EP1919888A2

EP1919888A2 - Method for producing nebivolol

Info

Publication number: EP1919888A2
Application number: EP06760790A
Authority: EP
Inventors: Christian Noe; Muhamed Jasic; Hermann Kollmann; Bodo Lachmann
Original assignee: Pharmacon Forschung und Beratung GmbH
Current assignee: Pharmacon Forschung und Beratung GmbH
Priority date: 2005-07-19
Filing date: 2006-07-17
Publication date: 2008-05-14
Also published as: MX2008000747A; KR20080027368A; BRPI0613610A2; CA2615832A1; ZA200800963B; AT502220A1; JP2009502750A; NO20080823L; WO2007009143A2; EA200800364A1; WO2007009143A3; AU2006272420A1; US20080221340A1; CN101243062A; IL188777A0

Abstract

The invention relates to a method for producing the racemic active ingredient Nebivolol, preferably in the form of the hydrochloride of formula (1), according to which diastereomer cyanhydrins of general formula (2) are produced and separated, and the separated diastereomers are coupled together following a transformation, preferably a partial or full reduction of the cyano group or a Pinner saponification.

Description

Process for the preparation of nebivolol

The invention relates to a process for the preparation of the racemic drug

Nebivolol as the free base or as a pharmaceutically acceptable salt, preferably as

Hydrochloride.

The drug nebivolol of formula 1,

which is marketed as hydrochloride belongs to the drug group of beta-receptor blockers. The molecule has 4 centers of chirality and is built with centrosymmetry. The approved drug nebivolol is used as a racemate. Because of its symmetrical structure, instead of 8 diastereomers (theoretically 16 enantiomers) only 6 diastereomers (R ^* R ^* R ^* R ^* , R ^* R ^* S ^* S ^* , R ^* R ^* R ^* S ^* , R * R ^*) S ^* R *, R * S * R * S ^* and R ^* S ^* S * R *) with 10 isomers should always be considered. Of these, the pure diastereomer designated R ^* R * R * S ^* , which is a 1: 1 mixture of the enantiomers of the absolute configurations RRRS and SSSR, is the actual approved active ingredient. A very special situation arises from the fact that both enantiomers of nebivolol with different profile synergistically contribute to its pharmacological action. Therefore, the highest possible standard is not the targeted synthesis of a pure enantiomer, but the synthesis of the racemic diastereomer with the desired relative configuration of the chiral centers.

In the literature, there is no directly useful synthesis for the racemic nebivolol itself. Although several syntheses have been described for the building blocks, chromatographic steps are used for the separation into the individual stereoisomers (eg EP 145067), the description of which is so unclear is that a fundamental technical usefulness can not be derived from it. Remarkably, there are relatively many more or less interesting syntheses for the pure enantiomer of nebivolol (e.g., BS Chandrasekhar, V. Reddy, Tetrahedron, 56 (2000), 6339-6344; CW Johannes, MS Visser, GS Weatherhead, AH Hoveyda, J Chem. Soc.120 (1998), 8340-8347). However, a transfer of these syntheses for the preparation of the racemic active ingredient would require the separate preparation of the enantiomers, which would then have to be mixed 1: 1. From the perspective of synthesis planning, therefore, the preparation of the racemic drug is more expensive than that of the pure enantiomer. Nebivolol is - apart from the central element - formally constructed of two identical to their relative stereochemistry parts of the molecule. The relative stereochemistry of their two centers of chirality is denoted by R ^* R ^* and R ^* S ^* . Regardless of the actual relative configuration below, the diastereomeric intermediates are differentiated with respect to their different configuration with A and B. Apart from a totally nonselective synthesis of nebivolol, in which all possible stereoisomers are formed and separated, there are strategies in which the synthesis occurs by linking two intermediates with relative stereochemistry A and B of the centers of chirality.

The present invention is a process for the preparation of nebivolol, wherein as intermediates racemic diastereomeric cyanohydrins - in the following diastereomers A and B - of the general formula. 2

be used, in which X is the meaning of X = H, or a cyanohydrins typical protecting group, for example a benzylic (eg benzyl or 4-methoxybenzyl) or acetalic protective group (eg Tetrahydropyranly, or MEM), preferably a silyl protecting group, most particularly preferred a tert-butyldimethylsilyl protecting group.

Further advantageous embodiments of the method according to the invention are disclosed according to the subclaims.

The invention further relates to α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetonitrile as a crystalline racemic diastereomer A.

The invention also relates. α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetonitrile as an oily racemic diastereomer B. The cyanohydrins can be prepared from the aldehyde 3

be prepared by a cyanohydrin reaction.

The aldehyde 3 can be obtained, inter alia, also by way of the ester 4 by reduction of the pyran ring, followed by direct or indirect (that is, by way of the alcohol) reduction of the ester group to the aldehyde.

The cyanohydrin reaction can be carried out stereoselectively or non-stereoselectively, with the preferred variant being non-stereoselective synthesis with O derivatization. Diastereomers of the compound of the formula 2 which bear silyl protective groups can also be prepared from the aldehyde 3 in one step with the aid of a corresponding silyl cyanide (preferably tert-butyldimethylsilyl cyanide). Further synthesis of the components prior to coupling is initiated with the separation of the diastereomeric cyanohydrins 2 with configuration A and B, both of which are needed for further synthesis. Particularly preferred according to the invention are derivatized diastereomers A and B, which have distinctly different crystallization properties, preferably those in which 1 diasteromer is in crystalline form and the other is oily. In this way, a technologically very particularly simple and efficient separation of the diastereomers by digestion in an organic solvent is made possible. Very particularly preferred according to the invention is the tert. Butyldimethylsilyl. One of the two diastereomers (A) crystallizes particularly well, while the other diastereomer (B) is obtained as an oil, from which when using an apolar solvent, preferably a lower alkane, especially hexane, even small amounts of A slightly under cooling by crystallization let disconnect. The crystalline diastereomer can be made to high purity by recrystallization from an apolar solvent, preferably a lower alkane, especially hexane.

In preparation for the linkage, the two parts of the molecule with configuration A or B are further differently converted. The use of cyanohydrins as intermediates proves to be particularly advantageous for this purpose because the cyanohydrin group can be further reacted in various ways in order to obtain optimum conditions for the linkage of the two molecular moieties (A and B). Preferred reactions for further reaction are: the reduction to the O-protected aldehyde of the general formula 5, wherein X has the meaning given for the formula 2, as well as the reduction to the O-protected or O-unprotected aminoalcohol of the general formula 6, wherein X has the meaning given for the formula 2, and the Pinner saponification to the O-unprotected hydroxyester of general formula 7 wherein R is branched or unbranched lower alkyl, or substituted or unsubstituted benzyl.

Both the crystalline cyanohydrin A of the formula 2 and the oily cyanohydrin B of the formula 2 can be reduced once to the aldehyde 5 or to the hydroxy ester 7 and the other time to the amine 6. This results in differences in the yields in the preparation and implementation of the subsequent reaction sequences.

The linkage and reaction to nebivolol is preferably accomplished by reacting an aldehyde with an amine in a reductive amination, via Schiff's base formation followed by reduction, preferably in a one-pot reaction using a complex hydride with limited reducing power, such as sodium cyanoborohydride or sodium triacetoxyborohydride the general formula 8,

wherein X has the meaning given for formula 2,

or it is carried out by reaction of an ester of the general formula 7 with an amine of the general formula 6 to the amide of the general formula 9, wherein X has the meaning given for the compound 2

9

and subsequent reduction of amide 9 - via the amine of general formula 10, wherein X has the meaning given for compound 2.

10

Nebivolol is obtained from the compounds of formulas 8 and 10, optionally after prior purification, by deprotection and optionally purified by recrystallization of the hydrochloride and / or the free base to nebivolol base or a pharmaceutically acceptable salt thereof in pharmaceutical grade.

The optional use of O-protected or O-unprotected derivatives in the coupling, in particular the coupling of an O-protected aldehyde with an O-unprotected amine, opens the possibility, after coupling by purification of the monoprotected nebivolol of the formula 10 optionally in small To remove amounts of by-product diastereomers particularly efficiently. These

Synthesis variant is for the case X = tert. Butyldimethylsilyl represented in the following formula scheme.

It should be noted that coupling a molecule of configuration A with configuration B does not produce a uniform diastereomer but a mixture of two diastereomers. When coupling a connection of the R ^* R ^* configuration with in fact, one of the R * S * configurations produces the diastereomers R * R * R * S * (nebivolol, consisting of the enantiomers RRRS and SSSR) and R * R * S * R * (consisting of the enantiomers RRSR and SSRS). In fact, racemic nebivolol is a very well crystallizing compound both as a free base and as a hydrochloride. Particularly advantageous is the fact that the diastereomer forming in the 1: 1 ratio coupling with the R * R ^* S * R * configuration is particularly easily depleted in the recrystallization of the free base and of the hydrochloride. Due to the significantly better solubility properties of the undesired diastereomer, pure nebivolol can thus be easily obtained by recrystallization of the diastereomer mixture. The invention is explained in more detail below with reference to possible embodiments for carrying out the invention:

Example 1: (R ^* , R * / R ^* , S ^* ) 6-Fluoro-3,4-dihydro-α-hydroxy-2H-2- [1] benzopyran-acetonitrile-racemic mixture of diastereomers

A solution of 33 g of (R * S ^* ) 6-fluoro-3,4-dihydro-2H- [1] benzopyran-2-carbaldehyde in 150 ml of MTBE and 150 ml of 80% acetic acid is added with 23.8 g of potassium cyanide and stirred for 1 h at room temperature under argon atmosphere. The reaction mixture is then slowly added dropwise with stirring in 600 ml of cooled saturated aqueous Natriumcabinatlösung and then while adding solid sodium carbonate until the reaction solution is neutral. It is then extracted several times with MTBE, the organic phases are washed with water, dried with Na ₂ SO ₄ , treated with a drop of phosphoric acid and the solvent removed in vacuo. Yield: 36.1 g (95%), yellowish oil. ¹ H-NMR: (CDCl ₃ ): δ (ppm) = 6.82-6.74 (m, 3H), 4.20-4.14 (dd, 1H), 4.20-4.14 (m , 1H) 2.84-2.79 (m, 2H), 2.21-2.02 (m, 1H), 2.00-1, 88 (m, 1H ₁ ).

Example 2: (R ^* , R * / R ^* , S ^* ) - -α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2-2H- [1] benzopyranacetonitrile-racemic mixture of diastereomers

Variant 1: 31.5 g of t-butyldimethylsilyl chloride are added to a solution of 25 g of imidazole in 150 ml of anhydrous dimethylformamide at 0 ^° C., and the mixture is stirred at 0 ^° C. for 15 minutes. Subsequently, a solution of 36 g of cyanohydrin (Example 1) in 150 ml of anhydrous dimethylformamide is added dropwise. After the addition is complete, the mixture is stirred for 15 minutes at 0 ⁰ C, then brought to room temperature and stirred for 2 h. Subsequently, the reaction mixture is between sat. NaHCO ₃ solution and MTBE distributed, the aqueous phase extracted with MTBE, the combined organic phases washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The DMF is towed several times with toluene and the product dried under high vacuum. Yield: 53.1 g (95%), yellow oil; ¹ H-NMR: (CDCl ₃ ): δ (ppm) = 6.84-6.79 (m, 3H), 4.75 / 4.62 (dd, 1H), 4.25-4.07 (m , 1H) 2.89-2.85 (m, 2H), 2.37-2.17 (m, 1H), 2.03-1, 85 (m, 1H), 0.97 (i.e. , 9H), 0.23 (t, 6H).

Variant 2: With the help of tert. Butyldimethylsilylcyanid

To a solution of (R * S *) 6-fluoro-3,4-dihydro-2H- [1] benzopyran-2-carbaldehyde 2 g in 20 ml of anhydrous DCM is added 1.77 g of zinc iodide. At -10 ⁰ C, 1.88 g tert. Butyldimethylsilylcyanid added and the mixture stirred for 2 hours at this temperature. Subsequently, the reaction mixture is partitioned between 5% NaHCO ₃ solution and MTBE, the aqueous phase is extracted twice with MTBE, the combined organic phases are washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. The product dried under high vacuum. Yield: 3.1 g (87%), yellow oil. ¹ H-NMR: (CDCl ₃ ): δ (ppm) = 6.83-6.79 (m, 3H), 4.73 / 4.61 (dd, 1H), 4.23-4.07 (m , 1H) 2.90-2.85 (m, 2H), 2.37-2.15 (m, 1H), 2.01-1.83 (m, 1H), 0.96 (d, 9H) , 0.21 (t, 6H).

Example 3: α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetonitrile - crystalline racemic diastereomer A

16 g of the racemic diastereomer mixture from Example 2 are dissolved in 20 times the amount of petroleum ether, brought to -45 ° C and inoculated with _^ a seed crystal of the crystalline diastereomeric component. After 4 hours, the mother liquor is decanted off, the crystals are digested with a little petroleum ether, cooled down, and the decanted off and the combined mother liquors are concentrated to one third of the volume of the original solution, re-inoculated and the procedure described repeated, whereby a second crop of product is obtained. This gives a crystalline fraction of the R ^* , S ^* diastereomer (residual content of R *, R ^* diastereomer 8%), which are dissolved for further purification in petroleum ether with heating and crystallized at low temperature. Yield: crystal fraction: 6.5 g = 40%, white crystals; Mp = 66 ⁰ C, ¹ H-NMR: (CDCI _3): δ (ppm) 6.83 to 6.73 (m, 3H), 4.71 (d, 1H), 4.09 to 4.05 ( m, 1H) 2.91-2.79 (m, 2H), 2.30-2.25 (m, 1H), 1, 97-1, 88 (m, 1H), 0.94 (s, 9H), 0.23 (s, 3H), 0.19 (s, 3H).

Example 4: α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetonitrile - oily racemic diastereomer B

After evaporation of the twice depleted mother liquor from the crystallization of the diastereomer A gives the diastereomer B (residual content of diastereomer = 10%); Yield: 9.0 g = 55%, yellow oil; ¹ H-NMR: (CDCl ₃ ): δ (ppm) 6.83-6.72 (m, 3H), 4.58 (d, 1H), 4.18-4.14 (m, 1H) 2.90-2.77 (m, 2H), 2.22-2.17 (m, 1H), 1 , 93-1, 85 (m, 1H), 0.92 (d, 9H), 0.24 (s, 3H), 0.16 (s, 3H).

Example 5: α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetaldehyde racemic diastereomer B

A solution of 8 g of the oily racemic diastereomeric cyanohydrin B from Example 4 in 80 ml of toluene is brought at 5 ° C with 18.25 ml of a 1, 5M solution of diisobutylaluminum hydride in toluene. The reaction mixture is stirred for 1 h at room temperature. Subsequently, the reaction mixture is added to 600 ml of 1N hydrochloric acid and diluted with 100 ml of MTBE. The phases are separated, the aqueous phase extracted three times with 200 ml MTBE. The combined organic phases are washed with saturated sodium chloride solution, dried over Na ₂ SO ₄ and the solvent removed in vacuo. Yield: 7.1 g (88%), yellow oil. ¹ H-NMR: (CDCl ₃ ): δ (ppm) = 9.79 (s, 1H), 6.84-6.77 (m, 3H), 4.32-4.25 (m, 1H), 3.73-3.65 (m, 1H), 2.84-2.79 (m, 2H), 2.00-1, 91 (m, 2H) 0.98 (d, 9H), 0.25 (t, 6H).

Example 6a: 6-Fluoro-3,4-dihydro-α-hydroxy-2H-2- [1] benzopyranethanamine - racemic diastereomer A

To a solution of 5 g of the crystalline racemic diastereomer A of α- [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2 / - / - 2- [1] benzopyranacetonitrile in 50 ml of toluene are added -20 ⁰ C 20.7 ml of a 1.5 M DIBAL solution was added dropwise in toluene. It is warmed to room temperature and stirred for 15 minutes. Thereafter, the reaction mixture is cooled to 0 ⁰ C and treated with 1.18 g of lithium aluminum hydride. Subsequently, the reaction mixture is stirred for 14 h at room temperature. Then another 20.7 ml of a 1, 5M DIBAL solution in toluene are added, stirred for 1 h at room temperature and 1 h at 35 ⁰ C. The reaction mixture is added to a cooled solution of 400 ml of ethyl acetate and 20 ml of MeOH. To this is added 300 ml of potassium tartrate solution and 30 ml of 2N NaOH and stirred for 1 h. This reaction mixture is filtered through Celite, the residue and the Celite are washed three times with 150 ml of ethyl acetate. The phases are separated, the organic phases washed with water, dried and the solvent removed in vacuo. There are obtained 3.49 g of crystalline crude product. This is recrystallized from MTBE. Yield: 2.15 g (65.5%), white solid; Mp = 124 ⁰ C, ¹ H-NMR: (CDCI _3): δ (ppm) = 6.81 to 6.77 (m, 3H), (m, 1 H) 4.02 to 3.95, 3, 71-3.65 (m, 1H), 3.00-2.81 (m, 4H), 2.04-1, 85 (m, 5H). Example 6b: 6-Fluoro-3,4-dihydro-α-hydroxy-2H-2- [1] benzopyranethanamine racemic diastereomer B

To a solution of 4 g of the racemic diastereomer B of α- [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2 [1] benzopyranacetonitril in 40 ml of toluene at -40 ⁰ C. 16.6 ml of a 1.5M DIBAL solution in toluene was added dropwise. It is warmed to room temperature and stirred for 15 minutes. Thereafter, the reaction mixture is cooled to 0 ⁰ C and treated with 1.18 g of lithium aluminum hydride. Subsequently, the reaction mixture is stirred for 14 h at room temperature. Thereafter, further 16.6 ml of a 1.5 M DIBAL solution in toluene was added, 1 h at room temperature and stirred for 1 h at 35 ⁰ C. The reaction mixture is added to a cooled solution of 300 ml of ethyl acetate and 20 ml of MeOH. To this is added 250 ml of potassium tartrate solution and 25 ml of 2N NaOH and stirred for 1 h. This reaction mixture is filtered through Celite, the residue and the Celite are washed three times with 120 ml of ethyl acetate. The phases are separated, the organic phases washed with water, dried and the solvent removed in vacuo. There are obtained 2.4 g of crystalline crude product. This is recrystallized from MTBE. Yield: 1.7g (64.6%), white solid; ¹ H-NMR: (CDCl ₃ ): δ (ppm) = 6.78-6.65 (m, 3H), 3.87-3.84 (m, 1H), 3.67-3.63 (m , 1H), 3.00-2.71 (m, 4H ₁ ), 2.51 (bs, 1H), 2.14-2.10 (m, 1H), 1, 84-1, 76 (m, 1H).

Example 7: N- {2 - [(tert -butyldimethylsilyl) oxy] -2- (6-fluoro-3,4-dihydro-2H-2- [1] benzopyranyl) ethyl} -6-fluoro-3,4- dihydro-α-hydroxy-2H-2- [1] benzopyran-ethanamine racemic A / B diastereomer

To a solution of 2.28 g of the racemic diastereomer A of 6-fluoro-3,4-dihydro-α-hydroxy-2H-2- [1] benzopyranethanamine and 7 g of the racemic diastereomer B of α- [(tert-butyldimethylsilyl ) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetaldehyde in 250 ml of THF and 50 ml of methanol are added 0.81 g of sodium cyanoborohydride. It is added 1 ml of glacial acetic acid and stirred for 14 h at room temperature. Thereafter, another 0.81 g of sodium cyanoborohydride is added. It is stirred for a further 18 h at room temperature. The reaction mixture is mixed with 400 ml of 5% NaHCO ₃ solution and extracted after 5 minutes stirring several times with ethyl acetate. The organic phases are dried and the solvent removed in vacuo. The crude product thus obtained (10.1 g) is purified by flash chromatography (LM, DCM / MeOH 50 + 1). There are obtained 4.2 g of yellow oil. ¹ H-NMR: (CDCl ₃ ): δ (ppm) = 6.81-6.75 (m, 6H), 4.09-3.95 (m, 4H), 2.92-2.65 (m , 8H), 2.10-1.98 (m, 2H), 1.87-1.72 (m, 2H), 0.94 (s, 9H), 0.18 (s, 3H), 0, 13 (s, 3H). Example 8: (R ^* , R ^* , R *, S ^* ) -α, α ^' - [! Minibis (methylene) bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] ] hydrochloride - nebivolol

A solution of 4.2 g of the racemic A / B diastereomer N- {2 - [(tert-butyldimethylsilyl) oxy] -2- (6-fluoro-3,4-dihydro-2f / -2- [1] Benzopyranyl) ethyl} -6-fluoro-3,4-dihydro-α-hydroxy-2H-2- [1] benzopyran-ethanamine in 75 ml of THF and 75 ml of MeOH is treated with 25 ml of 6N hydrochloric acid and at 70 ⁰ 1 h C stirred. The mixture is then concentrated by half, diluted with 350 ml of water and extracted with petroleum ether. The aqueous phase is basified with 2N NaOH and extracted several times with ethyl acetate. The combined organic phases are washed with water, dried and the solvent removed in vacuo. Yield: 3.2 g (97%), yellow oil. The oil is taken up in 30 ml of methanol, treated with 6 ml of 2N HCl in diethyl ether and allowed to crystallize at -20 ⁰ C for crystallization. Traces of diastereomeric impurities can be separated by recrystallization from methanol. Yield: 1.15 g (32.1%); ¹ H-NMR: (MeOH): δ (ppm) = 6.84-6.75 (m, 6H), 4.14-4.11 (m, 1H), 4.04-4.01 (m, 2H), 3.95-3.91 (m, 1H), 3.53 (dd, 1H), 3.44-3.34 (m, 2H), 3.26 (dd, 1H), 2.96 -2.78 (m, 4H), 2.29-2.22 (m, 1H), 2.05-1.89 (m, 2H), 1.84-1.74 (m, 1H).

In summary, it can be said that the racemic diastereomers of nebivolol with the desired relative configuration of the chiral centers are obtained with high yields and satisfactory degrees of purity by the process according to the invention. This is achieved according to the invention insofar as the corresponding diastereomeric cyanohydrins are prepared, separated and the separated diastereomers are coupled to one another after a transformation, preferably a partial or full reduction of the cyano group or a pinner saponification.

Claims

claims

1. A process for the preparation of the racemic drug nebivolol as a free base or as a pharmaceutically acceptable salt, preferably as a hydrochloride according to formula 1

characterized in that the synthesis via racemic diastereomeric cyanohydrins - in the following diastereomers A and B - of the general formula. 2

in which X is hydrogen or a protecting group typical of cyanohydrins, runs.

2. The method according to claim 1, characterized in that the protective group X typical for cyanohydrins is a benzylic, for example benzyl or 4-methoxybenzyl, or an acetalic, for example tetrahydropyranyl or MEM, protective group.

3. The method according to claim 1, characterized in that the protective group X typical for cyanohydrins is a silyl protective group, preferably a part. Butyldimethylsilylschutzgruppe is.

4. The method according to any one of claims 1 to 3, characterized in that the diastereomers A and B are separated from each other by crystallization.

5. The method according to claim 4, characterized in that a crystalline diastereomer A is separated by digestion of a non-crystalline diastereomer.

6. The method according to any one of claims 1 to 5, characterized in that in preparation for the linkage for the production of nebivolol, the two diastereomers of the general formula 2 with the configurations A and B are further reacted differently, reactions being the reduction to the aldehyde of the general formula 5,

wherein X has the meaning given for the formula 2, as well as the reduction to the amino alcohol of the general formula 6,

wherein X has the meaning given for the formula 2, and the Pinner saponification to the hydroxy ester of the general formula 7,

wherein R is branched or unbranched lower alkyl, or substituted or unsubstituted benzyl are preferred.

7. The method according to claim 6, characterized in that the reduction to the aldehyde of the general formula 5 is carried out with a complex hydride, for example with diisobutylaluminum hydride.

8. The method according to claim 6, characterized in that the reduction to the amine of formula 6 with a complex hydride, for example with lithium aluminum hydride, preferably in combination with diisobutylaluminum hydride.

9. The method according to claim 6, characterized in that the Pinner saponification to the hydroxy ester of formula 7 under cooling at temperatures below 10 degrees C in dry ether, preferably diethyl ether, THF or MTBE, in the presence of an excess of alcohol ROH and as an acid Hydrochloric acid introduced as gas or added as a solution in ether.

10. The method according to any one of claims 1 to 9, characterized in that in the synthesis sequence, the diastereomer B of general formula 2 is reduced to the aldehyde of formula 5, wherein X has the meaning given for formula 2, and the diastereomer A of the general formula 2 is reduced to the aminoalcohol of formula 6, wherein X = has the meaning given for formula 2, and the two components by a reductive amination with each other to the protecting group N-protected nebivolol of general formula 8th

8 are reacted, after which, optionally after prior purification, is obtained by cleavage of the protective groups X nebivolol and optionally purified by recrystallization of the hydrochloride or other good crystallizing salt and / or the free base to pharmaceutical grade.

11. The method according to any one of claims 1 to 9, characterized in that in the synthesis sequence, the diastereomer B of the general formula 2 is reduced to the oxygen-protected aldehyde of formula 5, wherein X has the meaning given for formula 2 with the exception of hydrogen, and the diastereomer A of the general formula 2 is reduced to the aminoalcohol of the formula 6, wherein X is hydrogen and the two components by a reductive amination with each other to the protected with a protective group X nebivolol of the general formula 10th

10 are implemented.

12. The method according to claim 10 or 11, characterized in that in the further reaction of the diastereomeric cyanohydrins A and B according to formula 2 to nebivolol, the diastereomer A of the general formula 2 is reduced to the aldehyde of formula 5 and the diastereomer B of the general formula is reduced to the aminoalcohol of formula 6.

13. The method according to any one of claims 1 to 12, characterized in that the further reaction of the diastereomeric cyanohydrins A and B of formula 2 to nebivolol by reaction of an ester of the general formula 7 with an amine of the general formula 6 to the amide of the general formula .

9

wherein X has the meaning given for the compound 2, followed by a reduction to the amine of the general formula 10,

Wherein X has the meaning given for the compound 2, from which, optionally after prior purification, is obtained by deprotection Nebivolol and optionally purified by recrystallization of the hydrochloride or other good crystallizing salt and / or the free base to pharmaceutical grade.

14. The method according to any one of claims 1 to 13, characterized in that for further reaction of the diastereomeric cyanohydrins A and B of formula 2 to nebivolol the diastereomer B of the general formula 2 is reduced by Pinner saponification to the hydroxy ester of the formula 7 and the diastereomer A of the general formula 2 to the oxygen-protected aminoalcohol of the general formula 6 is reduced.

15. The method according to any one of claims 1 to 14, characterized in that for further reaction of the diastereomeric cyanohydrins A and B of formula 2 to nebivolol the diastereomer A of the general formula 2 is reduced by Pinner saponification to the hydroxy ester of the formula 7 and the diastereomer B of the general formula 2 to the oxygen-protected aminoalcohol of the general formula 6 is reduced.

16. A process for the preparation of cyanohydrins having the general formula 2, characterized in that an aldehyde of the formula 3

reacted to the corresponding cyanohydrin and the protective group X, preferably a tert.Butyldimethylsilylschutzgruppe is introduced.

17. α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2 / - / - 2- [1] benzopyranacetonitrile as a crystalline racemic diastereomer A.

18. α - [(tert-butyldimethylsilyl) oxy] -6-fluoro-3,4-dihydro-2H-2- [1] benzopyranacetonitrile as oily racemic diastereomer B,