SU500747A3 - The method of obtaining derivatives of bornamine - Google Patents

Description

(S4) METHOD FOR LEARNING BORNANAMINE DERIVATIVES

one

The invention relates to a method for the noon day of new derivatives of bornobnob shoWs that are biologically active and can therefore be used in the pharmaceutical industry and mead.

There is a known method for obtaining barken-3 mics as in the stage form, in the label and in the optical optical isomers, by reduction of formoxime chambers by chemical gutum, for example, in alcohol, or by catalytic hydrogenation.

However, in the literature, information about the method of obtaining derivatives of borianamia, corresponding. general formula

SI,

U)

R

where R is alkyl or phenyl, which may be substituted;

Rj is lower alkyl, and at least. least one of the substituents R and R | t methyl with valuable properties. “The 11th way} is

Chro connection of the general formula

sn.

NHR.

(P)

R

where R and R, have the indicated meanings;

Splittable residue,

hydrolyze in the usual manner fiajspHsfe) with acid, followed by extracting the desired product as a base or its salt, as well as optically active itaOMepa.

Refluxing hydrolysis of a group refers to such groups as an acyl group, for example, alkynoyl, alkpopoil-, aroll-, aralKaftojij-, aralkenoip-, aralkinoipgruppenii, VII Complex (the group of Tyokvrbonic KUCTioTrc). nor -, arip-, aralkynyl-, aralkenyl-, as well as aralkynyl-residue of these acylgrush: for its part still to be, replaced by a residue of the formula

nooh oh

II

NH-C where R and R. have the indicated meanings. In this case, we can speak about the diameter of the joint P.

The hydrolysis of the amide of an acid of formula II can be carried out in a known manner, for example by heating with an acid or base, in the appropriate case in the presence of an organic solvent such as an alcohol, for example, in methanol, ethanol or ethylene glycol, but preferably with an acid.

Direct or branched 1c | alkylgroups with 1-6 carbon atoms of the genus such as methyl, ethyl, n-propyl, isopropyl, w-butyl, isobutyl, tert-butyl can be used as the lower alkyl groups; amyl, hexyl.

Halides, preferably bromine or chlorine, amino, hydroxy and lower alkoxy groups are used as substituents for phenylostrances.

Lower alkyl ether groups are used as the lower alkoxy group, where the lower alkyl residue has the indicated meaning.

The compounds of formula I can be obtained in the form of racemates, which can be separated into optical isomers, for example, by fractional crystallization of salts using optically active salts.

. As a starting material, compounds of the formula I, where / -: methyl and I, j "are hydrogen, can be obtained;

from fenkhona.I

 Used as source

the material of the compound of the formula I, where Rf -;

y,

methyl, and about OD ° P ° D can be derived, for example, from camphor when it interacts with the corresponding organometallic compounds.

Compounds of formula II and correspondingly compounds of general formula I, where |

i estemennoe phenyl, can be obtained. in such a way that the substituent is introduced, by known methods, into an unmixed fe l i nyl ring of the corresponding amide

Compounds of formulas I are bases and can be converted to salts J by reacting acids with p, for example, with hydrochloric, hydrobromic, sulfuric, phosphoric, or organic compounds.

acids, such as acetic, tartaric, maleic, fumaric, citric, oxalic, toluenesulfonic.

Primer p 1. 6, O g rac-N- (4-propyl-2-exo-Burnil) | -aaetamide; KI nt t under reflux for 64 hours with stirring in 30 ml of ethanol and 6O ml of 6 n. salt xyloslot The mixture of alcohol and water is evaporated, the residue is dissolved in water, brought to an alkaline reaction using 3 n. caustic soda solution, and the precipitated base is extracted with ether. The ether solution is washed to neutrality with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue is dissolved in a swirl, hydrochloric acid is added, and crystallized from alcohol - | j ocToro ether. 5.3 g of rac-4-propyl-2-exorbamine-hydroxy-hydrochloride with m.p. 294-296 S.,

Acetamide used as starting npo-j duct of rac-M - (4-prop-l-2-exo-borne) can be obtained as follows. To the 75 ml of glacial acetic acid is added 1O, 79 g of concentrated sulfuric acid (- 1.84). A heterogeneous mixture of 17.83 g of rac-2- (1-propylidene) -catan and 4.5 2 g of acetonitrile is then introduced. in 25 ml of glacial acetic acid. The reaction mixture is heated to 60 and stirred for 18 hours. The reaction material is cooled, poured onto approximately 500 g of ice and left to stand. The separated oil is absorbed by 300 ml of ether. A simple ether solution.

shake twice a day with water, 1OO ml each, twice with a saturated solution of carbonate carbonate, 1OO ml and two

water 100 ml. By drying the ether solution over sulfate

The sodium residue is chromatographed on ZOO g of silica gel (0.2-0.5 mm) using methipen-chloride as eluent. 136 fractions are collected in 20 ml. Fraction 11O-136 contains 13.5 g of rac-N - (4-proch1L-2-exobornil) -cetamide, the polymer is melted by crystallization from acetonitrile at 96-98 ° C. Example 2. 5 g of rac-N- (4-phenyl | -2-exobornyl) -acetates, 2OO ml of ejano: la and 400 ml of hydrochloric acid are heated together with reflux for 72 hours .. Then evaporated in vacuum and the residue is crystallized from methanol. Water. 4.22 g of raa-4-phenyl-2-exo-bornamine hydrochloride are obtained as colorless crystals of the Art. square 345--35 ° C. . To release the base to 4.2 g of hydrochloride, add 16 mt of sodium shekhek and mix the bin three times; ashes. The benzene phases are evaporated in a vacuum k, 3.7 g of amine are obtained, which are distilled in a tube with ball expansion at approximately 8 ° C / 0, O5 mm Hg. Art. The rac-fi (4-fen-2-2-Exo-borNile) -adata MFA used as the starting product can be obtained as follows. 34.5 g of 2 phenylborneol and 15.8 ml of a11 tononitrile are added dropwise to them; A few minutes at BO ° C to dissolve 32 g of concentrated sulfuric acid in 45O ml of glacial acetic acid. After 6 hours, 58.5 m of acetonitrile was added at 60 ° C and continued to stir for 15 hours at 6 ° C. Then pour over the ice and extract with methylene chloride. The combined methylene chloride phases were shaken with a saturated solution of sodium hydrogen carbonate, dried "with sodium sulfate and evaporated. The residue is crystallized from methylene chloride-hexane and 15.3 g of pau-.N - (4-phenyl-2-eksornyl) -acetamide are obtained, with an mp. 151-152 ° C. Romatogragana 4H stock solutions using methylene chloride on silica gel give another 6.6 g of pure amide. Total yield: 21.9 g. Example 3. 3.2 g of N .4- {p-nitrophenyl) -2-exocorn: Acetamnd is hydrogenated in ZOO ml of glacial acetic acid with O, 6 g of palladium on carbon catalyst. The catalyst is filtered off, evaporated in vacuo and the residue is boiled for 72 hours with 150 ml of ethanol and 30 ml of 6N hydrochloric acid. hydrochloric acid with reversed. cooler, evaporated in vacuo; The residue is crystallized from ethanol and | 4- (p-aminophenyl) -2-exoronic amine-dihydrochloride is obtained with m. Pl. 338 C. f Used as the starting, Kl, - L4 - (- nI trophenyl) -2-ecco, .. oornyl-acetamide can be obtained as follows. To 21.6 g of rac-M- (4-phenyl-2-exo-borntl) -acetamide (prepared according to example 3); 12 O ml of concentrated nitric acid was added. To the mixture aged at -10 ° C, the mixture is prepared with 72 ml of lactic acid with stirring. The mixture was incubated for 25 hours at -10 ° C, then heated to O, poured onto 1 kg of ice. Extracted with methylene chloride, the organic phase is dried with sodium sulfate and evaporated. The residue is crystallized from acetone-n-hexava and 14.9 g of rac-1-H nitrophenyl) -2-exoronic-acetamide are obtained with a melting point of mp. 2O5 2O6 ° C. . ... - - - ... Example 4. 603 mg of rac-N P-methoxyphenyl) -2-exonyl-acetamide are heated under reflux with 72 ml of 6 n hydrochloric acid and 36 ml of ethanol for 72 hour. It is then evaporated in vacuo until crystallization begins. After standing in the refrigerator, filter on suction and the residue is recrystallized from eTanopody., Receive. 0.2 rac-4 - (- methoxy-phenyl) -2 Kso-bornanamine-hydrochloride t. Pl. 309-310 ° C, / Rad-N (p-methoxyphenyl) -2-exocorn / fl-acetamide used as the starting material can be obtained as follows. 5.2 g of 2- {p-methoxyfennl) -orns; de11a- (2) and 2.1 ml of acetonitrile, dissolved-. In a small amount of acetic acid, they are pinned to a mixture of 4.26 ml of concentrated sulfuric acid and 6O ml of glacial acetic acid. After 8 hours of stirring at 60 ° C, 2.1 ml of acetoitrile are added and the mixture is stirred for 13 hours at 6 ° C. The mixture is then poured onto ice and extracted with methylene chloride. The methylene chloride phase is shaken with a saturated solution of sodium hydrogencarbonate, dried over sodium sulfate and evaporated. The residue from evaporation (1.4 g) is chromatographed first with methyl chloride, then with methylene chloride and methanol (98: 2) on 2O g of silica gel. Get 4O ml fraction. Fractions 22-33 contain 0.6 g of a substance that crystallizes from n-hexane-methylene chloride. 0.3 g of rac-N (p-methoxyphenyl) -2-exobornyl-acetamide with m.p. 156-157 ° С, П р and measures 5, 7 g N - 4- (P-chlorophenyl) -2-exo-borne, t-acetat (and boil for 96 hours with reverse cooling with 280 ml ethanol and 5 ml of 6N hydrochloric acid. After evaporation in vacuum, the product is dissolved in 140 ml of water and 210 ml of ethanol and concentrated in vacuo to crystallize the starting material. It is dissolved in the cold, sucked off and the mother liquor concentrated again to the onset of concentration, yielding 3.1 g of 4- {P-chlorophenyl) -2-exsoyl "jQ. -. namin-hydrochloride with t. pl. 345 C. Using N - 4- {p-chlorophenyl) -2-e "as the starting product; o-6-ornyl-acetamide can be obtained in a somewhat editable manner. 15 g of magnesium is activated with iodine. 50 ml of absolute r K3ctx ro ether is added to it, then a solution of 114.9 g of 4-bromo-chlorobenzene in 40 O ml of absolute npoctx ro is added dropwise within an hour. The mixture was then boiled under reflux for 14 hours. The reacon mixture was cooled to 0 ° C, and a solution of 76 g of camphor in 1OO ml of ether was added over 15 minutes. At the same time, the internal temperature does not exceed 3 ° C. Stir. 6O more hour at. Then, 2OO ml of a saturated ammonium chloride solution is added dropwise to the mixture. The phases are then separated and the aqueous phase is shaken with ether three times. The combined ether extracts are washed with Sodium Silk SI with water, dried over sodium sulfate and evaporated under vacuum. After removal of unreacted camphor in a water-jet vacuum, oil pulp is distilled under vacuum. 27.7 g of 2- (p-chlorine unip) -neurneol are obtained. A mixture of 22; 3 g of 2- (p-chlorophenyl) -boron ol, 8.9 ml of aceto-nitrile and a small amount of glacial acetic acid is added dropwise over several minutes to a mixture of 17.9 ml cooled to 60 ° C with stirring concentrated sulfuric acid and 25 O ml of glacial acetic acid. Continue to stir at 60 ° C. After 7 hours, another 8.9 ml of acetonitrile are added dropwise. 22 hours later, dripping onto ice and extracting with methylene chloride. The methylene chloride phase is shaken with water, to which solid sodium hydrogencarbonate is added, while CO „emission is observed. The LA chloride phase is dried over sulfate and three and evaporated. The rest of the chromatography1 is coziness on 420 g of silica gel, with first k5OT1 Lenhlo 3 u and then methylene chloride-methanol (98: 2) serve as solvent jicKf. Collect fractions of 300-450 ml. Fractions 11-20 contain 12 g of pure N - |} 1- (p-chlo} n) eepl) - 2-exo-boron 1 il1 - -ag.Ta.mida, which melts according to zrutallylachp from chgs.s. -hexanl prc. 10G -107 S .. 500 8 ..-, Example 6. Zg rad-C ,,, 4,7,7-tetramethyl-2-exo-norbornyl) -acetamide is suspended in 15 ml of alcohol, ZO mp 6 n. hydrochloric acid and refluxed for 46 hours. The reaction mixture is evaporated in a rotary evaporator and the residue is dissolved in water. The aqueous solution is shaken with ether and the aqueous phase is brought to alkaline sodium hydroxide and the free base is absorbed by simple EFF1F. The ether solution is washed to the nebrashpeya using nasysheknogo solution of salt, dried. shh sulphate oyrk, lt and evaporated. The preparation of a hydrous salt with alcoholic hydrochloric acid is prepared. 2.4 g of rats are obtained from the interstitial salts from ether; 1,4,7,7-tegrametnp-2-exo-norbornanamine-hydrochloride with t. Pl. above . The rac-N- (1,4,7,7-tetramethyl-2-exo-norbornyl) -chacetamide used as the starting material can be obtained as follows. 15.0 g of 1-methylcamphene are dissolved in 15O ml of acetonitrile, heated to 8 ° C, and 11.77 g of concentrated sulfuric acid are added with stirring over 2 hours. After 3 hours, the reaction mixture is cooled (and the contents of the flask are poured; Approximately ZOO g of ice. The precipitated substance excreted in May is taken up in ether, the ether phase is washed with water, dissolved over sodium sulfate, filtered and evaporated. The residue is recrystallized from petroleum ether (4O-45). 6.55 g of - (1,4,7,7-tetramethyl-2-exo-norbornyl) -aietamide are obtained, with an mp. 121 ° C 123 ° C Example 7. 1g S-methyl ester of para-N - (154,7,7-tetramethyl-2-exo-norbornyl) -thiocarbamic acid; a solution of o1 in 5 ml of ethanol, 2 o 6 ml of 6 n are added to it hydrochloric acid and refluxed for 1 h. The reaction material is evaporated, the residue is dissolved in water, shaken with ether, separated and the aqueous phase is made alkaline with sodium hydroxide. The liberated base is taken up in ether, dried over sodium sulfate, filtered and evaporated. A hydrochloride salt is made from the residue using alkagic hydrochloric acid. By recrystallization from alcohol-ether, O571 g of rac-1,4,7,7-tetramethyl-2-exo-norbornanamine hydrochloride is obtained. /. square high • The rac-N-methyl ester of rac-N - {1,4,7; 4. Trommethyl-.2-exo-norbornyl) -thiocarbamic acid, used as the initial pro- jukt, can be obtained as follows. 1.5, about 2 g of 1-methylcamphene are mixed with 1OO ml of glacial acetic acid and 19.62 hrs of ethyryl sulfuric acid, then 8.04 g of methylthiocyan1 a are added dropwise with stirring at room temperature for 15 min. After 2 hours while stirring the mixture, the reaction mixture is diluted

P o r ° m u l a and 3 o b e te n u

The method of obtaining derivatives of boron, H; ana; -L1No of the general formula

SI

.NH

(one)

where R is lower malignant or phenyl kb-, which may be substituted;

- lower alkyl, jump, mei-.

TO

one

at least one of the substituents R and |, c. - methyl,

 or salts thereof, characterized in that the compound of the general formula

NHR,

(AND)

where t, and R. have the indicated meanings;

R, is a cleavable hydrolysis residue,

subjected to hydrolysis in the usual way, for example with acid, followed by isolation of the target product in free form or in the form of a salt, in the form of a racemate or an optically active isomer in a known manner. 1 with ZOO ml of water and three times injected with ether in 15O ml each time. The organic phase is washed with water, a saturated solution of soda, water, dried over sodium sulfate, filtered and lighted. The residue was chromatographed over 16O g of silica gel (0.2-0.5 ml) using methylene chloride as eluent. Collect 170 fractions per 10 ml. The fractions contain 12, O g of a g-methyl ester (1,4,7,7-tvtrametil-2-0kso-vorbornil): thiocarbamic acid, which is digested at 100 IO ° C / 15 mm Hg. Art.