SU586835A3 - Method of preparing aminopropanol derivatives or their salts,racemates or optically active antipodes - Google Patents

Description

(54) METHOD FOR OBTAINING AMINOPROPANOL DERIVATIVES

OR THEIR SALTS, RACEMATS OR OPTICALLY ACTIVE ANTIPODS

one

The invention relates to a process for the preparation of new, not described in the literature, derivatives of aminopropanol or their salts, racemates or optically active antipodes that have biological activity and can be used in medicine,

The preparation of amines from benzylamines by hydrogenolysis using palladium on carbon (fl) as a catalyst is widely described in the literature.

In order to synthesize new derivatives

aminopropanol of general formula

CH2-CH-CH20H

TYANKG (I) 20

where hydrogen, halogen, hydroxy-, trifluoromethyl-, alkyl-, alkoxygroup each with 1-4 carbon atoms;

Ua is hydrogen, alkyl with 1-4 carbon atoms or benzyl, their salts, racemates, or optically active antipodes, a method for the preparation of these derivatives, based on 2

well known reaction and

that in the compound of the general formula

CH2-CH-CH20H

gan

AT 4

5 (P)

where R% i is hydrogen and methyl;

values of methoxy group;

% is R, benzyl or benzoyl, and at least one of the radicals Rj, d and B means or ss keep the indicated protecting group, is cleaved by 0-methyl- or .K. -benzoyl group with strong hydrochloric or hydrobromic acid or removed

N-benzyl group by catalytic hydrogenation in the presence of palladium on carbon in the medium of an organic solvent at a temperature from room temperature to the boiling point of the reaction medium, followed by isolation of the target product in free form or as a salt, as a racemate or an optically active antipode.

The cleavage of the 0-methyl or N. -benzoyl groups is preferably carried out in ethylene glycol at the boiling point of the reaction medium. The removal of / K-Senzyl groups is preferably carried out in methanol or its mixture with water at a temperature from room temperature to. The desired product is isolated in free form or converted into salt using hydrochloric or hydrobromic acid, as a racemate, or the resulting racemate is divided into optically active antipodes. Example 1. 2-Amino-3- (3,5-dioxyphenyl) -1-propanol bromohydrate. A. 2-Amino-3- (3, 5-dimeT hydroxyphenyl) -1-propanol hydrochloride. 6.8 g (28 mol) of 3,5-dimethoxyphenylalanine methyl ester is dissolved in 35 mm. of absolute tetrahydrofuran and added dropwise at 20–30 ° C to a stirred suspension of 3.2 g (Vmmol lithium aluminum hydride in 35 ml of absolute tetrahydrofuran, boiled for another 2 h with refluxing with 1c, cooled and carefully decomposed with water. Then extracted with acetic ether , the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is taken up with hydrochloric acid in ether to the hydrochloride. Yield 6.5 g (65%), mp. K. Bromohydrate 2-amino-3- ( 3,5-dioxyphenyl) -1-propanol. 4.5 g (18.5 mmol) of 2-amino-3- (3,5-dimethoxyphenyl) -1-propanol hydrochloride and boil for 1 h under reflux with 45 ml of hydrogen bromide. Then excess hydrobromic acid and the residue are distilled off in vacuo azeotropically with toluene-alcohol. The crystalline residue is recrystallized from isopropanol-ether to obtain the desired product, yield 1.8 g (37%), tpl, 118-120 C. PRI mme R 2. Bromhydrate 2-benzylamino-3- (3-hydroxy-4-methylphenyl) -1-propanol, A. 2-benzylamino hydrochloride -Z- (3-methoxy-4-methylphenyl) -1-propanol 55.5 g (0.16 mol) of ethyl ester I-Benzoyl-3- (3-methoxy-4-methylphenyl) alanium (m.p. ) is dissolved in 550 ml of absolute tetrahydrofuran and 37 ml (0.98 mmol) of lithium aluminum hydride in 1850 MP of absolute tetrahydrofuran are added dropwise to the stirred suspension in nitrogen atmosphere. It is then boiled for 5 hours under reflux, left to stand overnight and slowly decomposed with water. The inorganic precipitate is filtered off with suction and washed with tetrahydrofuran. The solvent is distilled off in vacuo, taken up in ether and treated with water. The ether phase is dried over sodium sulfate and distilled off. The residue is recrystallized from ne, trol 1 st ether, yielding 45.0 g (96.5%) of the base, which is dissolved in. acetic ether and the addition of hydrochloric acid in ether are converted into the hydrochloride, yield 49.5 g (95% f), m.p. 191 ° C, B. 2-Benzylamino-3- (3-hydroxy-4-methylphenyl) -1 -propanol. 20 g (62 mmol) of 2-benzylamino-3- (3-methoxy-4-methylphenyl) -1-propanol hydrochloride in 200 ml of 48% hydrobromic acid are refluxed for 1 hour, the precipitated crystals are precipitated, and recrystallization from water gives the desired product, yield 21.5 g (98.5%), mp, Example 3. 2-Amino-3-hydrobromic acid is (3-xi-4-methylphenyl) -1-propanol. 21 , 5 g (61 mmol) of the 2-benzylamino-3- (3-hydroxy-4-methylphenyl) -1-propanol bromohydrate obtained in Example 2 are dissolved in 250 ml of methanol and 6 g of palladium / / / carbon catalyst ( 5%), catalytically distilled, ben yl at 60 C and a pressure 5ati, hydrogenation After filtration, methanol was distilled off in vacuo and the residue dissolved in acetonitrile. Upon cooling, the target product crystallizes out, which is sucked out and dried, yield 13 g (81.5%), t, pl. 115-117 ° C. Example 4. 2-Amino-3- (3-hydroxy-5-methylphenyl) -1-propanol hydrobromide. A. Ethyl 3- (3-methoxy-5-methylphenyl) alaine ester. 56 g (0.33 mol) of 3-methoxy-5-methylbenzyl chloride is added dropwise to a solution of 56 g (0.33 mol) of acetamidocyanuacetic ester and 7.8 g of sodium in 330 ml of ethanol, boiling for 4 h. Return to the condenser, suction off the precipitated sodium chloride, and distill off the alcohol in vacuo. The residue is concentrated, boiled for 20 hours with 117 g of potassium hydroxide in 920 ml of water, acidified with concentrated hydrochloric acid and evaporated to dryness. The amino acid is extracted with ethanol (2x1 L), the alcohol is distilled off and the resulting amino acid hydrochloride (m.p. 184-185 ° C) is recrystallized from acetonitrile, yield 46 g (57%), m.p. . Ethyl ether is obtained by azeotropic esterification with a yield of 65%, B. 2-amino-3- (3-methoxy-5-methylphenyl) -1-propanol hydrochloride. 33 g of 2-amino-3- (3-methoxy-5-methylphenyl) -alanine ester hydrochloride are suspended in ether and, by adding dilute ammonia, transferred to the base, dried over sodium sulfate, the ether is distilled off in vacuo, redissolved in 330 ml of absolute ether, added dropwise to the stirred

a suspension of 13.6 g of lithium aluminum hydride in 700 ml of absolute ether, boil for 5 hours under reflux, decompose with water, suction and crymayOT in vacuum. The residue is dissolved in acetonitrile, the calculated amount of hydrochloric acid in ether is added, the hydrochloride precipitated is sucked off and the yield is dried 23 g (83%), m.p. 204-205 0.

B. 2-Amino-3- (3-oxy-5-methylphenyl) -1-propanol eromhydrate.

To 23 g (0.1 mol) of 2-amino-3- (3-methoxy-5-methylphenyl) -1-propanol hydrochloride are added .239 ml of 48% hydrobromic acid, refluxed for 1 hour, distilled A portion of hydrobromic acid is cooled, sucked off and recrystallized from aqueous aceto. nitrile receive the target product, yield 29 g (76%), mp,

EXAMPLE 5 A, 5Oiopihydrate 2-ben zylamino-3- (3-hydroxy-4-methoxyphenyl) -1-propanol.

13 ml of N-benzoyl-3- (3-hydroxy-4-methoxyphenyl) -alanine methyl ester (t, pl. 114-11bC) is dissolved in absolute tetrahydrofuran and added dropwise to a placed suspension containing 9 g of lithium aluminum hydride in 450 ml of absolute tetrahydrofuran. The mixture is boiled under reflux for 6 hours, allowed to stand overnight, then decomposed with water, sucked off, extracted twice with dimethylformamide and both organic solvents are evaporated to dryness. The residue is dissolved in 2 n. hydrochloric acid, extracted with ethyl acetate and alkalinized with potassium carbonate. The resulting 2-aminopropanol is extracted with ethyl acetate, dried with sodium sulfate, the solvent is distilled off in vacuo, the residue is dissolved in acetonitrile, mixed with the calculated amount of hydrochloric acid in ether and sucked off; yield 6 g (47%), so pl.

B. 2-Amino-3- (3-hydroxy-4-methoxyphenyl) -1-prog anol hydrochloride.

6 g (18.6 mmol) of 2-bezylamino-3- (3-hydroxy-4-methoxyphenyl) -1-propanol hydrochloride is dissolved in 60 ml of methanol, palladium / carbon catalyst (5%) is added, catalytically from gon benzyl. After the calculated amount of hydrogen was taken up, the catalyst was filtered off, the meth, nol was distilled off in vacuo and the desired product was obtained by recrystallization from acetonitrile, yield 4 g (92%), mp 181-182 ° C.

PRI me R 6. Bromhydrate 2-amin6-3- (3-hydroxyphenyl) -1-propanol.

A, 2-amino-3- (3-methoxyphenyl) -1-propanol hydrochloride,

29 g (0.139 mol) methyl ester

3- (3-methoxyphenyl) -alanine is dissolved in 170 ml of absolute tetrahydrofuran, and 10.6 g (0.278 mp) of alumiriddithium lithium in 170 ml of absolute tetrahydrofuran are boiled in a boiled 2 hours, perera. similarly to the previous examples, 2-amino-3- (3-methoxyphenyl) -1-propanol hydrochloride is obtained, a yield of 26.5%, mp,

B. 2-Amino-3- (3-hydroxy-phenyl) -1-propanol bromohydrate.

 . 8 g of 2-amino-3- (3-meter-xyphenyl) -1-propa-nola hydrochloride are boiled for 1 h under reflux in 80 ml of 5 48% hydrobromic acid. It is then evaporated to dryness in vacuo, dehydrated with xylene, and recrystallization after the solvent is distilled off from glacial acetic acid to give 0-6 g (66%) of the desired product, mp. 150-152 C, .

PRI me R 7, 2-Amino-3- (3,5-dioxyphenyl) -1-propanol bromohydrate,

A, 1- (3,5-dimethoxyphenyl) -2-nor5 troetan,

27 g (0.129 mol) of 2,5-dimethoxy-4-nitrostyrene is dissolved in 540 ml of benzene, nitrogen is passed, 1.3 g of tris (triphenylphosphine) -rodi (+1) chloride is added as a catalyst and at 60 ° C and a pressure of 5 MPa, the calculated amount of hydrogen, then after hydrogenation, benzene is distilled off and the residue is triturated with ether. At 5 this catalyst coagulates. The mixture is filtered off with suction, the ether is distilled off and recrystallized from methanol; yield 21.3 g (78.5%), so pl. 51-53 C,

B. 3- (3,5-dimethoxyphenyl) -2-nitro0 -1-propanol.

10 g (47.4 mmol) of 1- (3,5-dimethoxyphenyl) -2-nitroethane are dissolved in. 100 ml of ethanol, add 1 ml of con, a centered sodium hydroxide solution, then slowly drop in Bg (So mmol) of a 30% formalin solution, keeping the temperature below 20 ° C, leaving it at 70 hours at room temperature, maintaining the solution a alkaline, then acidified with 2H, acetic acid, the solvent is distilled off in vacuo / partitioned between glacial acetic acid and water, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo. The residue is triturated with warm toluene; crystallization product, yield 8.9 g (78%), mp, 81g-83 C,.

B. 2-Amino-3- (3,5-di. Methoxyphenyl) -1-propanol hydrochloride.

.. 8.5 g of 3- (3,5-dimethoxyphenyl) -2-nitro-1-propanol is dissolved in

Claims (3)

100 MP of methanol are hydrogenated under normal conditions after addition of platinum dibide. After absorption, the calculated amount of hydrogen is filtered off from the catalyst and evaporated to dryness in vacuo. The residue is dissolved in acetonitrile, by adding the calculated amount of hydrochloric acid in the ester to obtain the hydrochloride with m.p. 165 s, yield 5.3 g (71%). 2-Amino-3- (3,5-dihydrophenyl) -1-propanol bromohydrate is prepared as in Example 1. Example 1. Example 8. 2-Amino-3- (3-hydroxy-5-trifluoromethylphenyl; -1-propanol .., A.Z-Methoxy-5-trifluoromethylbenzaldehyde bromohydrate. 125 g of 3-methoxy-5-trifluoromethylanine are decomposed according to the Besch method in 3-methoxy-5-trifluoromethylben-3-aldehyde, bp 58-60 C / 0.1 mm Hg / p 1.4833. B. Methyl ester N-benzoyl-3-methoxy-5-trifluoromethylphenylalanine. methoxy-5-trifluoromethylbenzaldehyde with hippuric acid gives azolactone (mp. 149150 C), which is boiled in methanol in the presence of a catalytic amount of potassium carbonate and d-benzamido-3-meth hydroxy-5-t is obtained ifofluoromethyl cinnamic acid (m.p. 143 C), which is catalytically hydrogenated into methyl ester by H-bent 3 oyl-3-meth oxy-5-three ft of ormethylphenylalanine, mp. 133 C. B. hydrochloride 2-benzylamino-3- (3-methoxy-5-trifluoromethylphenyl) -1-propanol. 17 g of the ester prepared in B is reduced, as in Example 2A, to an amino alcohol. Mp. Hydrochloride I6l G. Bromohydrate 2-benzylamino (3-hydroxy-5- trifluoromethylphenyl) -1-propanol. 15 g of 2-benzylamino-3- (3-methoxy-5-trifluoromethylphenyl) -1-propanol hydrochloride is demethylated by boiling for one hour with 48% hydrobromic acid. Then the reaction mixture is cooled, the precipitated crystals are sucked off and dried. Output 11 g, so pl. 206-207 C, D. 2-Amino-3- (3-hydroxy-5-trifluoromethylphenyl) -1-propanol hydrobromide. Benzyl cleavage is carried out catalytically in methanol. After absorbing the calculated amount of hydrogen, it is filtered off from the catalyst, the solvent is distilled off in vacuo and the desired product is obtained by recrystallization from acetonitrile, m.p. 155-156 Example 9. 2-Amino-3- (3-chloro-5-hydroxyphenyl) -1-propanol hydrobromide In analogy to Example 8, 2-chloro-5-methoxybenzene aldehyde is obtained by condensation with hippuric acid aa lactone (m.p. ), and from it the corresponding hydrochloric acid methyl ester (mp 121-123 ° C) and, after reduction with lithium aluminum hydride, 2-benzylamino-3- (2-chloro-5-methoxyphenyl) -1-propanol hydrochloride, t. mp I67 i68 ° cl After catalytic distillation of benzyl (mp. 163-165 C) and imethylation with 48% hydrobromic acid, the expected product is obtained, mp. 174-175 ° C. Example 10. 2-ethylamino-3- (3,5-dioxyphenyl) -1-propanol thrombohydrate. A. Methyl EFIR- N-acetyl-3,5-dimethoxyphenylalanine. 3,5-Dimethoxybenzaldehyde is condensed with acetic acid into azolactone (mp. 142-143 C), yield 45%. By refluxing in the presence of potassium carbonate and subsequent hydrogenation, the methyl ester H-acetyl-3, 5 is obtained dimethoxyphenylalanine, t.pl 110-111 C. -B. 2-Ethylamino-3- (3,5-di-methoxyphenyl) -1-propanol bromohydrate. 42. G methyl ester of L-acet-yl-3, 5-dimethoxyphenylalanine is reduced in absolute-tetrahydrofuran with lithium aluminum hydride to 2-ethyl-amino-3- (3,5-dimethoxyphenyl) -1-propanyl- (.. 62-83 WITH) . Bromhydrate 175C. B. Bromohydrate 2-ethyl 1INO-3- (3,5-dirxyphenyl) -1-propanol. 10 g of the bromohydrate obtained in b. B is demethylated by boiling with 48% bromo-ester acid, the excess of which is then distilled off and recrystallization from acetonitrile gives the desired product, m.p. 167168 0. Example 11. 2-Methylamino-3- (3,5-dihydrophenyl) -1-propanol hydrobromide. Analogously to Example 10, y is formed, starting from If-formyl-3, 5-dimethoxyphenylalanine methyl ester, by reduction with lithium aluminum hydride 2-methylamino-3- (3,5-dimethoxyphenyl) -1-propanol hydride, m.p. . By demethylation with 48% hydrobromic acid, the desired product is obtained, mp. 183-186 ° C. Example 12. 2-Clmino-3- (3-hydroxy-2-methylphenyl) -1-propanol hydrobromide. A. Benzoyl-3-methoxy-2-methylphenylalanine methyl ester. Z-methoxy-2-methylaniline is metabolically decomposed according to the Besch method analogously to example 8 in Z-methoxy-2-methylbenzaldehyde, by reaction of which with hippuric acid, the corresponding azolactone (m.p.) is obtained, which by boiling in methanol in the presence of potassium carbonate and the subsequent catalytic hydrogenation is decomposed into N-benzoyl-3-methoxy-2-methylphenylalanine methyl ester, m.p. 143-144 C. B. 2-Gamino-3- (3-hydroxy -2-methylphenyl) -1-propanol bromohydrate. I-benzoyl-3-methoxy-2-methylphenylalanine methyl ester with lithium aluminum hydride is converted to 2-benzyl amino-3- (3-methoxy-2-methylphenyl) -1-propanol, m.p. hydrochloride 174 ° C. By boiling with 48% hydrobromic acid, 2-benzylamino-3- (3-hydroxy-2-methylphenyl) hydrochloride is obtained from it ;; 1-propanol, m.p. 153 C, which is catalytically distilled benzyl, is converted to the 2-amylo-3- {3-hydroxy-2-methylphenyl) -1-propaiol hydrobromide, m.p. .. Example 13. 2-ami no-3- (3-hydroxy-b-methylphenyl) -1-propanol hydrobromide. A. Methyl ester of N-benzoyl-3-methoxy-6-methylphenylalanine. 2,5-Cresotinic acid is methylated with dimethyl sulfate to 5-methoxy-0-toluic acid, m.p. 152154 ° C. Rosenmund obtained 5-methoxy-0-toluol aldehyde, b.p., via an acid chloride (bp. 81-83 ° C / 0.3 mm Hg.-). , 3 mm PT Then, as in Example 1, azolactone is prepared. 170-171 C and methyl ester K-benzoyl-3-methoxy-6-methylphenylalanine, so pl. 98 C. B. B. 2-Amino-3- (3-hydroxy-6-methyl-phenyl) -l-propanol bromohydrate. Obtained by reduction with lithium aluminum hydride, 2-benzylamino-3- (3-meth-6-methylphenyl) -1-propanol (m.p. 192-193 C is demethylated first (m.p. 166167 C) and then catalytically distilled benzyl , converted to 2-amino-3- (3-hydroxy-6-methylphenyl) -1-propanol hydrobromide, m.p. EXAMPLE 14 2-amy-3- hydrochloride (3.5 -dioxyphenyl) -1-propanol. A. 2-Benzamido-3- (3,5-dimethoxyphenyl) -1-propanol. To 34.3 g of methyl 3- (3/5-dimethoxyphenyl) -N-benzoyl methyl ether 350 tetrahydrofuran is added by stirring at room temperature, 4.2 g of sodium borohydride, stirred 30 m and to After cooling, the solvent was distilled off in vacuo and the residue was suspended in water and acidified with acetic acid. The crystals thus formed were filtered off with suction, water was taken up and dried, and 2-benzamido-3- ( 3,5-dimethoxyphenyl) -1-propanol, mp I7-118 C. B. 2-Amino-3- (3,5-dioxyphenyl) -1-propanol hydrochloride. 21 g 2-benzamido-3- ( 3,5-dimetoko. phenyl) -1-propanol is boiled in 200 ml of 6 n. hydrochloric acid for 8 hours under reflux. After cooling, the mixture is extracted three times with chloroform, evaporated in vacuo to dryness and recrystallization from glacial acetic acid to obtain 2-amino-3- (3,5-dioxyphenyl) -1-propanol hydrochloride, m.p. . Example 15. 2-Amino-3- (3,5-dihydroxyphenyl) -1-propanol hydrochloride .. A. Methyl ether .11-benzoyl-3, 5-dioxyphenylalanine. 31 g (0.067 mol) of 2-phenyl-4- (3,5-bis benzyl benzylidene) -5-oxazolone windows are suspended in a 10-fold amount of methanol and, after adding 1 g of anhydrous potassium carbonate, boil for 10 min. a fridge. The resulting solution is heated to a hydrogenation dL flask and, after the addition of nickel, Rene is hydrogenated until the absorption of hydrogen is complete. The catalyst is sucked off and the methanol is distilled off in vacuo. The residue is dissolved in a small amount of methanol, crystallized by the addition of water, then sucked off and dried .; yield 18 g (85%), so pl. . . . B .. 2-Benzamido-3- (3, 5-dioxyphenyl) -1-propanol. 12.7 g (0.144 mol) of calcium chloride is dissolved at room temperature in ZO1 ml of ethanol, then 18 g (0.057 mol) of JN-benzoyl-3,5-dioxyphenylschanin methyl ester is added and cooled to -6 ° C. With this 11 g (0.288 mol) of sodium borohydride was carefully added to the temperature, stirred for 1 hour at 1 hour at -5 ° C and 2 hours at. The alcohol is distilled off in vacuo (bath temperature 40-50 ° C). Water is added to the residue, cooling, acidified with 2N. hydrochloric acid, extracted 2-4 times with hot acetic ether, dried over sodium sulfate, and the solvent dissolved in a vacuum. The residue is dissolved in a small amount of methanol, crystalline precipitated by slowly adding water, sucked off and recrystallized once more from ethyl acetate; yield 12.5 g (76%), so pl. 132-134 S.V. 2-amnno-3- (3,5-Dioxyphenyl) -1-propanol hydrochloride. A mixture of 39 g (O, 136 mol) of 2-benzamido-3- (3, 5-dioxyphenyl) -1-prpanol in 390 ml 2 n. hydrochloric acid is heated under reflux for 18 h, cooled, benzoic acid is extracted with chloroform and distilled under vacuum to dryness. The residue is triturated with a. Acetonitrile before crystallization, sucked off, and -2-amino-3- (3,5-dioxyphenyl) -1-propanol hydrochloride is obtained, which is recrystallized from 150 ml of glacial acetic acid, 5 drops of a 40% solution are added sodium bisulfur and activated carbon; Yojo 25 g (84%), so pl. 166-167 ° C. In a similar manner, 2-benaylamino-3- (3,5-dioxyphenyl) -1-propano bromohydrate is obtained. Mp. 117-li9 C; 2-Benei hydrochloride amino-3- (3-hydroxy-4-methoxyphenyl) -1-propanol, m.p. . Claims 1. A method of producing aminopropanol derivatives of the general formula HO —C312 — SYa — CH20H 1 1 KHRe where fij is hydrogen, halogen, hydroxy, trifluoromethyl, alkyl or alkoxy, each with 1-4 carbon atoms, RJ hydrogen, alkyl with 1-4 carbon atoms or benzyl, or their salts, racemates or optically active antipodes, characterized in that in the compound of the general formula CMg-CH-CHgOH, j where R is hydrogen or methyl; or the method has a sigroup value; RJ is R, benzyl, or benzoyl, wherein at least one of the radicals H, R4 and d means or contains the indicated protecting group, / is cleaved by the O-methyl or M-benzoyl group with a strong hydrochloric or hydrobromic acid or is removed li-benzyl group by catalytic hydrogenation in the presence of palladium on carbon in the medium of an organic solvent at a temperature from room temperature to the boiling point of the reaction medium, followed by isolation of the target product in free form or as a salt, as a racemate or optically active antipode. 2. Method POP.1, distinguished by the fact that ethylene glycol is used as an organic solvent in the removal of 0-methyl or h-benzoyl groups and the process is carried out at the boiling point of the reaction medium. 3. Method POP.1, 9 is purifying with the fact that methanol or its mixture with water is used as an organic solvent when removing the H-benzyl group, and the process is carried out at a temperature from room temperature to. Sources of information taken into account in the examination of j. 1. Buhler, K., Pearson, D. Organic syntheses. M., Mir, 1970, p. 490-491.