dried under reduced pressure to give pale brown powder of indoline-2-carboxylic acid 3.
4 g was obtained (yield 42%).

Example 2 Synthesis of indoline-2-carboxylic acid ethyl ester To a 500 ml flask equipped with a condenser and a stirrer, 30 g of 2-chlorophenylalanine, 200 ml of ethanol and 10 ml of concentrated sulfuric acid were added, and the mixture was heated under reflux for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with 500 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 22.5 g of ethyl ester of 2-chlorophenylalanine.
(Yield 66%) was obtained.

Then 100 ml equipped with condenser, stirrer and dropping funnel
20 g of tripropylamine was placed in a flask having a volume of 1.0 g, and 1.0 g of anhydrous cupric chloride was gradually added at room temperature while blowing nitrogen. Next, the temperature was raised to 100 ° C., and 10 g of 2-chlorophenylalanine ethyl was added dropwise while blowing nitrogen.
The temperature is raised to 140 ° C. and heated under reflux for another 4 hours,
The reaction was completed. After cooling, the amine was removed under reduced pressure, extraction was performed with 200 ml of ethyl acetate, and the ethyl acetate layer was washed twice with 50 ml of water (100 ml in total). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a brown syrup.
This was crystallized from ethyl acetate-hexane (1: 5) to obtain 3.9 g of pale pink indoline-2-carboxylate (yield 47%).

Example 3 The procedure of Example 1 was repeated except that 2-bromophenylalanine was used instead of 2-chlorophenylalanine and triethylamine was used instead of diethanolamine to obtain 2.7 g of indoline-2-carboxylic acid ( Yield 33%).

Example 4 The procedure of Example 1 was repeated, except that the amine was changed to monoethanolamine to obtain 4.1 g of pale yellow powdery indoline-2-carboxylic acid monoethanolamide (yield 40%). .

Examples 5 to 7 In Example 2, the starting material I was replaced with the amine, the same operation as in Example 2 was performed under the reaction conditions shown in Table 1, and the results shown in the same table were obtained.

Claims (3)

[Claims] 1. A general formula I (Wherein X represents a halogen atom, Y represents a hydroxyl group, a substituted or unsubstituted alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted aryl oxy group, or an amide residue). General formula II, characterized in that 2-halogenophenylalanine, 2-halogenophenylalanine ester or 2-halogenophenylalanine amide is ring-closed using a copper catalyst in the presence of an amine. (In the formula, Y is the same as above.) A method for producing an indoline-2-carboxylic acid. 2. The method according to claim 1, wherein the amine is diethanolamine, tripropylamine, triethylamine, monoethanolamine, tributylamine or dibutylamine. 3. The production method according to claim 1, wherein the copper-based catalyst is anhydrous cupric chloride.