SYNTHESIS OF OPTICALLY ACTIVE ARYLOXYPROPANOLAMINES AND ARYLETHANOLAMINES

Abstract: A process for preparing a racemic or chiral aryloxypropanolamine (1) or arylethanolamine (2) of formula (1) or (2), wherein Ar is aryl, substituted aryl, heteroaryl, or aralkyl and R is alkyl, substituted alkyl, 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, -NR2CONR3R4, -NR2SO2R3, -NR2SO2NR3R4, or -NR2COOR5, where R2, R3, R4, and R5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R3 and R5 are not hydrogen when B is -NR2SO2R3 or -NR2COOR5, or R3 and R4 may together with N form a 5- to 7-membered heterocyclic group. The process can be used to prepare beta-blocking agents, useful in the treatment of cardiac conditions.

Description: -.*- ςYNTH-FSIS OF OPTICALLY ACTIVE ARYLOXYPROPANQLAMI NES AND ARYL THANOL AMI ES BACKGROUND OF THE INVENTION Aryloxypropanolamlnes (1) and ary I ethanol amines (2) are widely used therapeutic agents, particularly those compounds possessing potent beta- adrenerglc receptor blocking activity. These beta-adrenerglc blocking agents are widely used for a number of cardiovascular therapeutic Indica¬ tions, such as hypertension, angina pectcrls, cardiac arrhythmias, myocardlal Infarction and more recently In the treatment of glaucoma. In addition, certain aryloxypropanolamlnes possess potent beta-adrenerglc stimulating properties and such compounds are used as cardiac stimulants. Among beta-blocker oxypropanol amines, the R Iso ers are less active or essential ly devoid of beta-blocking activity as compared to their counter¬ part S Isomers. Similarly, the R-Isomer beta-agonists are more potent agents than their S- 1 saner c ' ounterparts. Conventional methods for preparing such compounds utll Ize the hydrolysis of the ketal 3 to give the dlol 4 fol lowed by the HBr/AcOH treatment to provide the brcmoacetoxy 5. Subsequently, the brcmoacetoxy 5 Is transformed Into an epoxlde which Is then treated with the corresponding amlne to provide the desired beta-blocker In separate stages. Such a procedure Is described by S. Irluchljlma and N. Kojlma, Agrlc. Blol . Chem. ≤. (5), 1153 (1982). In such a procedure, to prepare the optically active aryloxypropanolamlnes, four steps are required, starting from the ketal 3. An efficient and an economical process for preparing the separate Isomers Is therefore highly desirable. Ar-0- SUMMARY OF THE INVENTION I n accordance ith the present Invention, d i scl osed I s a process for prepar i ng a racem lc or ch lral ary l oxypropanol aml πe ( 1 ) or ary l ethanol amlne (2) of the formul a wherein Ar Is aryl, substituted aryl, heteroaryl, or aralkyl and R Is alkyl, substituted alkyl, aralkyl, or WB wherein W Is a straight or branched chain alkylene of frc 1 to about 6 carbon atc s and wherein B Is -NR2COR3, -NR2CONR3R4, - R2SO2R3, -NR2SO2NR3R4, or -NR2COOR5, where R2, R3, R4, and R5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aral yl, except that R3 and R5 are not hydrogen when B Is -NR2SO2R3 or -NR2COOR5, or R3 and R4 may together with N form a 5- to 7-membered heterocycl lc group. As an example, a specific embodiment of the method Involves the utll I- zatfon of an HBr/acetlc acid (AcOH) mixture to directly convert the ketal 3 to the brcmoacetoxy 5 without going through the Intermediate dlol 4. The brcmoacetoxy 5 Is then allowed to react with a selected amlne In an alcohol lc medium to provide the desired aryloxypropanol amlne. An alternative procedure for the latter reaction Is to convert the brcmoacetoxy 5 to an epoxlde followed Dy amfnatlon. The method offers the convenience of fewer reaction steps. More generally, a mixture of a strong acid, HX, where X Is chloro, brcmo or lodo, In an amount of frcm 0.1 to 50j£ 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 In accordance with the present Invention, disclosed Is a process for preparing optically active aryloxypropanolamlnes (1) or ary I ethanol a ines (2) of the formula wherein Ar Is aryl, substituted aryl, heteroaryl or aralkyl and R Is alkyl, substituted alkyl, aralkyl, or WB wherein W Is a straight or branched chain alkylene of frcm 1 to about 6 carbon atcms and wherein B represents -NR2COR3, -NR2CONR3R4, -NR 2 S0 R3, -NR2SO2NR3R4, or -NR 2 C00R 5 wherein R2, R3, R4 and R5 may be the same or different and may be hydrogen, alkyl of from 1 to about 10 carbon atoms and preferably from 1 to about 6 carbon atcms, al oxyalkyl wherein the alkyl groups may be the same or different and contain from 1 to about 10 carbon atcms and preferably fr.αm 1 to about 6 carbon atcms; cycloalkyl of frcm 3 to about 8 carbon atcms, alkenyl of from 3 to about 10 carbon atoms, alkoxyaryl wherein the alkyl group contains from 1 to about 5 carbon atcms, alkynyl of frcm 3 to about 10 carbon atcms, aryl which Includes substituted or uπsubstltuted onocycl lc or polycycl lc arcmatlc or heterocycl ϊc ring systems of frcm 6 to about 10 carbon atcms such as phenyl, thlenyl, Imldazole, oxazole, Indole, and the I Ike, or aralkyl wherein the alkyl portion contains from 1 to about 6 carbon atoms and the aryl portion represents substituted or unsubstltuted monocycl lc or polycycl lc aromatic or heterocycl lc ring systems of frcm 5 to about 10 carbon atcms such as benzyl, phenethyl, 3,4-dI ethoxyphenethy I, 1,1-dImethy l-2-(3-Indoly Dethy I and the l ike; except that R3 and R5 are not hydrogen when B Is -NR2SO2R3 or -NR2COOR5, or R3 and R4 may together with N form a 5- to 7-membered heterocycl lc group such as pyrrol Idlne, plperldlne, plperazlne, morphol Ine, or thromorphol Inβ. As used herein, the term "ary I " represents a phenyl cr naphthyl group which may be unsubstltuted or substituted with alkyl of frcm 1 to about 6 carbon atcms, alkenyl of frcm 2 to about 6 carbon atcms, alkynyl of from 2 to about ^0 carbon atcms, alkoxy wherein the alkyl group contains from 1 to about 6 carbon atcms, halo, acetamldo, amlno, amido, nitro, alkylamlno of frcm 1 to about 6 carbon atcms, hydroxy, hydroxyalkyl of from 1 to about 6 carbon atcms, cyano or arylalkoxy wherein the alkyl group contains frcm 1 to about 6 carbon atcms and the aryl group Is substituted or unsubstltuted phenyl. The term "heteroaryl" as used herein represents pyrldlne, pyrazlne, pyrrole, pyrazole, plperaztne,- thlophene, benzothlophene, furan, benzofuraπ, Imldazole, oxazole, Indole, carbazole, thlazole, thfadfazole, benzothfadlazole, trlazole, tetrazole, azeplne, 1, 2-dIazeplne, or 1,4-th I azeplne. Preferably, the heteroaryl Is selected frcm the group consisting of pyrldlne, pyrazlne, thlophene, benzothlophene, benzofuraπ, Indole, carbazole, thladlazole or benzothfadlazole, with the most preferred being pyrazlne, Indole, 1,2,5-thIadIazole, or benzofuran. • - The term "heterocycl lc" as used herein represents pyrrol Idlne, plperldlne, morphol Ine, or thlcmorphol fne. In the term "aralkyl" as used herein, the alkyl group contains from about 1 to about 6 carbon atcms and the aryl group represents substituted or unsubstltuted monocycl lc or polycycl lc aromatic or heterocycl lc ring systems of from 5 to about 10 carbon atcms, such as benzyl, phenethyl, 3,4-dImethoxyphenethyI, 1,1-dImethy l-2-(3-lndoly l)-ethyl and the l ike. Aromatic (Ar) substltuents may Include lower alkyl of from 1 to about 10 carbons atcms, alkenyl of frcm 2 to about 10 carbon atcms, alkynyl of frcm 2 to about 10 carbon atcms, alkoxy wherein the alkyl group contains from 1 to about 10 carbon atcms, halo, acetamldo, amlno, nitro, alkylamlno of from 1 to about 10 carbon atcms, hydroxy, hydroxyalkyl of from 1 to about 10 carbon atcms, cyano, arylalkoxy wherein the alkyl group contains from 1 to about 6 carbon atcms and the aryl group represents substituted or unsubstl¬ tuted phenyl and groups of The formula 0 n R3-O-C-A wherein R3 Is lower alkyl, aryl or aralkyl and A Is a direct bond, alkylene of from 1 to about 10 carbon atcms or alkenylene of from 2 to about 10 carbon atcms. The term "cycloalkyl" as used herein refers to cycl lc saturated al Iphatlc radicals containing 3 to 6 carbon atcms In the ring, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. As an example, the method Involves the utll Izatlon of an HBr/AcOH mixture to directly convert the ary loxypropanol a lne. The method can be used In the synthesis of beta-agonists or beta-b lockers. The following reaction schemes summarize the process of the present invention. Referring to the scheme, the (R)-(-) or S-(+)-2,2-dlmethy l-4-aryloxy- methyI-1,3-dloxol ane (3) can be made by known methods. For example, the S-enantlcmer can be prepared readily by reacting an appropriate phenoxtde with S-(+)-2,2-dImethy l-4-(hydroxymethyl )-1,3- dloxolane methanesul fonate or p-tol uene-su I fonate. The ary loxypropanol a lne (1) can be made by reacting the above dloxolane (or ketal) with HBr/Acetϊc acid, followed by amlnatlon with a selected amlne. If desired, the brcmoacetoxy 5 Is allowed to react with a suitable base to give the epoxlde 6, which Is then reacted with a selected amlne to prepare the desired ary loxypropanol amlne. A suitable base for reaction with the brcmoacetoxy would be a metal alkoxlde, metal hydroxide, metal hydride, metal carbonate or metal blcar- bonate wherein the metal Is sodium, potassium or calcium, or an ammonium hydroxide or a suitable organic base. Preferred organic bases are pyrldlne, dl ethy lamlnopyrldlne, dlmethylanl I Inβ, qulnol Ine, 1 ,8-D I azab I cycl oC5.4.0Hundec-7-ene (DBU) , 1 ,5-01 azab f cycl oC4,3.0_jnon-5-ene (DBN) or tertiary alky I amines. Preferred bases are sodium or potassium ethoxlde, ethoxlde or t-butoxlde or a tertiary alkyl amlne. -7- The ary I ethanol amines can be prepared as follows. The aryl ketal of 1,2-ethanedIol can be converted to the corresponding brcmoacetate by reacting It with 1-Br/AcOH. The resulting brcmohydrln then can be cycl Ized to an epoxlde by treating It with one equivalent of sodium methoxlde. The ary I ethanol amlne can be obtained by treating the epoxlde with one equivalent of amlne. The following beta-adrenerglc blocking agents, beta-agonfsts and partial agonists are representative of the compounds that can be made using the described process: Ar Compound Acebutolol roTό: Adimolol Afurolol Al pre ' nolol Ancarolol :α -< Atenolol CH 2 C0NH 2 -< Befunolol ■ 9 CH 2 C"H , 2 20-CH 2 -<] " < Betaxolol Ar Compound Bevantolol Bisprolol Bometolol ' Bornaprolol Bucindolol Bucumolol Bufetolol Ar Compound © 4- Bunitrolol Bunal ol Bupranolol Butocrolol Butofilolol Carazolol Carteolol Carvedilol Ar Compound Celiprolol- Cetamolol Chinoin-103 -< Cidoprolol Cloranolol Cl Diacetolol Exaprolol -< Ar Compound Indenolol :o Indopanolol c :α 4- Is xaprolol Levobunolol Mepindolol Metipranolol Ar Compound CH 3 0CH 2 CH «■ © - Metoprolol Moprolol Nadolol Nafetolol Oxprenolol Pacrinolol NHCONH—ζ - Pafenolol NHCOOCH. -< Pamatolol Ar R Compound :σ 4 Pargolol Penbutolol P ndolol Pirepolol Practolol Prenalterol Prizidilol Procinolol Ar Compound Propranolol Spirendolol Teoprolol Tertatolol Timolol Tiprenolol '-—(©I )>--'C0NH, Tolamolol Xibenolol Xamoterol Ar R Compound Albuterol Amosulalol -I- Bufuralol :σ nterol CH 2 S0 2 CH 3 4- Sul fo OH Ibuterol Miscellaneous Beta-Blockers Compound H-j- Arotinolol Bop ndolol • 18- In order to Illustrate the manner In which the above compounds may be made, reference Is made to the following examples, which, however, are not meant to limit or restrict the scope of the Invention \ n any respect. EXAMPLE 1 Preparation of (R)-f-)-2-(1-Naphthyloxy-3-bromo)prop I acetate A mixture of (R)-(-)-2,2-dImethyl-4-napthyloxymethy1-1,3-dIoxol ane (100 g. 0.38 m), 30$ HBr/AcOH (150 g) and AcOH (200 g) was allowed to stand at room temperature for 2 hours. Cyclohexane (1 L) was then added. T e resulting mixture was stirred and cooled In an Tee bath. The K2CO3 (300 g) was added portfonwfse. After the addition was completed, stirring was continued for 30 minutes. Ice water was then added slowly. The aqueous layer was discarded and the organic layer was further washed ith a saturated solution of aHCθ3. The extract was dried over MgSθ4 and evaporated to an oil (120 g, 9 %) . This was used In the next step without any further purification. -19- EXAMPLE 2 Preparat on of ( S)-(-)-propranolol - Method A A solution of (R)-(-)-2-(1-napthy loxy-3-brcmo)propy I acetate (20 g, 6.2 mM) and Ispropy lamlne (5 g) In methanol (50 mL) was refluxed for 1 h and evaporated to dryness. The residue was taken up with water, baslfled with K2CO3 and extracted twice ith ether. The organic layers were combined, washed with water, dried over MgSθ4, ffltered and addlfTed wi hydrogen chloride. The sol Id precipitate was filtered and recrystal I Ize from ethanol to afford 14.6 g (79.6$) of white crystalline product, m.p. 197-200° C, 25 = -26.1 (c 1, EtOH). -20- EXAMRE 3 Preparation of (S)-(+)-glvc dyI napththvl ether + MeONa/MeOH To a solution of (R ) - ( - ) -2-(1-napthy loxy-3-brcmo)propy I acetate (12 g, 0.37 m) fπ methanol (50 mL) was added a solution of 25$ MeONa In methanol ( 96 g). Sodium bromide was separated Instantaneously. After stirring for 30 minutes, cyclohexane (1 L) was added to the mixture whic was washed twice with water. The organic layer was dried over MgSθ4 and evaporated to an oil (70 g, 95$). The crude material was distilled unde reduced pressure to yield 62 g (85%) of pure product, bp 130-135° C ( 0.1-0.2 m Hg ) , D* D 5 +27.1 (C 1.1, EtOH). -M and IR were consistent wi the assigned structure. EXAMPLE 4 Preparation of (S)-(-)-propranolol - Method B A solution of (S)-(+)-glycIdy I naphthyl ether (20 g, 0.1 m) and Isopropylamlne (10 g, 0.17 m) In methanol (100 mL ) was refluxed for 1 hour and evaporated to dryness. The residue was taken up with ether (200 L), washed with water and dried over MgS0 . After filtering, the filtrate was acldldlfled ith gaseous HCI . The crude sol Id was recrystal I Ized from 25 ethanol to afford 24 g (81$) of pure l.-propranolol, mp 198-200° C, [C]Q -26.8 (c 1, EtOH). .MR and IR were consistent with the assigned structure. Uslng the same procedures as described In the above examples, the following compounds were prepared: Compound B.p.. °C. (M.p.) 25 GOo -18.6 (c 1, EtOH) 118-122 +25.3 (c 1.5, EtOH) (0.2 mmHg) Compounrl B.r... - » n. (M.p.) -a. 5 +7.9 ( c 0.66, MeOH S-(+) Decomposed R-(-) Decomposed R-(-) Compound -8.3 ( c 14, EtOH) (115-118) -10.5 (c 1, EtOH) s-(-) (100-102) -20.3 (c 1, EtOH)

Claims: -25- What Is claimed Is: 1. A method of preparing a racemlc or chlral aryloxypropanol amlne (1 or chlral aryIethanol amlne (2) of the formula wherein Ar Is aryl, substituted aryl, heteroaryl, or aralkyl and R Is alkyl, aryl, aralkyl, or WB wherein W Is a straight or branched chain alkylene of from 1 to about 6 carbon atcms and wherein B Is -NR2COR3, -NR2CONR3R4, -NR 2 S0 2 R3, -N 2SO2N 3R4, or -NR 2 C00R 5 , where R2, R3, R4, and R5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloal yl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R3 and R5 are not hydrogen when B Is - R2SO2R3 or -NR2COOR5, R3 and R4 may together with N form a 5- to 7-membered heterocycl f ' c group, which method comprises: reacting a selected racemlc or chlral dloxolane the formula wherein Ar Is defined as above and R- j and R2 are each Independently hydrogen, loweralkyl, cycloloweral ky I, or R and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group or aryl group, with a solution of HX, wherein X Is chloro, brcmo or lodo, In an organic acid of the formula Y-COOH wherein Y Is hydrogen, loweralkyl or cycloalkyl to prepare a racemlc or chlral compound of the formula wherein X and Y are as defined above, and reacting said compound with a selected amlne to prepare the desired aryloxypropanolamlne or aryIethanolamlne. 2. A method of preparing a racemlc or chlral aryloxypropanol amlne of the formula wherein Ar Is aryl, substituted aryl, heteroaryl, or aralkyl and R Is alkyl, aryl, aralkyl, or WB wherein W Is a straight or branched chain alkylene of from 1 to about 6 carbon atcms and wherein B Is -NR2C-03* -NR2CONR3R4, -NR2SO2R3, -NR2SO2NR3R4, or -NR2COOR5, where R2, R3, R4, and R5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R3 and R5 are not hydrogen when B Ts -NR2SO2R3 or -NR2COOR5, or R3 and R4 may together with N form a 5- to 7-membered heterocycl lc group, which method comprises: reactfng a selected racemlc or chlral dloxolane of the formula whereln Ar is defined as above and R and R2 are each Independently hydrogen, loweral yl, cycloloweral ky I, or R-j and R2 together ith the carbon atcm form a 3 to 6 member cycloalkyl group or aryl group, with a solution of HX, wherein X ts chloro, brc o or lodo. In an organic acid of the formula Y-COOH wherein Y Is hydrogen, loweralkyl or cycloal yl to prepare a racemlc or chlral compound of the formula Ar-0- 0C0Y wherein X and Y are as defined above, and reacting said compound with a selected amlne to prepare the desired ary loxypropanol ami nβ or ary I ethanol amlne. 3. A method of preparing a compound of the formula wherein Ar Is aryl, substituted aryl, heteroaryl, or aralkyl, X Is chloro, brcmo or lodo and Y Is hydrogen, loweralkyl or cycloloweral ky I, which method comprises: reacting a selected racemlc or chlral dloxolane of the formul a whereln Ar is defined as above and R-j and R2 are each Independently hydrogen, loweralkyl, cycl ol oweral ky I, or R-| and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group or aryl group, with a solution of HX, wherein X Is defined as above, In an organic acid of the formula Y-C00H wherein Y Is defined as above. 4. The method of Claim 3 wherein the mixture of strong acid of the formula HX In the organic acid of the formula Y-C00H comprises from 0.1 to 50$ strong aci . 5. The method of Claim 3 wherein the strong acid Is r&r and the organic acid Is acetic acid. 6. The method of Claim 5 wherein the HBr Is present In the acetic acid In an amount of from 0.1 to 50$ of the mixture. 7. A method of. preparing a racemlc or chlral aryloxypropanol a lne (1) or chlral ary Iethanol amlne (2) of the formula wherein Ar Is aryl, substituted aryl, heteroaryl, or aralkyl and R Is alkyl, aryl, aralkyl, or WB wherein W Is a straight or branched chain alkylene of frcm 1 to about 6 carbon atcms and wherein B Is -NR2COR3, -NR2CONR3R4, -NR2SO2R3, -NR2SO2NR3R4, or -NR2COOR5, where R2, R3, R4, and R5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl, except that R3 and R5 are not hydrogen when B Is - R2SO2R3 or -NR2COOR5, or R3 and R4 may together with N form a 5- to 7-membered heterocycl lc group, which method comprises: reacting a selected racemlc or chlral dloxolane of the formula •29- wherein Ar Is defined as above and R-j and R2 are each Independently hydrogen, loweralkyl, cycloloweralky I, or R-j and R2 together with the carbon atom form a 3 to 6 member cycloalkyl group or aryl group, with a solution of HX, wherein X Is chloro, brcmo or lodo, In an organic acid of the formula Y-COOH wherein Y Is hydrogen, loweralkyl or cycloalkyl to prepare a racemlc or chlral compound of the formula wherein X and Y are as defined above, reacting said compound with a suitable base to prepare the appropriate epoxlde, and reacting said epoxld with a selected amlne to prepare the desired ary loxypropanol amlne or ary I ethanol am I ne.

Inventors: MAI KHUONG H X, MATIER WILLIAM L, PATIL GHANSHYAM, MAI, KHUONG, H., X., MATIER, WILLIAM, L., PATIL, GHANSHYAM
Applicants: DU PONT, E. I. DU PONT DE NEMOURS & CO., (INC.)
Application year: 1986
Main classification: C07C57
IPC codes: C07C67, C07C213, C07C217, C07C231, C07C239, C07C301, C07C303, C07D209, C07D215, C07D235, C07D237, C07D239, C07D261, C07D285, C07D295, C07D303, C07D307, C07D311, C07D317, C07D335, C07D417, C07D473, C07D493