CS257194B1 - 1- (4- [2- (2-Propylamino) propyl] -benzenazo [piperidine] and methods for its preparation - Google Patents

Abstract

The subject is l-/4-/2-propylamino/propyl/benzenezo/piperidine of formula I. The substance I n serves as an intermediate in the production of N-isopropyl- ' -2-amino-l-/4-iodo-phenyl/propane labeled with χ short-lived radioactive isotopes of iodine (_) (123I, 125I and 131I), which is used for scintigraphic imaging of the brain and diagnosis of brain diseases. The methods for preparing substance I are based on N-isopropyl- -2-amino-l-phenylpropane, which is converted to the N-trifluoroacetyl derivative. From this, the final substance I is then obtained either via the 4-nitroso derivative or via the 4-nitro derivative. Both of these substances provide the reduction of the 4-amino derivative, the diazonium salt of which reacts with piperidine and the product is alkaline hydrolyzed.

Description

The present invention relates to 1- [4- (2- (2-propylamino) propyl) benzenazo piperidine] of formula (I) and to processes for its preparation.

The compound of formula I is novel and is useful for the rapid and simple preparation of N-isopropyl-2-amino-1- (4-iodophenyl) propane of formula II, labeled with short-lived radioactive isotopes of iodine 193 19 5 131 ^J , ³ I, and ^JX I. These amphetamine derivatives is used in clinical practice to scintigrafickému imaging of the brain and hence in the diagnosis of brain diseases.

The methods for preparing the compound of formula I according to the invention are based on the known N-isopropyl-2-amino-1-phenylpropane prepared, for example, according to Jacobsen E. et al. Scand. Sheet. Physiol. 79, 258, 279 (1938) of formula III and proceed through the common intermediate, N-trifluoroacetyl-N-isopropyl-2-amino-1-phenylpropane of formula IV. The trifluoroacetylation of the compound (III) is preferably carried out by heating with trifluoroacetanhydride in dichloromethane under catalysis with 4-dimethylaminopyridine. One method of preparation is then carried out via an organothallium derivative of formula V, which is prepared by reacting IV with trifluoroacetate in trifluoroacetic acid at room temperature. Reaction of the organothalium derivative of the formula V with nitrosyl chloride (generated in situ from amyl nitrite and hydrochloric acid) affords the 4-nitroso derivative of the formula VI, which is preferably reduced with sodium borohydride in the presence of 10% by weight of activated carbon. of palladium to the 4-amino derivative of formula VII. Diazotization of the amino derivative of formula VII at 0 ° C with nitrous acid and subsequent reaction with aqueous piperidine affords the triazene of formula VIIIa. Its hydrolysis, which is most preferably carried out by boiling in 10 wt. ethanolic potassium hydroxide solution, 1-C-4- (2- (propylamino) propyl) benzenazole-piperidine of formula I is obtained.

The second method also starts from the trifluoroacetyl derivative of formula IV, which by nitration with 100% nitric acid affords a mixture of the 2-nitro derivative of the formula IX and the 4-nitro derivative of the formula X in yields of 29 to 53%. The 4-nitro derivative of formula X, which is separated from the mixture by column chromatography, is preferably reduced with sodium borohydride in the presence of 10% palladium on carbon to the amino derivative of formula VII, which is further processed as described in the first process.

The compound of the formula I according to the invention has not been described in the literature. Its identity was assured by analytical and spectral methods. The compound of formula I is easy to store and allows the rapid and simple preparation of N-isopropyl-2-amino-1- (4-iodophenyl) propane of formula II immediately before its application directly in biological or clinical laboratories.

The following are examples of the preparation of the compound of formula I according to the invention. These examples are merely illustrative of the possibilities of the invention, but are not intended to describe all of the possibilities of the invention in a comprehensive manner.

Example 1

N-Trifluoroacetyl-N-isopropyl-2-amino-1-phenylpropane (IV)

N-isopropyl-2-amino-1-phenylpropane (III, 7 g) and 4-dimethylaminopyridine (5 mg) were dissolved in dichloromethane (50 mL). Trifluoroacetic anhydride (10 g) was added dropwise to the stirred solution at room temperature over 15 min. After the exothermic reaction was completed, the reaction mixture was heated at reflux for 1 h. After cooling, the mixture was washed with sodium carbonate solution (4 times, 15 mL, 5%), dried over anhydrous sodium sulfate, and concentrated in vacuo. The trifluoroacetyl derivative of formula IV was obtained as a colorless oil (7.2 g, 96%), b.p. 198 ° C, η 1.4730, crystallized on standing for a longer period, m.p. 42-44 ° C; Hydrochloride m.p. Mp 155-158 ° C.

N-Trifluoroacetyl-N-isopropyl-2-amino-1- (4-nitrosophenyl) propane (VI)

A solution of the trifluoroacetyl derivative of formula IV (3.27 g) and thallium trifluoroacetate (8.4 g) in trifluoroacetic acid (10 mL) was left at room temperature and in the dark in a sealed vial for 75 h.

Trifluoroacetic acid was then distilled off in vacuo, dichloromethane (10 ml) was added to the residue, and the mixture was again concentrated in vacuo (this was repeated 3 times). The distillation residue no longer containing trifluoroacetic acid was dissolved in dichloromethane (50 mL), amyl nitrite (4 g) was added dropwise with stirring, and the solution was stirred in the dark for 3 h. A mixture of hydrochloric acid (2.5 ml, conc.) And acetic acid (5 ml) was added. After stirring for 10 min, hydrochloric acid (2N, 20 mL) was added and the mixture was stirred for an additional 10 min. It was then filtered through glass wool, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The brown oil obtained (2.5 g) was chromatographed on a silica gel column (70 g, eluting with benzene). A bright green crystalline nitroso derivative of formula VI (1.1 g, 31%) of m.p. Mp 75-77 ° C (benzene).

N-Trifluoroacetyl-N-isopropyl-2-amino-1- (4-aminophenyl) propane (VII)

The nitroso derivative of formula VI (250 mg) was dissolved in methanol (10 mL), and the solution was stirred under helium in the presence of 10% by weight activated carbon. palladium (25 mg) 10 min. Sodium borohydride (120 mg) was then added and the mixture was stirred at room temperature for 1 h. After filtration, the mixture was diluted with water (40 mL) and extracted with chloroform (3 times, 25 mL). The chloroform extracts were combined and usually worked up. After concentration, the amine of formula VII was obtained as a yellowish oil (220 mg, 93%).

1- / 4- / 2- / 2-Propyltrifluoroacetylamino / propyl / benzenazo / piperidine (VIII)

The amine of formula VII (600 mg) was dissolved in ethanol (1 ml) and hydrochloric acid (1N, 10 ml) was added dropwise to the solution with stirring. A solution of sodium nitrite (170 mg) in water (5 mL) was added dropwise to the stirred mixture at 0 to -5 ° C. After 10 min, piperidine (920 mg) in water (7 mL) was added dropwise and the mixture was stirred for an additional 30 min. It was then poured into water (200 ml), adjusted to pH 10 with sodium carbonate solution (5%) and extracted with chloroform (3 x 25 ml). The chloroform extracts were combined, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was chromatographed on a silica gel column (30 g, eluting with petroleum ether-ether 85:15). 595 mg (75%) of triazene (VIII) of m.p. 107 DEG-108 DEG C. (methanol).

1- / 4- / 2- / 2-propylamino / propyl / benzenazo / piperidine (I)

Triazene of formula VIII (525 mg) was dissolved in 10 wt. solution of potassium hydroxide in ethanol (7 mL) and the mixture was heated to boiling in the dark for 16 h. After cooling, the reaction mixture was poured into water (50 mL) and extracted with ether (3 times, 25 mL). The combined ethereal portions were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The brown oil (500 mg) was chromatographed on a silica gel column (20 g, eluting with ethyl acetate: methanol: conc. Ammonium hydroxide - 17: 2: 1). The triazene I was obtained (290 mg, 73%), m.p. 178 DEG-180 DEG C. with decomposition (ether).

¹ H NMR (C ² HCl ₃ ): 0.96d, 3H (CH ₃ CH, J = 6.1 Hz); 1.03d, 6H (i-Pr, J = 6.1 Hz); 1.69 br S (5H); 2.45-3.25 (4H); 3.76 t (4H, J = 4.9Hz); 7.11 and 7.37 (AA ', BB', 4H, J _AB + J _AB , 8.6 Hz).

¹³ C NMR (C ² NC ₁₁ ): 20.7 q, 22.8 q, 23.8 q, 24.4 t, 25.3 t (2C), 43.4 t, 45.4 d, 48, 3 t (2C), 51.4 d, 120.5 d (2C), 129.8 (2C), 137.0 s, 149.2 s.

Mass spectrum, m / z (%, composition):

288 (M ⁺ , 3), 230 (4), 203 (16), 175 (5), 98 (8), 91 (14), 90 (16), 86 (100, C 8 H 8 N), 84 ( 14, C ₅ H ₁₀ N), 70 (10) 56 (8), 55 (10).

Example 2

Nitro derivatives of formula IX and X

The trifluoroacetyl derivative of formula IV (1.5 g) was slowly added dropwise to stirred -20 ° C cooled nitric acid (100%, 7.5 mL). The solution was stirred at room temperature for 2 h, poured into ice water (50 mL) and the mixture was extracted with benzene (3 x 30 mL). The benzene fractions were combined, washed with water (repeatedly) and dried over anhydrous sodium sulfate. Evaporation gave a yellow oil (1.5 g) which was chromatographed on a silica gel column (30 g, eluting with petroleum ether-ether, 19: 1). First, the 2-nitro derivative IX (510 mg, 29%) was obtained, m.p. 71-72 ° C (petroleum ether-ether).

Finally, the 4-nitro derivative of formula X (920 mg, 53%) was obtained, m.p. 65-68 ° C (petroleum ether-ether).

The amino derivative of formula VII

The nitro derivative of formula X (900 mg) was reduced in the same manner as the nitroso derivative of formula VI (Example 1). After work up, the amine of formula VXI was obtained as a yellow oil (760 mg, 93%).

Claims (3)

1. 1- (4-) 2- (2-Propylamino) propyl / benzenazo / piperidine of formula I. 2. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that N-isopropyl-2-amino-1-phenylpropane of formula (III) is converted by trifluoroacetylation to the N-trifluoroacetyl derivative of formula (IV), which is treated with thallium trifluoroacetate in trifluoroacetic acid. with nitrosyl chloride in situ transforms regioselectively into the 4-nitroso derivative of formula VI, which is reduced by sodium borohydride in the presence of activated carbon with 10 wt. palladium-on-carbon gives the 4-amino derivative of formula VII, diazotizing and reacting with piperidine to give the triazene of formula VIII with an NH-protected trifluoroacetyl and hydrolyzing it with boiling alkali hydroxide to give the final product of formula I. A process for the preparation of a compound of formula (I) according to claim 1, characterized in that the N-isopropyl-2-amino-1-phenylpropane of formula (III) is converted by trifluoroacetylation to the N-trifluoroacetyl derivative of formula (IV) which is nitrated to a mixture of 2- and 4-nitroderiyate. of formulas IX and X from which the 4-nitro derivative of formulas IX and X is chromatographically separated from which the 4-nitro derivative of formula X is chromatographically separated by reduction with sodium borohydride in the presence of palladium on carbon to the 4-amino derivative of formula VII reaction with piperidine affords triazene of formula VIII with an NH group protected with trifluoroacetyl and this is hydrolyzed with boiling alkali hydroxide to give the final product of formula I.