JPH0114221B2 - - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula

[Formula] [In the formula, R represents a benzyloxy group, a methoxycarbonyl group, or an amino group, and R ¹ is an acetyl group,
Represents a lower alkyl group. ] Regarding the 4-substituted-1-hydroxyindole and its derivatives, the compound of the present invention represented by the formula () is:
It is very important as an intermediate for producing 4-substituted indole derivatives. 4-Substituted indoles are useful as agricultural chemicals, medicines, and raw materials for the synthesis of alkaloids. For example, when R is a methoxycarbonyl group and R ¹ is a methyl group [A], [A] is reduced to 4-hydroxymethyl-1-methoxyindole, which is oxidized to 4-formyl- 1-
Methoxyindole [B] and [C] from [B]
4-(N
-alkylamino)methylindole is obtained. Further, [B] is reacted with acetone to obtain [D], and this [D] is cyclized to obtain ergot alkaloid [E]. Furthermore, when R is an amino group and R ¹ is a methyl group [F], [F] is converted to [G] by Sandmeyer reaction,
After reacting [G] with Mannitz reagent, the methoxy group is removed to obtain [H], which is then cyanated and hydrolyzed to form [I], 4-chloroindole vinegar. Acid is obtained. This substance is known as a natural auxin that has a plant growth promoting effect. The compound () of the present invention can be obtained according to the following formula, taking the case where R is a carbomethoxy group as an example. That is, 2-methyl-3-nitro-benzoic acid methyl ester was reacted with dimethylformamide methyl acetal (DMF-DMA) in the presence of DMF, reduced with titanium trichloride, and then acetylated with acetic anhydride. The invention compound () can be obtained. 2-methoxycarbonyl-6-nitro-trans-β- which is an intermediate for obtaining the compound () of the present invention
The present inventors have already discovered a method for obtaining 4-methoxycarbonylindole in high yield by reducing dimethylaminostyrene () with a large excess of titanium trichloride. As a result of further research, the present inventors discovered the novel fact that the compound of the present invention can be obtained by controlling the amount of titanium trichloride, which is a ring agent, and completed the present invention. If ammonium chloride and zinc dust are used as reducing agents instead of titanium trichloride, the yield of the compound of the present invention can be further increased significantly. When R is a benzyloxy group, it can be easily obtained by similarly reducing 2-nitro-6-benzyloxy-phenylacetaldehyde with a reducing agent such as titanium trichloride or zinc and ammonium chloride. Compounds of the present invention, 1-hydroxy-4-substituted indoles in which R ¹ is hydrogen, can be treated with acetic anhydride and pyridine to yield 1-acetyl-4-substituted indoles. Furthermore, 1-hydroxy-
4-Substituted indoles are reacted with alkyl halides such as methyl iodide to form 1-methoxy-4-
Substituted indoles can be obtained in high yields. When R is an amino group, when 1-hydroxy-4-nitroindole obtained by reducing 2,6 dinitro-trans-β-dimethylaminostyrene with titanium trichloride is reacted with an alkyl halide, such as methyl iodide, Roughly quantitatively 1-methoxy
4-Nitroindole can be obtained. 1-
Methoxy-4-nitroindole can be led to 1methoxy-4-amino-indole by reduction. The method for producing the compound of the present invention will be explained with reference to Examples. Example 1 After adding 20 ml of DMF to 2 g of 1-acetoxy-4-methoxycarbonyl isodole 2-methyl-nitro-benzoic acid methyl ester and 3.3 g of DMF-DMA.
Reflux for 15.5 hours. After the reaction, the solvent is distilled off under reduced pressure, and 2-methoxycarbonyl-6-nitro-trans-β-dimethylaminostyrene (2) is obtained almost quantitatively. Obtained dimethylaminostyrene body ()
Dissolve 0.5 g in a mixed solvent of 10 ml of methanol and 2 ml of water. 0.5 g of zinc powder and 0.5 g of ammonium chloride are added to this solution, and a reduction reaction is carried out for 2.5 hours with stirring at room temperature (25° C.). After the reaction, the zinc powder was filtered off, the solvent was distilled off under reduced pressure, and methanol-methylene chloride (5:95V/
The extract obtained in step V) is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off. Dissolve the remaining oily substance in 2 ml of acetic anhydride and 4 ml of pyridine.
ml for 15.5 hours at room temperature, the solvent was distilled off, the mixture was extracted with methylene chloride, the extract was washed with an aqueous sodium bicarbonate solution, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The product was separated by chromatography to obtain 1-acetoxy-4-methoxycarbonylindole in a yield of 40% (based on methyl 2-methyl-3-nitrobenzoate). The physical properties of this compound are as follows. Melting point: 76-77°C IR ^KBr _nax cm _-1 : 1802, 1701,
1439, 1258, 1172 NMR (CCl ₄ ) δ: 2.15 (3H, s) 3.83 (3H, s)
6.84-7.30 (4H, m) 7.73 (1H, d, d,
J = 6.2Hz) MSm/e: 233 (M ⁺ ) 202, 192, 175 Elemental analysis: Molecular formula: C ₁₂ H ₁₁ NO ₄ Calculated value (%) C61.80, H4.75, N6.01 Analysis value (% ) C61.64, H4.61, N5.96 Example 2 1-methoxy-4-aminoindole 108 mg of 2,6-dinitro-trans-β-dimethylaminostyrene and 4.5 ml of methylene chloride-water (2:1V/ Add 1.17 ml of titanium trichloride (4
molar equivalent) is added dropwise. After reacting at room temperature for 7 minutes, water was added and extracted with a methanol-methylene chloride mixed solvent. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent is distilled off. The residue was separated by chromatography to obtain 46.1 mg of 1-hydroxy-4-nitroindole in a yield of 57%. Obtained 1-hydroxy-4 nitroindole 20
180 mg of methyl iodide is added to a solution of 1 ml of methanol, 0.5 ml of 2N-NaOH, and the reaction is allowed to proceed at room temperature for 16 hours. Water and methylene chloride were added for extraction, and the methylene chloride layer was treated in a conventional manner to obtain 21 mg of 1-methoxy-4-nitroindole (yield 97.4%). Obtained 1-methoxy-4-nitroindole 13 mg
ammonium acetate in methanol solution (1 ml) of
135 mg, water 0.1 ml, and titanium trichloride 0.28 ml (6.5 mol equivalent) were added dropwise and allowed to react at room temperature for 5 minutes. 2N―
After making alkaline with NaOH, extracting with methylene chloride and treating according to the usual method, 1-methoxy-4
-10.1 mg (yield 91.3%) of aminoindole was obtained. The physical properties of this compound are as follows. IR ^film _nax cm _-1 : 3340, 1615, 1579 NMR (CCl ₄ ) δ: 3.55 (2H, br, s, NH ₂ ) 3.94 (3H, s), 6.00 (1H, d, J=4Hz) 6.09 (1H , d, d, J = 7.5, 2Hz) 6.65 (1H, t, J = 7.5Hz) 6.75 (1H, d, d, J = 7.5, 2Hz) 6.90 (1H, d, J = 4Hz) MSm/e: 162,076 (M ⁺ ) Example 3 1-Acetoxy-4-benzyloxindole 0.75 ml of titanium trichloride aqueous solution (4 molar equivalents) was added to a solution of 76.5 mg of 2-benzyloxy-6-nitrophenylacetaldehyde and 7 ml of methanol. Drip. After stirring for 5 minutes, add 10 ml of water, extract with methylene chloride, dry the methylene chloride layer over anhydrous sodium sulfate, and then concentrate. Add 1.5 ml of acetic anhydride and 3 ml of pyridine to the obtained oil.
ml and stir for 8 hours. The solvent was distilled off under reduced pressure and chromatographic separation was performed to obtain 1-acetoxy-4-
19 mg of benzyloxy was obtained (yield 24%). The physical properties of this compound are as follows. Melting point: 68.5-69℃ IR ^KBr _nax cm _-1 : 1819, 1808 NMR (CDl ₃ ) δ: 2.30 (3H, s), 5.12 (2H,
s), 6.40~7.46 (10H, m) MSm/e: 281, 104 (M ⁺ )

Claims (1)

[Claims] 1 General formula [Formula] [In the formula, R represents a benzyloxy group, a methoxycarbonyl group, or an amino group, and R ¹ represents an acetyl group or a lower alkyl group. ] 4-Substituted-1-hydroxyindoles and derivatives thereof represented by these.