JPH0149150B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 4-substituted indole derivatives. For more details, see General formula [] [In the formula, X represents a bromine atom or an iodine atom]
It relates to 4-substituted indole acetic acid represented by the following formula, salts thereof, and esters thereof.

All of the 4-substituted indole acetic acids represented by the above general formula [] are new compounds, and are useful as plant growth regulators, and are also important compounds as synthetic intermediates for other agricultural chemicals and medicines.

It has been known that indole-3-acetic acid and 4-chloroindole-3-acetic acid have auxin activity [OLHoffmann et al., J.
Biol.Chem., 196 , 437 (1952)]. In addition, as a method for producing indole-3-acetic acid derivatives,
It is known from the publication No. 17904, but there are 4
-Bromindole-3-acetic acid and 4-iodoindole-3-acetic acid are only included as general concepts, and not only the compounds are not specifically disclosed, but also their production methods and uses are not described. do not have.

The present inventor completed the present invention as a result of intensive research aimed at creating a 4-substituted indole derivative having pharmacological activity useful as a plant growth regulator.

4-Bromindole-3-acetic acid and 4-iodoindole-3-acetic acid in the present invention are
-Produce 4-halogenoindole-3-acetonitrile, a new compound, by reacting halogeno-3-dimethylindole with alkali cyanide in aqueous dimethylformamide, and then hydrolyzing this compound under alkaline conditions. Alternatively, 4-amino-1-methoxycarbonylindole-3-acetonitrile is diazotized and subjected to Sandmeyer reaction to form a new compound, 4-
Halogeno-1-methoxycarbonylindole-
It can be produced by obtaining 3-acetonitrile and then refluxing this compound in a methanol/alkaline aqueous solution to remove the alkoxycarbonyl group at the 1-position and hydrolyze the nitrile group all at once. Starting material 4
- Halogeno-3-dimethylaminomethylindole is obtained by methoxycarbonylation and reduction of 4-nitroindole to obtain 4-amino-1-methoxycarbonylindole, and after diazotization, 4-halogeno-1-methoxycarbonylindole is obtained by Sandmeyer reaction. [Kaneko et al., Proceedings of the 101st Annual Meeting of the Pharmaceutical Society of Japan, p. 377 (1981); M. Somei et al.
al., Chem.Pharm.Bull., vol. 29, p. 726 (1981
)], and further, by sequentially subjecting this compound to alkaline hydrolysis and Mannich reaction, 4-halogenoindole can be produced.
The other starting material, 4-amino-1-methoxycarbonylindole-3-acetonitrile, is obtained by sequentially Mannich reaction, cyanation, methoxycarbonylation, and reduction of 4-nitroindole to 3-dimethyl It can be produced via aminomethyl-4-nitroindole, 4-nitroindole-3-acetonitrile, and 1-methoxycarbonyl-4-nitroindole-3-acetonitrile.

EXAMPLES Hereinafter, the compounds and production methods according to the present invention will be explained in more detail with reference to Examples, and the production methods of raw material compounds will be explained in further detail with reference to Reference Examples.

Example 1 4-Bromindole-3-acetonitrile 971.2 mg (3.84 mmol) of 4-bromo-3-dimethylaminomethylindole was dissolved in 15.0 ml of dimethylformamide and 15.0 ml of water, and KCN (2.567 g) was added thereto for 1 hour. Stir and reflux. After adding water and extracting with benzene, washing with water and drying with _{Glauber 's} salt, the solvent was distilled off. Graphie was performed and 803.4 mg of 4-bromoindole-3-acetonitrile (yield 89.1%) was obtained.
Obtained. Recrystallization from methanol gave colorless crystals.

mp 156.0−157.0℃ Elemental analysis C% H% N% (C ₁₀ H ₇ BrN ₂ ) Calculated value 51.09 3.21 11.91 Measured value 51.19 2.90 11.93 MS m/e: 236234 (M ⁺ ) IR(KBr): 3390, 2255, 1650, 1616 NMR (10% _CD3OD in _CDCl3 ) δ: 4.12 (2H, S) 6.75-7.34 (4H, m) Example 2 4-Bromindole-3-acetic acid 4-Bromindole-3-acetonitrile
Dissolve 564.0mg in 20.0ml of methanol, 40%
Add 20 ml of NaOH and stir and reflux for 2 hours. After distilling off the methanol and making it acidic with 2N-HCl, salting out was performed by adding common salt, and ethyl acetate-methanol (95:
5, extract using V/V). After washing with saturated saline, drying with Glauber's salt and distilling off the solvent, the resulting residue was purified using silica gel with CH ₂ Cl ₂ -methanol (95:
Column chromatography was performed using 5, V/V) as the effluent solvent to obtain 4-bromoindole-3-
473.6 mg (yield 77.7%) of acetic acid was obtained.

Recrystallization from methanol gave colorless crystals.

mp 185.0−187.0℃ (decomposition) Elemental analysis C% H% N% (C ₁₀ H ₈ BrNO ₂ ) Calculated value 47.27 3.17 5.51 Measured value 47.37 3.14 5.49 MS m/e: 255, 253 (M ⁺ ) IR (KBr) : 3360, 3050 (br), 1697 NMR (50% CD ₃ OD in CDCl ₃ ) δ: 3.96 (2H, S) 6.78 (1H, tJ = 7.5H ₂ ) 7.01 (1H, br, S) 7.05 (1H. dd, J = 7.5and1.6H ₂ ) 7.09 (1H, dd, J = 7.5and1.6H ₂ ) Example 3 4-iodoindole-3-acetonitrile 4-iodo-3-dimethylaminomethylindole 47.3mg (0.16mmol ) was dissolved in 2.0 ml of dimethylformamide and 2.0 ml of H ₂ O, and 114.6 mg of KCK was obtained.
(1.71 mmol) and stirred and refluxed for 1 hour. Water was added, extracted with benzene, washed with water, dried with sodium sulfate, and the solvent was distilled off to obtain 44.0 mg of crude crystals. CH ₂ Cl ₂ -hexane (3:1, V/V) using silica gel as a carrier.
Thin layer chromatography was carried out using this as a developing solvent to obtain 41.6 mg (yield 93.6%) of 4-iodoindole-3-acetonitrile. Recrystallization from methanol gave colorless crystals.

mp 168.0−169.0℃ Elemental analysis C% H% N% (C ₁₀ H ₇ IN ₂ ) Calculated value 42.58 2.50 9.93 Measured value 42.75 2.45 10.07 MS m/e: 282 (M ⁺ ) NMR (20% CD ₃ in CDCl ₃ OD) δ: 4.15 (2H,
S), 6.72 (1H, dd, J = 8.0 and 7.0Hz).
7.27 (1H, dd, J=8.0 and 1.2Hz), 7.41
(1H, dd, J = 7.0 and 1.2Hz) IR (KBr): 3370, 2230, 1646, 1609 Example 4 4-iodoindole-3-acetic acid 4-iodoindole-3-acetonitrile
81.4 mg was suspended in a mixture of 3.0 ml of methanol and 2.0 ml of 40% NaOH, and the mixture was stirred and refluxed for 4 hours. After distilling off methanol and making acidic with 2N-HCl, extracting with CH ₂ Cl ₂ -methanol (95:5, V/V), washing with saturated brine, drying with sodium sulfate, and distilling off the solvent. 4-
Iodoindole-3-acetic acid as a single product, 83.1
mg (yield 99.0%) was obtained.

Recrystallization from methanol gave colorless crystals.

mp 170.0−171.0℃ Elemental analysis C% H% N% (C ₁₀ H ₈ INO ₂ ) Calculated value 39.89 2.68 4.65 Measured value 39.97 2.56 4.85 IR (KBr): 3360, 3030 (br.), 1698 MS m/e: 301 (M ⁺ ), 256 (M ⁺ −45) NMR (20% _CD3OD in _CDCl3 ) δ: 4.02 (2H,
S), 6.71 (1H, tJ=7.0Hz), 7.06 (1H, br.
S), 7.24 (1H, dd, J = 7.0 and 0.8Hz),
7.44 (1H, dd, J = 7.0 and 0.8Hz). Example 5 4-bromo-1-methoxycarbonylindole-3-acetonitrile 4-amino-1-methoxycarbonylindole-3-acetonitrile 50.4 mg (0.22 mmol) 4.7
% HBr solution was dissolved in 1.0 ml of tetrahydrofuran, a solution of 34.8 mg (0.50 mmol) NaNO ₂ dissolved in 1.0 ml of water was added, and the mixture was stirred at 5° C. or below under ice cooling for 20 minutes. Add 3.0 ml of ice-cold water, extract with 10.0 ml of ice-cold CH ₂ Cl ₂ , remove the aqueous layer, and add 674.3 mg of CuBr to 2.0 ml of concentrated hydrobromic acid.
After stirring at room temperature for 20 minutes, the mixture was boiled on a boiling water bath for 5 minutes. Extracted with CH ₂ Cl ₂ methanol (95:5, V/V), washed with saturated brine, dried with Glauber's salt, and distilled off the solvent to obtain the crude product.
Obtained 58.6 mg. CH ₂ −Cl ₂ using silica gel as a carrier
Thin layer chromatography was carried out using this as a developing solvent to obtain 52.9 mg (yield 82.1%) of 4-bromo-1-methoxycarbonylindole-3-acetonitrile. Recrystallization from CH ₂ Cl ₂ -methanol gave colorless crystals.

mp 159.5−161.0℃ Elemental analysis: C ₁₂ H ₉ BrN ₂ O ₂ C% H% N% Calculated value 49.17 3.10 9.56 Measured value 49.00 3.12 9.56 MS m/e: 294292 (M ⁺ ) IR (KBr): 2240, 1735 , 1604, 1558 NMR (10% CD ₃ OD in CDCl ₃ ) δ: 3.95 (3H, S) 4.05 (2H, d, J = 1.2Hz) 7.02 (1H, t, J = 8.0Hz) 7.26 (1H, dd , J = 8.0 and 1.0Hz) 7.58 (1H, t, J = 1.2Hz) 8.03 (1H, dd, J = 8.0 and 1.0Hz) Example 6 4-bromoindole-3-acetic acid 4-bromo-1-methoxy Carbonylindole-3-acetonitrile 28.2 mg methanol 5.0
ml, add 5.0 ml of 40% NaOH, and reflux for 2 hours. After cooling on ice and acidifying with 2N-HCl,
The extract was extracted with CH ₂ Cl ₂ -methanol (95:5, V/V), washed with saturated brine, dried over Glauber's salt, and the solvent was distilled off to obtain a crude product. Using silica gel,
Column chromatography was performed using CH ₂ Cl ₂ -methanol (95:5, V/V) as the effluent solvent.
22.9 mg (93.9% yield) of 4-bromoindole
3-acetic acid was obtained. What was obtained here is Example 2
All data were consistent with those obtained.

Example 7 4-Iodo-1-methoxycarbonylindole-3-acetonitrile 52.9 mg (0.23 mmol) of 4-amino-1-methoxycarbonylindole-3-acetonitrile was added to water (1.0 ml), 2H·HCl (1.0 ml), Dissolved in a mixture of tetrahydrofuran (1.0 ml) and cooled to below 5°C with ice cooling, 36.8 mg (0.51 mmol) of NaNo ₂ was added to water (1.0 ml).
ml) and leave for 15 minutes. ice water
Add 5.0 ml and extract with ice-cold CH ₂ Cl ₂ (10.0 ml). The aqueous layer was added to a solution of 1.087 g of KI dissolved in 2.0 ml of water, stirred at room temperature for 1 hour, and then boiled for 5 minutes on a boiling water bath. _{CH2Cl2 -} methanol (95:5, V/V)
The residue obtained by distilling off the solvent after washing with water and drying with Glauber's salt was extracted with CH ₂ Cl ₂ using silica gel as a carrier.
- Thin layer chromatography was carried out using hexane (3:1, V/V) as a developing solvent. 69.8 mg (yield:
88.9%) of 4-iodo-1-methoxycarbonylindole-3-acetonitrile was obtained.
Recrystallization from CH ₂ Cl ₂ -methanol gave colorless crystals.

mp 171.0−172.0℃ Elemental analysis: C ₁₂ H ₉ IN ₂ O ₂ ) C% H% N% Calculated value 42.37 2.67 8.24 Actual value 42.51 2.52 8.54 MS m/e: 341 (M ⁺ ) NMR (CDCl ₃ ) δ: 3.97 (3H, S) 4.08 (2H, d, J = 1.2Hz) 6.86 (1H, t, J = 8.0) 7.55 (1H, dd, J = 8.0 and 1.0) 7.61 (1H, t, J = 1.2Hz) 8.08 (1H, dd, J = 8.0 and 1.0Hz) IR (KBr): 2240, 1740, 1603 Example 8 4-iodoindole-3-acetic acid 21.9 mg of 4-iodo-1-methoxycarbonylindole-3-acetonitrile The suspension was suspended in a mixture of methanol (3.0 ml) and 40% NaOH (3.0 ml), and then refluxed for 2 hours. After cooling on ice, acidify with 2N-HCl, extract with CH ₂ Cl ₂ -methanol (95:5, V/V), wash with saturated brine, dry with Glauber's salt, and evaporate the solvent to obtain a residue. (19.9 mg) was dissolved in CH ₂ Cl ₂ -methanol (95:5,
Perform thin layer chromatography using V/V) as a developing solvent to obtain 4-iodoindole-3-acetic acid.
12.9 mg (yield 66.5%) was obtained. All data obtained here completely matched those obtained in Example 4.

Reference Example 1 4-Bromindole 1.198g of 4-bromo-1-methoxycarbonylindole was dissolved in 30ml of methanol to give a concentration of 40%
Add 30.0 ml of NaOH aqueous solution and stir and reflux for 1 hour. Methanol was distilled off, water was added, and the mixture was extracted with CH ₂ Cl ₂ . After washing with water and drying with sodium sulfate, the solvent was distilled off to obtain 879.9 mg of an oily substance. Using silica gel,
Column chromatography was performed using CH ₂ Cl ₂ -hexane (1:1, V/V) as the effluent solvent.
817.9 mg (yield 88.5%) of 4-bromuindole was obtained. It is oily at room temperature, but crystallizes when cooled with ice.
mp15℃ (colorless crystals).

Reference example 2 4-bromo-3-dimethylaminomethylindole 50% (CH ₃ ) ₂ NH aqueous solution 479.0 mg (5.31 mmol)
Add 2.0 ml of acetic acid under ice-cooling and stirring to 37% HCHO.
Add 362.4 mg (4.47 mmol) of the aqueous solution dissolved in 2.0 ml of acetic acid. After stirring at room temperature for 15 minutes, a solution of 781.1 mg (3.98 mmol) of 4-bromoindole dissolved in 2.0 ml of acetic acid was added, and the mixture was stirred at room temperature for 13 hours. 20%
After making it alkaline by adding NaOH, it was extracted with CH ₂ Cl ₂ -methanol (95:5, V/V), washed with saturated brine, dried with sodium sulfate, and the solvent was distilled off to give 971.2
mg (yield 96.3%) of 4-bromo-3-dimethylaminomethylindole was obtained as a single product. Recrystallization from methanol gave colorless crystals.

mp 146.0−147.0℃ Elemental analysis: C ₁₁ H ₁₃ BrN ₂ ) C% H% N% Calculated value 52.18 5.17 11.06 Measured value 52.04 5.01 11.12 IR (KBr): 3108, 1615, 1543 NMR (CDCl ₃ ) δ: 2.30 ( 6H, S) 3.80 (2H, S) 6.65-7.23 (4H, m) 8.85 (1H, br, S, NH) MS m/e: 254252 (M ⁺ ) Reference example 3 3-dimethylaminomethyl-4-nitro Indole 50% (CH ₃ ) ₂ NH aqueous solution 1.162g (12.9mmol)
Add 2.0 ml of acetic acid to the solution under ice-cooling, then add 957.7 mg (11.8 mmol) of a 37% aqueous HCHO solution dissolved in 2.0 ml of acetic acid, and stir at room temperature for 15 minutes. A solution of 1.739 g (10.7 mmol) of 4-nitroindole dissolved in 30.0 ml of acetic acid is added to this solution, and the mixture is stirred at room temperature for 12 hours. 20%
After making it alkaline by adding NaOH aqueous solution,
The extract was extracted with CH ₂ Cl ₂ -methanol (95:5, V/V), washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off to obtain 2.381 g of crude crystals. Using alumina gel as a carrier, CH ₂ Cl ₂ methanol (98:2, V/
Column chromatography was performed using V) as an effluent solvent to obtain 1.941 g (yield: 82.5%) of 3-dimethylaminomethyl-4-nitroindole.
Recrystallization from methanol gave yellow crystals.

mp 119.0-120.0℃ Reference Example 4 4-Nitroindole-3-acetonitrile Dissolve 336.6 mg (1.53 mmol) of 3-dimethylaminomethyl-4-nitroindole in 10.0 ml of dimethylformamide and 10.0 ml of water, and dissolve 1.015 g of KCN.
(15.1 mmol) was added, and the mixture was stirred and refluxed for 2 hours. Add water, CH ₂ Cl ₂ -methanol (95:5, V/V)
After extraction, washing with water and drying of Glauber's salt, the solvent was distilled off.
385.5 mg of residue was obtained. Using silica gel as a carrier,
Column chromatography was performed using CH ₂ Cl ₂ as the eluent solvent to obtain 156.6 mg (yield 50.7%) of 4-nitroindole-3-acetonitrile.
Recrystallization from CH ₂ Cl ₂ -methanol gave yellow crystals.

mp 202.5-203.5℃ Reference Example 5 1-Methoxycarbonyl-4-nitroindole-3-acetonitrile 196.2 mg (4.08 mmol) of 50% NaH was washed with benzene, and 236.0 mg (1.17 mmol) of 4 was added to this with stirring.
A solution of -nitroindole-3-acetonitrile in 3.0 ml of anhydrous dimethylformamide is added under ice cooling. After stirring at room temperature for 15 minutes, 311.6 mg
(3.30 mmol) of ClCOOCH ₃ dissolved in 1.0 ml of benzene was added, and the mixture was stirred at room temperature for 10 hours. Add water;
After extraction with CH ₂ Cl ₂ -methanol (95:5, V/V), washing with water and drying with Glauber's salt, the solvent was distilled off to obtain crude crystals.
1.277g was obtained. Column chromatography was performed using silica gel and CH ₂ Cl ₂ as the effluent solvent to obtain 262.0 mg (yield 86.2%) of 1-methoxycarbonyl-4-nitroindole-3-acetonitrile. Recrystallization from CH ₂ Cl ₂ -methanol gave pale yellow crystals.

mp 179.0-180.0℃ Reference Example 6 4-Amino-1-methoxycarbonylindole-3-acetonitrile Add TiCl to a solution of 97.6 mg (0.37 mmol) of 1-methoxycarbonyl-4-nitroindole-3-acetonitrile dissolved in 10.0 ml of tetrahydrofuran. ₃
Aqueous solution (16%, d=1.5, 5.0ml, 20.6mol, equivalent)
Add to the mixture while stirring at room temperature and leave for 20 minutes. 40% on ice
After making alkaline using NaOH and 2N-NaOH, CH ₂ Cl ₂ -methanol (95:5,
After extraction with V/V), washing with water and drying with Glauber's salt, the solvent was distilled off to obtain 81.8 mg of a crude product. Using silica gel, CH ₂ Cl ₂ -methanol (99.:1, V/
By performing thin layer chromatography using V) as a developing solvent, 67.0 mg (yield 77.6%) of 4-amino-1-methoxycarbonylindole-3-acetonyl was obtained. Recrystallization from CH ₂ Cl ₂ -methanol gave pale yellow crystals.

mp 176.0−177.0℃ Elemental analysis: C ₁₂ H ₁₁ N ₃ O ₂ C% H% N% Calculated value 62.87 4.84 18.33 Measured value 62.89 4.68 18.56 NMR (10% CD ₃ OD in CDCl ₃ ) δ: 3.93 (2H,
d, J = 1.2Hz) 3.94 (3H, S) 6.45 (1H, dd, J = 8.0 and 1.0Hz) 6.99 (1H, t, J = 8.0Hz) 7.33 (1H, t, J = 1.2Hz) 7.53 ( 1H, dd, J = 8.0 and 1.0Hz) IR (KBr): 3440, 3365, 2240, 1732 MS m/e: 229 (M ⁺ )

Claims (1)

[Claims] 1. General formula [In the formula, X represents a bromine atom or an iodine atom]
4-substituted indole acetic acid, salts thereof, and esters thereof.