NO155863B - INSTALLATION FOR A PATIENT TO PROVIDE AN OBJECT WITHIN A SURVEY AREA. - Google Patents

Abstract

The anti-theft means (34) comprising a semiconductor diode connected to a metal antenna loop (38) is configured to receive two separate radio frequency radiators. The diode (36) forms a bridge and a closed loop at one end of the antenna (38). ), thereby producing a tank circuit with a resonant frequency equal to twice that of a selected center frequency. A first transmitter (26) produces a tone modulated radio frequency (f) shifted to one side of the center frequency, while a second transmitter (30) produces a continuous radio wave having a frequency (f> shifted to the other side of the center frequency. separate dipole beam antenna strips (18, 19, 20, 21) on opposite sides of a monitoring area The dipole strips for the different frequencies are arranged at right angles to each other on each side of the monitoring area, while the dipole strips for the same frequency stand Such an antenna device produces cross-polarized radiation of both frequencies in the monitoring area, the diode (36) in the marking means (34) mixes the two frequencies received by the antenna loop (38), and brings the tank circuit to resonance at the sum of the two frequencies (twice the center frequency) This in LZ! resonance frequency is re-radiated to receiving antennas (22, 24) ^ on either side of the monitoring area for detection in a very narrowband receiver (42) which responds to the sum of the two frequencies. The modulation tone is then derived from the received signal and caused to trigger an alarm (44) when the detected signal is of sufficient strength and duration.

Description

Process for the production of a hitherto unknown, therapeutically active isoxazole derivative.

The present invention relates to a

method for the production of a hitherto unknown isoxazole derivative, which possesses valuable pharmacological properties. It was surprisingly found that the hitherto unknown 3-hydroxy-5-aminomethyl-isoxazole of formula I,

as well as its acid addition salts already in very small doses have an inhibitory effect on the central nervous system. In particular, a very strong potentiation of the effect of narcotics as well as a reduction of motility, catatonic and sedative effects, inhibition of tremor intremor and antiemetic effect can be noted. For the preparation of 3-hydroxy-5-aminomethyl-isoxazole of formula I, one hydrates or reduces a compound of the general formula II

where R means' hydrogen or the toenzyl group.

The hydrogenation of a compound with the general formula II can be carried out, e.g. in the presence of palladium on charcoal or of Raney nickel, as catalysts in an organic solvent, such as dioxane, ethanol, methanol or tetrahydrofuran at room temperature. The compound of formula I precipitates upon hydrogenation as a zwitterion and is thus to a large extent exempt from the further influence of hydrogen. Contaminants and by-products are soluble in organic solvents, which is why it is difficult to renounce the purification of the azidomethyl compound used for hydration.

The azidomethyl compounds of the general formula II are obtained, e.g. by reacting a reactive ester of 3-alkoxy-5-hydroxy-methyl-isoxazole with sodium azide in a suitable organic solvent, such as e.g. acetone, at room temperature or slightly elevated temperature.

Furthermore, the compound of formula I is obtained by hydrogenolyzing a compound of formula III,

where R' means the benzyl group, and transfers the 3-hydroxy-5-aminomethyl-isoxazole, if desired, to a salt with an inorganic or organic acid. The hydrogenolysis can take place simultaneously, i.e. in the same work process, with a hydration according to the above-described production method. Furthermore, 3-hydroxy-5-amino-methyl-isoxazole of formula I is reached, by treating a compound with formula IV,

in.

where R" means a lower alkyl residue or the benzyl group, with hydrobromic acid, chlorohydrochloric acid or with the hydrochloride or hydrobromide of any alkyl-substituted pyridine in heat, for example at temperatures between about 100° and 150°.

To the starting compounds of formula III and IV, where R' and R" mean the benzyl group, when in a manner known per se, e.g. 3-:bromo-5-aminomethylisoxazole is heated with benzyl alcohol in the presence of alkali hydroxide for a few hours The compounds of formula IV, where R" denotes a lower alkyl residue, are obtained in a manner known per se by heating a lower alkanol with 3-bromo-5-aminomethylisoxazole in the presence of alkali hydroxide.

A further method for producing the new isoxazole derivative of formula I involves reacting a reactive ester of 3-hydroxy-5-hydroxymethyl-isoxazole with formula V

with ammonia.

The turnover preferably takes place in a closed vessel.

As reactive esters of compounds

with formula V are particularly suitable halogenides, such as chlorine, bromine or iodine as well as sulfuric acid esters, <f. e.g. esters of tolylsulfonic acid, of p-bromosulfonic acid or of methylsulfonic acid.

The compound of formula V is dissolved in a lower alkanol or in water, saturated in the cold with dry ammonia and then stored for a few hours at an elevated temperature in a closed vessel. A 3-hydroxy-5-halomethyl-isoxazole with formula V is obtained, e.g. from y-halo-p,|3-dimethoxy-hydroxambutyric acid by treatment with hydrochloric acid. Finally, new oxazole derivatives of formula I are reached by hydrolyzing a compound of the general formula VI,

where Ac means a lower molecular weight acyl residue. The hydrolysis preferably takes place by treating the compound of the general formula VI with hydrochloric acid at boiling temperature. As low molecular weight acyl residues. comes e.g. the acethyl or benzoyl residue in question. .For compounds with the general formula VI when e.g. by hydrogenation of 3-benzyloxy-5-acylaminomethyl-isoxazole using catalytically activated hydrogen at room temperature.

If desired, the new isoxazole is transferred. derivative of formula I with inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanedisulfonic acid, 3-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid , citric acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid, to a salt.

The following examples explain in more detail the implementation of the method according to the invention. The temperature ranges are indicated in degrees Celsius.

Example 1.

a) g -from the mixture of 3-chloro-5-hydroxymethyl-isoxazole-<(3-chloro-5-isoxazole-methanol) and 3-chloro-5-[tetrahydropyran-(2')-oxymethyl]-isoxazole, prepared according to Gazz. chim. Italian 91, 47 (1961), and 80 g (approx. 400 per cent of the calculated amount) of potassium hydroxide are dissolved in 500 ml of methanol and heated for 24 hours in an autoclave at 100-110°. The dark methanol solution is decanted from the precipitated salt and evaporated in vacuo. The residue and the salt are dissolved together in 400 ml of water, the solution is made acidic with concentrated hydrochloric acid and extracted in a 500 ml Kutscher-Steudel apparatus for 5 hours with ether. The ether solution is dried over magnesium sulfate and evaporated. The residue is distilled below 0.001 torr at 60-90°. Halogen test negative. The NMR spectrum is consistent with the structure of 3-methoxy-5-hydroxymethyl-isoxazole, however, shows that next to the 5-hydroxymethyl compound, 25% of the 5-tetrahydropyranyloxymethyl compound is present.

b) 30 g of the mixture obtained after a) is stirred in 300 ml of absolute benzene with 15

ml of phosphorus tribromide 16 hours at 30 to 40°. The reaction mixture is washed twice with 300 ml of ice water and once with 300 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. When distilled below 12 torr, 3-methoxy-5-bromo-methyl-isoxazole passes over at 102-104° C. Structural evidence by NMR spectrum.

c) 19.2 g (0.1 mol) of the above-mentioned bromide, dissolved in 150 ml of acetone, are added

to a solution of 39 g (0.6 mol) of sodium azide in 150 ml of water and stirred for 12 hours at 30°. After dilution with 250 ml of water, the mixture is extracted 3 times each time with 200 ml of ether. The ether extracts are washed twice each time with 500 ml of water, dried over magnesium sulphate and evaporated under vacuum at 30°. 3-Methoxy-5-azido-methyl-isoxazole, which splits explosively at 200°, remains as a pale yellow liquid in quantitative yield. Evidence of structure by NMR + IR spectrum.

d) 5 g (32 mol) of the product from c) are heated with 10 g (87 mol) pyridine hydrochloride for 22 hours under nitrogen at 120°. After cooling, the reaction mixture is dissolved in 100 ml of water and 10 ml of concentrated caustic soda is added, after which the alkaline solution is extracted twice each time with 200 ml of ether. The organic phase is separated, washed with 300 ml of water and dilute hydrochloric acid, dried over magnesium sulphate and evaporated, whereby 15 per cent of the starting material used is recovered. The aqueous phase, a dark, alkaline solution, is adjusted to Congo acid with concentrated hydrochloric acid and extracted in a Kutscher-Steudel apparatus for 6 hours with ether. The ether solution is dried over magnesium sulphate and evaporated, the residue is dissolved in 50 ml of absolute ether and freed from a few undissolved flakes by treatment with activated carbon. After distillation of the ether at 30° under reduced pressure, 3-hydroxy-5-azidomethyl-isoxazole is returned in the form of light green crystals with a melting point of 78-80°.

e) Dissolve 6.7 g (48 mmol) of the product from d) in 140 ml absolute dioxane, add

6 g of 5 pst.ig palladium charcoal and treated for 3 hours at 25° above normal pressure with hydrogen. The catalyst is filtered off, washed with a little dioxane and slurried several times with water. The solution thus obtained is evaporated, the remainder is dissolved in a little water and clarified with activated charcoal. The by evaporating

The residue obtained from the clear solution is stirred in 50 ml of methanol for one hour, whereby the buttery by-product dissolves and 3-hydroxy-5-aminomethyl-isoxazole becomes crystalline again. It splits at 155°. By careful recrystallization from water and tetrahydrofuran, white crystals with a cleavage point of 175° are obtained.

Example 2.

a) Mix 600 ml of ethanol and 600 ml of technical conc. aqueous ammonia solution and saturates it all at room temperature with ammonia. To this mixture, 120.5 g (0.5 mol) of 3-bromo-5-bromomethyl-isoxazole are added drop by drop at room temperature and the solution, which gradually darkens, is allowed to stand for 24 hours. The reaction solution is then evaporated in vacuo to approx. 0.5 liter and set sour with

2-n. hydrochloric acid. The resinous byproducts

is removed by filtering with hyflo and charcoal.

The filtrate is washed twice with chloroform or methylene chloride and then made alkaline to release the basic reaction product with conc. baking soda. It is then extracted five times with chloroform or methylene chloride. The combined extracts are dried over potassium carbonate and evaporated in vacuo. The remaining liquid is dissolved in ether and any smearing or clouding present is removed by filtering with charcoal. The 3-br.om-5-amino-methyl-isoxazole remaining after evaporation of the ether is a light brown liquid and can be reacted without further purification.

b) 140 g potassium hydroxide (0.2 mol) is dissolved in 885 ml methanol, 88.5 g (0.5 mol)

raw 3-bromo-5-aminomethyl-isoxazole is added and boiled for 20-30 hours under reflux. After cooling, the potassium bromide and resinous parts are removed by hyflo, the clear methanolic filtrate is evaporated, the residue is taken up for approx. 0.5 1 water and extracted several times with chloroform. The combined extracts are dried over potassium carbonate and evaporated. The distillation of the residue gives at 0.01 torr and approx. 70° approx. 50-60 per cent of the theoretically calculated quantity of the reaction product. However, according to the NMR spectrum, the colorless liquid contains, next to the desired 3-methoxy-5-amino-methyl-isoxazole, another 20 percent starting material.

c) 65 g of the reaction product from b) is boiled with 650 ml of 24% hydrochloric acid for 4 hours

during reflux. The reaction solution is then diluted with the same volume of water and filtered with charcoal through hyflo. The pale yellow solution is evaporated in vacuo, the residue is dried, dissolved in 650 ml of methanol and 65 ml of triethylamine is added. It

clearly alkaline mixture is evaporated in vacuo, the residue is suspended in 650 ml of fresh methanol, 325 ml of tetrahydrofuran is added and the whole is cooled in a refrigerator. The precipitated 3-hydroxy-5-aminomethyl-isoxazole (5-aminomethyl-3-isoxazole) is washed first with methanol and then with ether.

For complete purification, the substance is dissolved in approx. the twenty-fold amount of water, methanol is added to the solution and filtered once or twice with charcoal through hyflo. Tetrahydrofuran is added to the colorless filtrate at room temperature until crystallization begins. After standing at room temperature, the substance is filtered off. After drying for several days at 12 torr over phosphorus pentoxide in a desiccator, it is analyzed and melts during cleavage at 175° C.

Example 3.

a) 8.80 g (50 millimoles) of 3-bromo-5-aminomethyl-isoxazole, 5.6 g (100 millimoles)

potassium hydroxide and 110 ml of benzyl alcohol are heated for 10 hours at 180°. After cooling to 20°, the fivefold amount of ether is added to the reaction mixture and extracted twice each time with 200 ml of 2 N hydrochloric acid. The acidic aqueous extract is washed 4 times each time with 300 ml of ether, made alkaline and finally extracted three times with methylene chloride. After drying the combined methylene chloride extracts over magnesium sulfate and distilling off the solvent, a yellow oil is obtained, which can be unequivocally identified by nuclear resonance spectrum as a mixture of 95% 3-benzyloxy-5-amino-methyl-isoxazole and 5% benzyl alcohol. b) 1.02 g (5 millimoles) of 3-benzyloxy-5-aminomethyl-isoxazole are hydrated in 50 ml abs.

dioxane in the presence of palladium-charcoal catalyst (5 per cent) at normal pressure and room temperature as long as up to 80 per cent of the equimolar amount of hydrogen calculated therein is taken up. The reaction mixture is then filtered, the filter material is washed with abs. dioxane and finally slurried in 20 ml of water, whereby the reaction product dissolves.

After filtering off the catalyst, the aqueous solution is evaporated. The remainder consists of pure 3-hydroxy-5-amino-methyl-isoxazole (5-aminomethyl-3-isoxazolol) with a melting point of 175° (under decomposition).

Example 4.

a) 2.7 ml abs. methanol is saturated at 0° C with dry hydrochloric acid gas. Added to that

a mixture of 10.0 g of γ-chloroacetate diester

(prepared after C. D. Hurd & J. L. Abernethy, J. Amer. Chem. Soc. 62, 1147 (1940)),' 20.0 g of orthoformic acid methyl ester and 13 g of abs. methanol. The mixture is boiled under water exclusion for four hours under reflux. The still warm reaction mixture is poured into 200 ml of ice water while stirring, immediately adjusted to pH 8 with 30% caustic soda and extracted four times with ether. The ether extract is dried over magnesium sulfate. After evaporation of the ether, the remaining oil is extracted in a 5 cm Vigreux column, a main fraction boiling between 101° and 103° at 11 torr, which does not react with aqueous FeCls solution.

■b) A solution of 35.0 g of hydroxylamine hydrochloride (0.5 mol) in 210 ml of hot abs. methanol is cooled briefly in an ice bath and added while stirring in a nitrogen atmosphere to a solution of 42 g of potassium hydroxide

(0.75 mol) in 155 ml of methanol, so that the temperature during the reaction dissolution does not rise above 20° C. After the addition of alkali is finished, it is stirred for 5 minutes in the ice bath, then the mixture is filtered off with suction through a glass filter and the goods are washed with a little methanol. A solution of 35.9 g of y-chloro-|3,p- is immediately added to the filtrate. dimethoxy-butyric acid ethyl ester in 20 ml of methanol and allowed to stand under nitrogen for 96 hours at room temperature. After a few hours a small crystal discharge is found

(KC1) place. The reaction solution is evaporated in vacuo. The residue is dissolved in twice the amount of water and separated on an anion exchange column (Dowex <®>). The column is neutral washed with water, then eluted with 2N acetic acid. At the tip of the acid zone, the eluate appears briefly alkaline, towards the end of this alkaline fraction the FeCl;! sample becomes positive (wine red).

The FeCl8-positive eluate is collected and evaporated in vacuum at 40°. The pale yellow crystalline residue is evaporated 5 times with water until acetic acid purity in vacuum, then dried at 40%, 5 torr for 15 hours. The light yellow product obtained is completely soluble in abs. methanol and melts at 107—110°.

For analysis, recrystallize three times from acetone, then sublimate at 120°/10-<3 >torr in a ball tube. The white sublimate has a melting point of 129—131°; sinters from 124°.

c) 5.0 g raw y-chloro-|3,|5 dimethoxy-hydroxy-butyric acid 1 130 ml glacial acetic acid is saturated under magnetic stirring first at room temperature. then at 0° with dry HC1 and then allowed to stand at room temperature for 16 hours. The light brown solution is evaporated at 40° in vacuum and the residue is evaporated 3 times with water. The yellow crystalline product thus obtained is extracted hot twice each time with 130 ml of ether, the yellow ether solution is filtered and evaporated, after which light yellow needles with a melting point of 90-95° remain. The still not completely pure product is unstable. A purification can be achieved by 'careful recrystallization from carbon tetrachloride or acetone or by high-vacuum sublimation (in small portions). The pure product is significantly more stable: white needles with a melting point of 97-101° (sinters from about 80°). Strong acid reaction in aqueous solution.

d) A solution of 3.1 g of crude hydroxy-5-chloromethylisoxazole in 40 ml of abs. methanol

saturated in a pressure autoclave with a glass insert at 0° C with dry ammonia, sealed and then kept for 10 hours at 100°. The dark brown reaction solution formed is evaporated in vacuo, the residue is taken up in water and filtered. The filtrate is separated on an ion-exchange column (Dowex <®> ). Elute with water until a colorless neutral chloride-free filtrate is obtained. The desired aminoisoxazolol is completely deposited on the column and is eluted with a 2% ammonia solution. (Testing of the eluate by paper electrophoresis). The aminoisoxazolol-containing fraction also reacts alkaline (pH 8) after complete removal of the ammonia. Aminoisoxazolol can be washed out with water. After evaporation of the fraction containing aminoisoxazol, yellow crystals remain: Recrystallization from water methanol gives 3-hydroxy-5-amino-methyl-isoxazole with melting point 175° (under decomposition).

Example 5.

a) 6.80 g (33 mmol) of 3-benzyloxy-5-amino-methylisoxazole are heated in 19 ml

(200 mmol) acetic anhydride and 100 ml glacial acetic acid for 15 hours in a steam bath. After adding 100 ml of methanol, boil for one hour under reflux and evaporate. The residue is taken up in 100 ml of chloroform, washed with 2n. sodium bicarbonate solution, water, 2n. hydrochloric acid and again with water and dried over magnesium sulphate. After evaporation, crystals are obtained, which melt after recrystallization from ether/pentane at 73-76°.

b) 492 mg (2 mmol) of 3-benzyloxy-5-acetylaminomethyl-isoxazole is hydrated in 10

ml of 95% ethanol or glacial acetic acid over pre-hydrated 10% palladium/coal at normal pressure and 20° for 6 minutes while absorbing 2 millimoles of hydrogen. After defil-

by evaporation of the catalyst, 3-hydroxy-5-acetylamino-methyl-isoxazole is obtained, melting point 132-135°.

c) 312 mg (2 mmol) of 3-hydroxy-acet-aminomethyl-isoxazole is heated in 20 ml

2n. hydrochloric acid for 2y2 hours under reflux. After evaporation and drying for two hours over solid potassium hydroxide at 50° and 0.1 torr, 3-hydroxy-5-amino-methyl-isoxazole hydrochloride is obtained, melting point 160° (decomposition).

Claims (1)

Process for the preparation of a previously unknown, therapeutically active isoxazole derivative of formula I, and its acid addition salts, characterized by) hydrogenating or reducing a compound of the general formula II, where R means hydrogen or the benzyl group, or b) by hydrogenolyzing a compound of the formula III, where R' means the benzyl group, or c) that a compound of formula IV, where R" means a lower alkyl residue or the benzyl group, is treated with bromohydrogen acid, chlorohydrogen acid or with the hydrochloride or hydrobromide of any alkyl-substituted pyridine in heat, or d) by reacting a reactive ester of 3-hydroxy -5-hydroxymethyl-isoxazole of formula V, with ammonia or e) by hydrolyzing a compound divide by the general formula VI, where Ac means a lower-molecular acyl residue, and transfers the obtained compound, if desired, to a salt with an inorganic or organic acid.