JPH0331257A - Production of indole derivative - Google Patents

Abstract

PURPOSE:To easily obtain the subject compound useful as an intermediate for pharmaceuticals, etc., in high efficiency with a one-pot reaction process by oxidizing a 2,3-dihydroindole derivative and, as necessary, alkylating the product. CONSTITUTION:The objective indole derivative of formula II (R<4> is H, lower alkyl or lower alkenyl) is produced by oxidizing a 2,3-dihydroindole derivative of formula I (R<1> is H; R<2> is H, lower alkyl, carboxyl, etc.; R<3> is H, halogen or nitro) and, as necessary, alkylating the oxidation product. The alkylation agent is methyl iodide, allyl bromide, etc., as well as diazomethane.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing indole derivatives.

More specifically, the present invention relates to pharmaceuticals, veterinary drugs,
Useful as agricultural chemicals or their manufacturing intermediates,
- Numerical formula (in the formula, R1 is a hydrogen atom, R2 is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, or a phenyl group, or R1 and R2 are bonded to each other and -(CH2) is the same or - C) I=CH-CH=
This invention relates to an efficient method for producing an indole derivative, which forms a CH- group, R3 is a hydrogen atom, a halogen atom, or a nitro group, and R4 is a hydrogen atom, a lower alkyl group, or a lower alkenyl group. It is.

BACKGROUND OF THE INVENTION Indole derivatives have various pharmacological effects, and many compounds useful as pharmaceuticals are known.

Furthermore, among N-hydroxyindole derivatives and N-alkoxyindole derivatives, various compounds have been found that exhibit pharmacological effects, including alkaloids having an N-methoxyindole skeleton, and their application to pharmaceuticals, etc. is being considered. There is.

For example, the natural product Neoxaline
has a central nervous system stimulating effect [Chemical and
Far 7 Schematic Bulletin (Chem.

Pharm.

Biol, Chem,) Volume 34, 1590 Hage,
1970] are known.

Until now, a method for producing N-methoxyindole derivatives using 2-nitroaniline as a starting material is known, in which N-methoxyindole is obtained in 6 steps with a total yield of 20-50% [Journal of Chemical Society Parkin transaction I (J,C
hem, Soc, Perkin I), 1978
year, 1117 pages].

However, this method requires a large number of steps (the operations are complicated,
Reproducibility was also poor.

Problems to be Solved by the Invention Although N-hydroxyindole derivatives and N-alkoxyindole derivatives are expected to be applied to pharmaceuticals due to their pharmacological effects, not much research has been conducted due to the difficulty of their synthesis. do not have.

An object of the present invention is to provide an efficient method for producing N-hydroxyindole derivatives and N-alkoxyindole derivatives represented by formula (1) above, which are useful as pharmaceuticals or intermediates for their production.

Means for Solving the Problems The present inventors conducted research to find an easy and efficient method for producing N-hydroxyindole derivatives and N-alkoxyindole derivatives, and found that 2-nitrotoluene was first used as a starting material. discovered and announced a method for producing N-methoxyindole in 3 steps with a total yield of 60% by using
cles), vol. 16, p. 1523, 1981;
Chemical and Fur 7 Schematic Bulletin (Chem, Pharm Bull), Volume 34,
677 pages, 1986].

However, this method was still unsatisfactory in terms of the number of steps and operations.

The present inventors continued intensive research to find a simpler method for synthesizing N-hydroxyindole derivatives and N-alkoxyindole derivatives, and as a result, they used a 2゜3-dihydroindole derivative as a starting material and synthesized it in an appropriate manner. The inventors have discovered that the desired product can be produced easily and in one batch by oxidizing with a suitable oxidizing agent and then alkylating with an alkylating agent if necessary, and have accomplished the present invention.

That is, the present invention provides for oxidizing a 2,3-dihydroindole derivative represented by the formula (1111.R2 and R3 have the same meanings as above) and then alkylating it as necessary. The present invention provides a method for producing an indole derivative represented by the formula (in which R', R2, R3, and R4 have the same meanings as described above).

Among the compounds of formula (1) obtained by the production method of the present invention, compounds in which R1, R2, and R3 are hydrogen atoms and R4 is a methyl group, and compounds in which R1, R3 are hydrogen atoms, R2 is a phenyl group, and R4 is hydrogen Compounds other than those that are atoms or methoxy groups are new.

Examples of the oxidizing agent used in the oxidation reaction of the production method of the present invention include metal peroxides and persulfuric acid. Metal peroxides are produced in a reaction system using metal oxide salts and peroxides, and examples of such salts include salts of tungstic acid, molybdic acid, and vanadate. Hydrogen peroxide can be cited as an oxide. Among these combinations of metal oxide and peroxide, the combination of sodium tungstate and hydrogen peroxide is the most preferred.

Further, the oxidizing agent is 0.0% with respect to the compound of formula (n) above.
It is used in combination of 0.05 to 1.0 moles of metal oxide and 1 to 10 times the mole of hydrogen peroxide, but 0.0 to 1.0 moles of metal oxide is used.
The most preferred ratio is 2 moles and 10 times the mole of hydrogen peroxide solution.

The formula (I) produced in the oxidation process of the production method of the present invention
) compounds in which R4 is a hydrogen atom are generally unstable and easily decomposed. In the case of a stable compound, such as a compound in which R2 is a phenyl group, it can be isolated and purified without alkylation.

In addition to diazomethane, examples of alkylating agents that can be used in such alkylation include alkylating agents such as alkyl halides and alkenyl halides used in ordinary alkylation reactions, such as methyl iosito and allyl bromide. I can do it.

In order to suitably carry out the manufacturing method of the present invention, the above-mentioned formula (
The compound of II) is dissolved in an inert organic solvent, such as methanol, and under water-cooled stirring, an oxidizing agent such as 0.2 times the mole of tungstic acid, an aqueous solution of IJum dihydrate, and a 10 times mole of tungstic acid are added thereto. Add a methanol solution of 30% hydrogen peroxide and stir at 10 to 20 t' for about 30 minutes. Then, if necessary, an alkylating agent such as an ether solution of diazomethane is added thereto for alkylation, followed by treatment and purification according to conventional methods to obtain the compound of general formula (1).

The compound represented by formula (1) obtained by the production method of the present invention is a compound useful as a pharmaceutical, an animal drug, an agricultural drug, or a production intermediate thereof.

Effects of the Invention The production method of the present invention can easily and efficiently produce the indole derivative represented by formula (I) above, which is useful as a pharmaceutical product or an intermediate for its production.

EXAMPLES The content of the present invention will be explained in more detail with reference to the following examples. Note that all melting points of compounds in each example are uncorrected.

Example 1 13.2 mg of sodium tungstate dihydrate (0, l m
ol eq,) dissolved in 0.5 mN of water and added thereto, and then 452.5 mg of 30% hydrogen peroxide solution (10 mol eq.
, ) was dissolved and added to the mixture in an amount of meta/ /L/ 1 mj2 L. After removing the water bath and stirring at room temperature (20° C.) for 30 minutes, an ether solution of diazomethane was added until no bubbling was observed. Water was added to the reaction mixture and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography using methylene chloride as a developing solvent to obtain 1-methoxyindole 2.
9.6 mg (50%) was obtained.

The physicochemical constants of the obtained 1-methoxyindole are based on the standard data (RoM, Acheson et al.
J.

Chem, Soc, Perkin I, 197
8.1117).

Example 2 42.2 mg of 1-methoxyindole 2,3-dihydroindole was dissolved in acetone-
Persulfuric acid (2KH3O, 1 (SO4, 2SO
4) 239.8 mg (1.1 mat eq.) was added and stirred at room temperature (19°C) for 10 minutes.

An ether solution of diazomethane was added to the reaction solution until no foaming was observed. Water was added to the reaction mixture and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sulfuric acid, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography on silica gel using methylene chloride as a developing solvent to obtain 6.0 mg (11%) of 1-methoxyindole.

The physicochemical constants of the obtained 1-methoxyindole were consistent with those of the standard product.

Example 3 1-methoxy-5-nitroindole 2.3-dihydro-5-nitroindole 44.8 mg
was dissolved in 3 mA of methanol at room temperature (17°C).
Sodium tungstate dihydrate 9. Qmg(0,
Dissolve 1 mol eq.
l eq,) was dissolved in methanol 1- and added. After stirring at room temperature (17°C) for 7 hours, an ether solution of diazomethane was added until no bubbling was observed. Thereafter, the same post-treatment as in Example 1 was carried out, and the obtained residue was separated and purified by preparative thin layer chromatography on silica gel using a mixed solvent of methylene chloride-〇-hexane (7:3.v/v) as a developing solvent. and 1-methoxy-6-nitroindole 31
．． 3 g (60%) was obtained.

Yellow needle crystals (methanol) Melting point = 90-91℃ IR (Br): 1613.1584.150B,
1358.1339°756,72Q c+++-'' H-NMR (CDC13) δ: 4.17 (311, s), 6.45 (18, d
d, J=3.4 andl, 0Hz), 7.52(
1)1. d, J=3.4)lz), 7.60(1
)1. d, J=8.8Hz), 7.98(IH,
dd, J=8.8and 2.2Hz), 8.38
(LH,brd,J=2.2Hz)MS m/z:
192 (M”) Elemental analysis value: (as CsHaN203) 0%
N% N% Calculated value 56.25 4.20 14.58 Actual value 56.21 4.17 14.73 Example 4 1-methoxy-5-nitroindole 2.3-dihydro-5-nitroindole 40. 8mg
, sodium tungstate dihydrate 16.4 mg
(0,2111016Q,), 30% hydrogen peroxide solution 2
A reaction was carried out in the same manner as in Example 1 using 82.0 mg (10 moleq, ), 0.5 m of water and 5 ml of methanol, followed by post-treatment. The obtained residue was separated and purified by preparative thin layer chromatography on silica gel using methylene chloride as a developing solvent to obtain 23.2 mg (49%) of 1-methoxy-5-nitroindole.

Pale yellow plate crystals (methanol) Melting point: 89.5-90.5°C IR (KBr)
: 1615. 15g0. 1512. 1324
．． 1066.737 cm-1'H-NMR (C port C1,) δ: 4.14 (3H, s), 6.54 (IH,
dd, J=3.6 ando, 8Hz), 7.
38 (IH, d, J=3.6)1z), 7.4
4 (IH, d, J=9.0Hz), -8,12 (L
H, dd, J=9.0and 2.1Hz),
8.54 (IH, d, J=2.1Hz) MS m/
z: 192 (Ma elemental analysis value' (as CsHaN203) 0%
8% N% Calculated value 56.25 4.20 14.58 Actual value 56.25 4.17 14.50 Example 5 7-iodo-1-methoxyindole 2.3-dihydro-7-iodoindole 218.7m
Sodium tungstate dihydrate 14.7@g (
0.05 mol eq.) was added, and 303.6 rBg (3 mol eq.) of 30% hydrogen peroxide solution dissolved in 4 d of methanol was further added. Take a water bath and store at 24℃ for 5 minutes.
After stirring for an hour, an ethereal solution of diazomethane was added until no bubbling was observed. Thereafter, the same post-treatment as in Example 1 was carried out, and the obtained residue was subjected to silica gel column chromatography and silica gel fractionation using a methylene chloride-n-hexane (1:5, v/v) mixed solvent as the eluent and developing solvent. Separation and purification by thin layer chromatography yielded 62.6 m of 7-iodo-1-methoxyindole.
g (26%) was obtained.

Colorless plate crystals (n-hexane) Melting point: 35-35.5°C IR (KBr): 1544.1333.1276, 1
033.948°775 cm-''tl-NMR (C[1C13) δ: 4.0B (3H, s), 6.31 (IH, d,
J=3.4)1z).

6.82 (1M, t, J=7.6)1z), 7.
29 (IH, d, J=3.4Hz), 7.54 (I
L da, J = 7.6 and 1) Iz).

7.68(E, dd, J=7.6 and 1)l
z) uS m/z; 273 (M”) Elemental analysis value: (as CsHstNo) 0%
8% N% Calculated value 39.59 2.95 5.12 Actual value 39.53 2.99 5.13 Example 6 ■-Methoxyindole-2-carboxylic acid methyl ester 2.3-dihydroindole-2-carvone Acid 51.5
mg.

Sodium tungstate dihydrate 20.8ng (0
, 2 mol eq, ), 30% hydrogen peroxide solution 358.2
mg (10 mol eq.), water 0.5 and methanol 5 ml, the same reaction as in Example 1 was carried out at room temperature (
16° C.) for 15 minutes. The reaction with diazomethane and post-treatment were carried out in the same manner as in Example 1, and the resulting residue was separated and purified by preparative thin layer chromatography on silica gel using methylene chloride as a developing solvent to obtain 1-methoxyindole-
11.4 mg (18%) of 2-carboxylic acid ester was obtained.

Colorless plate crystals (methanol) Melting point 7 40.5-41.5℃ IR (KBr): 1723.1239.1209.1
085.738 cm-''H-NMR (CDCl2) δ: 3.93 (3H, s), 4.19 (3H,
s), 7.08 (IH.

d, J=1.2)1z), 7.02~7.5
4 (311, m).

7.61 (IH, dt, J=7.9 and 1.
0Hz) MS m/z: 205 (Ma elemental analysis value) (C++HzN (as h)) 0%
8% N% Calculated value 64,38 5,40 6.83 Actual value 64.19 5.45 -7.00 Example 7 9-methoxy-1,2,3,4-tetrahydrocarbathy 1,2.3 .4.4a, 9a-hexahydrocarbazole 50.6 mg, sodium tungstate dihydrate 19.3 mg (0.2 mol eQ,), 30% hydrogen peroxide solution 331.6 mg (10 mol eq;), water 0 The same reaction as in Example 1 was carried out using 5ml of methanol and 5ml of methanol, and the same post-treatment was carried out. The resulting residue was diluted with methylene chloride-〇-hexane <773. 9-methoxy-1,2,3,4 was purified by preparative thin layer chromatography on silica gel using a mixed solvent of
-tetrahydrocarbazole 32.2 mg (55%)
I got it.

Colorless oil IR (film): 2942.2842.1459.
1443.1230°1046,735 cm-'H-NMR (CDCI3) δ: 1.68-2.08 (4H, m), 2.52-
2.92 (41°brm), 3.99 (3H,s),
6.88-7.48 (411゜m) MS m/z: 201 (M") Old gh MS: m/z (as C+sll+sN mouth) Calculated value 201.1152 Actual value 201.1 [34 Example 8 9 -Methoxycarbazole 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (00 units) 469 to a solution of 188.9 mg of 9-methoxy-1,2,3,4-tetrahydrocarbazole dissolved in 30 mj2 of benzene .4 mg (2,2mo
l eq, ) was added thereto, and the mixture was stirred at room temperature (14°C) for 3 hours. The undissolved precipitate was removed through a thin layer of silica. The thin layer of silica was washed with methylene chloride, the filtrate and washings were combined, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography using n-hexane-ethyl acetate (9:1. v/v) mixed solvent as an eluent to obtain 121.1 mg of 9-methoxycarbazole.
(65%).

Colorless needle crystals (methanol) Melting point: 40-41t IR (KBr): 1601.1450.1320.1
233.1052゜946 c+c''H-NMR (CDCI δ: 4.12 (3H, s), 7.19 (01, dd
, J=7.3 and2.7Hz), 7.25(L
H, dd, J=7.3 and2.7Hz), 7.
34-7.58 (411, m), 8.02 (2H.

dt, J=7.3 and 1.0Hz) MS m/
z: 197 (M”) Elemental analysis value (as C+J++NO) 6%
8% N% Calculated value 79.1? 5.62 7.10
Actual value 79.36 5.55 7.21 Example 9 Tungsten was added to a solution of 51.5 mg of 1-hydroxy-2-phenylindole 2.3-dihydro-2-phenylindole dissolved in 4.0-methanol under water cooling and stirring. Sodium acid trihydrate 17.4 mg (0.2 mol
Dissolve eq,) in 0.5 fart of water, add and add 30%
299.4 mg (10 mol eq) of hydrogen peroxide solution was dissolved in methanol ld and added. After taking a water bath and stirring at room temperature (20°C) for 30 minutes, water was added to the reaction mixture.
Extracted with methylene chloride. Wash the extract with saturated saline,
After drying over anhydrous sulfuric acid (IJ), the solvent was distilled off under reduced pressure. The obtained residue was diluted with methylene chloride-methanol (98%
:2. The residue was purified by preparative thin layer chromatography on silica gel using a mixed solvent (v/v) as a developing solvent to obtain 30.9@g (56%) of 1-hydroxy-2-phenylindole.

Pale yellow needle crystals (chloroform) Melting point: 174-175℃ (dec
) (lit", mp 175℃) IR (KBr): 2400.1625.1370.7
56.740°683 cnr' III-NMR (10% CD30D In CDCI3
) δ: 6.52 (0,2H,s, 3rd position proton,
0.88), 6.88-7.62
(711, m).

7, 68-7.92 (2H, m) MS m/z: 209 (M+) Book B, Fischer, Chem,
Ber,, 29. 2062 (189
6).

J,) 11M, H eyes 1. D, P, G11vert,
and^, Fe1dsoff, J, Org, Che
m9.40.3735 (1975) Example 10 30.9 mg of 1-methoxy-2-phenylindole-nihydroxy-2-phenylindole was dissolved in methanol 3
．． An ether solution of diazomethane was added to the solution dissolved in Oml until no bubbling was observed, and a slight excess was added, followed by stirring at room temperature (14° C.) for 12 hours. The crude crystals obtained by distilling off the solvent under reduced pressure were mixed with n-hexane-ethyl acetate (4:l).

Silica gel preparative thin layer chromatography using Vc) as a developing solvent was performed to obtain 28.3 mg (86%) of 1-methoxy-2-phenylindole.

Pale yellow plate crystals (methanol) Melting point = 47~48℃ (1it0.mp 49~51t') IR (niO
r): 1597.956.760.741 cm-'
') l-NMR (CDCI, ) δ: 3.73 (31 (, s), 6.56 (ill,
s), 7.00-7.66 (7N, m), 7.
73-7.91 (2tl, m) Elemental analysis value' (C
+sH+JO) 0% 8% N% Calculated value 80.69 5.87 6
．． 27 Actual value 80.77 5,91 6.
04 pieces N, Sugiyama, M,
Akutagawa, T., Ga5ha
, Y.

Saiga, and H. Yamamoto, Bu.
ll, Chem, Sac.

Japan, 40.347 (1967) Example 1
1 1-methoxy-2-phenylindole 2.3-dihydro-2-phenylindole 52.3 mg.

Sodium tungstate dihydrate 17.7 mg (0
, 2 mol eq, ), 3Q% hydrogen peroxide solution 304.1
The same reaction as in Example 1 was carried out using 0.5 d of water and 5 ml of methanol, and the same post-treatment was carried out. The obtained residue was separated and purified by silica gel preparative thin layer chromatography using n-hexane-ethyl acetate (5:1. v/v) mixed solvent as a developing solvent to obtain 1-methoxy-2-phenylindole. 4
0.0 mg (67%) was obtained.

All data of the 1-methoxy-2-phenylindole obtained here coincided with the compound obtained in Example 10.

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a hydrogen atom, R^2 is a hydrogen atom, a lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, or a phenyl group. , or R^1 and R^2
are combined with each other to form -(CH_2)_4- or -CH=
After oxidizing the 2,3-dihydroindole derivative represented by CH-CH=CH-, where R^3 is a hydrogen atom, a halogen atom, or a nitro group,
There are general formulas▲mathematical formulas, chemical formulas, tables, etc.▼ that are characterized by alkylation if necessary▼ (R^1, R^2 and R^3 in the formula have the same meaning as above, R^ 4 is a hydrogen atom, a lower alkyl group, or a lower alkenyl group). (2) A 2,3-dihydroindole derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1, R^2 and R^3 in the formula have the same meanings as above) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by alkylation after oxidation ▼ (R^1, R^2 and R^3 in the formula have the same meanings as above, and R^ 5 is a lower alkyl group or a lower alkenyl group). (3) Claim 1, characterized in that the oxidation is carried out using sodium tungstate dihydrate and hydrogen peroxide solution.
The manufacturing method according to item 1 or 2. (4) The production method according to claim 2, wherein the alkylation is carried out using diazomethane.