Europaisches Patentamt European Patent Office 00 Publication number: 0 249 610 B1 Office europeen des brevets © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification: 25.08.93 © Int. CI.5: C07C 57/00, C07C 67/02, C07C 217/14, C07D 209/82, © Application number: 86907140.7 C07D 215/36, C07D 237/02, C07D 239/02, ' C07D 261/06, w© Daten * of,„■ filing:fl ing: a 14.11.86« oc C07D 265/30,, C07D 277/04 © International application number: PCT/US86/02407 © International publication number: WO 87/03584 (18.06.87 87/13) SYNTHESIS OF OPTICALLY ACTIVE ARYLOXYPROPANOLAMINES AND ARYLETHANOLAMINES. © Priority: 04.12.85 US 804407 © Proprietor: THE DU PONT MERCK PHARMA- CEUTICAL COMPANY @ Date of publication of application: Barley Mill Plaza, Building 25 23.12.87 Bulletin 87/52 Wilmington, Delaware 19880(US) © Publication of the grant of the patent: @ Inventor: MAI, Khuong, H., X. 25.08.93 Bulletin 93/34 4751 N Pulaski RD Chicago, IL 60630-431 2(US) © Designated Contracting States: Inventor: PATIL, Ghanshyam CH DE FR GB IT LI SE 340 Albert Drive Vernon Hills, IL 60061 (US) © References cited: Inventor: MATIER, William, L. US-A- 4 202 978 1214 Parliament Court Libertyville, IL 60048(US) AGRIC. BIOL. CHEM., May 1982, vol. 46, no. 5, pages 1153-1157; S. IRIUCHIJIMA et al, "Asymmetric Hydrolysis of Representative: Seaborn, George Stephen et (plus/minus)-1,2-Diacetoxy-3-chloropropane al and Its Related Compounds with Lipase. c/o Edward Evans & Co. Chancery House 00 Synthesis of Optically Pure (S)-Propranolol" 53-64 Chancery Lane London WC2A 1SD (GB) CO CM Note: Within nine months from the publication of the mention of the grant of the European patent, any person ® may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition CL shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee LU has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.6/3.3. 1) EP 0 249 610 B1 Description Aryloxypropanolamines (1) and arylethanolamines (2) are widely used therapeutic agents, particularly those compounds possessing potent beta-adrenergic receptor blocking activity. Use beta-adrenergic bloc- 5 king agents are widely used for a number of cardiovascular therapeutic indications, such as hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction and more recently in the treatment of glaucoma. In addition, certain aryloxypropanolamines possess potent beta-adrenergic stimulating properties and such compounds are used as cardiac stimulants. Among beta-blocker oxypropanolamines, the R isomers are less active or essentially devoid of beta- io blocking activity as compared to their counterpart S isomers. Similarly, the R-isomer beta-agonists are are potent agents than their S-isomer counterparts Ar^****^ Ar-0^sv^s^NHR or 20 Conventional methods for preparing such compounds utilize HBr/AcOH treatment of the diol 4 to provide 25 the bromoacetoxy 5. Subsequently, the bromoacetoxy 5 is transformed into an epoxide which is then treated with the corresponding amine to provide the desired beta-blocker in separate stages. Such a procedure is described by S. Iriuchijima and N. Kojima, Agric. Biol. Chem. 46 (5), 1153 (1982). The diol 4 may be prepared by hydrolysis of the ketal 3, or, as described by Iriuchijima and Kojima, by reaction of 1 ,2- diacetoxy-3-chloropropane with a phenol. In such conventional methods, to prepare the optically active 30 aryloxypropanolamines, four steps are required, starting from the ketal 3 or 1 ,2-diacetoxy-3-chloropropane. An efficient and an economical process for prepare the separate isomers is therefore highly desirable. ft-V" 35 OH QAc Ar- 40 US-A-4 202 978 discloses a process wherein a ketal is hydrolysed to the corresponding diol which is reacted with a trialkylorthoacetate to give a cyclic orthoacetate which is converted to a 1-aralkyl-3-halo- 45 propylacetate. SUMMARY OF THE INVENTION In accordance with the present invention, there is provided a method of preparing a compound of the 50 formula 55 EP 0 249 610 B1 wherein Ar is aryl, substituted aryl, heteroaryl, or aralkyl, X is chloro, bromo or iodo and Y is hydrogen, loweralkyl or cycloloweralkyl, which method comprises: reacting a selected racemic or chiral dioxolane of the formula Ar-0 or 10 wherein Ar is defined as above and Ri and R2 are each independently hydrogen loweralkyl, cycloloweral- 15 kyl, or R1 and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group or aryl group, with an acid of formula HX, wherein X is defined as above, in solution in a organic acid of the formula Y-COOH wherein Y is defined as above. A racemic or chiral (i.e. optically active) aryloxypropanolamine (1) or arylethanolamine (2) may be prepared by reacting the compound prepared by the method specified in the preceding paragraph with an 20 amine or by reacting the compound with a base to prepare an epoxide and reacting the epoxide with an amine. OH NHR 25 • JL Ar^*^ Ar-O^^N^^NHR• n ^\uuO ora* Ar^^*^s^ 30 In Formula (1) and (2) R is alkyl, aryl, aralkyl or WB wherein W is a straight or branched chain alkylene of from 1 to about 6 carbon atoms and wherein B is -NR2COR3, -NR2CONR3R+, -NR2SO2R3, -NR2S02NR3R4, 35 or -NR2COOR5, where R2, R3, R+, and R5 may be the same or different and may be hydrogen, all preferably of from 1 to 10 carbons, more preferably from 1 to 6 carbon atoms, alkoxyalkyl, wherein the all groups may be the same or different and preferably contain from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms, alkoxyaryl, wherein the all groups contain from 1 to about 6 atoms, cycloalkyl, preferably of from 3 to 8 carbon atoms, alkenyl, preferably of from 3 to 10 carbon atoms, alkynyl, preferably 40 of from 3 to 10 carbon atoms, aryl, which may be selected from substituted and unsubstituted monocyclic and polycyclic aromatic and heterocyclic ring systems of from 6 to about 10 carbon atoms such as phenyl, thienyl, imidazole and oxazole, indole, heteroaryl, or aralkyl, except that R3 and R+ may together with N form a 5-to 7-membered heterocyclic group. A specific embodiment of the invention involves the utilization of an HBr/acetic acid (AcOH) mixture to 45 directly convert the ketal (3) to the bromoacetozy (5) without going through the intermediate diol (4). The bromoacetoxy (5) is then allowed to react with a selected amine in an alcoholic medium to provide the desired aryloxypropanolamine. An alternative procedure for the latter reaction is to convert the bromacetoxy (5) to an epoxide followed by amination. The method offers the convenience of fewer reaction steps. More generally, a mixture of a strong acid, HX, where X is chloro, bormo or iodo, in an amount of from 0.1 to 50 50% in an organic acid, Y-COOH where Y is hydrogen, loweralkyl or cycloalkyl, is used to convert the ketal (3). DETAILED DESCRIPTION OF THE INVENTION 55 As used herein, the term "aryl" may represent a phenyl or naphthyl group which may be unsubstituted or substituted with alkyl of from 1 to about 6 carbon atoms, alkenyl of from 2 to about 6 carbon atoms, alkynyl of from 2 to about 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms, halo, acetamido, amino, amido, nitro, alkylamino of from 1 to about 6 carbon atoms, hydroxy, EP 0 249 610 B1 hydroxyalkyl of from 1 to about 6 carbon atoms, cyano or arylalkoxy wherein the alkyl group contains from 1 to about 6 carbon atoms and the aryl group is substituted or unsubstituted phenyl. The term "heteroaryl" as used herein may represent pyridine, pyrazine, pyrrole, pyrazole, piperazine, thiophene, benzothiophene, furan, benzofuran, imidazole, oxazole, indole, carbazole, thiazole, thiadiazole, 5 benzothiadiazole, triazole, tetrazole, azepine, 1, 2-diazepine, or 1 ,4-thiazepine. Preferably, the heteroaryl is selected from the group consisting of pyridine, pyrazine, thiophene, benzothiophene, benzofuran, indole, carbazole, thiadiazole or benzothiadiazole, with the most preferred being pyrazine, indole, 1 ,2,5-thiadiazole, or benzofuran. The term "heterocyclic" as used herein may represent pyrrolidine, piperidine, morpholine, or thiomor- io pholine. In the term "aralkyl" as used herein, the alkyl group may contain from about 1 to about 6 carbon atoms and the aryl group may represent substituted or unsubstituted monocyclic or polycyclic aromatic or heterocyclic ring systems of from 5 to 10 carbon atoms, such as benzyl, phenethyl, 3,4-dimethoxyphenethyl and 1 ,1-dimethyl-2-(3-indolyl)-ethyl Aromatic (Ar) substituents may include lower alkyl of from 1 to 10 is carbons atoms, alkenyl of from 2 to 10 carbon atoms, alkynyl of from 2 to 10 carbon atoms, alkoxy wherein the alkyl group contains from 1 to 10 carbon atoms, halo, acetamido, amino, nitro, alkylamino of from 1 to 10 carbon atoms, hydroxy, hydroxyalkyl of from 1 to 10 carbon atoms, cyano, arylalkoxy wherein the alkyl group contains from 1 to 6 carbon atoms and the aryl group represents substituted or unsubstituted phenyl and groups of the formula 20 O a Ry-O- C- A 25 wherein R3 is lower alkyl, aryl or aralkyl and A is a direct bond, alkylene of from 1 to 10 carbon atoms or alkenylene of from 2 to 10 carbon atoms. The term "cycloalkyl" as used herein refers to cyclic saturated aliphatic radicals, which may contain 3 30 to 6 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. R3 and R4 may together with N form a 5- to 7-membered heterocyclic group such as pyrrolidine, piperidine, piperazine morpholine, or thiomorpholine.