02-08-03 08:45
No 405636
Patent GB846675
Production of 2-nitro-4-fluoro-toluene, II.
(A) Formation of 3-nitro-4-methyl-benzene diazonium fluoborate
90 cc. of water and 270 cc. of concentrated hydrochloric acid are added to 137 g. of 2 nitro- 4 - amino - toluene, followed by stirring until the orange colouration disappears and then cooling to 00. The resulting hydrochloride is diazotised by the addition of 67.5 g. of sodium nitrite in 180 cc. of water. Stirring is effected until a homogeneous solution is obtained, raking care to maintain the mixture at a low temperature. 210 cc. of 40% fluoboric acid are then added and allowed to stand at 0 for 30 minutes with stirring. After filtration with suction, washing with water and with methanol, drying is effected to obtain 182 g.
(equal to 77%) of pink crystals of 3 - nitro 4 - methylbenzene diazonium fluoborate.
(B) Its decomposition
182 g. of fluoborate obtained in accordance with (A) are intimately mixed with 325 g. of dry sand and directly heated in the flame.
Heating is maintained for 30 minutes, the interior temperature reaching 1800 C. After cooling, the carbonaceous mass it taken up in water and steam distilled. The fractions distilled over are extracted with ether and the extracts are dried, filtered and evaporated to dryness. The residue, 60 g. (equal to 44%) of a brownish - yellow liquid, is redistilled at 770 C. at a vacuum of 3 mm. of Hg. The product comes over at a fixed point The refractive index of the resulting yellow oil, II, is 1.522 at 250 C.; it is in agreement with the values in the literature on the subject.
2. Production of ethyl 6-fluoro-indole-2-carboxylate, III.
Dry potassium ethylate, equivalent to 7.9 g. of potassium, is covered with 100 cc. of ether, 27.2 cc. of ethyl oxalate are added with cooling and stirring and then 31 g. of compound II, obtained as above added very slowly. The reaction mixture is allowed to stand at room temperature for 40 hours, then filtered with suction and the residue washed with anhydrous ether and dried in a vacuum to recover 44 g. of violet crystals of the potassium salt of ethyl 41 ~ fluoro-21-nitro-phenyl ~ pyruvate.
The product is dissolved in 280 cc. of alcohol and 28 cc. of acetic acid and the solution added dropwise to a mixture, held at 900, of 100 g. of iron filings, 400 cc. of water and 14 cc. of concentrated hydrochloric acid. Alcohol distils over during the course of this addition which lasts 30 minutes. Heating with stirring is continued for a further hour and cooling and filtration with suction are effected.
The iron and cyclised compound are washed with water and then extracted with hot ethanol.
The extracts, evaporated in a vacuum, yield 20 g. (equal to a yield of 50n, Ó in respect to 2 - nitro - 4 - fluoro - toluene) of compound III, m.p. = 140 1400 C.
For analysis it is recrystallised from ethanol, m.p. =1420 C. This new compound occurs as white needles, soluble in ether and chloroform, less soluble in acetone, alcohol and benzene and insoluble in water and dilute aqueous acids or alkalis.
3. Production of 6-fluoro-indole-2-carboxylic acid, IV.
20 g. of compound III, obtained as above, are mixed with 120 cc. of ethanol, 10 g. of potassium hydroxide pellets and 100 cc. of water. It is heated to the boil at reflux for one hour. Filtration is effected and 150 cc. of water are added to the filtrate, which is then acidified by the addition of hydrochloric acid.
On cooling acid IV is obtained in the form of a beige precipitate which is filtered with suction and washed with water. It has then redissolved, with warming, in 200 cc. of water and 20 cc. of concentrated ammonia, animal charcoal is added and filtration and reacidification with hydrochloric acid are effected.
After filtration with suction and washing again with water, drying at 800 C. yields 10.9 g.
(equal to 630/n) of compound IV, m.p. greater than 2200 C. It is soluble in alcohol, ether and acetone, insoluble in water, benzene and chloroform. It is recrystallised from aqueous methanol for analysis.
This compound has not been described in the literature.
4. Production of 6-fluoro indole, V.
17.1 g. compound IV, obtained as above, are introduced into 85 cc. of quinoline containing 1.7 g. of copper chromite and heated at a temperature within the range of 2102200 for 1hours. After cooling the mixture ii poured into 200 cc. of water and extracted with ether. The ethereal solution is extracted repeatedly with concentrated hydrochloric acid until distinctly acid, then washed with water and dilute ammonia and again with water until neutral. The ethereal solution after drying over sodium sulphate is evaporated to dryness.
The residue is triturated with petroleum ether, filtered with suction and dried in a vacuum.
Yield: 11 g. of crystals of compound V, which are purified by steam distillation using steam super-heated to 1700 C. Distillation lasts 30 minutes, the distillate is cooled, filtered with suction and dried in a vacuum to yield 10.3 g. (equal to 80%) of compound V, m. p. =730
C. This compound, not described in the literature, occurs as small white needles, soluble in alcohol, acetone, benzene, ether and chloroform and insoluble in water and dilute aqueous alkalis and acids.
5. Production of 6-fluorogramine, VI.
A mixture of 26 cc. of dimethylamine in 23. 4% aqueous solution, 18 cc. of acetic acid and 11 cc. of 30 /r, formaldehyde is prepared at a temperature below 50, it is allowed to warm up to room temperature and mixed with 13.5 g. of 6 - fluoro - indole, V, obtained as above. The reaction mixture is stirred for one hour, it is then diluted with 300 cc. of water and made alkaline with dilute sodium hydroxide. A white precipitate is filtered with suction and washed with water until neutral and dried in a vacuum to yield 18.1 g. (equal to 94%) of compound VI, m.p.=136.50 C.
For analysis it is recrystallised from toluene, the melting point remaining constant. This compound, which has not been described in the literature, is soluble in alcohol, ether, acetone, chloroform and in dilute aqueous acids, sparingly soluble in cold benzene and insoluble in water and dilute alkalis.
Production of 6-fluoro-3-indolyl acetonitrile, VII.
(A) 6-fluoro-gramine methosulphate
A solution of 6 - fluoro - gramine obtained as above, in 20 cc. of tetrahydrofuran and 0.1 cc. of glacial acetic acid, is added dropwise with stirring to a mixture of 11.1 cc. of methyl sulphate, 11.1 cc. of tetrahydrofuran and 0.2 cc. of glacial acetic acid. Stirring is continued for 45 minutes. 6 - fluoro - gramine methosulphate is filtered with suction, triturated with ether and used as such for the following reaction.
(B) Formation of nitrile
4.5 g. of potassium cyanide are added to the methosulphate obtained in accordance with (A), dissolved in 100 cc. of water and the reaction mixture heated to 60--650 with stirring for one hour. Cooling and filtering with suction are effected, the resulting precipitate is washed with water, dilute hydrochloric acid then again with water and dried in a vacuum to yield 4.6 g. (equal to 85%) of crude compound VII. It may be used directly for the continuation of synthesis. For analysis it is purified by sublimation at 1100 C. and a pressure of 0.1 mm. Hg. Melting point=51 520 C.
This compound, which has not been described in the literature, is soluble in alcohol, ether, acetone and chloroform, sparingly soluble in benzene and insoluble in water and dilute aqueous acids and alkalis.
7. Production of 6-fluoro-tryptamine, I.
4 g. of compound VII, obtained as above in solution in 40 cc. of methanol saturated with ammonia are hydrogenated in the presence of 4.5 g. of Raney nickel. After two hours of hydrogenation the volume of hydrogen consumed is 850 cc. The catalyst is filtered and the methanol is evaporated in a vacuum. The residue is dissolved in 10% acetic acid, made alkaline with 10% sodium hydroxide until the pH value is 8, cooled, treated with animal charcoal and filtered. Sodium hydroxide is added again to the filtrate until distinctly alkaline to phenolphthalein. An oil separates which crystallises on cooling and scratching.
6. Fluoro - tryptamine I is filtered with suction, washed with water and dried in a vacuum.
Yield: 2 g. (equal to 50%), m.p.=800 C.
This compound, which is not described in the literature, is only slightly stable and yellows rapidly in the air.
To produce the picrate of compound I, 5.47 g. of this tryptamine is dissolved in 25 cc. of absolute alcohol and mixed with 7.7 g. of picric acid in 54 cc. of alcohol. The picrate crystallises in orange needdles which are filtered after cooling and washed with a little chilled alcohol. Drying is effected to yield 11.3 g. (equal to 90%) of the salt of 6 - fluoro tryptamine, I, m.p. =2640 C. Recrystallisation from methanol does not cause any change in melting point This new compound is soluble in acetone, in the warm in alcohol and sparingly soluble in chloroform, benzene and ether.
It decomposes in dilute aqueous alkalis and acids.
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