DE946058C - Process for the preparation of 3-aminoindanes - Google Patents

Description

Process for the preparation of 3-aminoindanes Aminoindanes, in which the amino group is in the five-membered ring are already known. Such connections were z. B. obtained by reacting chlorine indane with amines or ammonia. Even you already have these substances from the corresponding ketones by conversion into the oximes, which in turn can be reduced to amines again (see König, Liebigs Ann. der Chemie, Vol. 275, 1893, p. 348; Courtout and Dondelinger, Compt. rendus hebd. Seances Acad. Soc., Vol. 177, 19a3 ,. P. 537, and vol. 178, 1924, P. 493, also Ann. de Chimie [io], vol. q., 1925, p. 258; Chem. Zentralblatt, z936,11, P. 3955 [U.S. Patent 2,0q.8781]).

It has now been found that therapeutically valuable 3-aminoindanes can be obtained if one starts from compounds which contain in the i position, in the hydrogen or hydrogen means a substituted or unsubstituted alkyl radical. Here, m_ an expediently uses indanes which carry halogen, in particular chlorine, in the 3-position as starting materials, and converts them with ammonia or the corresponding amines. It is essential here that the work is carried out absolutely free of water, since the presence of just a few l) /, water extremely lowers the yield of amines. It is therefore advisable to dry the amines to be reacted very carefully, e.g. B. a pre-drying over potassium hydroxide and a subsequent treatment with sodium.

Compounds with the general formula are obtained in which R is hydrogen or alkyl and Am is an unsubstituted, mono- or disubstituted amino group and the disubstitution of the amino group can also be effected by a ring, so that, for. B. Am also one of the leftovers can mean. Those compounds in which the amino group is substituted by alkyl and / or aralkyl have proven particularly useful. The phenyl ring of the indane, like the phenyl radical in the i: position, can be substituted, e.g. B. by alkyl, halogen, oxy, alkoxy or amino groups.

The i-phenyl-3-chloroindanes required as starting materials can be prepared via the i-phenylindanones- (3), which are accessible according to Auwers (Ber. Der deutsch. Chem. Ges., Vol. 52, igig, p. Iio) by catalytic hydrogenation, e.g. B. in the presence of Raney nickel catalysts according to patent 912 093. The i-Phenyhndanole- (3) can then, for. B. by means of thionyl chloride, in an inert solvent, e.g. B. chloroform, can be converted into the i-phenyl-3-chloroindane.

Another route to the compounds according to the invention, as far as they the 3-amino- or mono- or dialkylated 3-aminoindanes concern, goes from the 3-oximes, in turn from the corresponding ketones by reaction with Hydroxylamine can be obtained. In particular, the oximes become catalytic in the presence reduced by palladium-carbon and the amines formed, if necessary .in per se alkylated in a known manner.

The compounds obtained in this way are therapeutically of Significance or serve as starting materials for the manufacture of pharmaceuticals.

They show spasmolytic effects over a considerable range, namely on the gastrointestinal tract and biliary system; there are also local anesthetics and vascular effects in appearance.

. Effects of this kind were different from those described in the literature, therapeutically effective indanamine derivatives of comparable constitution not known. The products of the process described in U.S. Pat. No. 2,573,644 on next standing, unsubstituted in i-position, but in a special way am According to the inventors, N-substituted 3-anninoindanes show adrenolytic or sympatholytic and antihistaminic effects. From others in the literature as Indanamino derivatives known to be therapeutically effective (cf. the USA. patent 2 625 567, also Journ. of Amer. Chem. Soc., Vol. 70, 1948, p. 1386, Paragraph i, Journ. of Organic Chem., Vol. 14, 1949, p. 907, para. i, and Compt. rend. Soc. biol., Vol. 139, 1945, pp. 944J945), all of which as 2-amino derivatives are the products of the process are even less close, only broncholytic properties are mentioned. The 2-aminomethylindenes are considered to be the indanamine derivatives still further from the process products the USA.-Patent 2,441,069 called, the uterotonic effects like the Show ergotamins.

The completely different, especially spasmolytic effects the products of the process were therefore by no means foreseeable. You mean one Valuable enrichment of the drug treasure, especially the pharmacological check has shown that such effects even with very closely related aminoindanes strongly recede, as the following comparison shows. To your understanding the following explanation of the examination technique may serve: the spasmolytic effect the products of the process were isolated on the isolated guinea pig small intestine after. method determined by Magnus.

For this purpose, a piece of intestine suspended in Tyrode's solution (cf. der Pharmaceutical Practice, supplementary volume 1944, p. 1129). It is then determined which dose of the compound to be tested, after 30 seconds of exposure time, cancels the contraction effect of a dose of barium chloride or lentine of the specific size that is immediately applied.

The numbers in the table indicate the amount of compound to be tested, which completely inhibits the Tyrode solution or i mg of barium chloride per 100 cc of Tyrode solution cause releasable spasm.

For comparison, those under the same conditions are shown at the beginning Papaverine and the »Dolantina (i-methyl-4-phenyl-4-carbethoxy-piperidine hydrochloride) known under the trade name determined values are included in the table.

“D 1 50” is understood to mean that dose at which 50% of the test animals die. Toxicity Quantity required for suppression D 1 5o intravenous of the spasm, triggered by Tested compound in mg ' per kg rat r mg BaCh I iy lentin 1 Papaverine: .................................. 22 150 y 150 y y a, Dolantina ..... ........................... 76 30 to 50 y 20 y i-Pheny1-3-dimethylaminoindane hydrochloride .... 61 ioo y 50 i-phenyl-3-piperidylindane hydrochloride. . . . . . . . . . 43 ioo y ioo y i-methyl-i pheny1-3-dimethylaminoindanhydro- y chloride .................................... 6o 50 y 15 to 20 i-methyl-r-phenyl-3-diethylaminoindanhydro- chloride ............ ....................... 43 15 y 47 i-methyl-i-pheny1-3-piperidyl hydrochloride ...... 53 * 50 Y 3-Aminoindane hydrochloride .................... 305 iooo y I iooo y 2-Plienyl-3-aminoindane hydrochloride ............ 97 iooo y iooo y 2-phenyl-3-dimethylaminoindane hydrochloride ..... 49 2500 y 500 y (from the above connection by di- methylation! F = 198 to igg °) i-Phenyl-2-dimethylaminoindane Hydrochloride .... 63 - - 400 y still without #Ieffect 2-Aminoindane hydrochloride ............ e ....... , 143 2000 y 2000 y 'Awareness through 5 to io y Example i i-Phenyl-3-dimethylaminoindane To prepare i-Pheny1-3-chloroindane, io g of i-phenylindanol- (3) are reacted with 6.7 g of thionyl chloride in chloroform (alcohol- and anhydrous) at 50 " After evaporation of the chloroform in vacuo at 50 °, the residue is taken up in ether and the solution is washed successively with aqueous bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and the ether is evaporated off in vacuo 50 ° in vacuum. The obtained crude i-Plieny1-3-chlorindane can be used directly for the reaction with amines. The crystallized i-phenyl-3-chloroindane has a melting point of 59 to 62- 'after recrystallization from hexane It will gradually decompose when stored.

22.5 g of i-Pheny1-3-chlorindan are mixed with an excess of dimethylamine (25 g), which also serves as a solvent, in a pressure bottle for 24 hours ditched. The amine is then allowed to evaporate at room temperature and taken the residue up in water and ether. In the separating funnel, the still adhering Dimethylamine and the dimethylamine hydrochloride by washing the ethereal solution with Water removed. To obtain the i-phenyl-3-dimethylaminoindans, the following can be used Proceed as follows: a) The ethereal solution is dried with potassium carbonate and precipitated the i - phenyl - 3 - dimethylaminoindan by ethereal hydrochloric acid as hydrochloric acid Salt from, yield 56% of theory, based on i-phenyl-3-oxyindane; b) one pulls the i-phenyl-3-dimethylaminoindan from the ethereal solution with hydrochloric acid, e.g. B. i n-HCl, fractionates out and evaporates the fractions on the steam bath. Here receives one oily products which become crystalline after trituration with acetone.

The separated compounds can be dissolved in alcohol and with ether be felled. Drying takes place at 100 ° in vacuo over phosphorus pentoxide.

If you put z. B. crude i-Phenylindano1- (3) for chlorination and used after the reaction with dimethylamine, the work-up method b) is obtained one individual fractions with variable melting points between 140 and i95 °. But if i-phenyl-indanol- (3) with a melting point of 92 to 94 ° is used and works according to method a), then a product is obtained which is at 159 to 164 ° melts. This i-phenyl-3-dimethylaminoindane hydrochloride contains r (2 mol Crystal water.

Example 2 i-phenyl-3-piperidyl-indane hydrochloride 1o, 7 g of crude i-phenyl-3-chloroindane, prepared from crude i-phenyl-indanol- (3), 25 cc of piperidine are added Left to stand for 24 hours at room temperature. The excess piperidine distilled off in vacuo at low temperature (50 °). After recording of the residue in water and benzene, the benzene solution is washed neutral with water and then with Fractionally extracted in n-hydrochloric acid. the Evaporation residues from the individual fractions are triturated with acetone and filtered off with suction. After recrystallization from butanol, the i-phenyl-3-piperidyl-indane hydrochloride has it the melting point 246 to 2q.8 °. Yield 410 /, of theory, based on i-phenyl-3-chloroindane.

Example 3 i-Pfienyl-3-diethylamino-indan tartrate 12.49 Crude i-phenyl-3-chloroindan, prepared from ix g i-phenylindanol- (3), are mixed with anhydrous diethylamine in excess, which is also used as a solvent is used, implemented in the pressure pipe at 8o °. The excess amine is then distilled off at low temperature in vacuo and the residue is taken up in water and ether. The ether solution is washed neutral with water and then extracted with aqueous hydrochloric acid. The base is precipitated from the acidic solution with sodium bicarbonate, which is taken up again in ether and dried over potassium carbonate. Then the ether is gently distilled off in vacuo after excluding air. The residue, 7.9 g, is a colorless oil.

The oil is converted into the neutral tartrate. The melting point is not characteristic because there is a mixture of cis-trans isomers. F. = 68 to g3 ° after drying over phosphorus pentoxide. Yield 56.6% of theory, based on i-phenyl-3-oxyindane. . Example 4 i-Methyl-i-phenyl-3-dimethylaminoindanhydrochloride The unknown i-methyl-i-phenyl-indanol- (3) required as starting material is derived from i-methyl-iphenyl-indanone- (3), represented by CF. Koelsch, Journ. At the. Chem. Soc., Vol. 65, 1943, p. 59, obtained by hydrogenation. For example, 38.6 g of i-methyl-i-phenyl-indanone- (3), dissolved in 26 ° C. of methanol, are hydrogenated using Raney nickel as a catalyst at normal pressure and 40 ° with hydrogen. After working up, 38 g of i-methyl-iphenyl-indanol- (3) are obtained, which as a cis-trans isomeric mixture has an elongated melting point. F. = go to i15 °. The i-methyl-i-phenyl-indanol- (3) is used as an isomer mixture for the further reactions.

12.8 g of crude i-methyl-i-phenyl-3-chloroindane, obtained from 11.7 g of i-methyl-i-phenyl-indanol- (3) by reacting with thionyl chloride in chloroform, with excess anhydrous Dimethylamine left in a vial for 12 hours at room temperature: After the dimethylamine has been evaporated off, the residue is taken up in water and ether on. The ether solution is washed neutral with water and dried over potassium carbonate. The hydrochloride, which is obtained from butanol-ether, is then precipitated with ethereal hydrochloric acid is recrystallized. The compound which crystallizes out first, 3.4 g, _ possesses the melting point 228 to 23i °. After the mother liquor has been worked up, one obtains another 5.8 g of compound with a melting point of 180 to 186 °. The two crystals are cis trans-isomers. Yield 61 ° 10 of theory, based on i-phenyl-imethyl-3 = oxyindane.

Example 5 i-Methyl-i-phenyl-3-diethylaminoindane hydrochloride 14 g crude i-methyl-i-phenyl-3-chloroindane, obtained from ii, 7 g of i-methyl-i-phenyl-indanol- (3), are reacted with excess, anhydrous diethylamine in the pressure pipe at $ o °: -After evaporation of the excess amine in vacuo, the residue is in water and ether absorbed. The ether solution is washed with water and then neutral extracted with aqueous hydrochloric acid. Those made from the acidic solution with sodium bicarbonate precipitated base is taken up again in ether and the ethereal solution over potassium carbonate dried. The hydrochloride is precipitated with ethereal hydrochloric acid. For cleaning of the hydrochloride it is reprecipitated from butanol ether. F. = 156 to i62 °. yield 24.80% of theory, based on i-phenyl-i-methyl-3-oxyindane.

50 g of i-phenyl-i-methylindanol- (3) are dissolved in 100 cc of chloroform and reacted with 22 g of phosphorus tribromide. It is allowed il /, standing hours at room temperature and ilj2 hours at 5o °. After cooling, the solution is washed a few times with water and once with sodium bicarbonate solution and dried over calcium chloride. The solvent is evaporated off in vacuo and the remaining crude i-phenyl-i-methyl-3-bromoindane is dried in a vacuum desiccator. The compound is used directly to react with diethylamine. Raw yield 6o g.

53 g of crude i-phenyl-i-methyl-3-bromoindane are reacted with 50 cc of diethylamine by refluxing for 71/2 hours and then allowing the batch to stand overnight at room temperature. Then the mixture is taken up in ether and water. The excess diethylamine and the diethylamine hydrobromide are washed out with water. The ethereal solution is dried over potassium carbonate and the hydrochloride is precipitated from the ethereal filtrate with ethereal hydrochloric acid. 46.7 g of i-phenyl-imethyl-3-diethylaminoindane hydrochloride are obtained, corresponding to 7.6.5% of theory.

The melting point after reprecipitation from butanol ether is about 160 up to i65 °.

Example 6 z-Phenvl-r-methyl-3-amino- or 3-dimethylaminoindane hydrochloride io g of i-phenyl-i-methylindanon- (3) are dissolved in 3occm pyridine and with a solution. 3.8 g of hydroxylamine hydrochloride in 12 cc of dilute alcohol are added. One leaves the mixture for 48 hours at room temperature and then the reaction solution is stirred in 150 cc of water. The oxime initially precipitates as an oil, but it does so when rubbed becomes solid. The precipitate is filtered off with suction and washed out with water. After this Recrystallization from methanol melts the oxime at 169-172 °. 7.5g of the i-phenyl-i-methylindanon- (3) oxime are dissolved in 150 cc of methanol, the 1.3 g of hydrogen chloride contain, under normal pressure at 5o ° with hydrogen in the presence of palladium black hydrogenated as a catalyst. After 3 hours the hydrogen uptake is 2 mol. The catalyst is separated off and the filtrate is evaporated in vacuo. That as a residue remaining i-phenyl-i-methyl-3-aminoindanhydro-chloride-is made from methanol-ether fell over. F. = 275 to 278 ° with decomposition.

This primary amine is dimethylated by treatment with 90% formic acid and excess 38% formaldehyde solution on the steam bath to give i-phenyl-i-methyl-3-dimethylaminoindane. Yield 72% of theory based on the oxime. Example 7 i-Phenyl-i-methyl-3-piperidinoindane hydrochloride io g of i-phenyl-i-methyl-indanol- (3) are reacted in chloroform with 6.4 g of thionyl chloride as usual. The crude 1-phenyl-i-methyl-3-chloroindane formed is left to stand with 24 cc of piperidine at room temperature for 48 hours and then heated to 50 ° for 4 hours. The mixture is taken up in ether and water. The excess piperidine is then washed out of the solution with water and the ethereal solution is dried over potassium carbonate. The hydrochloride is precipitated with ethereal hydrochloric acid. Yield 7.2g. The compound can be reprecipitated from methanol-ether. F. = 197 to 20 °, after previous sintering at 19q. °, after it has previously been dried in vacuo at 100 ° and then still contains 1/2 mole of water.

Claims (4)

PATENT CLAIMS: i. Process for the preparation of 3-aminoindanes of the general formula in which R denotes hydrogen or alkyl and Am denotes an unsubstituted, mono- or disubstituted amino group and the disubstitution of the amino group can also be brought about by a ring, characterized in that the keto group of 3-ketoindanes of the general formula in the. R has the same meaning "as above = given", in a manner known per se by treatment with reducing and then with aminating agents in the group On convicted. 2. The method according to claim i, characterized in that the mentioned 3-ketoindanes by treatment with reducing agents first in the corresponding indanols (3) converted, the hydroxyl group of which is replaced by halogen and the 3-haloindanes formed are then reacted with ammonia or amines. 3. Procedure according to claim i, characterized in that said 3-ketoindanes are also used Hydroxylamine is first transformed into its oximes, these catalytically becoming the primary ones Hydrogenated 3-aminoindanes and, if desired, alkylated on nitrogen. Into consideration Extracted publications: Beilstein's Handbook of Organic Chemistry, Vol. XII, 4. Ed., 1929, main work, S. iigi, supplementary work 1I, 4th ed., 195o, p. 651; Journ. Chem. Soc., Vol. 71, 1897, p.250; Elxuier's Encyclopaedia of Organic Chemistry, Vol. 12 A, 1948, Series III, p. 15i.