SU585813A3 - Method of preparing 1-phenoxy-3-amino-propane-2-ol derivatives or salts thereof - Google Patents

Description

The temperature ranges from 20 ° C to the boiling point of the solvent with an alkali or silk-earth metal borohydride. Preferred starting compounds of the general formulas II, III or IV are those in which the phenyl nucleus A is mixed with methyl, ethyl, propyl, butyl, vinyl, allyl, metal, crotyl, cyclopentyl, diclohexyl, cyclopentenyl, methoxy, ethoxy, propoxy, i-propoxy, butoxy, p-pentyloxy, allyl oxy, metalloxy, propargyloxy, p-octyl oxy, ({) enyl, chlorine atom, bromine atom or residual SJE where T is methyl, ethyl, acetyl or benzoyl and an atom prenatal, methyl or ethyl. The substituents of the phenyl core A may be the same or different. According to the present invention, possible stereoisomers, optically active compounds and mixtures of this compound, in particular its racemate, are also included in the compounds of formula I. The preparation of compounds of the general formula is described in the examples. In many cases, the compounds are distilled oils, so in some cases the melting point is not indicated. In all cases, the indicated structure is confirmed by elemental analysis, IR spectrum or NMR spectrum, Example, A mixture of 15.0 g of racemic 1- (2,4-dimethyl-5-pyrimidyl) -3-l- (o-ethoxy-phenoxy ) -2-hydroxypropyl-3-amino-6yT-2-eH-c31ia-l, 140 ml of ethano 5O ml of water and 4.0 g of sodium borohydride are heated for 3 hours to 7 ° C, and then evaporated under reduced pressure and a residue is obtained in water and pentan-1-ole. The clear solution of pentanol is again evaporated and the residue is stirred with complex ethyl ester of acetic acid and VODID; at pH 6. The acetic acid ethyl ester is separated, the aqueous solution is adjusted to pH 10 with an alkali and again transferred with ethyl acetate. By evaporation of this ethyl acetate, 8.3 g of crude racemic 1- (2,4-dimethyl-5-pyrimidyl) -3-1- (O-egoxy-4-oxoxy) -2-hydroxypropyl-3- AminoJ-butan-l-ola in the form of a viscous oil, which is further purified by column chromatography. Calculated,%: C 64.8; H 8.0; W 10.8; O 16.4 i si 3 Found,%: C 64.5; H 8.1; N 10.7; About 16.66 IF, instead of the specified racemic starting material, levorotatory) (щий) (2,4-dimethpl-5-pyrimidyl) -3 -; {1- (o-ethoxy-phenoxy) -2-hydroxypropyl-3- amnno) 1 - but-2-ect-one-1, then a levogyrate (-), 4-dimethyl-5-pyrimidyl) -3- - (o-ethoxy-phenoxy) -2-hydroxypropyl-3 is obtained - am1sho) -butan-1-ol in the form of a viscous oil; , 4 The crude yield is 89% (from theoretical), the yield after chromatographic purification is 63% (from theoretical). Calculated,%: C 64.8; H 8.0; N 1O, 8; C 16.4 C 21 Found: C 64.8; H 7; 9; H 10.6; About 16.8 IF in the specified example to vary the reduction temperature and the reaction time, then get listed in table. 1 youxoobtj Table

60 60 45 35 35 25

85 89 78 69

73 57 PRI mme R 2. A mixture of 5.6 g of 1- (4-acetamine ofenose and) -3-am Opr opan-2-ol a, 5.3 g of 2,4-dimethyl-5- prynmyaiparbonylacetone and 50 ml of ethanol-free ethanol is heated for 20 hours. nri-40 C. o The reaction mixture at 70 Q is added in portions of 3.0 g of sodium borohydride and heated for 7 more hours to 70 ° C. Then evaporated under reduced pressure and get the rest in water and n-pentanol. The pentanol solution is stirred with water and adjusted to pH 6.5 by addition of dilute sulfuric acid, the clear aqueous solution is isolated and stirred at pH 9.5 again with n-pentanoic. Evaporation of pentanol from this solution yields 4.5 g of 1- {2,4-dimethyl-5-t-1-imidyl) -3- (1- ((acetaminophene and) -2-ox ypr opil-3-mino butan-1 -ola in the form of a viscous oil, Crude yield 90% (from theoretical); yield after chromatographic purification 6O% (from theoretical). EXAMPLE 3 1.33 g of sodium borohydrideDa is stirred for 45 minutes at room temperature in 21 ml of absolute ethanol and then a solution of 2.32 g of calcium chloride in 21 ml of absolute ethanol is added at O C. A cloudy mixture is formed and the temperature rises to 15 C. Then the mixture is oh 3.45 g of 1- (2,4-dimethyl-5-pyrimidyl) (pn-butoxyphenoxy) -2-ox ypropyl-3-min (-but -2-en-1-one dissolved in 56 ml of absolute ethanol. The temperature rises to 30 ° C. The mixture is stirred overnight at room temperature, and the temperature first rises to 37 ° C. With strong stirring, add 5.9 ml 10N aqueous solution of sodium hydroxide. Immediately add more 12 ml of water and mix vigorously for .5 min. Then, without stirring, the residue is Calculated,%: C, 62.7; H 7.5; M 13.9; About 15.9. Found,%: C 62.4; H 7.5; N 13.7; O 16.2 To the solution of the base in Etc. Add O, 48 molar equivalents of (Ij, (+) - tartaric acid, evaporate the reaction mixture under reduced pressure and stir the residue repeatedly with pure ethyl ester of acetic acid. White hygroscopic crystals are obtained, 1- (2,4-dimethyl-5-pyrmidip) -3-l- (p-ats & taminophenoxy) -2-hydroxypropyl-3-amino-butane-1-ol neutral tartrate; tel. 83-87 C (decomposition {s): Calculated,%: C 53.8; H 7.3; S Yu. E; O 28.0 OT; Found,%: C 53.6; H 7.4; N 10.8; O 28.3 If in the indicated example the temperature of the reduction is varied and Then, the yields are given in Table 2. Tablets 2 are allowed to stand for 30 minutes at room temperature, the mixture is sucked through a small amount of celite and the residue is washed with absolute ethanol. 9 ml of glacial acetic acid is added to the filtrate and the filtrate is concentrated in vacuo to dryness at 5 ° C. To the concentrated residue are added 12 ml of aqueous 10N, sodium hydroxide solution and 12 ml of water and extracted three times with ethyl acetate. The combined acetic ether phases are washed twice with water, dried with calcined sodium sulphate and concentrated in vacuo. The resulting oil is dissolved in a small amount of 2N hydrochloric acid, a small insoluble fraction is sucked off. The filtrate is extracted thrice with ethyl acetate. The aqueous solution is adjusted to pH 4.5 with a 15% soda solution and extracted twice with ethyl acetate. The aqueous solution is adjusted to pfl with 8.5 soda solution.

and extracted trinhdy acetic ether. The acetic ester phases obtained upon extraction of an aqueous solution with pH 8.5 are washed three times with water, dried with calcined sodium sulphate and concentrated in vacuo.

3.1 g of 1- (2,4-dimethyl-5-pyrimidyl) -3-1- (pn-6-oxyphenoxy) -2-hydroxypropyl-3-amino-T-butan-X-ol are obtained in the form of a colorless oil. Output 899o (from theoretical), about

Claims (1)

Calculated,%: C, 66.2; H, 8.4; Vi 10.1; About 15.3 g 35 Found,%: C 66.3; H 8.3; W 10.С; About 15.4 The salt of this compound, with 1/2 mol of naphthalene-1,5-disulfonic acid, melts at C (decomposition). The invention method for producing 1-phenox-3-aminopropan-2-.ola derivatives of the general formula Clij AV 0-CH-r H- (H, -NH-C f- (H2-Cl1 II U Jk OHCli.OH H1b where phenyl core A can be substituted with one-, two-, or three-fold alkyl with 1-4 carbon atoms, alkenyl or alkynyl each having up to 6 carbon atoms, cycloalkyl or cycloalkenyl, the ring having 5-8 carbon atoms, alkoxy having up to 8 atoms carbon. alkenyloxy or apkinyloxy having up to 5 carbon atoms, phenylgyl, halogen atom or MG residue, and alkyl with 1-4 carbon atoms or acyl, iiMeio to 11 carbon atoms, and R hydrogen atom or alkyl having 4 carbon atoms, or their salts, characterized in that the compound of general formula II, III or IV Cui (111 where the phenyl core A has the indicated values, is reduced in a lower aliphatic alcohol or in an alcohol-water mixture at a temperature of from 20 ° C to the boiling point of the solvent with an alkali or alkaline earth metal borohydride, followed by isolation of the desired product in free form or in the form of salt. Sources of information taken into account in the examination: 1, UK Patent N ° 1185О46, cl. С 2 С, published, 1У70.