Synthesis of Optically Active Aryloxypropanolamines and Arylethanolamines

Europaisches Patentamt European Patent Office 00 Publication number: 0 249 610 B1 Office europeen des brevets

© 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© nDate * of,„■ filing:fl ing: a 14.11.86« oc C07D 265/30,, C07D 277/04 © International application number: PCT/US86/02407

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)

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

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-

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

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^

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. The invention can be used in the synthesis of beta-agonists or beta-blockers. The following reaction schemes incorporate the method of the present invention. 35 * _* ^ HX/YC0OH ArO'Na* ♦ *0X J J ► Mr "] | > 00 0 0

H2NR

55 EP 0 249 610 B1

Ar HX/YC00H

YCOO X V

Rl R2

Base RNH, 70

Ar RNH, NHR 75 OH

20 Referring to the scheme, the (R)-(-) or S-( + )-2,2-dimethyl-4-aryloxymethyl-1 ,3-dioxolane (3) can be made by known methods. For example, the S-enantiomer can be prepared readily by reacting an appropriate phenoxide with S-( + )-2,2-dimethyl-4-(hydroxymethyl)-1,3- dioxolane methanesulfonate or p- toluene-sulfonate. 25 The aryloxypropanolamine (1) can be made by reacting the above dioxolane (or ketal) with HBr/Acetic acid, followed by amination with a selected amine. If desired, the bromoacetoxy 5 is allowed to react with a suitable base to give the epoxide 6, which is then reacted with a selected amine to prepare the desired aryloxypropanolamine. A suitable base for reaction with the bromoacetoxy is a metal alkoxide, metal hydroxide, metal hydride, 30 metal carbonate or metal bicarbonate wherein the metal is sodium, potassium or calcium, or an ammonium hydroxide or a suitable organic base. Preferred organic bases are pyridine, dimethylaminopyridine, dimethylanlline, quinoline, 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,5-Diazabicyclo[4,3.0]non-5-ene (DBN) or tertiary alkylamines. Preferred bases are sodium or potassium methoxide, ethoxide or t-butoxide or a tertiary alkyl amine. 35 The arylethanolamines can be prepared as follows. The aryl ketal of 1 ,2-ethanediol can be converted to the corresponding bromoacetate by reacting it with HBr/AcOH. The resulting bromohydrin then can be cyclized to an epoxide by treating it with one equivalent of sodium methoxide. The arylethanolamine can be obtained by treating the epoxide with one equivalent of amine. The following beta-adrenergic blocking agents, beta-agonists and partial agonists are representative of 40 the compounds that can be made using the described process:

55 EP 0 249 610 B1

OH Ar-O' •NH-R

Ar Compound

HN + MO Acebutolol 70 l COCH. CH2 CH2 CH, 75

4-CH2CH2-{^)jh Adimolol

20 0

+ Afurolol 25

CH2CH=CH2 -< Alprenolol

NH + Ancarolol 35

-< Atenolol 40 CH2CONH2

45 Befunolol

50 CH2CH20-CH2-<] Betaxolol

55 EP 0 249 610 B1

Ar Compound

n O V- CH2CH2-/ (J 0CH3 Bevantolol 0CH„

70 Bisprolol

CH2-0-CH2CH2-0-< 75

CH2CH2 OCH- Bometolol 20 OCH. CH? C-CH, c- ii 3 0 25

Bomaprolol 30

Bucindolol 35

40 Bucumolol

+ Bufetolol 50

55 EP 0 249 610 B1

Ar Compound

Bunitrolol CN 70

+ Bunalol

CI -h Bupranolol 20 CH-

OH 0

25 Butocrolol

0 30 CH3(CH2)2-C Butofilolol

-< Carazolol

40 H

Carteolol 45

CH2CH2 0 CH30 50 Carvedilol

55 EP 0 249 610 B1

Ar Compound

COCH.

Cel iprolol Et2NCOHN + 70

OCH0CONHCH,

75 + Cetamolol

Chinoin-103 20

|>-CH20CH2CH20-/O>- -< Cidoprolol

CI + Cloranolol 30 CI

35 COCH-

Diacetolol

40 CH3C0HN

Exaprolol 50 -<

55 EP 0 249 610 B1

Ar Compound

IPS-339

+ N-0-

Indenolol

CI CH 20 Indopanolol

30 + Isoxaprolol

+ 40 Levobunolol If 0

45 CH Mepindolol

COOCH '3 CH. CH, -< 50 Metipranolol CH.

10 EP 0 249 610 B1

Ar Compound

CH30CH2CHKO Metoprolol

OCH. 70

+ Moprolol

+ Nadolol 20

+ Nafetolol 25 OH

30 — < Oxprenolol

CH3 C=CH-CN 35 OCH. OCH. Pacnnolol

45 NHCONH — < -< Pafenolol

50 NHCOOCH- Pamatolol

11 EP 0 249 610 B1

Ar R Compound

~\~ Pargolol

70 4" Penbutolol

75 Pindolol

20 Pirepolol

I 0' "CH- CH3 25

CH3CONH2

30 Practolol

35 Prenalterol

T OH 40

HNH-

+ Prizidilol 45

50 Procinolol

12 EP 0 249 610 B1

Ar Compound

-< Propranolol

70 + Spirendolol

75 CH.

Teoprolol N N 0 I 20 CH,

+ Tertatolol 25

+ Timolol 30 H

SCH. 35 Tiprenolol

CH. CONH„ Tolamolol 40

CH. + Xibenolol CH. 45

Xamoterol

50 OH

13 EP 0 249 610 B1

OH •NH-R

Ar Compound

70 OH

OH -f~ Al buterol

CH,CH,0—

H2N02 OCH- Amosulalol 20

+ Bufuralol

+ Sulfonterol

CH2S02CH3 35 OH

Ibuterol

14 EP 0 249 610 B1

Miscellaneous Beta-Blockers Compound

Arotinolol 70

-CONH,

Bopindolol 25

30 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 in any respect.

35 EXAMPLE 1

Preparation of (R)-(-)-2-(1-Naphthyloxy-3-bromo)propyl acetate

+ HBr/AcOH

OAc Br 45

A mixture of (R)-(-)-2,2-dimethyl-4-napthyloxymethyl-1 ,3-dioxolane (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 50 then added. The resulting mixture was stirred and cooled in an ice bath. The K2CO3 (300 g) was added portionwise. 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 with a saturated solution of NaHC03. The extract was dried over MgSCU and evaporated to an oil (120 g, 96%). This was used in the next step without any further purification. 55

15 EP 0 249 610 B1

EXAMPLE 2

Preparation of (S)-(-)-propranolol - Method A

MeOH OAC Br 70 00 + ^

A solution of (R)-(-)-2-(1-napthyloxy-3-bromo)propyl acetate (20 g, 6.2 mM) and ispropylamine (5 g) in methanol (50 mL) was refluxed for 1 hour and evaporated to dryness. The residue was taken up with water, basified with K2CO3 and extracted twice with ether. The organic layers were combined, washed with water, 20 dried over MgSCU, filtered and acidified with hydrogen chloride. The solid precipitate was filtered and recrystallized from ethanol to afford 14.6 g (79.6%) of white crystal ins product, m.p. 197-200° C, a^5 = -26.1 (c 1, EtOH).

EXAMPLE 3 25 Preparation of (S)( + )glycidyl napththyl ether

30 MeONa/MeOH

To a solution of (R)-(-)-2-(1-napthyloxy-3-bromo)propyl acetate (120 g, 0.37 m) in 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 which was washed twice with water. The 40 organic layer was dried over MgSCU and evaporated to an oil (70 g, 95%). The crude material was distilled under reduced pressure to yield 62 g (85%) of pure product, bp 130-135° C (0.1-0.2 mmHg), [a]g5 +27.1 (c 1.1, EtOH). NMR and IR were consistent with the assigned structure.

EXAMPLE 4 45 Preparation of (S)-(-)-propranolol - Method B

50 MeOH H2N

A solution of (S)-( + )-glycidyl naphthyl ether (20 g, 0.1 m) and isopropylamine (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

16 EP 0 249 610 B1

(200 mL), washed with water and dried over MgSCv After filtering, the filtrate was acididified with gaseous HCI. The crude solid was recrystallized from ethanol to afford 24 g (81%) of pure l-propranolol, mp 198- 200° C, [a]g5 -26.8 (c 1, EtOH). NMR and IR were consistent with the assigned structure.

5 Using the same procedures as described in the above examples, the following compounds were prepared:

Compound B.n.. °C. (M.p.) cog5 70

CH,

15 CHJCH,0,C// \ 150-160 -7.76 (neat) (0.1-0.2 mmHg) R-(-) V

152-164 -5.42 25 (neat) (0.1-0.3 mmHg)

0,CH,

150-165 -18.6 (c 1, EtOH) (1.2-1.8 mmHg)

118-122 +25.3 (c 1.5, EtOH) s-(+) (0.2 mmHg) 50

17 EP 0 249 610 B1

Compound

150-156 +7.9 (c 0.66, MeOH) 70 (0.1-0.15 mmHg) 0,CH,

S-(+)

140-155 +13.08 (c 15, EtOH) (1.0-1.5 mmHg) 20

25 II OCCH,

CH,CH,0,C Decomposed 30 R-(-)

o 35 ll OCCH,

Decomposed 40

R-(-) 45

18 EP 0 249 610 B1

25 Compound R-P- °n. (M.p.)

OCCH,

70 165-175 -8.3 (c 14, EtOH) (1.00 mmHg)

CH,CH,0,C 20 •Maleic Acid (115-118) -10.5 (c 1, EtOH) s-(-)

25 OH \/i\^*H— ( .HC1

(92-94) -19.6 (c 1, MeOH 30 0,CH, s-(-)

OH \^4s^NH— CH,CH,0,C ( .HC1 40 (100-102) -20.3 (c 1, EtOH) S-(-)

Claims

1. A method of preparing a compound of the formula 50

Ar-0 X or Ar^ *

55 OCO-Y OCO-Y

19 EP 0 249 610 B1

70 R R

75 wherein Ar is defined as above and Ri and R2 are each independently hydrogen, loweralkyl, cycloloweralkyl, 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 an organic acid of the formula Y-COOH wherein Y is defined as above.

20 2. The method of Claim 1 wherein the solution of acid of the formula HX in the organic acid of the formula Y-COOH comprises from 0.1 to 50% acid.

3. The method of Claim 1 or 2 wherein HX is HBr and the organic acid is acetic acid.

25 4. The method of Claim 3 wherein the HBr is present in the acetic acid in an amount of from 0.1 to 50% of the solution.

5. A method of preparing a racemic or chiral aryloxypropanolamine (1) or chiral arylethanolamine (2) of the formula 30

OH • 1 ^NHR Ar-O^^/^NHR or Ar^*^^ OH 1 2

40 wherein Ar is as defined in claim 1 and R is alkyl, aryl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to 6 carbon atoms and wherein B is -NR2COR3, -NR2CONR3R+, -NR2SO2R3, -NR2SO2NR3R4, or NR2COOR5, where R2, R3, FU, and R5 may be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or 45 aralkyl, except that R3 and R5 are not hydrogen when B is -NR2SO2R3 or -NR2COOR5, or R3 and R+ may together with N fom a 5- to 7-membered heterocyclic group, which method comprises: carrying out a method according to any of claims 1 to 4 to prepare a recemic or chiral compound of the formula

50 0C0Y

Ar^s^ Ar-O^Sf^X or

wherein X and Y are as defined in claim 1, and reacting said compound with amine to prepare the

20 EP 0 249 610 B1

aryloxypropanolamine or arylethanolamine.

6. A method of preparing a racemic or chiral aryloxypropanolamine (1) or chiral arylethanolamine (2) of the formula

NHR

70 Ar-0 NHR or

75 wherein Ar is as defined in claim 1 and R is alkyl, aryl, aralkyl, or WB wherein W is a straight or branched chain alkylene of from 1 to 6 carbon atoms and wherein B is -NR2COR3, -NR2CONR3R+, -NR2SO2R3, -NR2SO2NR3R4, or -NR2COOR5, where R2, R3, FU, and R5 and be the same or different and may be hydrogen, alkyl, alkoxyalkyl, alkoxyaryl, cycloakyl, alkenyl, alkynyl, aryl, heteroaryl, or 20 aralkyl, except that R3 and R+ are not hydrogen when B is -NR2SO2R3 or -NR2COOR5, or R3 and R+ nay together with N form a 5- to 7-membered heterocyclic group, which method comprises: carrying out a method according to any of claims 1 to 4 to prepare a racemic or chiral compound of the formula

25 0C0Y Ar-0 or Ar

0C0Y 30

wherein X and Y are as defined in claim 1 , reacting said compound with a base to prepare an epoxide, and reacting said epoxide with amine to prepare the aryloxypropanolamine or arylethanolamine.

35 Patentanspruche

1. Verfahren zur Herstellung einer Verbindung der Formel

40 Ar Ar-0 oder

OCO-Y OCO-Y

45 worin Ar Aryl, substituiertes Aryl, Heteroaryl oder Aralkyl ist, X Chlor, Brom oder lod ist, und Y Wasserstoff, Niederalkyl oder Cyclo-Niederalkyl ist, umfassend die Umsetzung eines ausgewahlten racemischen oder chiralen Dioxolans der Formel

oder 55

21 EP 0 249 610 B1

worin Ar wie oben definiert ist, und Ri und R2 jeweils unabhangig Wasserstoff, Niederalkyl oder Cyclo- Niederalkyl sind, oder R1 und R2 zusammen mit dem Kohlenstoff-Atom eine 3- bis 6gliedrige Cycloalkyl-Gruppe oder Aryl-Gruppe bilden, mit einer Saure der Formel HX, worin X wie vorstehend definiert ist, in Losung in einer organischen Saure der Formel Y-COOH, worin Y wie vorstehend 5 definiert ist.

2. Verfahren nach Anspruch 1 , wobei die Losung der Saure der Formel HX in Losung in der organischen Saure der Formel Y-COOH 0,1 bis 50% Saure umfaBt.

10 3. Verfahren nach Anspruch 1 oder 2, wobei HX HBr ist und die organische Saure Essigsaure ist.

4. Verfahren nach Anspruch 3, wobei HBr in der Essigsaure in einer Menge von 0,1 bis 50% der Losung vorhanden ist.

15 5. Verfahren zur Herstellung eines racemischen oder chiralen Aryloxypropanolamins (1) oder eines chiralen Arylethanolamins (2) der Formel

20 Ar-0 NHR oder

worin Ar wie in Anspruch 1 definiert ist, und R Alkyl, Aryl, Aralkyl oder WB ist, worin W ein lineares oder verzweigtkettiges Alkylen mit 1 bis 6 Kohlenstoff-Atomen ist und worin B -NR2COR3, -NR2CONR3R4, -NR2SO2R3, -NR2SO2NR3R4 oder -NR2COOR5 ist, worin R2, R3, R+ und R5 gleich 30 oder verschieden sein konnen und Wasserstoff, Alkyl, Alkoxyalkyl, Alkoxyaryl, Cycloalkyl, Alkenyl, Alkinyl, Aryl, Heteroaryl oder Aralkyl sind, auBer dal3 R3 und R5 nicht Wasserstoff sind, wenn B -NR2SO2R3 oder -NR2COOR5 ist, oder R3 und R+ zusammen mit N eine 5- bis 7gliedrige heterocycli- sche Gruppe bilden konnen, umfassend die Durchfuhrung eines Verfahrens nach irgendeinem der Anspruche 1 bis 4, urn eine racemische oder chirale Verbindung der Formel 35 0C0Y Ar-0 oder Ar 40 0C0Y

herzustellen, worin X und Y wie in Anspruch 1 definiert sind, und die Umsetzung der Verbindung mit einem Amin, urn das Aryloxypropanolamin oder Arylethanolamin herzustellen. 45 6. Verfahren zur Herstellung eines racemischen oder chiralen Aryloxypropanolamins (1) oder eines chiralen Arylethanolamins (2) der Formel

50 Ar-0 NHR oder

worin Ar wie in Anspruch 1 definiert ist, und R Alkyl, Aryl, Aralkyl oder WB ist, worin W ein lineares

22 EP 0 249 610 B1

oder verzweigtkettiges Alkylen mit 1 bis 6 Kohlenstoff-Atomen ist und worin B -NR2COR3, -NR2CONR3R4, -NR2SO2R3, -NR2SO2NR3R4 oder -NR2COOR5 ist, worin R2, R3, R+ und R5 gleich oder verschieden sein konnen und Wasserstoff, Alkyl, Alkoxyalkyl, Alkoxyaryl, Cycloalkyl, Alkenyl, Alkinyl, Aryl, Heteroaryl oder Aralkyl sind, auBer dal3 R3 und R+ nicht Wasserstoff sind, wenn B 5 -NR2SO2R3 oder -NR2COOR5 ist, oder R3 und R+ zusammen mit N eine 5- bis 7gliedrige heterocycli- sche Gruppe bilden konnen, umfassend die Durchfuhrung eines Verfahrens nach irgendeinem der Anspruche 1 bis 4, urn eine racemische oder chirale Verbindung der Formel

0C0Y ^ * ^ I Ar-0-^X\X oder x Ar OCOY

15 herzustellen, worin X und Y wie in Anspruch 1 definiert sind, Umsetzung der Verbindung mit einer Base, urn ein Epoxid herzustellen, und Umsetzung des Epoxids mit einem Amin, urn das Aryloxypro- panolamin oder Arylethanolamin herzustellen.

20 Revendicatlons

1. Un procede de preparation d'un compose de la formule

25 ou Ar-O'^^Y^^* Ar� ^

OCO-Y

30 dans laquelle Ar est un groupe aryle, aryle substitue, heteroaryle, ou aralkyle, X est un atome de chlore, brome ou iode et Y est de I'hydrogene, un groupe alkyle inferieur ou cyclo(alkyle inferieur), ce procede consistant a : faire reagir un dioxolane racemique ou chiral choisi de la formule

35 Ar-O'^'N— ^ ou

dans laquelle Ar est tel que defini ci-dessus et R1 et R2 sont chacun independemment de I'hydrogene, un groupe alkyle inferieur, cyclo (alkyle inferieur), ou R1 et R2 ensemble avec I'atome de carbone forment un groupe aryle ou un groupe cycloalkyle comportant de 3 a 6 chaTnons, avec un acide de 45 formule HX, dans laquelle X est tel que defini ci-dessus, en solution dans un acide organique de la formule Y-COOH dans laquelle Y est tel que defini ci-dessus.

2. Le procede de la revendication 1 dans lequel la solution d'acide de la formule HX dans I'acide organique de la formule Y-COOH comprend de 0,1 a 50 % d'acide. 50 3. Le procede de la revendication 1 ou 2 dans lequel HX est HBr et I'acide organique est de I'acide acetique.

4. Le procede de la revendication 3 dans lequel le HBr est present dans I'acide acetique dans une 55 quantite allant de 0,1 a 50 % de la solution.

5. Un procede de preparation d'une aryloxypropanolamine (1) racemique ou chirale ou d'une arylethanolamine (2) chirale de la formule

23 EP 0 249 610 B1

w dans laquelle Ar est tel que defini dans la revendication 1 et R est un groupe alkyle, aryle, aralkyle, ou WB dans lequel W est un groupe alkylene a chaTne lineaire ou ramifiee de 1 a 6 atomes de carbone et dans lequel B est - NR2COR3, -NR2CONR3R+, -NR2S02R3, -NR2S02NR3R+, ou NR2COOR5, ou R2, R3, R+ et R5 peuvent etre identiques ou differents et peuvent etre de I'hydrogene, un groupe alkyle, alcoxyalkyle, alcoxyaryle, cycloalkyle, alcenyle, alcynyle, aryle, heteroaryle, ou aralkyle, si ce n'est que 15 R3 et R5 ne sont pas de I'hydrogene lorsque B est -NR2S02R3 ou - NR2COOR5, ou R3 et R+ peuvent ensemble avec N former un groupe heterocyclique comportant de 5 a 7 chaTnons, ce procede consistant a : mettre en oeuvre un procede selon I'une quelconque des revendications 1 a 4 pour preparer un compose racemique ou chiral de la formule

20 OCOY

Ap� Ar-0-^N^\x ou x

25 OCOY

dans laquelle X et Y sont tels que definis dans la revendication 1 , et faire reagir ledit compose avec une amine pour preparer I'aryloxypropanolamine ou I'arylethanolamine. 30 6. Un procede de preparation d'une aryloxypropanolamine racemique ou chirale (1) ou d'une arylethanolamine chirale (2) de la formule

Qy^^f/^^HHR ou

dans laquelle Ar est tel que defini dans la revendication 1 et R est un groupe alkyle, aryle, aralkyle, ou WB dans lequel W est un groupe alkylene a chaTne lineaire ou ramifiee de 1 a 6 atomes de carbone et 45 dans lequel B est - NR2COR3, -NR2CONR3R+, - -NR2S02R3, -NR2S02NR3R+, ou -NR2COOR5, ou R2, R3, R4 et R5 peuvent etre identiques ou differents et peuvent etre de I'hydrogene, un groupe alkyle, alcoxyalkyle, alcoxyaryle, cycloalkyle, alcenyle, alcynyle, aryle, heteroaryle, ou aralkyle, si ce n'est que R3 et R4 ne sont pas de I'hydrogene lorsque B est -NR2S02R3 ou - NR2COOR5, ou R3 et R+ peuvent ensemble avec N former un groupe heterocyclique comportant de 5 a 7 chaTnons, ce procede 50 consistant a : mettre en oeuvre un procede selon I'une quelconque des revendications 1 a 4 pour preparer un compose racemique ou chiral de la formule

24 EP 0 249 610 B1

OCOY

Ar-0 ou Ar

OCOY

dans laquelle X et Y sont tels que definis dans la revendication 1 , faire reagir ledit compose avec une io base pour preparer un epoxyde, et faire reagir ledit epoxyde avec I'amine afin de preparer I'aryloxypropanolamine ou I'arylethanolamine.