JPS6379873A - Production of 6-hydroxyindoles - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a synthetic intermediate for indole alkaloid (a medicine), in high yield and selectivity, by subjecting an 1-acylindole to acylation, oxidation, rearrangement and solvolysis. CONSTITUTION:A 1-acylindole is acylated by general Friedel-Crafts reaction comprising the reaction with a carboxylic acid in the presence of a protonic acid to obtain a 1,6-diacylindole. The product is oxidized and rearranged by general Baeyer-Villiger reaction comprising the reaction with a peracid in the presence of a strong acid or with hydrogen peroxide in the presence of an acid or base. The obtained 6-acyloxy-1-acylindole is hydrolyzed by conventional method to obtain the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 6-hydroxyindoles useful as intermediates for the synthesis of indole alkaloids. The present invention relates to a method for producing 6-hydroxyindoles by introducing a hydroxyl group into 6-hydroxyindoles.

Compounds having an indole skeleton, such as natural alkaloids, are often useful as medicines due to their unique physiological activities, and are the subject of many researchers. however,
It has been considered extremely difficult to chemically modify the benzene ring portion of the indole ring during the course of synthesis or at the final stage, particularly to introduce a hydroxyl group, an alkoxy group, etc. That is, in most conventional methods, a benzene derivative is chemically modified and then closed to an indole ring, or the indole ring is once induced into an indoline skeleton, the benzene ring portion is chemically modified, and the benzene ring is returned to an indole ring. In addition, even if the benzene ring portion of the indole ring is directly chemically modified,
For example, Tetrahedron Letters 1980 3187
Page, 1981, p. 1403 and Tetrahedron No. 4
As described in Vol. 1, p. 2125 (1985), the process was complicated, the yield was low, and the industrial value was low.

While Akira tries to solve it.

An object of the present inventors is to provide a method for selectively introducing a hydroxyl group into the 6-position of indoles. That is, the object of the present invention is to provide a method for introducing a hydroxyl group into the benzene ring portion (6-position) of indoles useful as pharmaceuticals during the synthesis or at the final stage.

Question 11. Steps for Determination The present inventors have investigated various methods for selectively obtaining 6-hydroxyindoles in good yields. As a result, they discovered that when the 1-position of indoles is acylated, an acyl group is unexpectedly selectively introduced into the 6-position of the indoles through a Friedel-Crafts acylation reaction, and this can be easily converted into a hydroxyl group. The invention has been completed.

That is, the present invention converts 1-acylindoles into 1,6-diacyl indoles by a Friedel-Crafts reaction, and then converts them into 6-diacyl indoles by a Bayer-Villiger reaction.
This is a method for producing 6-hydroxyindoles, which is characterized in that the acyloxy-1-acylindoles are prepared and the 6-hydroxyindoles are further solvolyzed.

In the present invention, 1-acylindoles refer to compounds having an indole nucleus acylated at the 1-position. Since the method of the present invention is a method for selectively introducing a hydroxyl group into the 6-position of the indole nucleus, it is clear that any substituent that does not participate in the reaction may be present at other positions.

The acyl group at position 1 may be a linear, branched or cyclic aliphatic acyl group or an aromatic acyl group,
For example, formyl group, acetyl group, propionyl group,
Examples thereof include butyryl group, valeryl group, pivaloyl group, acroyl group, methylacryloyl group, crotonoyl group, benzoyl group, toluoyl group, and nititchnoyl group.

The manufacturing method of the present invention will be explained in detail below.

First, 1-acylindoles are acylated by Friedel-Crafts reaction. This acylation is selectively performed at position 6 of the indole nucleus. The conditions for the Friedel-Crafts reaction may be conventional conditions, ie, 1-acylindoles are reacted with a carboxylic acid in the presence of a protic acid, or with an acid halide or acid anhydride in the presence of a Lewis acid. Examples of protonic acids include hydrofluoric acid, sulfuric acid, and polyphosphoric acid. As the Lewis acid, for example, aluminum chloride is usually used, and zinc chloride, ferric chloride, tin chloride, antimony pentachloride, boron trifluoride, aluminum bromide, etc. are also used depending on the case.

In addition, carboxylic acids include linear, branched, or cyclic aliphatic carboxylic acids and aromatic carboxylic acids, and these include acid halides and acid anhydrides, which may have substituents. are acid halides and acid anhydrides corresponding to the carboxylic acid. Examples of these carboxylic acids, acid halides and acid anhydrides include acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, acetic acid chloride, acetic bromide, 1-chloroacetic acid chloride, propionic acid chloride, inpropionic acid chloride, propionic acid promide,
1-chloropropionic acid bromide, acetic acid chloride, valeric acid chloride, isovaleric acid chloride, pivalic acid chloride,
These include cyclohexanecarboxylic acid chloride, acetic anhydride, propionic anhydride, acetic anhydride, benzoic anhydride, acetic propionic anhydride, and the like. The acyl group introduced by this acylation reaction is a group that is converted into an acyloxy group by the Bayer-Villiger reaction described below and eliminated by solvolysis. Therefore, the above-mentioned carboxylic acid, acid halide and acid anhydride may be any of them in order to achieve the object of the present invention. In addition, reaction solvents commonly used in this reaction include carbon disulfide, methylene chloride, nitromethane, 1.
2-dichloroethane, benzene, nitrobenzene, carbon tetrachloride, etc., but these are converted as appropriate depending on the type of Lewis acid and reaction conditions.The reaction temperature varies depending on the starting material, Lewis acid, reagent used, etc., but - 20°C
is the boiling point of the solvent.

The 1-acylindoles used as starting materials can be easily obtained by acylating the 1-position of indoles by a conventional method.

The 1,6-diacyl indoles thus obtained are oxidized and rearranged by the Bayer-Villiger reaction, resulting in 6-
It can be acyloxy-1-acylindoles. The Bayer-Villiger reaction may be carried out in a general manner similar to the Friedel-Crafts reaction, i.e., the formation of 6-diacylindoles of 1,6-diacylindoles with peracid in the presence of a strong acid or with hydrogen peroxide in the presence of an acid or base. -Acyl group is easily oxidized and converted to 6-acyloxy group. The strong acid used in this reaction is sulfuric acid, trifluoroacetic acid, etc., and the preferred peracid is m-chloroperbenzoic acid, but other acids include triple oloperacetic acid, peracetic acid, monopermaleic acid, perbenzoic acid, and Caroic acid. etc. can also be used. When using a peracid, the addition of disodium hydrogen phosphate as a buffer facilitates isolation of the 6-acyloxy form.

In addition, acids or bases used with hydrogen peroxide include hydrochloric acid, perchloric acid, sodium hydroxide, etc.As for the reaction solvent, any solvent that does not participate in the reaction can be used, but usually methylene chloride, chloroform, etc. , acetic acid,
Trifluoroacetic acid, -.n-hexane, water, methanol, etc. are used.

The reaction temperature is from 0°C to the boiling point of the solvent.

The 6-acyloxy-1-acylindoles obtained by the Bayer-Villiger reaction can be easily converted into 6-hydroxyindoles by mW hydrolysis. Solvolysis in the present invention refers to ordinary hydrolysis. Decomposition may be carried out, for example by sodium carbonate or aqueous sodium hydroxide in methanol, but in some cases decomposition products are produced, so alcoholysis with, for example, sodium methoxide in methanol, yields the 6-hydroxyindoles.

Previously, it was difficult to directly introduce a substituent into the benzene ring of indoles, and even if such a method existed, it was of low industrial value. It has become possible to selectively introduce a hydroxyl group into the benzene ring moiety (6th position) with good yield.The present invention is a method that can introduce an oxygen functional group during the synthesis of indoles or at the final stage of synthesis. Therefore, it is useful in the production of alkaloids and medicines having an indole skeleton.

Example EXAMPLES Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 (1) 1-acetyltryptamine acetamide (m,
p, 164.0-164.9℃) 200mg (0,8
2 mmol) was added with 30 mQ of 1,2-dichloroethane, 500 mg (3.8 mmol) of aluminum chloride, and 0.1Tr111 (1.5 mmol) of chloroacetyl chloride, and the mixture was stirred at 60°C for 35 minutes. The mixture was poured into an aqueous sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was crystallized from ether-methanol to obtain 196 mg of 1-acetyl-6-chloroacetyltryptamine acetamide.

m, p, 175.8-176.9℃NMR(C
DCf3) δ (ppm); 1.98 (31, s) 2, 65 (3H, s) 2, 96 (2H, t, J=7.5Hz>3.63 (2H
, dt, J=7.5Hz, 7.5Hz) 4, 80 (2H
, s) 5, 64 (IH, bs) 7.50 (IH, s) 7.63 (LH, d, J = 8.5Hz) 7, 95 (IH
, bd, J=8.5Hz) 9, 02 (IH, bs) UV ACH"Hnm (E); ax 222 (21800), 235 (22700),
294 (13500).

KBr-1゜IRν maxcOI' 1646.1708.3330 (2) 20 m (<(0.06 mmol)) of 1-acetyl-6-chloroacetyltryptamine acetamide obtained in (1) above was dissolved in 0.6 td of chloroform, After adding 200 mg of disodium hydrogen phosphate and 20 mg (1.5 mmol) of m-chlorobenzoic acid and stirring at room temperature for 100 minutes, the mixture was poured into an aqueous solution of sodium thiosulfate and sodium bicarbonate, and extracted with methylene chloride. The methylene layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain 9.0 mg of 1-acetyl-6-chloroacetoxytryptamine acetamide.

N M R (CDCj23) δ (ppo+); 1
, 96 (3H, s) 2, 粍 (3H, s) 2.91 (2H, t, J=7.5Hz) 3.58 (2H
, dt, J=7.5Hz, 7.5Hz) 4, 33 (2H
,s) 5,60(IH,bs) 7,05(IH,dd, ,C8,5Hz, 2Hz)
7, 28 (LH, s) 7, sl (LH, d, J=8.5Hz>8, 20
(LH, d, J = 2Hz> (3) 25 mg of 1-acetyl-6-chloroacetoxytryptamine acetamide obtained in (2) above (0,07
4 mmol) in methanol 1.25+nQ,
Normal sodium hydroxide aqueous solution 0.6ml (8 mmol)
was added, stirred at room temperature for 40 minutes, and further heated at 40"C for 5oC.
Stir for a minute. The mixture was neutralized with a 1N aqueous hydrochloric acid solution, an excess of an aqueous sodium bicarbonate solution was added, and the mixture was extracted with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel thin layer chromatography (R opening solvent = 5% methanol/methylene chloride) to obtain 12.1 mg of 1-acetyl-6-hydroxytryptamine. Obtained.

m, p, 196.8-198.5°C NMR (CD, OD) δ (ppm); 1, 90 (
3H, s) 2, 86 (2H, 't, J = 8Hz) 3, 43 (2H, t, J = 8Hz) 6, 57 (LH, dd, J = 8Hz, 2Hz>6,
73 (LH, d, 2Hz) 6.88 (IH, s) 7, 33 (LH, d, J=8Hz) UV; kC”OHnm (E); ax 205 (sh), 212 (28300), 27
4 (4300).

285 (4800> KBr -1.

IRV,, xam + 1632.3120.3350.3440 Example 2 (1) Chloracetyl chloride 60mQ (0,75
89 g of aluminum chloride (0,6 mol)
It was added dropwise to 600 mQ of 1,2-dichloroethane containing 75 mol) at 0°C, and after stirring for 20 minutes, the temperature was raised to room temperature.
Stir for a minute.

This was followed by 1-pivaloylindole (m, p, 67,
8-68.8'C) 30 g (0.15 mol) to 16
After the reaction was completed, the reaction solution was poured into an aqueous solution of Seniet's salt and sodium bicarbonate at 0° C., and extracted with methylene chloride. The methylene chloride layer was washed twice with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was crystallized from methanol to obtain 6-chloroacetyl-1-pivaloylindole. The mother liquor was further purified by silica gel column chromatography (developing solvent: 2% methanol/ether).

Yield: 30g.

m, p, 107.8~tos, z℃N M R (C
DCI! 3>8 (ppm); 1.52 (9H, s) 4.82 (2H, s) 6, 67 (IH, d, J = 3.9Hz) 7, 62 (IH
, d, J=8.5Hz) 7.91 (LH, dd, J:
1.5Hz, 8.5Hz>7, 92 (LH, d, J=
3.9Hz) 9.12 (IH, bs) UV ACH"Hnm (E); 018 to 221 (23300), 233 (23300),
291 (16500).

KII Jr-1゜ IRν　IIIJlxcIll.

(2) 23.4 mg (0,084 mmol) of 6-chloroacetyl-1-pivaloylindole obtained in (1) above
Oyohi crushed disodium hydrogen phosphate 0.2g (7)
80% m-
22 mg (1.2 equivalents) of chloroperbenzoic acid was gradually added at room temperature and stirred at room temperature for 50 minutes. After the reaction, the mixture was poured into an aqueous solution of sodium thiosulfate and sodium bicarbonate, and extracted three times with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel thin layer chromatography (developing solvent: ethyl acetate) to obtain 19 mg of 6-chloroacetoxy-1-pivaloylindole.

m, p, 65.9-66.8°C (recrystallized from n-hexane) NMR<CDCR5) l; (ppm);1.
51 (9H, s) 4.31 (2H, s) 6.61 (LH, d, J = 4.0Hz) 7, 05 (LH
, dd, J=2.2Hz, 8.4Hz>7, 54(
LH, d, J = 8.4Hz) 7.75 (LH, d, J =
4.0Hz>s, 32(IH,d, J=2.2Hz
>UV λC”0Hnn+(E); max 238 (21900), 260 (11800),
288 (5340).

KBr-1゜IRν max CrIA, T 1780.1685 (3) 27.0 mg (0.10 mmol) of 6-chloroacetoxy-1-pivaloylindole obtained in (2) above
was dissolved in 0.8 ml of methanol and heated to -2 under nitrogen stream.
3.0N sodium methoxide/methanol 36P11 (0.11 mmol) was added at 0°C, and after 3 minutes, the mixture was poured into a mixture of aqueous hydrochloric acid and methylene chloride, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel thin layer chromatography (developing solvent = 5% methanol/methylene chloride) to obtain 1-pivaloyl-6-hydroxyindole 1.
8.7 mg was obtained.

m, p, 134-2~134.6°C (ether-
recrystallized from n-hexane) NMR (CDCj23
) S (ppm); 1.51 (9H, s) 5, 90 (IH, bs) 6, 54 (IH, d, J = 3.8Hz) 6, 88 (IH
, dd, J=2.3Hz, 8.8Hz)7, 39(
LH, d, J = 8.5Hz>7.61 (LH, d, J
= 3.8Hz) 8, 14 (IH, d, J = 2.3Hz>
UV λCH"Hnm(E); max 202 (18600), 243 (22600),
249 (22400).

KBr-1°IRν max Cm・1675.3430 According to Example 1 or Example 2, the following compound was obtained.

6-hydroxy-3-methylindole m, p, 154
°C (decomposition) NMR (CDCR3) 8 (ppm)
;2, 28 (3H, bs) 6, 62 (IH, dd, J: 8.5Hz, 2Hz)
6, 76 (LH, d, J=2Hz) 6, 82 (IH, bs) 7, 38 (LH, d, J=8.511z) U V AC
HaOHnm (E); max 206 (sh), 222 (26300), 27
4 (4200).

I Rl/KBrcm-1; max 6-hydroxy-3-indoleacetic acid methyl ester NMR (CDCN3) S (ppm); 3
, 64 (3H, s) 3, 67 (2H, s) 6, 32 (IH, d, J=2Hz) 6.65 (IH, dd, J=8.5Hz, 2) 1z) 6
．． 79 (LH, d, J = 2 Hz) 7, 32 (11, d, J = 8.5 Hz > 7.73 (IH
, bs) UvACHsOHnfll(ε); max 204(sh), 218(27900), 27
0 (4400).

CHCρ3-1.

IRνwax　　　’ 1731, 3340, 3490, 3600.

N-acetyl-6-hydroxytributophane methyl ester NMR (CDCR3) l; (ppm); 1
, 96(3)1. s) 3, 27 (2H, m) 3, 70 (3H, s) 4, 70 (IH, bs) 4.94 (LH, m) 5, 98 (11, bs) 6.68 (LH, bd, J=8.5Hz)6.81(L
H, bs) 6, 85 (IH, bs) 7, 35<LH, d, J: 8.5ttz) 7, 90 (I
H, bs) 2-acetyl-7-hydroxy-1,2,3,4-tetrahydro-β-calporin m, p, 248.0-249.0°C N M R (C
DCI! 3) δ (ppm): 1.45 (3H, d
, J=7.0Hz) 1, 54 (IH, d, J=7.0H
z) 2, 17 (3H, bs) 2.18 (3H, bs) 2, 52-2.80 (2) 1. m) z, 96 (LH, m) 3.40 (11, m) 3.99 (LH, m) 4, 75 (IH, m) 5, 03 (3) 1. bq, ,C7,0Hz)5,5
6 (IH, bq, J = 7.0Hz) 6.57 (LH, d
d, J=8.5Hz, 2Hz) 6, 73 (IH, d,
J=2Hz>7.18<LH, d, J=8.5Hz) UV ACH
"Hnm (ε); ax 206 (sh), 223 (28300), 267 (45
00).

KBr-1゜ IRν　　　Cm　　　1 ax

Claims (1)

[Claims] (1) 1-acylindoles are converted to 1,6-diacylindoles by Friedel-Crafts reaction, then 6-acyloxy-1-acylindoles are converted to 6-acyloxy-1-acylindoles by Bayer-Villiger reaction, and this is further solvolyzed. A method for producing 6-hydroxyindoles, characterized by: