PROCESS FOR PREPARING 1-AMINO-3-ARYLOXY-2-PROPANOLS AND 1-AMINO-2-ARYL-2-ETHANOLS

Abstract: Process for preparing 1-amino-3-aryloxy-2-propanols and 1-amino-2-aryl-2-ethanols by reacting a 1,2-epoxy-3-­ aryloxy-propane and, respectively, a 1,2-epoxy-2-aryl-ethane with a primary or a secondary amine in the presence of a catalytic amount of a Lewis acid.

Description: PROCESS FOR PREPARING 1-AMINO-3-ARYLOXY-2-PROPANOLS AND l-AMINO-2-ARYL-2-ETHANOLS. * * * * * * This invention relates to the preparation of l-amino -3-aryloxy-2-propanols and 1-amino-2-aryl-2-ethanols by reacting a 1,2-epoxy-3-aryloxy-propane and, respectively, a 1,2-epoxy-2-aryl-ethane with a primary or secunda ry amine in the presence of a catalytic amount of a Lewis acid. l-amino-2-aryl-2-ethanols and 1-amino-3-aryloxy-2propanols are widely used as drugs; examples of such compounds include acetobutolol, alprenolol, atenolol, bevantolol, bufetalol, bufuralol, bunitrolol, carazolol, carteolol, dichloroisoproterenol, isoproterenol, levobu nolol,metoprolol, mepindolol, nadolol, oxprenolol, pen butolol, pindolol, practolol, pronethalol, propanol, so talol, timolol, tiprenolol, tolamolol. It is known that l-amino-3-aryloxy-2-propanols and l-amino-2-aryl-2-ethanols may be prepared by reacting an amine with a 1,2-epoxy-3-aryloxy-propane and, respectively, with a 1,2-epoxy-2-aryl-ethane; good yields are obtained when the reaction is carried out at high temperature, usually at the boliling temperature of the reaction mixture and in a sealed vessel. When the preparation is carried out at the boiling temperature in an opened vessel it is necessary to combine the reaction vessel with expensive equipments in order to capture the amine which flows out. When the reaction is carried out in a sealed vessel, it is impossible to watch the progress of the reaction and the process implies the well-known risks connected with the high pressure. Now it has been found that the above d.fficulties may be overcome without affecting the yields when the reaction is carried out at room tempera ture in the presence of a Lewis acid. According to a preferred embodiment of this inven tion the Lewis acids are selected from the group com prising the metal salts and the metal oxydes such as FeCl2, FeCl3, AlCl3, Al2O3, BFS, MgI2, MgBr2, MgCl2, CuSO4, CuCl2, Cu203, Cu(OCOCH3)2, NiCl2, CoCl2, ZnC12 2, ZnBr2, SnCl2, SnCl4, SbCl3, MnCl2, Hg2C12, HgC12, BaC12 Al(C H 0) and CaCi2. 37 3 The catalyst may be introduced directly into the rea ction medium; alternatively it is formed "in situ". The Lewis acid is preferably used in catalytic a mount; larger quantities do not afford appreciable ad vantages. When the epoxyde is not soluble in the amine a suita ble diluent is added to the reaction mixture, example of such diluent include pyridine, picoline, benzene,to luene, methylene chloride, chloroform, carbon tetrachlo ride, eptane and octane. The following specific examples are given to enable those skilled in the art to understand more clearly and practice this invention. It should not be considered as a limitation upon the scope of the invention but merely as being illustrative and representative thereof. EXAMPLE 1 3-[p-(2-methoxyethyl)-phenoxy]-1,2-epoxy-propane (90 g; 0.46 mol) is added to FeCl3 (3.5 g; 0.02 mol.) solu tion in isopropylamine (270 g; 4.57 mol). The solution is stirred at room temperature for 6 hrs. Isopropylamine is removed by evaporation and the residue is dissolved in toluene (300 ml). Toluene solution is extracted with diluted hydrochloric acid (1 N). The aqueous phase is basified with sodium hydroxyde (1 N) and extracted with toluene (300 ml X 3); by distilling off the solvent, Metoprolol is obtained. Yield: 80 g, corresponding to 79% of the theoretical amount. Metoprolol (20 g; 0.075 mol) is added to hot acetoni trile (100 ml) under stirring; d-tartaric acid (5.62 g; 0.0375 mol) is added to the hot reaction mixture-under stirring. The reaction mixture is then kept under reflux and under stirring for 1 hour; after cooling the precipitate is collected by sunction and dried at 800 C under reduced pressure. It is so obtained Metoprolol tartrate; 24.85 g (96.98% of the theoretical amount). m.p. 119 -122 C. Using different Lewis acid the following results ha ve been obtained: AlCl3 (3.5 g; 0.03 mol); Yield, 96% CuCl2 (3.5 g; 0.03 mol); yield, 80% MgCl2 (3.5 g; 0.04 mol); yield, 82% BF (3.5 g; 0.05 mol); yield, 92% 3 MgI2 (13.9 g; 0.05 mol); yield 98% Al(C H 0) (10.2 g; 0.05 mol); yield, 78% 37 3 NiBr2 (10.9 g; 0.05 mol); yield, 68% Co(CH COO) (11.8 g; 0.05 mol); yield, 64% 3 3 CuO (4 g; 0.05 mol); yield, 62% EXAMPLE 2 3-(1-naphtoxy)1,2-epoxy-propane (20 g; 0.1 mol) is added to AlCl3 (1.3 g; 0.01 mol) solution in isopropyla mine (59 g; 1 mol). The solution is stirred at 150-200C for 5 hours. Isopropylamine is removed by evaporation and the residue is dissolved in methylene chloride (70 ml). Methylene chloride solution is extracted with diluted hydrochloric acid (1 N). The aqueous phase is basified with sodium hydroxyde (1 N) and extracted with methylene chloride (70 ml X 3); after removal of the solvent Propanolol is obtained. m.p.= 94 -95 C Yield: 22.3 corresponding to 86% of the theoretical amount. EXAMPLE 3 3-[(p-carbamoylmethyl)-phenoxy]-1,2-epoxy-propane (20.7 g; 0.1 mol) is added to a AlCl3 (1.3 g; 0.01 mol) solution in isopropylamine (59 g; 1 mol) and pyridine (280 mol). The solution is stirred at 15 -20 C for 7 hours. Isopropylamine and pyridine are removed by evaporation; the residue is treated with hydrochloric acid (1 N) and filtered. The aqueous solution is basified with sodium hydroxy de and filtered; the solid is collected and dried at 1000 C under reduced pressure. Yield: 23.3 g (875% of the theoretical amount) of Atenolol melting at 119 -122 C. * * * * With the procedures of Examples from 1 to 3 the fol lowing products have been prepared: Acebutol ol Pindolol Practolol Bunitrolol Pronethalol

Claims: WHAT IS CLAIMED IS: 1. Process for preparing a product having the following formula: Ar-(OCH2)n-CHOH-CH2-NR1R2 where n is O or 1 Ar is an aryl radical selected from the group comprising a substituted phenyl ring, a phe nyl fused with a heterocyclic ring, a sub stituted phenyl fused with a heterocyclic ring, a phenyl fused with a substituted he terocyclic ring, a phenyl fused with a cy cloaliphatic ring, a phenyl fused with a substituted cycloaliphatic ring, a substitu ted phenyl fused with a cycloaliphatic ring, a heterocyclic ring, a substituted hetero cyclic ring, a naphtyl ring and a substitu ted naphtyl ring; and R1 is H or an alkyl radical having from 1 to 5 carbon atoms; and 4 R2 is an alkyl radical having from 1 to 5 car bon atoms or -CH2-CH2 (O) n7Ar1 where n has the above mentioned meaning and Ar is a substituted phenyl ring which comprises the reaction of a product having the following formula EMI6.1 with an amine of formula HNR 1R2 where Ar,n,R1 and R2 have the above mentioned meanings at room temperature and in the presence of a catalytic amount of a Lewis acid. 2. Process according to claim 1 wherein the Lewis acid is a metal salt or a metal oxyde 3. Process according to claim 1 wherein the amine is a primary amine. 4. Process according to claim 1 and 3 wherein the amine is selected from the group comprising isopropylamine and sec. butylamine. 5. Process according to claim 1 wherein the reaction is carried out in the presence of a diluent selected from the group comprising pyridine, picoline, benze ne, toluene, methylene chloride, chloroform, carbon tetrachloride, eptane and octane.

Inventors: GIORDANO, CLAUDIO, MALGUZZI, ROMUALDO
Applicants: BLASCHIM S.P.A.
Application year: 1981
Main classification: C07C93
IPC codes: C07C237, C07C233, C07C217, C07D209, B01J23, C07C235, B01J27, C07C67, B01J21, B01J31, C07C213