JPH11158145A - Production of 4,4,4-trifluoro-3-(3-indolyl)lactic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply obtain the subject compound useful as a plant growth promoter in a single step by reacting indoles with a base having a definite strength or above and reacting the resultant compound with a trifluorocrotonic acid derivative. SOLUTION: Indoles of formula I (X is H, a lower alkyl or a halogen) are reacted with (B) a base in which pKa of conjugate acid is larger than pKa of the component A (e.g. an alkyl metal compound such as methyllithium or a metal alkoxide such as sodium ethoxde) and then reacted with (C) 4,4,4- trifluorocrotonic acid derivative of formula II (R is an ester type or amide type protecting group of carboxylic acid part) to provide the objective 4,4,4- trifluoro-3-(3-incolyl)lactic acid (TFIBA) of formula III. Furthermore, the component C is preferably used in 0.7-1 equivalent amount based on the component A. According to this method, TFIBA whose carboxyl group is protected can be obtained in a single step.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to 4,4,4-trifluoro-3- (3) which is known as a plant growth promoting substance.
-Indolyl) butyric acid derivatives.

[0002]

2. Description of the Related Art With the worldwide population increase, attention has been paid to plant growth promoting substances capable of increasing the yield of crops per unit area of farmland from the viewpoint of securing sufficient food. It has long been known that indole-3-acetic acid and its derivatives have a plant growth promoting effect, but recently, 4,4,4-trifluoro-3- (3-indolyl) butyric acid (in the cited document) 4,4,4-trifluoro-
Same as 3- (indole-3-) butyric acid. Hereafter referred to as TFIBA. ) And its derivatives have been reported to have remarkable plant growth promoting activity. (Report of the Annual Meeting of the Japanese Society of Phytochemical Regulation, p. 31: Proceedings of the 16th Fluorochemical Symposium p. 47 (1991) : JP 5-279331: JP 6-5
6774). TFIBA has very interesting activities such as promoting root growth of rice, Chinese cabbage, corn, etc., increasing potato yield, promoting female flower differentiation of cucumber, and promoting maturation of tomato (BIO INDUSTRY, Vol. 12, No. 2, 34 (1995 )). However, the synthesis method is complicated and requires a large number of steps, and a simple synthesis method has not been known. In addition, this TFIBA is frequently optically resolved because the (S) -isomer has higher activity than the (R) -isomer among the two optical isomers (J. Ferment. Bioeng., 82 (4 ), 355,
(1996)). In that case, the method of hydrolyzing the ester of TFIBA with an enzyme is used, so it is necessary to react the synthesized TFIBA with alcohols to obtain the TFIBA ester.In addition to the complicated synthesis operation, further esterification must be performed. In many cases, it had to be done. In addition, TFIBA is known to have a growth-promoting activity even when its carboxylic acid moiety is protected to form an ester or amide (Japanese Patent Application Laid-Open No. 7-267803). Again, after the synthesis of TFIBA, the carboxyl group had to be separately protected.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a simple method for synthesizing a derivative of TFIBA, which is a useful plant growth promoting substance but whose simple method is not known. .

[0004]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned disadvantages of the prior art, and as a result, after reacting indoles with a base having a certain strength or more, The present inventors have found that a TFIBA derivative can be synthesized in one step by reacting with a 4,4-trifluorocrotonic acid derivative, and thus completed the present invention.

That is, the present invention provides the following general formula (I)

Embedded image (Wherein, X represents a hydrogen atom, a lower alkyl group, or a halogen atom)
After reacting Ka with a base larger than the pKa of the indole, the following general formula (II)

[0006]

Embedded image

Characterized by reacting with a 4,4,4-trifluorocrotonic acid derivative represented by the formula (wherein R represents an ester-type or amide-type protecting group for a carboxyl group), )

[0008]

Embedded image

4,4,4-trifluoro-3 represented by
The present invention relates to a method for producing-(3-indolyl) butyric acid derivative (wherein X and R are as defined above).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The above general formula (I) in the present invention
Among X in the above, as the lower alkyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group,
Examples thereof include an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a hexyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Further, the above-mentioned general formula (II) and general formula (II)
R in I) is an ester-type or amide-type protecting group for a carboxyl group, and examples of the ester-type protecting group include lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropyloxy, butoxy, and tert-butyloxy groups. An aryloxy group such as a phenoxy group, an aralkyloxy group such as a benzyloxy group, an methoxymethyloxy group, an alkoxy group having an ether bond such as a tetrahydropyranyloxy group, a 2,2,2-trichloroethyloxy group, Examples thereof include a halo-substituted alkoxy group such as a 2,2-trifluoroethyloxy group, an alkenyloxy group such as an allyloxy group and a vinyloxy group, and a tri (lower alkyl) silyloxy group such as a trimethylsilyloxy group. Amide-type protecting groups include an amino group, N,
Examples thereof include a di (lower alkyl) amino group such as an N-dimethylamino group, a cyclic amino group such as a pyrrolidino group and a piperidino group, and a substituted or unsubstituted hydrazino group such as a hydrazino group and a phenylhydrazino group.

As the indole represented by the general formula (I) and the 4,4,4-trifluorocrotonic acid derivative represented by the general formula (II), commercially available ones can be used as they are. The 4,4,4-trifluorocrotonic acid derivative can also be synthesized from 4,4,4-trifluorocrotonic acid using a known esterification method, amidation method, or the like.

In the present invention, it is an essential condition that the indole is reacted with a base having a pKa of the conjugate acid larger than that of the indole. The pKa varies somewhat depending on the substituent X. For example, the pKa of indole is 1
A value of 6.97 ± 0.10 has been reported (RJ Sundber
g, "The Chemistry of Indoles", Academic Press, p.1
9 (1970)). Bases in which the conjugate acid has a higher pKa include alkylmetals such as methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, methylmagnesium bromide, ethylmagnesium bromide, diethylzinc, and triethylaluminum. Compounds, phenyllithium, aryl metal compounds such as phenylmagnesium bromide, alkenyl metal compounds such as vinylmagnesium bromide and allylmagnesium bromide, alkynylmetal compounds such as ethynyl sodium and 2-phenylethynyl sodium, benzylmagnesium bromide, tribenzylmagnesium Aralkyl metal compounds such as phenylmethyl sodium; metal hydrides such as sodium hydride and potassium hydride; metal amides such as sodium amide and lithium diisopropylamide; sodium ethoxide; potassium tert-butyl It can be exemplified metal alkoxides such as Kishido.

For the purpose of improving the yield of the target compound and suppressing side reactions, the indole may be reacted with a strong base and then treated with an appropriate metal salt. Examples of the metal salt include chlorides, bromides, iodides, and cyanides of zinc, cadmium, mercury, copper, and silver. The amounts of these organometallic reagents and metal salts to be used are arbitrary, but from the viewpoint of the yield of the desired product and economical efficiency, the amount of the organometallic reagent and the metal salt is not more than 1 indole.
It is preferred that it is about equivalent.

In the method of the present invention, the target compound is produced by reacting the 4,4,4-trifluorocrotonic acid derivative represented by the above general formula (II). At this time, it is desirable to use about 0.7 to 1 equivalent of the 4,4,4-trifluorocrotonic acid derivative to the indole.

In carrying out the present invention, it is preferable to carry out the reaction in a solvent which does not participate in the reaction, and a non-proton such as ether, tetrahydrofuran (THF), acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, etc. More preferably, the reaction is performed in a polar solvent.

The reaction temperature can be appropriately selected from the temperature range of -100 ° C to 200 ° C, and is 0 ° C to 50 ° C.
C. is preferred.

According to the present invention, TFIBA having a protected carboxyl group can be obtained in one step. This is useful as it is as a plant growth promoting substance, but can be easily converted into TFIBA by deprotecting it by a known method. In addition, by using 4,4,4-trifluorocrotonate as a raw material, a TFIBA ester can be obtained in one step and can be used as it is for optical resolution by enzymatic hydrolysis.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Embodiment 1

[0020]

Embedded image

Indole (0.6 mm)
ol) and THF (0.7 ml) as a solvent, a hexane solution of butyllithium (1.68 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then added with ethyl 4,4,4-trifluorocrotonate. (0.5 mmol) and further stirred at room temperature for 5 hours. The reaction mixture was extracted with ether / water, tetradecane was added to the ether layer as an internal standard substance, and GLC analysis was performed.
It became clear that TFIBA ethyl ester was formed. After the ether layer was dried over anhydrous magnesium sulfate, the solvent was distilled off by heating under reduced pressure, and the residue was subjected to preparative thin-layer chromatography to isolate TFIBA ethyl ester.

Ethyl 4,4,4-trifluoro-3- (3-indolyl) butyrate (TFIBA ethyl ester) ¹ H-NMR (TMS, CDCl ₃ ): δ = 1.09 (t, J = 7.2 Hz, 3H) , 2.
93 (dd, J = 15.8 Hz, 9.3Hz, 1H), 3.10 (dd, J = 15.8 Hz,
5.5 Hz, 1H), 4.02 (q, J = 7.1 Hz, 1H), 4.03 (q, J = 7.2 H
z, 1H), 4.29 (dqd, J = 9.3 Hz, 9.2 Hz, 5.5 Hz, 1H),
7.12-7.25 (m, 3H), 7.32-7.36 (m, 1H), 7.65-7.69 (m, 1
H) ¹⁹ F-NMR (CFCl ₃ , CDCl ₃ ): δ = -71.28 (d, J = 9.2 Hz)

Embodiment 2

[0024]

Embedded image

Indole (0.6 mm)
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
Ethyl 4-trifluorocrotonate (0.5 mmol) was added, and the mixture was further stirred at room temperature for 5 hours. The reaction mixture was extracted with ether / water, and tetradecane was added to the ether layer as an internal standard. GLC analysis revealed that the desired TFIBA ethyl ester had been produced in a yield of 16%. .

Embodiment 3

Indole (0.6 mm)
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. -Ethyl trifluorocrotonate (0.5 mm
ol) and further stirred at 0 ° C. for 5 hours. The reaction mixture was extracted with ether / water, and tetradecane was added to the ether layer as an internal standard substance.
It was found that the desired TFIBA ethyl ester had been produced in a% yield.

Embodiment 4

[0029]

Embedded image

Indole (0.6 mm)
ol) and THF (0.5 ml) as a solvent, a hexane solution of diethylzinc (1.00 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then added with ethyl 4,4,4-trifluorocrotonate. (0.5 mmol) and further stirred at room temperature for 5 hours. 1M hydrochloric acid (0.5 m
l), and extracted with ether. Tetradecane was added to the ether layer as an internal standard, and GLC analysis revealed that the desired TFIBA ethyl ester was formed in a yield of 20%. .

Embodiment 5

[0032]

Embedded image

Indole (0.6 mm)
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. In another test tube, put zinc chloride (0.6 mmol), heat and dry under reduced pressure,
The above indole solution was gradually added thereto, and the mixture was further stirred at room temperature for 1 hour. Then, ethyl 4,4,4-trifluorocrotonate (0.5 mmol) was added, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1M hydrochloric acid (0.5 ml), extracted with ether, tetradecane was added to the ether layer as an internal standard, and GLC analysis was carried out. As a result, the target TFIBA ethyl ester was produced in a yield of 50%. It became clear that there was.

Embodiment 6

In the test tube with cap, indole (0.6 mm
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. In another test tube, put zinc chloride (0.6 mmol), heat and dry under reduced pressure,
The temperature was kept at 0 ° C., and the above-mentioned indole solution was gradually added thereto. The mixture was further stirred at 0 ° C. for 1 hour, and then ethyl 4,4,4-trifluorocrotonate (0.5 mmol) was added thereto.
For 24 hours. 1M hydrochloric acid (0.5 ml) in the reaction mixture
Was extracted with ether, tetradecane was added to the ether layer as an internal standard substance, and GLC analysis was performed.
It was found that the desired TFIBA ethyl ester had been produced in a yield of 54%.

Embodiment 7

[0037]

Embedded image

Indole (0.6 mm) was placed in a test tube with a cap.
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Put zinc bromide (0.6 mmol) in another test tube, heat and dry under reduced pressure,
The above indole solution was gradually added thereto, and the mixture was further stirred at room temperature for 1 hour. Then, ethyl 4,4,4-trifluorocrotonate (0.5 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was added with 1M hydrochloric acid (0.5 ml), extracted with ether, and tetradecane was added to the ether layer as an internal standard. GLC analysis showed that the target TFIBA ethyl ester was formed in a yield of 57%. It became clear that there was.

Embodiment 8

[0040]

Embedded image

Indole (0.6 mm)
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Zinc iodide (0.6 mmol) was placed in another test tube, heated and dried under reduced pressure, and the above-mentioned indole solution was gradually added thereto. The mixture was further stirred at room temperature for 1 hour. -Ethyl trifluorocrotonate (0.5 mmol) was added and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added 1 M hydrochloric acid (0.5 ml), extracted with ether, and tetradecane was added to the ether layer as an internal standard substance. GLC analysis showed that the target TFIBA ethyl ester was produced in a yield of 54%. It became clear that there was.

Embodiment 9

[0043]

Embedded image

Indole (0.6 mm)
ol) and THF (0.5 ml) as a solvent, a THF solution of methylmagnesium bromide (0.92 M, 0.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. In another test tube, put copper iodide (0.6 mmol) at 0 ° C., gradually add the above-mentioned indole solution, stir at 0 ° C. for 1 hour, and then add 4,4,4-trifluorocroton Ethyl acid (0.5 mmol) was added and the mixture was stirred at 0 ° C for 24 hours. To the reaction mixture was added 1M hydrochloric acid (0.5 ml), extracted with ether,
Add tetradecane as an internal standard substance to the ether layer,
GLC analysis showed that the target TFIBA
It became clear that ethyl ester had been produced.

[0045]

The present invention provides a simple method for producing a 4,4,4-trifluoro-3- (3-indolyl) butyric acid derivative known as a plant growth promoting substance.

Claims (1)

[Claims] 1. A compound represented by the following general formula (I) (Wherein, X represents a hydrogen atom, a lower alkyl group, or a halogen atom)
After reacting Ka with a base larger than the pKa of the indole, the following general formula (II): (Wherein R represents an ester-type or amide-type protecting group of the carboxylic acid moiety), characterized by reacting with a 4,4,4-trifluorocrotonic acid derivative represented by the following general formula (III): Chemical formula 3] Wherein X and R are the same as described above.
A method for producing a 4-trifluoro-3- (3-indolyl) butyric acid derivative.