AU638801B2

AU638801B2 - Production of homochiral chloropropanolamines

Info

Publication number: AU638801B2
Application number: AU72249/91A
Authority: AU
Inventors: Lena Andersson; Bo Birgersson; Aina Westfelt; Lars Westfelt
Original assignee: Nobel Chemicals AB
Current assignee: Nobel Chemicals AB
Priority date: 1990-01-22
Filing date: 1991-01-15
Publication date: 1993-07-08
Anticipated expiration: 2011-01-15
Also published as: SE9000206L; FI923305A0; EP0512020A1; SE9000206D0; WO1991010642A1; JPH05506008A; AU7224991A; FI923305A; SE468211B; CA2074075A1

Description

ANNIOUNCEMENT OF THE LA TER PUBUCA 7701V OF RE VISED VERSIONSI% OF INTERAM770NAL SEARCH REPORTS 2, it I) 1 9 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 International Publication Number: WO 91/10642 C07C 215108, 217/32, 309/75 Al(4)ItrainlPbiainD te2Juy91(5.79) C07D 303/12, 303/16, 303/14 (3 nentoa ulcto ae 5Jl 91(50.1 (21) International Application Number: (22) International Filing Date: I Priority data: 9000206-4 22iJanua PCT/SE9I/00022 I 5 January 1991 (15.01.9 1) ry 1990 (22.0 1.90) SE /VO'66 eClscwlZ5. 19e (71) Applicant (for all designated States except US): +ieeE-L CIIEMiCAt- [SE/SE); S-691 85 Karlskoga (SE).

(72) Inventors- and Inventorst Applicants (for US only) WESTFELT, Lars [SE/ SE]; Sjbgdtrdesvtigen 5, S-691 44 Karlskoga WEST- FELT, Aina [SE/SE]; Sj~rgirdesvtigen 5, S-691 44 Karlskoga BIRGERSSON. Ho [SE/SE]; Trestegsvligen 18, S-69 1 54 Karlskoga ANDERSSON, Lena [SE/ SE]; Bigatan 3A, S-69 1 36 Karlskoga (SE).

(74) Agent: FALK, Bengt; Nobel Koncernservice AB, S-691 84 Kariskoga (SE).

(81) Designated States: AT (European patent), AU, BE (European patent), CA, CH (European patent), DE (European patent), DK (European patent), ES (European patent), Fl, FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, LU (European patent), NL (European patent), NO, SE (European patent), US.

Published With a revised version of the international search report.

Before the expiration of the time limit for amending the claims and to be republished in tihe event of the receipt of amendments.

(88) Date or publication of the revised vers~ion ot the international search report: 22 August 1991 (22.08.91)

'IV

(54) Title: aRROGESS lZ01 22EPARIblC, J-IfMfCIRA! AM1NFq AND PRDCF.R FOR PRFPARNWlC lNTFRZMFDI -ATFS FOR THE ,FARTQ THERE=F, AND THEITRMDAE PREPARED IN4 ACCOREANCE PRsOD-"rit OF N HOCdHi~aaL.

(57) Abstract The present invention relates to a process for preparing S- and R-enantiomers of certain substituted 3-aryloxy-2-hydroxypropylarnines us-d as beta blockers, and to the S- and R-enantiomers of certain intermediates used for this preparative stage.

(f~.urred to in PCTr Gazuthu No. 0/1491I, Scction 11) PRODUCTION OF HOMOHCHIRAL CHLOROPROPANOLAMINES The present inrvention relates to a process for preparing Sand R-enantiomers of substituted 3-aryloxy-2hydroxypropylamines used as beta-receptor-blocking substances (hereinafter called beta blockers) and with the following respective formulae: OH Ar 3/ 2J. 3X^ S-BETA BLOCKERS R-BETA BLOCKERS in which Ar, substituted benzene or naphthalene radical and R, isopropyl, tertiary butyl, 2- (3,4 -dimethoxyphenyl) ethyl, 2-(2-methoxyphenoxy)ethyl, 2-(4-hydroxyphenylacetylamino)ethyl or 2-(N-morpholinocarbonylamino)ethyl radical.

According to the invention, these beta blockers can be prepared via intermediates in the form of the S- or Renantiomers of the amines defined below.

25 9

S

S. 'a S.oS qH ,L or //NR 3

R

Z

C.,

WO 91/10642 2 PCT/SE91/00022 NR or

NR

The abovementioned definitions for R 3 apply here, while

R

4 will be hydrogen or a protecting group which can be easily removed by means of hydrogenolysis, for example an optionally substituted benzyl radical with one or more identical or different substituents, for example methyl, alkyl, methoxy, alkoxy, hydroxyl or nitro, it being preferable, however, for the protecting group to consist of an unsubstituted benzyl radical.

The abovementioned intermediates designated 9a or 9b and 8a or 8b can in turn be obtained from other intermediates included in the invention and discussed later in the text, with the following general formulae in their R- or S-forms.

Y'H

0o A j 03 S-r, 04 o r R-f101and 4 -/Q0SrA or in which Ar substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character.

WO 91/10642 3 PCT/SE91/00022 PRIOR ART Beta blockers are used as drugs primarily for cardiovascular diseases, such as hypertension, angina pectoris and certain arrhythmias, and for glaucoma (an ophthalmic disease). Most beta blockers consist of substituted 3-aryloxy-2-hydroxypropylamines. These have a chiral centre at carbon atom number 2, as a result of which each of them can exist as two enantiomers, the R-form and the S-form. Those substances consisting of equal parts of R-form and S-form will hereinafter be called racemic or racemate, and those which consist principally of one of these two forms will be called homochiral.

In the case of some beta blockers, it is known that it is their S-form which possesses the pharmacological effect which is desirable in cardiovascular diseases, while the same beta blocker's R-form is virtually inactive. In contrast, both the enantiomers have been found to be approximately equally effective against glaucoma (Keates, E U, Stone, R: Am J Ophthalmol 98, 73 (1984)). It has therefore been proposed to use these R-beta blockers against glaucoma in order to prevent any effect on the cardiovascular system, while the S-form should be used for cardiovascular diseases. There is therefore considerable interest in establishing the simplest possible synthesis routes for preparing both the S- and R-forms of homochiral beta blockers.

Synthesis routes for preparing certain homochiral beta blockers are described in the literature. Thus, it is already known, for example from US patent 4,408,063, that S- or R-propranolol can be prepared from S- or R-glycidyl 4-toluenesulphonate (la or Ib) in accordance with the general Scheme I below (in this and in subsequent general formula schemes, steps and definitions obvious to the person skilled in the art have been omittea, to the extent that this has simplified the presentation. In many cases text which follows also makes direct reference WO 91/10642 4 PCT/SE91/00022 to the reference numbers given in these general formulae and schemes).

Scheme I q0 OH 0 OOi S-PROPRANOLOL.

O

R-PROPRANOLOL

O

OH L C.- There are also other previously known beta blockers which contain a substituted benzene radical instead of a substituted naphthalene radical. For these beta blockers too, the general designation Ar 2 will therefore be considered, as earlier on page 1, as representing both substituted benzene and naphthalene radicals. GB Patent 1,269,776 describes a method for preparing suuh beta blockers taking as a starting point certain specific amines hereinafter designated 2a, 2b, 3a and 3b, in accordance with the general method defined below (Scheme II). Here, R, alkyl radical, R 2 hydrogen or an alphaarylalkyl radical and Z a halogen atom. Scheme II shows on the one hand the product obtained when R. hydrogen and when the S- or R-beta blocker in question is obtained directly, and when R 2 is not =hydrogen and when a product is obtained which is certainly not the desired product WO 91/10642 5 PCT/SE91/00022 but which can be converted to it by means of hydrogenolysis. Scheme II A c- 08 ai ,-e A r zL- ,6 /crAeao Y A2- OH R-Le#c~ /Joc*errd t 3 Hitherto, it has only been possible for the above amines in question 2a, 2b, 3a and 3b, which include the amines 8a, 8b, 9a and 9b in question on page 2, to be prepared in homochiral form from corresponding racemates by separation via salts (so-called resolution of racemates).

It is also previously known, for example from SE-A-7414017-9 (425.971), corresponding to GB Patents 1458392 and 1458393, to prepare S-beta blockers according to the general Scheme III below, from any of the starting substances designated 4, 5, 6 or 7, in which Ar, has the same meaning as before, and in which Y an easily removable protecting group, while Z, a substitutable radical.

WO Q1/1i64? eM/ini 6 r',/oLY1uuU A Scheme III 0/ S-BETA BLOCKER 7 DESCRIPTION OF THE INVENTION The present invention now includes, inter alia, a orocess for preparing any desired enantiomers of amines 8a or 8b

I

and 9a or 9b (see page 2) from easily accessible raw materials. This involves S- or R-glycidyl esters of sulphonic acids (glycidyl sulphonate) initially being reacted with hydrogen chloride for converting the epoxy group contained therein to 1,2-chlorohydrx.n group in order to give the corresponding chloropropanediol sulphonate which in turn is reacted with an amine to give the corresponding chloropropanolamine (9a or 9b, depending on which enantiomer constituted the starting substance), or alternatively by means of a further treatment with a base, if appropriate in the presence of a phenol, completely or partially reacted to give the second amine (8a or 8b). The amines 9a, 9b, 8a and 8b are included in the general formulae for the amines 2 and 3 discussed earlier.

For preparing the glycidyl sulphonates which are used as intermediates in the process according to the invention and which are designated 10a and 10b in the formulae, the raw materials which can be employed include commercially available substances such as R- or S-glycidol, or esters thereof, for example R-glycidyl butyrate, which can be converted, by means of techniques known to the person skilled in the art, to 10a or 10b, respectively, according to the following scheme: WO 91/1 0"7 Dr"/cer/'ln 0 2nr n Scheme A IO -for R- fo ,S-/or H H in which Ar 1 is a substituted benzene or naphthalene radical in which at least one substituent is of an electron-attracting character, for example one or more chlorine, bromine or iodine atoms, one or more nitroso, nitro, cyano, trifluoromethyl, trichloromethyl or tribromomethyl groups, one or more optionally substituted sulphinyl, sulphonyl, phosphonyl, phosphoryl or carbonyl groups, or combinations of these atoms and groups, at any chosen positions on the benzene or naphthalene rings, it being preferable for Ar 1 to be a substituted benzene radical in which at least one substituent is a nitro, an optionally substituted sulphonyl or an optionally substituted carbonyl group at any chosen position on the benzene ring. In the most interesting alternative, Ar is a substituted benzene radical in which at least one substituent is a nitro group at any chosen position on the benzene ring.

Alternatively, the glycidyl sulphonate', 10a and 10b can be prepared starting from allyl alc>nol which, by means of enantioselective epoxidation, is converted to S- or R-glycidol, which is then reacted to give 10a or respectively, again using the known technique for example, Klunder, J M, Ko, S Y, Sharpless, K B: J Org Chem 3710 (1986)).

The preparation of the amines 9a and 9b by reacting the glycidyl sulphonates 10a and 10b, respectively, with hydrogen chloride followed by treatment with an amine can be illustrated as follows: WIO 91/10642 8 PCT/SE91/00022 Scheme IV 0 1>O<S-A 1 C KSy r 1

R

3 RPU^'C'vk^ NP 3 S 013.A r? o,9 e /9 C in which Arl, R 3 and R, have the same meanings as above.

As can be seen, R changes to S and S to R upon reaction with hydrogen chloride. We have chosen to use references a and b to follow the chemistry, rather than the prefixes R and S which derive from nomenclature conventions.

The amines 9a and 9b can be completely or partially converted to amines 8a and 8b, respectively, by treatment with a base, for example hydroxides, alkoxides or carbonst:as of lithium, sodium, potassium, calcium or magnesium and optionally substituted ammonia, it being preferable for the base to consist of sodium or potassium hydroxide or of sodium or potassium alkoxide, for example methoxide, ethoxide or tertiary butoxide, optionally in the presence of a phenol, as is clear from the relevant part of Scheme V.

The advantage of the new procedures for preparing amines 8 and 9 in homochiral form is that they permit utilization of 100% of the raw material, whereas, with the earlier method, a maximum of 50% of the employed raw material could be utilized, and also the earlier methods involve the use and recovery of a frequently expensive homochiral salt-former.

As mentioned earlier, the invention furthermore relates to new routes for the preparation of S- and R-beta blockers. These routes are via the amines 9a or 9b and 8a or 8b, for which reason the starting substances for this part of the invention too are R- and S-glycidyl WO 91/10642 9- WO 9110642PCr/SE9l /00022 esters of sulp~onic acids (10a or 10b) which are reacted to give the amines 9a or 9b. These amnines are then further treated in accordance with the following scheme.

Scheme V C O 7~ O V 'Jf~1 C A,

AIR

N£4se+.rz- X- Ie,4 /aerp 3 4 ea, S/e in which R 3 and R 4 have the same meanings as above. When

R

3 is isopropyl, Arz is any one of the radicals given in Table 1 below.

rN WO 91/10642 10 W091/0642PCrISE9I100022 Table 1 Order no. S- (15a) or without R- (15b) f orm of spec Radical Arz (generic nam~e) significance 1 2-acetyl-4-(butyrylamino)phenyl acebutolol 2 2-al lylphenyl alprenolol 3 4-carbainoylmethylphenyl atenolol 4 4- (2-cyclopropylmethoxyethyl )phenyl betaxolol 4- (2-isopropoxyethoxymethyl )phenyl bisoprolol 6 4- (2-cyclopropylmethoxyethoxy)phenyl cicloprolol 7 2-acetyl-4- (acetylamino )phenyl diacetolol 8 2-methoxyphenyl levomoprolol 9 4- (2-methoxyethyl )phenyl metoprolol 3-nitroxy)cromanyl nipradilol 11 2-allyloxyphenyl oxprenolol 12 4-inid:lyl pindolol 13 1-naphthy. propranolol 14 4 -cyanomethylphenyl In addition, when R 3 is tertiary butyl, Ar 2 is any one of the radicals according to Table 2.

Table 2 Order no. S- (15a) or without R- (15b) form of spec Radical Ar 2 (generic name) significance 2 -acetyl-4 -(diethylcarbamoylamino )phenyl 2 -methylcarbainoylmethoxyphenyl 1- -oxo-5 8-tetrahydronaphthyl) 1-(cis-6,7-hydroxy-5,6,7,8tetrahydronaphthyl) 2 -cyc lopentyl 8 -thiocromanyl celiprolol cetamo lo 1 levobunolol nadolol penbutolo 1 tertatolol WO 91/10642 11 PCT/SE91/0022 When R 3 is 2-(3,4-dimethoxyphenyl)ethyl Ar 2 is 3-methylphenyl or 4-(2-cyano-1-methylethenyl)phenyl, when R 3 2- (2-methoxyphenoxy)ethyl Ar 2 is 4-carbazolyl, and when R 3 is 2-(4-hydroxyphenylacetylamino)ethyl Ar 2 is 2-cyanophenyl, and finally when R 3 is 2-(N-morpholinocarbonylamino)ethyl Ar 2 is 4-hydroxyphenyl. Examples of the base shown in the scheme have already been mentioned above.

The S- or R-form of the beta blockers is thus obtained.

Of these, number 3, i.e. when Ar 2 4-carbamoylmethylphenyl or R-form of atenolol), can also be obtained by hydrolysis of number 14 (Ar 2 4-cyanomethylphenyl), for example by treating with aqueous acids or bases.

The procedures according to the invention for preparing, on the one hand, amines 8a and 9a or 8b and 9b and, on the other hand, S-beta blockers or R-beta blockers consist, as has been partially described above, in the respective glycidyl sulphonate (10a or 10b) being reacted with hydrogen chloride to give a chloropropanediol sulphonate, which in turn is reacted with an amine, for example isopropylamine, to give the corresponding chloropropanolamine 9a or 9b. By treating the chloropropanolamines thus obtained with a phenol 13, under the action of a base illustrated above, substances are obtained which, when R4 represents hydrogen, are S- or R-beta blockers 15a or 15b but which, when R 4 does not represent hydrogen, have the general structure 14a or 14b. The substances with structure 14a or 14b are converted to corresponding S- or alternatively R-beta blockers (15a or by being subjected to reaction conditions which bring about hydrogenolysis, for example treatment with hydrogen gas in the presence of metal catalysts, for example palladium. When treating the amines 9a or 9b with a phenol in the presence of a base, two parallel reactions take place. The one consists in direct conversion to 14a or 14b or 15a or 15b, the second taking place via previously mentioned amine 8a or 8b as intermediate WO 91/10642 12 PCr/SE91/00022 product. If so desired, such an intermediate product 8a or 8b can be isolated by crystallisation or distillation.

The feature which essentially distinguishes the procedure according to the invention for tie preparation of homochiral beta blockers from previously known procedures starting from homochiral glycidyl esters of sulphoni.c acids is that an extra reaction step is included in the synthesis sequence, in which an epoxy group is converted to a 1,2-chlorohydrin group (conversion of 10a or 10b to lla or llb in Scheme IV).

The advantage of adding this new reaction step is the following. The chloropropanediol sulphonates lla and llb have been found to give lower proportions of by-products, in the form of C3-aminated by-products, than corresponding glycidyl sulphonates 10a and 10b. This is very important since the presence of a C3-aminated impurity in amines 8a, 8b, 9a or 9b leads to formation of impurities in the homochiral beta blockers prepared from these and consisting of the same beta blockers of the opposite chiral form (R-beta blocker as an impurity in an S-beta blocker or S- as an impurity in an Impurities which are related to the main component in this way are generally difficult to remove.

The reason why, as has been mentioned above, Ar will contain at least one group of electron-attracting character is likewise that a lower proportion of C3aminated by-product is in this way obtained.

As examples of some previously unknown substances which can be used in the procedures according to Schemes IV and V, the following may be mentioned: R-glycidyl 4-nitrobenmenesulphonate, certain S- or R-glycidyl esters of sulphonic acids of formulae 10a or in which Arl has the meaning given earlier, and S- or R-3-chloro-1,2-propanediol l-sulphonates of formulae lla IW" 1 /1llA l r 13 rPLI/~iS I/uuV L2 or lib, for example, S- or R-3-chloro-1,2-prcpanediol 1-(4-nitrobenzenesulphonate).

-This j.mAng thai th invention also inclnm-js int n iat of the following general formulae in th r R- and S-forms: 7 or lrm namely the S orm in which Ar 1 4-nitrophenyl and the Rand but with the e ception of previously known subFstances, namely the S orm in which Ar, 4-nitrophenyl and the Rand S-for in which Ar, 2- or 3-nitrophenyl, 4-chlorophenyl .r A-chloro-3-nitropheny3 In the reactions, described above and forming part of the invention, of raw materials via intermediates to give desired final products and in the isolation of both intermediate and final product, the choice of the chemical conditions, such as solvents, concentrations, temperatures, pressure etc. is not critical for those results which are the aim of the invention to be achieved, and instead generally known practice in organic synthesis can be used in each particular case. The same applies of course to the following examples in which these data have for this reason not always been included.

As examples of some solvents which are suitable in connection with the process according to the invention, mention may be made of dichloromethane, tetrahydrofuran, dimethyl sulphoxide, methanol, water, toluene and ethyl acetate. The concentrations are expediently chosen between about 0.1 M and the saturation concentrations in the reaction mixtures in question, and the temperatures WO 01/104 PrT/SrQ1/0I0 '2 rrv J 71 a 14 are chosen between about -20 0 C and 150'C and the pressure between 0.01 and 20 bar.

The invention, which has been defined in the subsequent patent claims, will now be further illustrated in its different parts in the following examples. In order to facilitate reading of the examples, these have in each particular case been provided with references to the relevant formula schemes, and at the same time there are also included some of the reference numbers appearing in these formula schemes and relating to the various compounds and their enantiomers.

Example 1 (Scheme IV) g of R-glycidyl 3-nitrobenzenesulphonate (10a; Ar 3-nitrophenyl; 99% R-form) were dissolved in 90 ml of dichloromethane in a glass flask, after which hydrogen chloride gas was introduced into the solution until highpressure liquid chromatography (HPLC) showed that more than 99% of the benzenesulphonate had been converted.

Removal of the excess HC1 and the dichloromethane gave S-2-hydroxy-3-chloropropyl 3-nitrobenzenesulphonate (lla; Ar. 3-nitrophenyl) in the form of an oil which slowly crystallised. Nuclear magnetic resonance spectroscopy (NMR) with deuterochloroform as solvent gave the following result: 62.7 (1 H, singlet), 3.60 (2 H, doublet), 4.2 (1 H, multiplet), 4.24 (2 H, doublet), 7.80 (1 H, triplet), 8.24 (1 H, triplet of doublets), 8.50 (1 H, triplet of doublets), 8.74 (1 H, triplet) ppm.

Purity according to HPLC about 98%. The greatest impurity may be a product formed by the opposite opening of the epoxide ring.

Example 2 (Scheme IV) Carried out as in Example 1, but with 4-isomer (10a; Ar 1 4-nitrophenyl; 99% R-form) instead of 3-isomer, giving S-2-hydroxy-3-chloropropy) 4-nitrobenzenesulphonate WO 91/10642 15 WO 9110642PCr/SE91 /00022 (11a; Ar 1 4-nitrophe,,,yl) NMR: 82.5 (1 H, singlet), 3.61 (2 H, doublet), 4.2 (1 H, multiplet), 4.26 (2 H, doublet), 8.12 (2 H, doublet), 8.41 (2 H, doublet) ppm.

Example-3 (Scheme IV)~ Carried out as in Example 1, but with concentrated hydrochloric acid (200 ml) instead of hydrogen chloride gas and dichioromethane, which gave the same result.

Example 4 (Schemes IV and V) Isopropylamine (12; R 3 isopropyl, R 4 H, 1.2 ml) and dichloromethane (0.35 ml) were added to S-2-hydroxy 3-chioropropyl 3-nitrobenzenesulphonate (11a; Ar 1 3nitrophenyl) prepared in accordance with Example 1 (0.20 The solution was allowed to stand for one hour at about 20*C, after which volatile constituents were stripped of under r.,duced pressure. After dissolving in dimethyl suiphoxide (DXSO, 0.5 ml), a solution of 2-(4hydroxyphenyl)acetamide (13; Ar 2 4-carbamoylmethyiphenyl, 0.43 g) and potassium tert-butylate (0.68 g) in DMSO. (1.3 ml) was added. After two hours at 80 0

C,

HPLC (column: Chiral AGP, ChromTech) on the reaction mixture showed that 4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetamide (15a; Ar 2 4-carbamoylmethylphenyl, R 3 isopropyl) had been f ormed and that the ratio between its S-form and R-form was 99:1.

Example 5 (without conversion of epoxy group to 1,2chlorohydrin group).

Carried out as in Example 4 but with R-glycidyl 3-nitrobenzenesulphonate (10a; Ar 1 3-nitrophenyl) instead of S-2-hydroxy-3-chloropropyl 3-nitrobenzenesulphonate (11a; Ar, 3-nitrophenyl). In this case the ratio between the S- and R-forms of the product was 97:3.

Exam le 6 (Scheme IV) Isopropylamine (12; R 3 isopropyl, R, 1, 60 ml) and dichioromethane (10 ml) were added to S-2-hydroxy-3- WO 91/10642 16 PCT/SE91/00022 chloropropyl 3-nitrobenzenesulphonate (lla; Arl 3-nitrophenyl) prepared according to Example 1 (20 The solution was allowed to stand for two hours at Removal of volatile constituents under reduced pressure gave a crystalline product (27 HPLC showed that it principally consisted of a mixture of 3-nitrobenzenesulphonic acid salts of isopropylamine and S-2-hydroxy- 3-chloropropylisopropylamine (9a; R 3 isopropyl, R, As a reference for identifying the latter, a racemic product was used which "as obtained by reacting epichlorohydrin with isopropylamine.

Example 7 (Scheme IV) Carried out as in Example 6, but starting from 4-isomer (lla; Ar 4-nitrophenyl) instead of 3-isomer. The crystalline product obtained in this case differed from that obtained in Example 6 only in that it consisted of 4- instead of 3-nitrobenzenesulphonic acid salts of isopropylamine and S-2-hydroxy-3-chloropropylisopropylamine (9a; R 3 isopropyl, R, H).

Example 8 (Scheme IV) Stage A.

A solution of S-2-hydroxy-3-chloropropyl 3-nitrobenzenesulphonate (lla; Ar 1 3-nitrophenyl) prepared according to Example 1 (1.48 g) and benzylisopropylamine (12; R 3 isopropyl, R. benzyl, 1.16 g) in methanol ml) was heated for five hours at 40'C. The methanol was then stripped off under reduced pressure.

Stage B.

The product was chromatographed on silica gel with ethyl acetate/dichloromethano as eluent. S-2-hydroxy-3chloropropylbenzylisopropylamine (9a; R3 isopropyl, R, benzyl) in the form of a viscous oil (0.1 g) was obtained in this case.

NMR: 61.02 (6 H, two doublets), 2.55 (2 H, multiplet), 2.96 (1 H, septet), 3.2 (1 H, broad singlet), 3,5 (5 H, WO 91/10642 17 PCT/SE91/00022 multiplet), 7.16 (5 H, singlet) ppm.

Example 9 (Scheme V! A product containing S-2-hydroxy-3-chloropropylisopropylamine (9a; R 3 isopropyl, R 4 H) prepared in accordance with Example 7 (46.1 g) was suspended in methanol (22 m3), and a solution of potassium hydroxide (16.6 g) in methanol (95 ml) was added. After heating for one hour at 40'C, volatile constituents were stripped off, water was added, and the mixture was extracted with dichloromethane. The extract was evaporated, and this gave S-2,3-epoxypropylisopropylamine (8a; R, isopropyl, R4 H) in the form of an oil which was purified by vacuum distillation (bp 380 at 1 torr). Identification was carried out by HPLC, the reference used being a racemic product obtained by potassium tert-butylate-induced hydrogen chloride elimination from the reference used in Example 6.

Example 10 (Scheme V) A product containing S-2-hydroxy-3-chloropropylisopropylamine (9a; R 3 isopropyl, R 4 H) prepared in accordance with Example 7 (46.1 g) was suspended in methanol (22 ml), and a solution of 2-(4-hydroxyphenyl)acetamide (13; Ar 2 4-carbamoylmethylphenyl, 57.0 g) and potassium hydroxide (35.7 g) in methanol (195 ml) was added. After heating for two hours at 50'C, HPLC showed that complete conversion had taken place, partially via 8a (R 3 isopropyl, R, Isobutanol was added, and the mixture was filtered and most of the methanol stripped off from the filtrate. The solution which remained was washed with water after which the volatile constituents in the organic phase were stripped off. The product was recrystallised from isopropyl alcohol, this giving S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetamide (15a; Ar 2 4-carbamoylmethylphenyl, R 3 isopropyl, 6.2 NMR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R-form in the product was 99:1.

WO 91/10642 -18 PCT/SE9I /00022 Example 11 (Scheme Vj_ Carried out as in Example 10, but with 1-naphthol (13; Ar 2 l-naphthyl, 54.4 g) instead of 2-(4-hydroxyphenyl)acetainide. In this case S-1-(2-hydroxy-3-isopropylaminopropoxy)riaphthalene (15a; Ar 2 1-naphthyl, R 3 isopropyl) was obtained, the ratio between S- and R-form being 99%.

Example 12 (Scheme V) A product containing S-2-hydroxy-3-chloropropylbenzylisopropylamine (9a; R 3 iSopropyl, R4 benzyl) prepared in accordance with stage A in Example 8 (6.7 g) was suspended in methanol (5 ml), and a solution of 2-(4hydroxyphenyl)acetamide (13; Ar 2 4-carbamoylmethyiphenyl, 5.7 g) and potassium hydroxide (3.6 g) in methanol (20 ml) was added. After heating for three hours at 60*C, the mixture was filtered and the filtrate was evaporated. Water was added and the mixture was extracted with dichioromethane. After evaporation, the extract was dissolved in methanol (50 ml), palladium/charcoal 0.21 g) was added, and the mixture was stirred in a hydrogen gas atmosphere. The reaction was discontinued when HPLC showed that all the starting material had been consumed. The suspension was filtered and the methanol was stripped off. Recrystallisation from isopropyl alcohol gave S-4- (2-hydroxy-3-isopropylaminopropoxy) phenylacetamide (15a; Ar 2 carbamoylmethyiphenyl,

R

3 isopropyl, 0.9 NMR identical with racemic reference. HPLC (column: Chiral AGP) showed that the ratio between S- and R-form in the product was 99:1.

Example 13 (Scheme V) Carried out as in Example 10, but with 2-(4-hydroxyphenyl)acetonitrile (13; Ar 2 4-cyanomethylphenyl, 50.2 g) instead of 2-(4-hydroxyphenyl)acetamide. In this case S-4- (2-hydroxy-.3-isopropylaminopropoxy)phenylacetoniitrile was obtained (15a; Ar 2 4-cyanomethylphenyl, R, isopropyl, 5.7 g).

WO 91/10(42PCSE/02 -1 19 PCr/SE91/00022 ExaMple 24 (2-hydroxy-3-isopropylaminopropoxyl) henylacetonit':-ile Ar 2 4-cyanomethyiphenyl, R 3 =isopropyl) prepared in accordance with Example 13 (2.5 g) was stirred at with concentrated hydrochloric acid (15 ml). After three hours, the mixture was cooled in an ice bath and the pH was adjusted -to 12 using a solution of potassium hydroxide in water. The mixture was saturated with sodium chloride and was filtered. After recrystallisation from isopropyl alcohol, S-4-(2-hydroxy-3-isopropylaminopropoxy)phenylacetamide (15a; Ar 2 4-carbamoylmethyiphenyl, R 3 isopropyl, 1.5 g) was obtained, with identity and purity as in Example (Scheme IV') Carried out as in Example 2, but with S-isomer (10b; Ar, 4-nitrophenyl) instead of R-isomer, giving R-2-hydroxy- 3-chiorapropyl, 4-nitrobenzenesulphonate (11b; Ar 1 4nitrophenyl).

Example 16 (Scheme IV') Carried out as in Example 7, but with R-isomer (l1b; Ar 1 =4-nitrophenyl) prepared in accordance with Example 14 instead of S-isomer, giving 4-nitrobenzenesulphonic acid salt of isopropylamine and R-2-hydroxy-3-chlorop--opylisopropylamine (9b; R3 isopropyl, R, H).

Exwnp1e 17 (Scheme V) Carried out as in Example 10, but with R-isomer (9b; R 3 isopropyl,, R. H) prepared in accordaxce with Example instead of S-isomer, giving R-4-(2-hydroxy-3-isopropylazninopropoxy)phenylacetamide (15b; Ar 2 4-carbamoylmethyiphenyl, R 3 isopropyl). The ratio between Rand S-form was 99:1.

Claims

1. A process f or preparing S- and R-enantiomers of chioropropanolamines having the general fnmulae HO C1 NR 3R4 HOH and C 1\,N R R 4 CR-f orm) (S-form) respectively from and S-glycidyl eaters of suiphonic acids (glycidy. suiphonate) with the formulae 0 3S--Ar H O 0 3S-Ar1 (R-form) (S-form) 25 in which Ar, substituted benzene or naphthalene radical in which at least one substituent is of an electron- attracting character comprising reacting the starting substance in form of the respective glycidyl sulphonate with hydrogen chlorile for converting the epoxy groul, contained therein to a 1,2-chlcrohydrin group in order to give the corresponding chloropropanedioj. suiphonate. which in turn is reacted with an amine of the general formula A, R 4 NH in which R, isopropyl, tertiary butyl,

2- 4-dimethoxyphenyl)ethy. 2- (2-methoxyphenoxy,)ethyl, 2- (4-hydroxyphenylacetyltuaino) ethyl or a 2- (N-morpholinecarbonylamino) ethyl radical and R, is hydrogen or a prot~ecting group which can be easily removed by means of hydrogenolysis, to give the desired chioropropanolamine. 2. Process for preparing S- and R-enantiomers of 2,3-epoxypropylanines of the general formulae H V NP R R 8 a (S-form) 8b (R-forn) from r1,orresponding S- and R-chloropropanolamines prepared in ecocordance with Claim 1, in which the starting substance is treated with a base optionally in the presence of a phenol.

3. Process for preparing S- and R-beta blockers having the gene'ral formulae /rOH pN /V7 R Of S-BETA BLOCKERS R-BETA BLOCKERS 3 S F 555 starting from the or R-chloropropanolamines prepared in accordance with Claim 1, by treating the S- or R- chloropropanolami,es in the presence of a base, with a rhenol of the genaral formula 22 Ar 2 OH in which, when R, isopropyl, Ar 2 is a radical of 2 -acetyl -4 (butyrylamino) phenyl, 2 -allyiphenyl, 4 -carbamoylmethyiphenyl, 4 (2 -cyc lopropylmethoxyethyl phenyl, 4 (2 isopropoxyethox-ymethyl pheny.l, 0 4 (2 -cyc lopropylmethoxyethoxy) phenyl, 2 -acetyl 4- (acetyl amino) phenyl, 2 -me thoxyphenyl, 4 (2 -methoxyethyl phenyl, 8 (3 -nitroxy) chromanyl, 2-allyloxyphenyl,

4-indolyl, 1 -naphthy) or 4- cyanomethyiphenyl and, when R, tertiary butyl, Ar, is one of the radicals :0 of I V., 2 -acetyl (diethylcarbamoylamino )phenyl, methylcarbamoylmethoxyphenyl, 1 -oxo 6 ,83- te trahydronaphthyl) 1 (c is 7- hydroxy 6, 7, 8- te trahydronaphthyl) 2-cyclopenthyl, or 8 -thiochromanyl and, when R, is 2- (3,4-dimethox-yphenyl) ethyl, Ar, is 3- methylph'inyl or 4- (2 -cyano- 1-methylethenyl )phenyl and, when R 3 is 2- (2-methoxyphenoxy) ethyl, Ar 2 iso 4-carbazolyl and, wh~en R, 2- (N-morpholinocarbonylaxnino) ethyl, Ar 2 is 4- hydroxyphenyl and, when R. 2 -hydroxyphenylace tyl amino) ethyl, Ar 2 is 2 cyanophenyl, after which the reaction. product when R, is not identical to H, is subjected to reaction conditions which result in hydrogenolysis and/or, when Ar, 4-cyanomethyiphenyl, is optionally subjected to reaction conditions which result in hydrolysis. 4. Process for preparing S- and R-beta blockers having the general formulae /7r O 0;4N V/ 1 S-BETA BLOCKEh'S 2 O 3 R-BETA BLOCKERS starting from the S- or R-2,3-epoxypropylamines prepared in accordaxace with Claim 2, hy treating S- or R-2,3- epoxypropylamines, in the presence of a base, with a phenol of the general formula S* SO *II* S 4.. ArOH in which, when R 3 isopropyl, Ar, is one of the radicals of 2-acetyl-4- (butyrylamino)phenyl 2 -allylphenyl, 30 4 -carbamoylmethylphenyl, 4- (2 -cyclopropylmethoxyethyl )phenyl, 4- (2-i sopropoxyethoxymethyl.) phenyl, -cyclopropylmethoxyethoxy) phenyl, 2-acetyl--4- (acetylamino)phenyl, U 24 2 -methoxyphenyl, 4- (2-me thoxyethyl )phenyl,

8- (3-nitroxy)chromanyl, 2 -allyloxypbanyl, 4-indolyl, I1-naphthyl, or 4- cyanomethyiphenyl and, when R, tertiary butyl, Ar, is one of the radicals of 2 -acetyl-4- (diethylcarbamoylamino)phenyl, 2 -methylcarbamoylmethoxyphenyl, 1-(5-oxo-5,6,7,8-tetrahydronaphthyl), 1- (cis-6, 7-hydroxy-5, 6,7, 8-tetrahydronaphthyl), 2 -cyclopenthyl, or 15 8-thiochromanyl and, when R, is 2- (3,4-dimethoxyphenyl) ethyl, Ar 2 is 3- methyiphenyl or 4-(2-cyano-1-methylethenyl)phenyl and, when R 3 is 2-(2-methoxyphenoxy)ethyl, Ar 2 is 4-carbazolyl and, when R, 2- (N-morpholinocarbonylamino) ethyl, Ar 2 is 4 -hydroxy-phenyl aand, when R, 2 -hydroxyphenyl acetyl amino) ethyl, Ar 2 is 2 -cyanophenyl, after which the reaction product when R, is not identical Cto H, is subjected to reaction conditions which result in hydrogenolysis and/or, when Ar 2 4-cyanomethyiphenyl, is optionally subjected to reaction conditions which result in S Chydrolysis. 5. Process for preparing S- and R-enantioners of substituted 3-aryloxy-2-hydroxypropylamines used as beta blockers, with the following respective formulae: OH H Ar 2 0 \vN HR 3 S-BETA BLOCKERS R-BETA BLOCKERS in which when R, isopropyl, Ar, is a radical of 2-acetyl-4- (butyrylamino)phenyl, 2 -allyiphenyl, 4 -carbamoylmethyiphenyl, 4 (2 -cyc lopropymeth.cyethy1 phenyl, 4- (2-isopropoxy-ethoxymethyl)phenyl, 4 (2 -cyc lopropylmethoxyethoxy.) phenyl, 2-acetyl-4- (acetyiamino)phenyl, 2 -methoxyphenyl, 4- (2 -methoxyethyl )phenyl, 8-(3-nitroxy)chromanyl, 2-allyloxyphenyl, 4-indolyl, 1-naphthyl, or 4 -cyanomethyiphenyl and, when R 3 tertiary butyl, Ar, is one of the radicals of 2-acetyl-4- (diethylcarbamoylamino~phenyl, 2 -methylcarbamoylmethoxyphenyl, I--(5-oxo-5,6,7,8-tetrahydronaphthyl), 1 is 7 -*.,droxy 6, 7, 8- te trahydronaphthyl), 2-oyclopenthyl, or 8 -thiochromanyl and, wqhen R 2 is 2- (3,4-dimethoxyphenyl) ethyl, Ar 2 is 3- methyiphenyl or 4-(2-cyano-1-methylethenyl)phenyl and, when 26 R, is 2- (2-methoxyphenoxy) ethyl, Ar 2 is 4-carbazolyl and, when R, 2 -(N-morphol1inocarbonyl amino) ethyl, Ar, is 4- hydroxcyphenyl and, when R, 2 -hydroxyphenylacetyl amino) ethyl, Ar, is 2-cyanophenyl, after which the reaction product when R, is not identical to H, is subjected to reaction conditions which result in hydrogenolysis and/or, when Ar 2 4-cyanomethylphenyl, is optionally subjected to reaction conditions which result in hydrolysis and in which a R- o~r S- glycidol or ester thereof is converted in accordance with the scheme bel~ow to the respective glycidyl sulphonate H 0 0 OSrO-< "'C3 7 7\0 io 2O 10 0SAr 15 3 O **R-.form S-form R-form CIO 2SAr OH r 0 0 H 03 Sr lOb in which Ar. is a substituted benzene or naphthalene radical in which at least one substituent. is of an electron-attracting character, or alternatively the same glycidyl sulphonate is prepared from alkyl alcohol by enantioselective epoxidation, after which the glycidyl sulphonate thus obtained is reacted with hydrogen chloride and treated with an amine to give the corresponding chioropropanolamine according to the following scheme OHAOH1 0 H~~C l 0 ,S R N i C 1 O NP R loa PR-FOrmR 1 a S 9a S-Eormx H OH H 0 0 3 S-Ar 1 Li§f-c C O H S-Ar 1 +R R NH--CI NP RR k I \X 1 4 3 4 lob S-Form 11b R-Lzorm 12 9b R-f orn in which R, is hydrogen or a protecting group easily removed by hydrogenolysis, and R, and Ar, have the meanings indicated above, after which the chloropropanolamine thus obtained is treated with a phenol under the action of a base in accordance with the following scheme R H OH OHH base a'vdrogen- 1 NRR +Ar2H Ar C NR 3Rs. i0Ar NS, HR3 9a 13 R -S-betaolocker OH CH "i H OH Sase h r 0q en' NC NR b4+Ar2-OH -r NR3 'ol/sis0 \NHR 3 9b 13 R-betablocker 6. Process according to Claim 5, in which the chloropropanolamine obtained after hydrogen chloride reaction and treatment with the amine is first treated with a base and thereafter with the phenol in accordance with the scheme below OH OH C NR Ar 2 Oy>R R O\ NHR 9a Ii., H, :,cablocker \I'NR 3 R AAr OH 8a 13 25 OH CH.. H O C 1X Cl R 3 R 4 Ar2 0 N NHiR S9b Ibs 1" oase R--betabIlo ksr H I *OW NR R +Ar-OH b ase] 30 8b 13 where the hydrogenolysis stage is carried oat only when R, is not identical t.o H and, when Ar, 4-cyanomethyl-phenyl, is optionally subjected to those reaction conditions which result in hydrolysis. G~ 28 7. A process substantially as hereinbefore described with reference to any one of the foregoing examples. 8. A compound forming the subject matter of and when made by the process of any one of claims 1 to 7. Dated this 30th day of April 1993 NOBEL CHEMICALS By their Patent Attorneys: GRIFFITH HACK CO. Fellows Institute of Patent Attorneys of Australia. i u 6 a flVISIC1, D VEVRSION INTERNATIONAL SEARCH REPORT International Application No PCT/SE 91/00022 I CLASSIFICATION OF SUBJECT MATTER (if several c assification symbols apply, indicate all) Accorrang tr :nternational Patent Classii: ation (IPC) or to both National Classification and IPC C 07 C 215/08, 217/32, 309/75, C 07 D 303/12,16,34 II. FiELDS SEARCHED Minimum Documentation Searched' Classification System Classification Symbols C 07 C; C 07 D Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included in Fields Searched 8 SE,DK,FI,NO classes as above itl. DOCUMENTS CONSIDERED TO BE RELEVANT s Category Citation of Document, 11 with indication, where appropriate, of the relevant passages 2 Relevant to Claim No.'3 X US, A, 4408063 (JOHN J BALDWIN ET AL) 1-4,6-8 4 October 1983, see the whole document X WO, Al, 8800190 (MASSACHUSETTS INSTITUTE OF 1-5,7-8 TECHNOLOGY) 14 January 1988, see the whole document X J.ORG.CHEM., Vol. 51, 1986 Janice M. Klunder et 7 al: "Asymmetric epoxidation of Allyl Alcohol: Efficient Routes to Homochiral beta-Adrenergic Blocking Agents", see page 3710 page 3712 X Chemical Abstracts, volume 113, no. 1, 2 July 1990, 6 (Columbus, Ohio, US), see page 572, abstract 590 8p, JP,, 1287064 ((AMANO, MASAKI et al)) 1989 Special categories of cited documents:10 T later document published after the international filing date document dlning the ieneral state of the art which is not or priority date and not in conflict with the application but considere loe of pacular relevancecited to ndersland the principle or theory ui lerlying the consilered to be of paricular relevance inventioa earlier document but published on or alter the international d o p r t c t ling dale document of particular relevance, the claimed invention cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step which is cited to establish the publicalion date of another citation or other special reason (as specified) Y' document of particular relevance the claimed invention cannot be considered to involve an inventive step when the Sdocumentferring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- othe t o n o r a l i sc l o su r e u se o r reerrn ments, such combination being obvious to a person skilled er means In the art. documer' published prior to the international filing date but document member of the same pate family later than the priority date claimed "&'document member of the same patet amily IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 3rd July 1991 1991 -07- 3 International Searching Authority Signature of Authorized Officer ,I SWEDISH PATENT OFFICE Eva Johansson Form PCT/ISA/210 (second sheet) (January 1985) Ti 6q UTS IT UT= ~r rr I I rn~ ur. International Application No. PCT/SE 91/00022

111. DOCUMEN rs CONSIDERED TO BE RELEVANT (CONTINUED FROM THE SECOND SHEET) CaegryCitation of Document, with indication, where appropriate, of the relevant passages I Relevant to Claim No Patent Abstracts of Japan, Vol 11, No 398, C466, abstract of JP 62-158250, pubi 1987-07-14 (KANEGAFUCHI CHEM IND CO LTD) DE, Al, 3734219 (DEGUSSA AG) 20 April 1989, see the whole document 6 7,8 GB, A, 1269776 (IMPERIAL CHEMICAL LIMITED) 6 April 1972, see the whole document GB, A, 1458392 (IMPERIAL CHEMICAL LIMITED) 15 December 1976, see the whole document INDUSTRIES INDUSTRIES I Form PCT/XSA/21O (extre shout) tjanuary 1985) SU!3STITUT2 7: International Application K. PCT/SE 91/00022 FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET V. O OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE This international search report has not been established ;n respect of certain claims under Article 17(2) for the following reasons: 1. O Claim because they relate to subject matter not required to be searched by this Authority, namely: 2. Claim because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaninglul international search can be carried out, specifically. O Claim because they are dependent claims and are not drafted in accordance a second and third sen- tences of PCT Rule 6.4(a). VI. 3 OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING This International Searching Authority found multiple inventions in this international application as follows: I Claims 1-4 and 7-8 drawn to the process of making intermedia- te compounds and the multi-stage process of making final products. II Claims 5-6 drawn to intermediate compunds. See PCT Rule 13.2. 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims of the international application. 2. As only some of the required additional search fees were timely paid by the applicant, this International search report covers S only those claims of the international application for which lees were paid, specifically claims: 3. No required additional search fees were timely pqid by the applicant. Consequently, this international search report is restrict- ed to the invention first mentioned in the the claims. It is covered by claim numbers: 4. O As all searchable claims could be searched withoull effrt justifying an additional fee, the International Searching Authority Sdid not nvite payment ol any additonal lee. Remark on Protest I The additional search fees were accompanied by applicant's protest. ID No protest accompanied the payment of additional seach fees. 7ors PCT/1SI/Zl0 (supplemntil sheet (January 19515) See notes on accompanying sheet T A.r ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO.PCT/SE 91/00022 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the Swedish Patent Office EDP file nn 91 05-29 The Swedish Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) dale US-A- 4408063 83-10-04 US-A- 4588824 86-05-13 AT-T- 2672 86-03-15 EP-A-B- 0006615 80-01-09 JP-B- 1030828 89-06-22 JP-A- 1193260 89-08-03 JP-A- 1193262 89-08-03 JP-C- 1545839 90-02-28 JP-A- 55007286 80-01-19 WO-A1- 8800190 88-01-14 US-A- 4946974 90-08-07 DE-A1- 3734219 89-04-20 NONE GB-A- 1269776 72-04-06 NONE GB-A- 1458392 76-12-15 CH-A- DE-A-C- FR-A-B- GB-A- JP-C- JP-A- JP-B- SE-B-C- SE-A- US-A- US-A- 611866 2453324 2250752 1458393 1347813 50077331

61007...: 425971 7414017 4085136 4182911 79-06-29 75-05-22 75-06-06 76-12-15 86-11-13 75-06-24 86-03-06 82-11-29 75-05-12 78-04-18 80-01-08 SJBSTITUTE Y-W?