(Hive Addict)
12-21-03 14:09
No 478255
(Rated as: excellent)
Patent GB919864
Patent DE1123668
Abstract:
Indole derivatives substituted in the 5 and/or 7 position with halogen or nitro groups are prepared by reacting a salt of an indoline-2-sulphonic acid of formula wherein R is an acyl radical and Me is a metal ion e.g. sodium or potassium, with a halogenating or nitrating agent, and subsequently splitting off the acyl radical and the SO3-Me+ group. Chlorine in glacial acetic acid, chlorine water, or an alkali hypochlorite, bromine, and potassium iodide with iodine monochloride, concentrated sulphuric and nitric and acetyl nitrate in acetic anhydride are used as halogenating and nitrating agents respectively. The hydrogen sulphite and protecting acyl groups are split off by treatment with an alkali such as potassium or sodium hydroxide. Examples describe the preparation of the sodium salt of N-acetyl-indoline-2-sulphonic acid from the sodium salt of indoline-2-sulphonic acid and of 5-bromo, 5-iodo, and 5- and 7-nitro indoles therefrom.
Experimental:
sodium indoline-2-sulfonate
50 grams of indole are dissolved in 70 ccm of ether and shaken with a mixture of 150 ccm of commercial sodium hydrogen sulfite solution of 40%, 50 ccm of water and 300 ccm of alcohol of 96%, for 10 hours. The colorless crystals are separated by suction, washed with methanol and ether and dried.
sodium N-acetyl-indoline-2-sulfonate
15 grams of the sodium salt of indoline-2-sulfonic acid, 15 grams of sodium hydrogen sulfite and 150 ccm of acetic anhydride are subjected to fast stirring at 50°C. After about 1/2 hour the mixture starts to swell. After a total period of 3 hours the product is sucked off and can be used in crude condition in the subsequent reactions.
5-bromoindole
Sodium salt of N-acetyl-indoline-2-sulfonic acid freshly prepared from 10 grams of sodium salt of indoline-2-sulfonic acid, is dissolved under stirring in 50 ccm of water and separated from undissolved material by filtration. In the course of 1 hour 15 grams of bromine are introduced dropwise at 0°-5°C into the solution. Subsequently, the reaction mixture is stirred at 0°C for one hour, stirred at room temperature for a further hour, diluted with 200 ccm of water and the clear solution is rendered alkaline at 20-30°C with sodium hydroxide solution of 20%. After standing over night the crystals formed are sucked off and washed with water. After recrystallisation from alcohol of 30-40%, or after purification by steam distillation, colorless needles having a melting point of 90-91°C are obtained.
5-iodoindole
80 grams of the sodium salt of indoline-2-sulfonic acid are acetylated in the manner described in the above Example 1(b). The sodium salt of N-acetyl-indoline-2-sulfonic acid is dissolved under cooling in 300 ccm of water and filtered. Subsequently 40 grams of potassium iodide are added and during 10 minutes 40 ccm of iodine monochloride are dropwise added at 0-4°C. The mixture is then stirred for one hour under cooling with ice, and then stirred for an additional hour at room temperature, 1500 ccm of water are added, the precipitate formed is separated by filtration and the filtrate is rendered alkaline with concentrated sodium hydroxide solution at 20°C. After standing over night the precipitate formed is sucked off, washed with water and dried. Needles of a weak yellow color are obtained, which are purified by reprecipitation with water from ethanol solution and have then a melting point of 99-100°C.
5- and 7-nitroindole
The sodium salt of N-acetyl-indoline-2-sulfonic acid prepared from 15 grams of the sodium salt of indoline-2-sulfonic acid in the manner described above, is dissolved under cooling and with stirring in 200 ccm of water. To the filtered solution at 0-5°C a cold mixture of 50 ccm of nitric acid of 65% with 50 ccm of concentrated sulfuric acid are dropwise added within 30 minutes. The temperature should hereby remain below 0°C. Subsequently, the reaction mixture is stirred for one hour at 0°C and for an additional hour at room temperature, then diluted with 150 ccm of water and rendered alkaline with concentrated sodium hydroxide solution under cooling below 40°C. At a change point the previously light-brown solution suddenly becomes dark-brown and yellow crystals start to separate. After standing over night the crystals are sucked off and washed with a small quantity of cold water. The precipitate consists of a mixture of 5-nitroindole with 7-nitroindole. The still wet mixture is suspended in one liter of water and distilled with steam. The distillate thus obtained is repeatedly extracted with ether and the ether solution is evaporated after drying over sodium sulfate. The residue yields, after being subjected to chromatography in a column of aluminium oxide, by elution with a benzene-cyclohexane mixture (2:1) 7-nitroindole in the form of yellow needles havine a melting point of 94-97°C.
The still hot residue of the steam distillation is sucked off. from the filtrate upon cooling the 5-nitroindole crystallises in almost pure form. It is separated by filtration and dried. A further amount of 5-nitroindole can be recovered by boiling with water the residue found on the suction filter. By recrystallizing the 5-nitroindole from benzene-cyclohexane, yellow needles having a melting point of 140-141°C are obtained.
It's a pity that nowhere in the patent yields are stated, but it should be reasonable to assume that these will be acceptable.
A very similar procedure can be found here:
Synthesis of 5-Bromo Indole (../rhodium /5-br-i
The Other War (http://www.markfiore.com/animation/drug
