Europaisches Patentamt European Patent Office © Publication number: 0 558 824 A1 Office europeen des brevets

EUROPEAN PATENT APPLICATION

© Application number: 92200310.8 mt ci s C07C 213/00

@ Date of filing: 04.02.92

@ Date of publication of application: 140 08.09.93 Bulletin 93/36 NL-1380 AC Weesp(NL) Inventor: van der Gen, Arne © Designated Contracting States: c/o OCTROOIBUREAU ZOAN B.V., P.O.Box NL 140 NL-1380 AC Weesp(NL) © Applicant: DUPHAR INTERNATIONAL Inventor: Kruse, Chris G. RESEARCH B.V c/o OCTROOIBUREAU ZOAN B.V., P.O.Box C.J. van Houtenlaan 36 140 NL-1381 CP Weesp(NL) Applicant: RIJKSUNIVERSITEIT LEIDEN NL-1380 AC Weesp(NL) Ensteinweg 5 NL-2333 CC Leiden(NL) © Representative: Breepoel, Peter M. et al @ Inventor: Brussee, Johannes Octrooibureau Zoan B.V. P.O. Box 140 c/o OCTROOIBUREAU ZOAN B.V., P.O.Box NL-1380 AC Weesp (NL)

© Method for the preparation of vicinal aminoalcohols and optically active O-protected derivatives thereof.

© The present invention is concerned with the preparation of N-substituted vicinal aminoalcohol derivatives from the corresponding hydroxyl-protected cyanohydrin derivatives by successive partial reduction, tran- simination using a primary , reduction of the resulting and optional removal of the hydroxyl- protecting group. The products are obtained either as a racemate or in an optically pure form, depending upon the stereochemical composition of the cyanohydrin derivatives. The present invention is also concerned with optically active intermediate products of this reaction having the general formula 9 O-P

(9)

NHR2

CM 00 00 m

Rank Xerox (UK) Business Services (3. 10/3.6/3.3. 1) EP 0 558 824 A1

A large number of pharmaceutical^ active agents belong to the class of phenyl or phenoxy substituted vicinalamino derivatives, e.g. the ^- agents propanolol, timolol, nifenolol, sotalol, isoproterenol and denopamine. All these active agents contain a chiral centre in their molecular structure and therefore give rise to optical 5 isomerism. It is generally known in the art that only one of the enantiomers displays the desired biological activity (the so-called eutomer) and that the presence of the optical antipode may lead to side effects. Therefore, is is generally deemed more and more desirable to administer the biologically active agent in the form of its pure eutomer rather than the . The classical method for the preparation of racemic vicinal aminoalcohols consists of a reduction of the io corresponding aminoketone. The alternative attractive method of the reductive amination of the correspond- ing hydroxyaldehyde has not been practised in view of the known instability of the latter class of compounds. For the preparation of enantiomerically pure vicinal aminoalcohols a number of alternative methods are possible. Optical resolution by chemical or enzymatic methods however leaves the problem behind of the 75 unwanted isomer, that should be recycled into the process. Obviously, the use of a chiral precursor is the preferred method. This was illustrated by Corey and Lerik (J. org. chem. 1991, 65, p.442) who prepared an optically pure O-silylated aminoalcohol by a lengthy procedure with the aid of a chiral catalyst. Furthermore, they showed the possibility to use this protected aminoalcohol as a precursor for the enantiomerically pure biologically active agent by a deprotection step. 20 The present invention relates to a simple one-step procedure of preparing both protected and unprotected aminoalcohols, either as a racemate or in an enantiomerically pure form starting from readily available racemic or chiral pure cyanohydrins. According to the present invention an N-substituted vicinal amino-alcohol derivative of formula 1

25 O-P NHR2 h-c-c'h.

wherein - P is a group protecting the hydroxyl group; - Ri is a monocyclic or bicyclic aryl or heteroaryl group substituted with one or more groups X, wherein 35 X is a hydroxy, alkoxy(1-5C), alkyl(1-5C)carbonyloxy, amino, alkyl(1-5C)carbonylamino, alkyl(1-5C)- sulphonylamino, nitro, alkyl(1-5C)sulphonyl, alkyl(1-5C)carbonyl, halogen, cyano, alkyl(1-5C), cycloalkyl(5-12C), or a cyclic group annelated with the aryl group or heteroaryl group, or wherein Ri is a saturated or unsaturated straight or branched alkyl group having 1-30 C-atoms which may be substituted with halogen, alkoxy(1-5C), alkylthio(1-5C), phenyl or phenoxy optionally substituted with 40 one or more groups X, and - R2 is a saturated or unsaturated straight or branched alkyl (1-1 OC), or phenyl or an arylalkyl(7-10C) or heteroarylalkyl, optionally substituted with one to three groups X can be prepared by reacting a hydroxyl-protected cyanohydrin derivative of formula 2

45 O-P R, - C MH CN 50 (2)

with a reducing reagent of formula 3

55 A - H (3)

wherein A represents a hydrogen atom or a metal atom selected from the group of alkali, earth alkali or early transition metal atoms

2 EP 0 558 824 A1

yielding a partially reduced compound of formula (4)

O-P N-A 5 H-C-C F< H <4> io followed by a transimination reaction using a primary amine of formula 5

R2-NH2 (5)

and reduction of the resulting N-substituted imine, wherein P, Ri and R2 have the abovementioned 15 meanings. A similar procedure including the transimination reaction has recently been described by Brussee (Reel. Trav. Chim. Pays-Bas 1991, 25, p. 110) for the preparation of products with an additional substituent R in the aminoalcohol chain of formula 6

2° O-P N H R2 H-C-C-H (6)

R, R 25 It is however not obvious that application of this method to products where R has been replaced by a hydrogen atom would lead to acceptable results. For this analogous procedure a partial reduction of the protected cyanohydrin to produce the intermediate compound of general formula 4 should be carried out as the first step. However, Panunzio (Tetrahedron Letters 1990, 31, p. 3841) and Schlosser (Helv. Chim. Act. 30 1978, 61, p. 1903) describe moderate to very poor results for this transformation starting from racemic protected cyanohydrins, since the protected hydroxyaldehydes - resulting from immediate and quantitative hydrolysis of the compound of formula 4 - or products of the general formula 6, resulting from an addition reaction with an R-metal reagent, were only isolated in low yields. Moreover, application of this method to enantiomerically pure protected cyanohydrins was reported to 35 lead to partial racemization by Effenberger (Chem. Ber. 1991, 124, p. 1651). It is therefore surprising that the method according to the present invention not only gives high to excellent over-all yields of the vicinal aminoalcohols but also shows no loss of optical purity. Thus, after the last reduction step the protected aminoalcohols of formula (1) can be isolated in high yields (usually >80%) in a one-pot procedure. The method according to the present invention avoids the 40 lengthy procedures described in the art and makes use of the smooth reductive amination procedure on the imine intermediate (4) without the necessity of isolating the corresponding unstable a-hydroxyaldehydes. Moreover, by carrying out partial reduction under carefully controlled reaction conditions racemization of the starting enantiomerically pure cyanohydrins could be completely suppressed. This partial reduction can be carried out with organometallic reagents containing an active hydrogen 45 atom or with hydrogen and a selected metallic catalyst. Suitable organomethalic reagents are e.g. aluminium or boron hydrides, such as diisobutylaluminium hydride or sodium di(2-methoxyethoxy) aluminum hydride. These reductions are preferably carried out in apolar solvents such as ethers, , alkanes or aromatics or mixtures thereof. The transimination reaction of intermediate (4) is preferably carried out after the addition of a proton 50 donating agent such as an alcohol (e.g. methanol) or an ammonium salt (e.g. ). This converts the imine of formula 4 into the corresponding primary imine with A replaced by hydrogen. The subsequent addition of the primary amine of formula 5 gives rise to a fast and irreversible transimination reaction under the liberation of NH3, giving a secondary imine analogous to the method described by Brussee for the corresponding substituted derivatives. 55 The final step in this preparation involves a reduction step of the resulting secondary imine. This reduction can be established by the usual reagents employed for the conversion of into secondary amines, as described by Harada in "The Chemistry of the Carbon-Nitrogen Double Bond", pp. 276-293. Useful examples are (earth)alkali metal aluminumhydrides and borohydrides, (earth)alkali metals in protic

3 EP 0 558 824 A1

solvents, and hydrogen gas in the presence of a metal catalyst. Advantageously use is made of regents of the general structure Mi M2(A)nH4_n, wherein Mi is a metal from the group IA or IIA of the periodic system of elements, M2 is boron or alumina, n is an integer having the value 0-3, and A is an electron-withdrawing substituent, e.g. of the type CN, halogen, alkoxy or dialkylamino. In particular, use can be made of reagent 5 wherein M2 is boron, n is 0 or 1 and A is CN. The resulting enaritomerically pure products with formula (1) are new with the exception of the compounds described by Corey, with the formulas 10, 11 and 12

OTES w

(10)

They are useful as intermediates for the production of pharmaceutical active agents of the aminoalcohol 35 structural class. Alternatively, both racemic and enantiomerically pure aminoalcohols can be obtained directly in the process according to the present invention if the protecting group is removed during the isolation procedure after the final reduction step. This can be acomplished by e.g. treatment with aqueous acid in the case of acid labile protecting groups, such as the trimethyl-silyl or the methoxy-1-methylethyl group. 40 EXAMPLE 1

(R)-( + )-[(2-Methoxy-iso-propyl)oxy]benzeneacetonitrile

45 9.0 g (68 mmol) of (R)-( + )-a-hydroxybenzeneacetonitrile was dissolved in 2-methoxypropene (25 ml), one drop of POCh was added and the solution was stirred for 45 minutes at room temperature. Three drops of triethylamine were added, the mixture was taken up in ether (100 ml) and washed successively with water (25ml) and a saturated NaHC03 solution (25 ml). The organic phase was dried on MgSCU and concentrated in vacuo. so Yield: 13.75 g (99%) of a clear oil. Analytical data. 1H-NMR (200 MHz, CDCI3, TMS): 1.40 and 1.58 (s, 6H, C(CH3)2); 3.22 (s, 3H, OCH3); 5.47 (s, 1H, CH(OR2)- ); 7.43 (m, 5H, arom.). 13C-NMR (50 MHz, CDCI3, CDCI3): 24.0 and 24.6 (C(CH3)2); 49.5 (OCH3); 61.1 (CH(OR2)); 102.5 (C(CH3)2; 55 119.0 (CN); 126.7, 128.7 and 129.0 (C arom.); 134.8 (C1 arom.). [a]g° = +47° (c = 1 CHCb); e.e. > 98.5% (HPLC)).

4 EP 0 558 824 A1

EXAMPLE 2

(R)-( + )-[(2-Methoxy-iso-propyl)oxy]-4-methoxybenzeneaceton itrile.

5 Prepared in the same manner as described in EXAMPLE 1, using (R)-( + )-(a-hydroxy-4-methoxyben- zeneacetonitrile as the cyanohydrin. Yield: 99% (colorless crystals), mp 70-73 °C. Analytical data 1H-NMR (200 MHz, CDCI3, TMS): 1.38 and 1.56 (s, 6H, C(CH3)2); 3.21 (s, 3H, OCH3); 3.82 (s, 3H, p-OCH3); 10 5.41 (s, 1 H, CH(OR2)); 6.92 (d, 2H, J = 8.7 Hz, arom.); 7.40 (d, 2H, J = 8.7 Hz, arom.). 13C-NMR (50 MHz, CDCI3, CDCI3): 23.9 and 24.4 (C(CH3)2); 49.2 (OCH3); 54.7 (p-OCH3); 60.5 (CH(OR2)), 102.2 (C(CH3)2); 113.9 C3 and C5 arom.); 119.1 (CN); 126.9 (C1 arom.); 128.1 (C2 + CG arom.); 158.7 (C+ arom). [a]g° +41 • (c = 1 CHCb); e.e. > 99% (HPLC)). 15 EXAMPLE 3

(R)-(-)-(a-[(Methylamino)methyl]benzenemethanol, (R)-Halostachine.

20 To a cooled (-70 0 C) solution of 1 .02 g (5 mmol) of of the product of EXAMPLE 1 (e.e. > 98.5% (HPLC)) in 40 ml of dry ether was added 12.5 ml of a 1 mol/l DIBAL solution in hexane (12.5 mmol). After stirring at -70 °C for 3 hours 1.25 g NH+Br (12.5 mmol) in 20 ml of dry methanol was added. The cooling bath was removed and 3 ml of an 8.03 mol/l CH3NH2 solution (24 mmol) in was added. Stirring was continued for 45 minutes (-70 0 C -> room temperature). The mixture was cooled in an ice bath and 0.37 g 25 of NaBH+ (10 mmol) was added in three portions. The reaction mixture was stirred overnight at room temperature. Ether (25 ml) and a 1 mol/l HCI solution (70 ml) were added and extracted. The water layer (pH = 3) was basidified with 5 N NaOH until a clear solution appeared and extracted with ether (4x 50 ml). These four combined ether layers were dried (K2C03) and concentrated to leave a clear oil. Yield: 0.59 g (79%). 30 Analytical data 1H-NMR (200 MHz, CDCI3, TMS): 2.2 (broad, 2H, OH and NH); 2.46 (s, 3H, NCH3); 2.74 (dd, ABX, 1H, CH2, JAB= 11-8 Hz JAx = 4.6 Hz); 2.81 (dd, ABX, 1H, CH2, JAB = 1 1 .8 Hz JBX = 4.6 Hz); 4.74 (dd, 1H, CH(OH), J = 4.6 and 8.7 Hz); 7.32 (m, 5H, arom.). 13C-NMR (50 MHz, CDCI3, CDCI3): 35.6 (NCH3); 59.0 (CH2); 71.4 (CH(OH)); 125.6, 127.1 and 128.1 (C 35 arom.); 143.2 (C1 arom.). This product was converted into the HCI salt and crystallized from iso-propanol for and melting point measurements. [a]g°-53° (c = 1 H20), literature: [a]g° -52.46 • . mp 102-1 04 °C, literature mp 113-1 14° C. 40 EXAMPLE 4

(R)-(-)-a-[(Methylamino)methyl]-a-[(tert-butyldimethylsilyl)oxy]benzenemethane.

45 Prepared in the same manner as in EXAMPLE 3, using R-( + )-(ter.butyldimethylsilyloxy)- benzeneacetonitrile (e.e. > 99% (HPLC)) as the cyanohydrin. After the NaBH+ reduction the reaction mixture was poored into water (100 ml) and extracted with ether (3x 50 ml). The combined ether layers were washed with water ( 50 ml), dried (K2C03) and concentrated in vacuo. Yield: 97% (clear oil). 50 Analytical data 1H-NMR (200 MHz, CDCI3, TMS): -0.15 and 0.04 (s, 6H, Si(CH3)2); 0.89 (s, 9H, C(CH3)3)); 1.8 (broad, 1H, NH); 2.44 (s, 3H, NCH3); 2.63 (dd, ABX, 1H, CH2, JAB = 1 1 .8 Hz, JAx = 8.2 Hz); 2.79 (dd, ABX, 1H, CH2, JAB = 11-8 Hz, Jbx = 4.1 Hz); 4.81 (dd, 1H, CH(OTBS), J = 4.1 and 8.2 Hz); 7.31 (m, 5H, arom.). 13C-NMR (50 MHz, CDCI3, CDCI3): -5.0 and -4.5 (Si(CH3)2); 18.1 (C(CH3)3); 25.8 (C(CH3)3); 36.1 (NCH3); 55 60.1 (CH2); 74.0 (CH(OTBS)); 126.0, 127.3 and 128.1 (C arom.); 143.4 (C1 arom.). [a]g° -68° (c = 1 CHCb).

5 EP 0 558 824 A1

EXAMPLE 5

(R)-(-)-(a-[[(l-Methylethyl)aminolmethylibenzenemethanol.

5 Prepared in the same manner as in EXAMPLE 3, using iso-propylamine in the transimination reaction. Yield: 74% (white solid). Analytical data 1H-NMR (200 MHz, CDCI3, TMS): 1.08 (d, 6H, CH(CH3)2), J = 6.2 Hz); 1.9 (broad, 2H, OH + NH); 2.64 (dd, ABX, 1H, CH2, JAb = 11-8 Hz, JAx = 8.7 Hz); 2.83 (sept, 1H, CH(CH3)2, J = 6.2 Hz); 2.93 (dd, ABX, 1H, CH2, 10 JAB = 1 1 -8 Hz, JBX = 3.6 Hz); 4.66 (dd, 1 H, CH(OH), J = 3.6 and 8.7 Hz); 7.32 (m, 5H, arom.). 13C-NMR (50 MHz, CDCI3, CDCI3): 23.0 (CH(CH3)2); 48.6 (CH(CH3)2); 54.8 (CH2); 71.9 (CH(OH)); 125.7, 127,3 and 128.2 (C arom.); 142.4 (C1 arom.). This product was converted into the HCI salt and crystallized from iso-propanol for optical rotation and melting point measurements. 15 [a]g° -48° (c = 1 H20).

EXAMPLE 6

(R)-(-)-(a-[[(l-Methylethyl)amino]methyl]-(a-[(tert-butyldimethylsilyl)oxy]benzenemethane. 20 Prepared in the same manner as in EXAMPLE 4, using iso-propylamine in the transimination reaction. Yield: 96% (slightly yellow oil). Analytical data 1H-NMR (200 MHz, CDCI3, TMS): -0.16 and 0.05 (s, 6H, Si(CH3)2; 0.90 (s, 9H, C(CH3)3)); 1.02 and 1.06 (d, 25 6H, CH(CH3)2, J = 6.2 Hz); 2.3 (broad, 1H, NH); 2.72 (d, 2H, CH2, J = 6.2 Hz); 2.81 (sept, 1H, CH(CH3)2, J = 6.2 Hz); 4.78 (t, 1H, CH(OTBS), J = 6.2 Hz); 7.31 (m, 5H, arom.). 13C-NMR (50 MHz, CDCI3, CDCI3): -5.5 and -5.0 (Si(CH3)2); 17.6 (C(CH3)3); 22.2 and 22.5 (CH(CH3)2); 25.3 (C(CH3)3); 47.7 (CH(CH3)2); 56.0 (CH2); 74.0 (CH(OTBS)); 125.5, 126.9 and 127.5 (C arom.); 143.0 (C1 arom.). 30 [a]g° -63° (c = 1 CHCb); e.e. > 99% (HPLC)).

EXAMPLE 7

(R)-(-)-(a-[(Methylamino)methyl]-4-methoxybenzenemethanol. 35 Prepared in the same manner as in EXAMPLE 3, using the product of EXAMPLE 2 (e.e. > 99% (HPLC)) as the cyanohydrin Yield: 90% of (5e) (yellow solid). Analytical data 1H-NMR (200 MHz, CDCI3, TMS): 2.2 (broad, 2H, OH + NH); 2.47 (s, 3H, NCH3); 2.70 (dd, ABX, 1H, CH2, 40 JAB = 12.3 Hz, JAx = 8.2 Hz); 2.80 (dd, ABX, 1H, CH2, JAB = 12.3 Hz, JBX = 4.1 Hz); 3.81 (s, 3H, OCH3); 4.69 (dd, 1H, CH(OH), J = 4.1 and 8.2 Hz); 6.88 (d, 2H, arom., J = 8.7 Hz); 7.29 (d, 2H, arom., J = 8.7 Hz). 13C-NMR (50 MHz, CDCI3, CDCI3): 35.8 (NCH3); 55.1 (OCH3); 59.2 (CH2); 71.1 (CH(OH)); 113.6 (C3 and C5 arom.); 126.9 (C2 and CG arom.); 135.3 (C1 arom.); 158.8 (C+ arom.). This product was converted into the HCI salt and crystallized from iso-propanol for optical rotation and 45 melting point measurements. [af-45° (c = 1 H20). mp: 137-1 39 °C.

EXAMPLE 8 50 (R)-(-)-(a-[(Methylamino)methyl]-a-[(tert-butyldimethylsilyl)oxy]-4-methoxybenzenemethane.

Prepared in the same manner as in EXAMPLE 4, using R-( + )-(tert.butyldimethylsilyloxy)-4-methoxyben- zeneacetoniltrile (e.e. > 99% (HPLC)) as the cyanohydrin. 55 Yield: 94% (slightly yellow oil). Analytical data 1H-NMR (200 MHz, CDCI3, TMS): -0.15 and 0.03 (s, 6H, Si(CH3)2); 0.88 (s, 9H, C(CH3)3)); 1.9 (broad, 1H, NH); 2.44 (s, 3H, NCH3); 2.59 (dd, ABX, 1H, CH2, JAB = 1 1 .8 Hz, JAX = 8.2 Hz); 2.74 (dd, ABX, 1H, CH2,

6 EP 0 558 824 A1

Jab = 11-8 Hz, Jbx = 4.6 Hz); 3.80 (s, 3H, OCH3); 4.76 (dd, 1H, CH(OTBS), J = 4.6 and 8.2Hz); 6.85 (d, 2H, arom., J = 8.7 Hz); 7.23 (d, 2H, arom., J = 8.7 Hz). 13C-NMR (50 MHz, CDCI3, CDCI3): -5.1 and -4.7 (Si(CH3)2); 17.9 (C(CH3)2); 25.6 (C(CH3)3); 35.9 (NCH3); 54.9 (OCH3); 60.6 (CH2); 73.5 (CH(OTBS)); 113.3 (C3 and C5 arom.); 127.0 (C2 and CG arom.); 135.4 (C1 5 arom.); 158.6 (C+ arom.) [a]g° -67° (c = 1 CHCb).

EXAMPLE 9

10 (R)-(-)-(a-[[(l-Methylethyl)aminolmethyl]-4-methoxybenzenemethanol.

Prepared in the same manner as in EXAMPLE 7, using iso-propylamine in the transimination reaction. Yield: 78% of (5g) (slightly yellow solid). Analytical data 15 1H-NMR (200 MHz, CDCb, TMS): 1.07 (d, 6H, 2X CH3, J = 6.2 Hz); 2.0 (broad, 2H, OH + NH); 2.64 (dd, ABX, 1H, CH2, JAB = 1 1 .8 Hz JAX = 9.2 Hz ); 2.83 (sept, 1H, CH(CH3)2, J = 6.2 Hz); 2.90 (dd, ABX, 1H, CH2, JAB = 11-8 Hz Jbx = 3.6 Hz); 3.81 (s, 3H, OCH3); 4.61 (dd, 1H, CH(OH), J = 3.6 and 9.2 Hz); 6.88 (d, 2H, arom., J = 8.7 Hz); 7.34 (d, 2H, arom., J = 8.7 Hz). 13C-NMR (50 MHz, CDCb, CDCb): 22.7 and 22.9 (CH(CH3)2); 48.6 (CH(CH3)2); 54.8 (CH2); 55.1 (OCH3); 20 71.5 (CH(OH)); 113.6 (C3 and C5 arom.); 126.9 (C2 and CG arom.); 135.3 (C1 arom.); 158.8 (C+ arom.). This product was converted into the HCI salt and crystallized from iso-propanol for optical rotation and melting point measurements. [a]g° -63° (c = 1 H20). mp: 157-1 59 °C. 25 EXAMPLE 10

(R)-(-)-a-[[(Methylethyl)amino]methyl]-(a-[(tert-butyldimethylsilyl)oxy]-4-methoxybenzenemethane.

30 Prepared in the same manner as in EXAMPLE 8, using iso-propylamine in the transimination reaction. Yield: 80% (slightly yellow oil). Analitical data 1H-NMR (200 MHz, CDCb, TMS): -0.17 and 0.04 (s, 6H, Si(CH3)2); 0.88 (s, 9H, C(CH3)3; 1.02 and 1.06 (d, 3H, CH(CH3)2, J = 6.2 Hz); 2.2 (broad, 1H, NH); 2.71 (d, 2H, CH2, J = 6.3 Hz); 2.81 (sept, 1H, CH(CH3)2)„ 35 J = 6.2 Hz); 3.80 (s, 3H, OCH3); 4.75 (t, 1H, CH(OTBS), J = 6.3 Hz); 6.85 (d, 2H, arom., J = 8.2 Hz); 7.23 (d, 2H, arom., J = 8.2 Hz). 13C-NMR (50 MHz, CDCb, CDCb): -5.0 and -4.5 (Si(CH3)2); 17.9 (C(CH3)3); 22.6 and 22.9 (CH(CH3)2); 25.7 (C(CH3)3); 48.2 (CH(CH3)2); 55.0 (OCH3); 56.5 (CH2); 73.9 (CH(OTBS)); 113.4 (C3 and C5 arom.); 127.1 (C2 and CG arom.); 135.6 (C1 arom.); 158.7 (C+ arom.). 40 [a]g° -62° (c = 1 CHCb); e.e. > 99% (HPLC)).

Claims

1. Method for the preparation of an N-substituted vicinal aminoalcohol derivative of formula 1 45

O-P \ (i) H-C-

50 R

wherein - P is a group protecting the hydroxyl group; 55 - Ri is a monocyclic or bicyclic aryl or heteroaryl group substituted with one or more groups X, wherein X is a hydroxy, alkoxy(1-5C), alkyl(1-5C)carbonyloxy, amino, alkyl(1-5C)carbonylamino, alkyl(1-5C)sulphonylamino, nitro, alkyl(1-5C)sulphonyl, alkyl(1-5C)carbonyl, halogen, cyano, alkyl- (1-5C), cycloalkyl(5-12C), or a cyclic group annelated with the aryl group or heteroaryl group, or

7 EP 0 558 824 A1

wherein Ri is a saturated or unsaturated straight or branched alkyl group having 1-30 C-atoms which may be substituted with halogen, alkoxy(1-5C), alkylthio(1-5C), phenyl or phenoxy option- ally substituted with one or more groups X, and - R2 is a saturated or unsaturated straight or branched alkyl (1-1 0C), or phenyl or an arylalkyl(7- 10C) or heteroarylarylalkyl, optionally substituted with one to three groups X by reacting a hydroxyl-protected cyanohydrin derivative of formula 2

O-P R« - C H CN

with a reducing reagent of formula 3

A - H (3)

wherein A represents a hydrogen atom or a metal atom selected from the group of alkali, earth alkali or early transition metal atoms yielding a partially reduced compound of formula (4)

O-P N-A H-C-C ' x (4) R, H

followed by a transimination reaction using a primary amine of formula 5

R2-NH2 (5)

and reduction of the resulting N-substituted imine, wherein P, Ri and R2 have the abovemen- tioned meanings.

Method according to claim 1 wherein use is made of one of the enantiomers of the compound of formula 2 thereby yielding an optically pure derivative of the compound according to formula 1 .

Method for the preparation of a compound of formula 8

OH N H R2 H-C-C H2 ' (8) Ri

by using the method according to claim 1 or 2 and subsequently removing the hydroxyl-protecting group P of the compound of formula 1 , wherein P, Ri , and R2 have the abovementioned meanings.

Method according to claim 3 wherein P is removed without intermediate isolation of compound of formula 1 during a work-up step following the reduction of N-substituted imine.

Chirally pure compound according to formula 1 wherein P, Ri and R2 have the abovementioned meanings, with the exception of the compounds of formula (10), (11) and (12)

8 EP 0 558 824 A1 Patent pjiubdct European EUROPEAN SEARCH REPORT Application Office EP 92 20 0310 Page 1 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant ULA&airiUAiiurn ur itu, Category of relevant passages to daim APPLICATION qnt. Q.S ) X EP-A-0 104 888 (ELI LILLY AND COMPANY) ;07C213/00 * examples 2,4,15-20 *

X EP-A-0 099 707 (BEECHAM GROUP PLC) * page 48 * X 'ATENT ABSTRACTS OF JAPAN ,ol. 4, no. 61 (C-009)8 May 1980 i, JP-A-55 028 914 ( TANABE SEIYAKU CO. .TD. ) * abstract *

iELVETICA CHIMICA ACTA /ol . 71, 1988, BASEL CH iages 320 - 336 i. GOODMAN ET AL. 'Optically Pure Isoproterenol Analogues with Side Chains Containing an Amide Bond: Synthesis and Biological Properties' * page 324; figure 32 * rETRAHEDRON LETTERS SEARCHED (Int. C1.5 ) /ol. 31, no. 5, 1990, OXFORD GB Dages 601 - 604 C07C E.J. COREY ET AL. 'The first C07F snantioselective synthesis of pure R- and 5-isoproterenol ' * page 603; figure 7 *

D,X JOURNAL OF ORGANIC CHEMISTRY, vol. 56, 1991, WASHINGTON DC US pages 442 - 444 E.J. COREY ET AL. 'A Catalytic Enantioselective Synthesis of Denopamine, a Useful Drug for Congestive Heart Failure' * page 442; figure 8 * -/--

The present search report has been drawn up for all claims Place of March LMII at COMapKHOB 01 UN Mara THE HAGUE 06 OCTOBER 1992 PAUWELS G.R.A. CATEGORY OF CITED DOCUMENTS T : theory or principle underlying tne invention E : earlier patent document, but published on, or X : particularly relevant If taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological Background O : non-written disclosure A : member of the same patent family, corresponding P : intermediate document document Patent numim J) European EUROPEAN SEARCH REPORT Application Office EP 92 20 0310 Page 2 DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant iXASSineAiiuiM ur iiu. Category of relevant passages to claim APPLICATION qnt. Cl.S ) 1ELVETICA CHIMICA ACTA -4 /ol. 61, no. 8, 1978, BASEL CH jages 3028 - 3037 K. FISCHLI '287. Cob(I)alamin als (atalysator 2.Mitteilung [1]. Reduktion /on gesattigten Nitrilen in wasserfreier .b'sung1 * page 3020: Schema 3 * EP-A-0 142 070 (BASF AG.) -4 * page 2 *

D,A IECUEIL DES TRAVAUX CHIMIQUES DES PAYS-BAS L-4 /ol. 110, no. 1, January 1991, DEN HAAG NL sages 25 - 26 J. BRUSSEE ET AL. 'Transimination. Conversion of Nitriles into Secondary \mines in a One-Pot Reaction' * the whole document *

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The present search report has been drawn up for all claims Place of tetftk Date of eampuan or im uarca THE HAGUE 06 OCTOBER 1992 PAUWELS G.R.A. CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date Y : particularly relevant if combined with another D : document cited in the application document of the same category L : document cited for other reasons A : technological background O : non-written disclosure A : member of the same patent family, corresponding P : intermediate document document