DE102014107132A1 - Process for the preparation of epoxides which can be used in the preparation of nebivolol and its derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of epoxides which are useful as intermediates in a process for the preparation of nebivolol or desfluorinated nebivolol derivatives, by reacting an E-allyl alcohol to a dialcohol and converting the primary alcohol of the dialcohols into a leaving group and subsequent treatment with a base or by reacting an epoxide by converting the primary alcohol of the epoxides to a leaving group, optionally removing the protecting group, and carrying out an intramolecular cyclization.

Description

Subject of the invention

The present invention relates to a novel process for the preparation of epoxides, which are particularly useful in the preparation of the active ingredient nebivolol and its desfluoro derivatives.

introduction

a, a '- [iminobismethylene] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] - known as nebivolol as an active ingredient - is a highly potent and selective beta-blocker that has been used in the art Treatment of hypertension is used ( EP 0145067 ; Mol. Pharmacol. 34 (1988), 843; J. Cardiovasc. Pharmacol. 11 (1988) 552 ). A general approach to this class of compounds, as well as the first synthesis suitable for scale-up to industrial production, was first introduced by Janssen in US 4,654,326 and EP 0145067 respectively. EP 0334429 described.

The active substance nebivolol is marketed as an HCl salt and is prepared and applied as a racemate, which consists of the two enantiomers (+) - and (-) - nebivolol (d-nebivolol * HCl) and (l-nebivolol * HCl) ( WO 96/19987 ; Clin. Drug Invest. 3 (1), 1991, 25-30 ).

Tabelle 1: Diastreomere von Nebivolol NBV 1/2, NBV 3/4, NBV 5/6, und NBV 7/8 bilden jeweils Enantiomerenpaare, während es sich bei NBV 9 und NBV 10 um meso-Verbindungen handelt.

Nebivolol has 4 chiral centers, so theoretically 16 diastereomers result. However, due to the plane of symmetry passing through the nitrogen atom, the number of diastereomers is limited to a total of 10 compounds as shown in Table 1.

Table 1: Nebivolol NBV 1/2 diastereoisomers, NBV 3/4, NBV 5/6, and NBV 7/8 form pairs of enantiomers, while NBV 9 and NBV 10 are meso compounds.

A considerable number of syntheses for nebivolol have since been described in the patent literature and in the public domain field, eg in US 4654362 A (JANSSEN) EP 0334429 A1 (JANSSEN) WO 2004/041805 A1 (EGIS) WO 2006/016376 A1 and WO 2007/083318 A1 (HETERO DRUGS), WO 2006/025070 A2 (Torrent), WO 2008/010022 A2 (CIMEX) WO 2008/064826 A2 and WO 2008/064827 A2 (ZACH) WO 2009/082913 A1 . CN 101463024 A . WO 2010/049455 (ZACH) and WO 2010/089764 A1 (ZACH).

Usually, the last step in these syntheses is the catalytic hydrogenation of N-benzyl-nebivolol (14a / b). One of the possible side reactions in this step is the defluorination, which can lead to various desfluorinated compounds as shown in Scheme 1. Due to the stereochemical properties of nebivolol, two enantiomeric pairs of monofluorocompounds (15 a '/ b', 15 a '' / b '') can occur during defluorination and 2 completely de-fluorinated enantiomers (15 a '''/b''' ).

Schema 1: Potentielle Nebenprodukte bei einer Darstellung von Nebivolol mittels einer Hydrierung; a) H₂, Pd/C, MeOH; Bn = Benzyl The potential byproducts of a nebivolol preparation are shown in Scheme 1.

Scheme 1: Potential by-products in a presentation of nebivolol via hydrogenation; a) H ₂ , Pd / C, MeOH; Bn = benzyl

This defluorination is for the first time in WO 2010/049455 (Zach) has been described. It is reported to be> 2% under standard conditions, which is unacceptable for the synthesis of a pharmaceutically active substance, as this poses significant cleaning problems, ultimately leading to higher manufacturing costs. Basically, this desfluorination can be significantly reduced by using the chemical transfer hydrogenation (eg WO 2010/049455 (Zach) EP 14155300 (Corden)). Unfortunately, with regard to a pharmaceutical release analysis as well as in process controls in the hydrogenation so far there are no relevant structural data for the different isomers of desfluorinated compounds, since the desfluorination in WO 2010/049455 generally derived only from MS data, without a concrete structure assignment was performed.

Theoretically, the simplest access to the desfluorinated compounds 15 a '/ b', 15 a '' / b '' and 15 a '''/b''' results from carrying out the catalytic hydrogenation of 14 a, b under forced conditions , around then separate the desfluoro compounds by chromatography. However, this path proved too laborious due to the preparatively difficult separation.

A preparative approach to the desfluorinated nebivolol compounds is in principle in US 4654362 and EP 0334429 respectively. EP 0145067 described. The pathway shown therein starts with a racemate resolution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid by means of chiral 1-phenylethylamine or dehydroabiethylamine, which, however, gives only unsatisfactory yields. The same applies to the racemate resolution of 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid, which is the starting material for the synthesis of nebivolol.

It should be noted that, in principle, the defluorination can also be observed with all diastereomeric secondary compounds resulting in a nebivolol synthesis, since the starting material used is 6-fluoro-3,4-dihydro-1H-1-benzopyran-2-carboxylic acid Basis of the manufacturing process also contains the desfluoro compound as a minor component. However, since this minor component can be limited to a maximum proportion of 0.1%, all secondary compounds NBV 3-10 resulting from this secondary component are obtained in negligible amounts in the end product.

Recently was in WO 2011/091968 a new, highly efficient and economical approach to nebivolol by enzymatic reduction as a key step. This synthesis avoids unnecessary chromatographic purification and allows complete control of all stereocenters. Although this approach allows the synthesis of all diastereomers of nebivolol, it does not allow access to the fluorinated compounds, since using (chiral) 3,4-dihydro-1H-1-benzopyran-2-carboxylic acid, a chlorination step included in the synthetic sequence also leads to a chlorination of the aromatic nucleus.

The object of the present invention is therefore to find intermediates and a preparation process for them which enable a modular and selective access both for the preparation of nebivolol and for the preparation of all isomers of desfluoro-nebivolol (monodesfluoro- and bis-desfluoro-nebivolol).

Summary of the invention

umfassend die Schritte

• i. Umsetzung eines E-Allylalkohols der Formel 2
  
  zu einem Dialkohol der Formel 3a bis 3d
  
  
  und Umwandlung des primären Alkohols der Dialkohole der Formel 3a bis 3d in eine Abgangsgruppe und anschließender Behandlung mit einer Base; oder
• ii. Umsetzung eines Epoxids der Formel 4a bis 4d
  
  wobei PG eine Hydroxy-Schutzgruppe oder H ist, mittels einer Umwandlung des primären Alkohols der Epoxide der Formel 4a bis 4d in eine Abgangsgruppe, Entfernung der Schutzgruppe (wenn PG nicht H ist) und Durchführung einer intramolekularen Cyclisierung, wobei R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.

A first aspect of the invention relates to a process for the preparation of epoxides of the formula 1a to 1d,

comprising the steps

• i. Reaction of an E-allyl alcohol of the formula 2
  
  to a dialcohol of formula 3a to 3d
  
  
  and converting the primary alcohol of the dialcohols of the formula 3a to 3d into a leaving group and subsequent treatment with a base; or
• ii. Reaction of an epoxide of the formula 4a to 4d
  
  wherein PG is a hydroxy-protecting group or H, by converting the primary alcohol of the epoxides of formula 4a to 4d into a leaving group, removing the protecting group (when PG is not H) and performing an intramolecular cyclization, wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

durch Umsetzung der Epoxiden der Formel 1a bis 1d, welche nach einem Verfahren gemäß dem ersten Aspekt synthetisiert werden, mit einem Amin der Formel H₂NP, wobei P eine Amin-Schutzgruppe ist und R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.A second aspect of the invention relates to a process for the preparation of aminoalcohols of the formula 7a to 7d,

by reacting the epoxides of the formulas 1a to 1d, which are synthesized by a process according to the first aspect, with an amine of the formula H ₂ NP, where P is an amine-protecting group and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F, is.

oder deren Salze, insbesondere deren Hydrochloride,
wobei mit * ein Stereozentrum gekennzeichnet ist, welches eine E oder Z Konfiguration aufweisen kann,
mittels einer Kupplungsreaktion von

• a. jeweils einem Epoxid ausgewählt aus Gruppe der Verbindungen dargestellt durch die Formeln 1a bis 1d,
  
  welche nach einem Verfahren gemäß dem ersten Aspekt synthetisiert werden,
• b. mit jeweils einem Aminalkohol ausgewählt aus Gruppe der Verbindungen dargestellt durch die der Formel 7a bis 7d,
  
  welche insbesondere nach einem Verfahren gemäß dem zweiten Aspekt synthetisiert werden, wobei P eine Amin-Schutzgruppe ist und R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist und anschließendem Entfernen der Schutzgruppe, insbesondere mittels Transfer-Hydrierung.

A third aspect of the invention relates to processes for the preparation of nebivolol derivatives of the formula 15,

or their salts, in particular their hydrochlorides,
where * denotes a stereocenter, which may have an E or Z configuration,
by means of a coupling reaction of

• a. in each case an epoxide selected from the group of the compounds represented by the formulas 1a to 1d,
  
  which are synthesized by a method according to the first aspect,
• b. in each case with an aminal alcohol selected from the group of the compounds represented by those of the formulas 7a to 7d,
  
  which are synthesized in particular by a process according to the second aspect, wherein P is an amine protecting group and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F, and then removing the Protecting group, in particular by means of transfer hydrogenation.

Detailed description:

umfassend die Schritte

• i. Umsetzung eines E-Allylalkohols der Formel 2
  
  zu einem Dialkohol der Formel 3a bis 3d
  
  
  und Umwandlung des primären Alkohols der Dialkohole der Formel 3a bis 3d in eine Abgangsgruppe und anschließender Behandlung mit einer Base; oder
• ii. Umsetzung eines Epoxids der Formel 4a bis 4d
  
  wobei PG eine Hydroxy-Schutzgruppe oder H ist, mittels einer Umwandlung des primären Alkohols der Epoxide der Formel 4a bis 4d in eine Abgangsgruppe, optional Entfernung der Schutzgruppe, und Durchführung einer intramolekularen Cyclisierung, wobei R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.

The first aspect of the invention relates to a process for the preparation of epoxides of the formula 1a to 1d,

comprising the steps

• i. Reaction of an E-allyl alcohol of the formula 2
  
  to a dialcohol of formula 3a to 3d
  
  
  and converting the primary alcohol of the dialcohols of the formula 3a to 3d into a leaving group and subsequent treatment with a base; or
• ii. Reaction of an epoxide of the formula 4a to 4d
  
  wherein PG is a hydroxy-protecting group or H, by means of a conversion of the primary alcohol of the epoxides of formula 4a to 4d into a leaving group, optionally deprotecting, and carrying out an intramolecular cyclization, wherein R is selected from the group of F, Cl, Br , I or H, in particular from the group of H or F.

umfassend die Schritte:
Umsetzung eines Epoxids der Formel 4a bis 4d

wobei PG eine Hydroxy-Schutzgruppe oder H ist,
mittels einer Umwandlung des primären Alkohols der Epoxide der Formel 4a bis 4d in eine Abgangsgruppe, optional Entfernung der Schutzgruppe, und Durchführung einer intramolekularen Cyclisierung,
wobei R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.An alternative of the first aspect relates to a process for the preparation of epoxides of the formula 1a to 1d,

comprising the steps:
Reaction of an epoxide of the formula 4a to 4d

where PG is a hydroxy-protecting group or H,
by converting the primary alcohol of the epoxides of the formula 4a to 4d into a leaving group, optionally removing the protective group, and carrying out an intramolecular cyclization,
wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

The conversion of a primary alcohol into a leaving group is one of the standard tasks of a person skilled in the art of chemical syntheses and can be carried out by any suitable method. For example, the primary alcohol having an OSO ₂ R or OSO ₂ Ar group, wherein R is a C ₁ to C ₆ alkyl, preferably methyl and Ar is an aromatic radical, in particular phenyl, 4-nitrophenyl, tosyl or comparable compounds thereof replaced become. For further details reference is made to the experimental section.

Likewise, the removal (and attachment) of the protecting group (deprotection of a hydroxy function) is one of the standard tasks of one skilled in the art of chemical syntheses, which may be taken from any basic literature (see, for example PGM Wuts, "Greene's Protective Groups in Organic Synthesis," 4th ed. (2006, Wiley; ISBN 978-0-471-69754-1; 5th edition June 2013, Wiley-Blackwell) , For further details reference is made to the experimental section.

synthetisiert, wobei PG eine Hydroxy-Schutzgruppe oder H ist, und R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.In one embodiment, the epoxide of formula 4a to 4d is prepared by asymmetric Sharpless epoxidation of the allyl alcohols of formula 6a and 6b

wherein PG is a hydroxy-protecting group or H, and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

Sharpless asymmetric epoxidation (SAE) is one of the standard tasks of a person skilled in the art of chemical syntheses (see, for example, US Pat Tsutomu Katsuki, K. Barry Sharpless: The first practical method for asymmetric epoxidation. In: Journal of the American Chemical Society. 102, No. 18, 1980, pp. 5974-5976 ).

The use of enantiomerically pure diethyl tartrate ((S, S) -diethyl tartrate is hereinafter referred to as (-) DET and (R, R) -diethyl tartrate with (+) DET) enables the enantioselective preparation of the chiral epoxides of the formula 4a to 4d.

In one embodiment, the allyl alcohols of formula 6a and 6b are synthesized by Wittig olefination of chroman-2-ol derivatives of Formal 9. Wittig olefination allows the stereoselective preparation of the allylic alcohols of formula 6a and 6b.

können leicht aus einer Reduktion der Derivate des 1,2-dihydrobenzopyranon der Formel 10

dargestellt werden. Dabei ist R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F. Dies kann beispielsweise mittels DIBAL (Diisobutylaluminiumhydrid) erfolgen.The derivatives of chroman-2-ol of formula 9

can be easily obtained from a reduction of the derivatives of 1,2-dihydrobenzopyranone of formula 10

being represented. In this case, R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F. This can be done for example by means of DIBAL (diisobutylaluminum hydride).

Schema 2a

Schema 2b

Schema 2c An overview of the overall synthesis is shown in Schemes 2a to c.

Scheme 2a

Scheme 2b

Scheme 2c

Schemes 2a to 2c: total synthesis of the chiral epoxides of the formula 1a to 1d starting from the derivatives of 1,2-dihydrobenzopyranone of the formula 10; a) reduction with DIBAL; b) Wittig olefination; c) and d) Sharpless asymmetric epoxidation with (-) DET and (+) DET, respectively; e) Conversion of the primary alcohol into a leaving group, removal of the hydroxy protecting group, and an intramolecular cyclization.

1,2-dihydrobenzopyranone 10 is a suitable starting material for this sequence which can be readily reduced to lactol 9 with DIBAL. Subsequent Wittig olefination leads stereoselectively via the unsaturated esters to the allylic alcohols 6a and 6b, which can then be converted enantioselectively into the chiral epoxides 4a, 4b, 4c and 4d. These represent the starting material for the preparation of the epoxides of the formula 1a to 1d, which are prepared by means of the intramolecular cyclization described above.

As part of our work, we found that in the Z series (6b), unlike data reported in the literature ( Synthesis 2009, 1886-1896; Tetrahedron 2000, 56, 6339-6344 ) observed only moderate enantioselectivities in the formation of 4c and 4d via the SAE route.

Better enantioselectivities can be achieved via the following alternative of the first aspect of the invention.

umfassend die Schritte
Umsetzung eines E-Allylalkohols der Formel 2

zu einem Dialkohol der Formel 3a bis 3d

und Umwandlung des primären Alkohols der Dialkohole der Formel 3a bis 3d in eine Abgangsgruppe und anschließender Behandlung mit einer Base,
wobei R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.A further alternative of the first aspect of the invention relates to a process for the preparation of epoxides of the formula 1a to 1d,

comprising the steps
Reaction of an E-allyl alcohol of the formula 2

to a dialcohol of formula 3a to 3d

and conversion of the primary alcohol of the dialcohols of the formula 3a to 3d into a leaving group and subsequent treatment with a base,
wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

The conversion of a primary alcohol into a leaving group is one of the standard tasks of a person skilled in the art of chemical syntheses and can be carried out by any suitable method. For example, the primary alcohol having an OSO ₂ R or OSO ₂ Ar group, wherein R is a C ₁ to C ₆ alkyl, preferably methyl and Ar is an aromatic radical, in particular phenyl, 4-nitrophenyl, tosyl or comparable compounds thereof replaced (see formulas 12a and 12b of Scheme 3). For further details reference is made to the experimental section.

Treatment with a base, in particular a strong base such as sodium methoxide, leads to an intramolecular ring closure with elimination of the leaving group and formation of the desired chiral epoxide of formula 1a (from the reaction of dialcohol 3a) or 1b (from the reaction of dialcohol 3b ).

durch eine asymmetrische Sharpless-Epoxidierung (SAE) des E-Allylalkohols der Formel 2

und anschließender Öffnung des entstandenen Epoxids mittels einer geeigenten Base, insbesondere mittels einer Hydroxidverbindung (wie besspielsweise NaOH), synthetisiert,
wobei R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.In one embodiment, the dialcohols of formula 3a and 3b

by an asymmetric Sharpless epoxidation (SAE) of the E-allyl alcohol of the formula 2

and subsequent opening of the resulting epoxide by means of a suitable base, in particular by means of a hydroxide compound (such as, for example, NaOH), synthesized,
wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

Sharpless asymmetric epoxidation (SAE) is one of the standard tasks of a person skilled in the art of chemical syntheses (see, for example, US Pat Tsutomu Katsuki, K. Barry Sharpless: The first practical method for asymmetric epoxidation. In: Journal of the American Chemical Society. 102, No. 18, 1980, pp. 5974-5976 ).

The use of enantiomerically pure diethyl tartrate ((S, S) -diethyl tartrate is referred to hereinafter as (-) DET and (R, R) -diethyl tartrate with (+) DET), allows the enantioselective preparation of the chiral epoxides of the formula 4a to 4d.

Likewise, the opening of epoxides by means of a suitable reactant for the preparation of chiral dialcohols is one of the standard tasks of a person skilled in the art of chemical syntheses. For more details, please refer to the experimental section.

synthetisiert, wobei R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist. In one embodiment, the E-allyl alcohol of Formula 2 is prepared from a reduction of a propargyl alcohol of Formula 5

wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

The reduction is carried out using sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al). Details are discussed in the experimental part. Alternatively, other reducing agents suitable for the reduction of a triple bond, such as LiAlH ₄ , may also be used.

über eine Reduktion (z.B. mit DIBAL) zu den Derivaten von Chroman-2-ol der Formel 9

und anschließender Bromierung (z.B. mittels CBr₄) und Ringöffnung des Lactols 9.The Propargylakohol 5, as a central intermediate, is accessible in the sense of a one-pot reaction according to a Corey-Fuchs protocol using n-BuLi and para-formaldehyde from the Dibromoverbindung 11. The representation of Dibromoverbindung 11 is made from the derivatives of 1,2- dihydrobenzopyranone of formula 10

via a reduction (eg with DIBAL) to the derivatives of chroman-2-ol of formula 9

and subsequent bromination (eg by CBr ₄ ) and ring opening of the lactol 9.

In this case, R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F.

Schema 3: a) DIBAL, THF, –78°C, 4 bis 5 Stunden (h), 63 bis 78% (die angegeben Ausbeuten sind abhängig von den jeweils eingesetzten Rest R); b) CBr₄, PPh₃; CH₂Cl₂, 0°C, 3h, 52 bis 77%; c) n-BuLi, THF, (CHO)_n, –78 bis 0°C, 4h, 69 bis 97%; d) Red-Al, 83%, e) 1. SAE, (–)-DET, 2. NaOH, 66%; f) TsCl, pyridin (py), CH₂Cl₂, 0°C bis Raumtemperatur (rt), 19h, 93%, g) NaOMe, i-PrOH, rt; h) 1. SAE, (+)-DET, 2. NaOH, 67%, i) TsCl, py, CH₂Cl₂, 0°C bis rt, 19h, 68%; j) NaOMe, i-PrOH, rt An overview of the overall synthesis is shown in Scheme 3.

Scheme 3: a) DIBAL, THF, -78 ° C, 4 to 5 hours (h), 63 to 78% (the indicated yields are dependent on the particular R used); b) CBr ₄ , PPh ₃ ; CH ₂ Cl ₂ , 0 ° C, 3h, 52 to 77%; c) n-BuLi, THF, (CHO) _n , -78 to 0 ° C, 4h, 69 to 97%; d) Red Al, 83%, e) 1. SAE, (-) - DET, 2. NaOH, 66%; f) TsCl, pyridine (py), CH ₂ Cl ₂ , 0 ° C to room temperature (rt), 19h, 93%, g) NaOMe, i-PrOH, rt; h) 1. SAE, (+) - DET, 2. NaOH, 67%, i) TsCl, py, CH ₂ Cl ₂ , 0 ° C to rt, 19h, 68%; j) NaOMe, i-PrOH, rt

The 2-chromanone derivatives 10 are converted into the lactol 9 in high yield by reduction with DIBAL-H. Reaction of 9 with tetrabromomethane in the presence of triphenylphosphine leads to the formation of the geminal dibromide 11, which is converted into the propargyl alcohol 5 under the action of 2 equivalents of butyl or hexyl lithium and formaldehyde. Red Al reduction without difficulty leads to the formation of E-allylic alcohol 2 in 83% yield. From compound 2, the required diols 3a and 3b are obtained by Sharpless epoxidation and in situ opening of the resulting epoxides by NaOH. Both enantiomeric series are accessible by the use of (-) - or (+) - DET in the epoxidation. Transformation of 3a into tosylate 12a generates the syn-epoxide 1a after treatment with sodium methylate. In analogy to this sequence, syn-epoxide 1b is shown.

aus den Dialkoholen der Formel 3a und 3b synthetisiert. Die Dialkohole der Formel 3a und 3b werden analog zum oben beschriebenen Verfahren hergestellt. Anschließend erfolgt eine Inversion der Dialkohole der Formel 3a und 3b mittels einer Mitsunobu-Inversion unter Bildung eines Diesters und anschließender Reduktion des Diesters zu den gewünschten Dialkoholen der Formel 3c und 3d.In one embodiment, the dialcohols of formula 3c and 3d

from the dialcohols of the formula 3a and 3b synthesized. The dialcohols of the formula 3a and 3b are prepared analogously to the process described above. Subsequently, an inversion of the dialcohols of the formula 3a and 3b takes place by means of a Mitsunobu inversion to form a diester and subsequent reduction of the diester to the desired dialcohols of the formula 3c and 3d.

The Mitsunobu reaction can be carried out with diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (TPP). Alternatively, diethyl azodicarboxylate (DEAD) can be used. The formed diesters can then be reduced to the diols 3c and 3d.

gebildet werden, die im Anschluss zu den gewünschten Dialkohole der Formel 3c und 3d reduziert werden.The Mitsunobu reaction described above can be carried out in the presence of 4-nitrobenzoic acid (PNB), the diesters of the formula 13c and 13d

are formed, which are subsequently reduced to the desired dialcohols of the formula 3c and 3d.

The reduction of diesters to the corresponding diols is achieved by means of a suitable reactant which belongs to the standard tasks of a person skilled in the art of chemical syntheses. For example, strong bases such as sodium methoxide can be used. For more details, please refer to the experimental section.

Schema 4: DIAD = Diisopropyl azodicarboxylate (CAS 2446-83-5); PNB = 4-Nitrobenzoesäure (CAS 62-23-7), TsCl = Tosyl chloride (CAS 98-59-9), a) DIAD, PPh3, PNBA, THF, –20°C bis rt; b) NaOMe, MeOH, rt, 42%, (2 Schritte); c) TsCl, py, CH₂Cl₂, 0°C bis rt, 58%; d) NaOMe, i-PrOH, rt; e) DIAD, PPh₃, PNBA, THF, –20°C bis rt; f) NaOMe, MeOH, rt, 38%, (2 Schritte) g) TsCl, py, CH₂Cl₂, 0°C bis rt, 68%; h) NaOMe, i-PrOH, rt An overview of the overall synthesis is presented in Scheme 4.

Scheme 4: DIAD = diisopropyl azodicarboxylate (CAS 2446-83-5); PNB = 4-nitrobenzoic acid (CAS 62-23-7), TsCl = tosyl chloride (CAS 98-59-9), a) DIAD, PPh3, PNBA, THF, -20 ° C to rt; b) NaOMe, MeOH, rt, 42%, (2 steps); c) TsCl, py, CH ₂ Cl ₂ , 0 ° C to rt, 58%; d) NaOMe, i-PrOH, rt; e) DIAD, _PPh3, PNBA, THF, -20 ° C to rt; f) NaOMe, MeOH, rt, 38%, (2 steps) g) TsCl, py, CH ₂ Cl ₂ , 0 ° C to rt, 68%; h) NaOMe, i-PrOH, rt

Access to the trans-configured epoxides 1c and 1d thus opens up to diols 3a and 3b by applying a Mitsunobu reaction with diisopropyl azodicarboxylate (DIAD) and triphenyl phosphine (TPP). This leads to the diesters (using PNBA, for example, to diesters 13c and 13d) with no loss of enantioselectivity, which can be reduced to diols 3c and 3d. Reaction of 12c and 12d with sodium methylate then leads directly to the trans-epoxides 1c and 1d.

By applying a Mitsunobu reaction, the selectivities of the epoxides 1a to 1d (in particular with respect to the trans-epoxides 1c and 1d) could be increased. At the same time, a simple and robust access to all required stereoisomers is provided.

durch Umsetzung der Epoxiden der Formel 1a bis 1d, welche nach einem Verfahren gemäß dem ersten Aspekt synthetisiert werden, mit einem Amin der Formel H₂NP, wobei P eine Amin-Schutzgruppe ist und R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist.A second aspect of the invention relates to a process for the preparation of aminoalcohols of the formula 7a to 7d,

by reacting the epoxides of the formulas 1a to 1d, which are synthesized by a process according to the first aspect, with an amine of the formula H ₂ NP, where P is an amine-protecting group and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F, is.

The removal and attachment of an amine protecting group P, such as benzyl, is one of the standard tasks of a person skilled in the art of chemical syntheses, which can be found in any basic literature (see, for example, US Pat PGM Wuts, "Greene's Protective Groups in Organic Synthesis," 4th ed. (2006, Wiley; ISBN 978-0-471-69754-1; 5th edition June 2013 Wiley-Blackwell ). For further details, please refer to the experimental section.

Schema 5: a) BnNH₂ (Bn = Benzyl), i-PrOH, 80°C, 4h quant.; alternative Schutzgruppen P sind denkbar. An overview is shown in Scheme 5:

Scheme 5: a) BnNH ₂ (Bn = benzyl), i-PrOH, 80 ° C, 4h quant .; alternative protecting groups P are conceivable.

oder deren Salze, insbesondere deren Hydrochloride,
wobei mit * ein Stereozentrum gekennzeichnet ist, welches eine E oder Z Konfiguration aufweisen kann,
mittels einer Kupplungsreaktion von

• a. jeweils einem Epoxid ausgewählt aus Gruppe der Verbindungen dargestellt durch die Formeln 1a bis 1d,
  
  welche nach einem Verfahren gemäß dem ersten Aspekt synthetisiert werden,
• b. mit jeweils einem Aminalkohol ausgewählt aus Gruppe der Verbindungen dargestellt durch die der Formel 7a bis 7d,
  
  
  welche insbesondere nach einem Verfahren gemäß dem zweiten Aspekt synthetisiert werden, wobei P eine Amin-Schutzgruppe ist und R ausgewählt aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ist und anschließendem Entfernen der Schutzgruppe, insbesondere mittels Transfer-Hydrierung.

A third aspect of the invention relates to processes for the preparation of nebivolol derivatives of the formula 15,

or their salts, in particular their hydrochlorides,
where * denotes a stereocenter, which may have an E or Z configuration,
by means of a coupling reaction of

• a. in each case an epoxide selected from the group of the compounds represented by the formulas 1a to 1d,
  
  which are synthesized by a method according to the first aspect,
• b. in each case with an aminal alcohol selected from the group of the compounds represented by those of the formulas 7a to 7d,
  
  
  which are synthesized in particular by a process according to the second aspect, wherein P is an amine protecting group and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F, and then removing the Protecting group, in particular by means of transfer hydrogenation.

Schema 6: Kupplung der Aminalkohol der Formel 7a bis 7d mit den Epoxiden der Formel 1a bis 1d; a) i-PrOH, 4 bis 6h. Dabei wird R der Verbindung 1 und R der Verbindung 7 unabhängig voneinander – je nach Art des gewünschten Produktes – aus der Gruppe von F, Cl, Br, I oder H, insbesondere aus der Gruppe von H oder F, ausgewählt. An overview of the coupling reaction is shown in Scheme 6

Scheme 6: Coupling of the amine alcohol of the formula 7a to 7d with the epoxides of the formula 1a to 1d; a) i-PrOH, 4 to 6h. In this case, R of compound 1 and R of compound 7 are selected independently of one another-depending on the nature of the desired product-from the group of F, Cl, Br, I or H, in particular from the group of H or F.

Schema 7 Transfer-Hydrierung der geschützten Verbindungen 14; a) cyclohexene, Pd/C, conc. HCl_aq, THF/H₂O (6:1), reflux. Finally, a transfer hydrogenation analogous to the method of the EP 14155300 (Corden) debenzylation and leads to the hydrochlorides of all nebivolol-desfluoro compounds in high stereochemical purity and yield (see Scheme 7). For more details, please refer to the experimental section.

Scheme 7 Transfer hydrogenation of the protected compounds 14; a) cyclohexenes, Pd / C, conc. HCl _aq , THF / H ₂ O (6: 1), reflux.

Experimental section

Chroman-2-ol (9):

Dihydrocoumarin 10 (10 g, 67.49 mmol, 1.00 eq) was dissolved under nitrogen in THF (472 mL) (7 mL / mmol) and cooled to -78 ° C. While stirring, DIBAI-H (1 M in hexane, 81 ml, 81 mmol, 1.20 eq) was added dropwise at -78 under temperature control within 20-30 minutes and then the mixture was added until complete conversion (about 4 hours). Stirred 78 ° C. For workup, water was added (20 ml) and warmed to room temperature over 2 hours. With vigorous stirring, anhydrous MgSO ₄ (50 g) was added and the reaction mixture was subsequently filtered. The filter cake was washed with hexane (100 ml) and the combined filtrates were concentrated in vacuo. The crude product was either used directly in the next reaction or purified by chromatography on SiO ₂ (hexane / EtOAc (9: 1 to 4: 1).) The product 9 was obtained as a colorless oil (7.89 g, 52.54 mmol, .. 79% of theory) ¹ H NMR (CDCl _3): δ = 7:14 to 7:15 (m, 2H), 6.90-6.81 (m, 2H), 5.61 (dd, 1H, J = 2.71 Hz, 1 05 Hz), 3.32-3.05 (br, OH), 3.07 (ddd, 1H, J = 5.33 Hz, 10.45 Hz, 16.43 Hz), 2.08-1.98 (m, 2H).

2- (4,4-dibromo-but-3-enyl) -phenol (11):

A solution of CBr ₄ (169 g, 468.15 mmol, 2 eq) in CH ₂ Cl ₂ (750 mL) was cooled to 0 ° C under a nitrogen atmosphere. A solution of PPh ₃ (245.58 g, 936.30 mmol, 4 eq) in CH ₂ Cl ₂ (500 mL) was added dropwise over 90 minutes and the resulting mixture stirred at 0 ° C for a further 30 minutes. Subsequently, a solution of 9 (35.19 g, 234.07 mmol, 1.00 eq) in CH ₂ Cl ₂ (175 mL) was added over 20 minutes. After stirring at 0 ° C. for 60 minutes, water (400 ml) was added and the mixture was warmed to room temperature. The phases were separated and the organic phase extracted with CH ₂ Cl ₂ (3 x 150 ml). The combined organic phases were washed with sat. NaCl solution (600 ml) and dried over Na ₂ SO ₄ . After filtration, the mixture was concentrated in vacuo and then combined with MTBE (1 L) for the precipitation of PPh ₃ O. After renewed filtration, MTBE (1 L) was again added. After filtration, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on SiO ₂ (eluent: 7: 1 hexane / MTBE). 11 was obtained in 72% yield (52.01 g, 169.57 mmol) ¹ H NMR (400 MHz, CDCl _3): δ = 7:14 to 7:14 (m, 2H); 6.89 (t, J = 7.45 Hz, 1H); 6.74 (d, J = 8.49 Hz); 6.45 (t, J = 7.10 Hz, 1H); 4.81 (s, 1H); 2.74 (t, J = 7.41 Hz, 2H); 2.43 (q, J = 7.84 Hz, 2H).

2- (5-Hydroxy-pent-3-ynyl) -phenol (5):

A solution of 11 (38.31 g, 124.91 mmol, 1.00 eq) in THF (424 mL) was cooled to -78 ° C under N ₂ . n-Buli (2.5 M in hexanes, 180.89 ml, 452.19 mmol, 3.62 eq) were metered in over 60 minutes so that the temperature did not rise above -72 ° C. The mixture was then stirred at -78 ° C for 60 min. Paraformaldehyde (11.20 g, 374.74 mmol, 3 eq) was added in one portion at -78 ° C, then the reaction mixture was heated to 0 ° C within 2 h and stirred for a further 60 min. It was hydrolyzed with sat. NH ₄ Cl solution (600 mL) and diluted with EtOAc (150 mL). The phases were separated and the aqueous phase extracted with EtOAc (3 x 150 ml). The combined organic phases were dried over Na ₂ SO ₄ and filtered. After removal of the solvent and purification by flash chromatography on SiO ₂ (eluent: hexane / EtOAc 7: 3 to 1: 1), 5 was obtained as a colorless oil (19.81 g, 112.56 mmol, 90% of th. ) ¹ H NMR (400 MHz, CDCl _3): δ = 7:16 to 7:06 (m, 2H); 6.87 (t, J = 7.44 Hz, 1H); 6.77 (d, J = 7.87 Hz, 1H); 5.89-5.55 (br, 1H, OH); 4.23 (t, J = 2.13 Hz, 2H); 2.84 (2.84, J = 7.45, 2H); 2.53 (m, 2H); 2.35-1.86 (br, 1H, OH).

(E) -2- (5-Hydroxy-pent-3-enyl) -phenol (2):

Red-Al (65% in toluene) (47.71 mL, 153.39 mmol, 2.47 eq) was diluted under N ₂ with MTBE (64 mL) and the solution then cooled to 0 ° C. A solution of 5 (10.93 g, 62.10 mmol, 1.00 eq) in MTBE (44 mL) was added over 10 min. It was then warmed to room temperature and stirred for 18 h. It was cooled to 0 ° C and to the mixture was carefully added a saturated aqueous solution of Rochelle's salt (366 ml). The mixture was stirred for 1 h at 0 ° C and then warmed to room temperature. After extraction with EtOAc (3 × 100 ml), the organic phases were dried over Na ₂ SO ₄ . After filtration and concentration in vacuo, the crude product was purified by flash chromatography on SiO ₂ (eluent: hexane / MTBE 1: 1 to 3: 7). 2 (9.21 g, 51.74 mmol) was obtained in 83% yield. ¹ H NMR (400 MHz, CDCl _3): δ = 7:12 to 7:03 (m, 2H); 6.85 (t, J = 7.58 Hz, 1H); 6.74 (d, J = 7.86 Hz, 1H); 5.81-5.61 (m, 2H); 4.08 (d, J = 5.61 Hz, 2H); 2.70 (t, J = 7.30 Hz); 2.37 (q, J = 7.30 Hz and 14.60 Hz, 2H).

Synthesis of chroman diols 3a and 3b in the one-pot process via Sharpless Asymmetric Epoxidation (general procedure):

Step 1. Sharpless Asymmetric Epoxidation (SAE):

A suspension of activated 4 ° A molecular sieve (0.5 g / mmol) in CH ₂ Cl ₂ (5 mL / mmol) was cooled to -20 ° C under N ₂ . A solution of the required eanetiomerically pure diethyl (1.09 eq) in CH ₂ Cl ₂ (2.5 ml / mmol) was added. Subsequently, Ti (OiPr) ₄ (1.20 eq) was added, followed by TBHP (5.5 M in nonane, 3.92 eq). The mixture was stirred for 20 minutes at -20 ° C after. Subsequently, a solution of E-Allylallkohols 2 (1.00 eq) in CH ₂ Cl ₂ (2 ml / mmol) was added dropwise within 30 min. After complete conversion (about 4 h), the reaction mixture was warmed to 0 ° C and into a freshly prepared solution of FeSO ₄ . Add 7H ₂ O (0.330 g / mmol) and tartaric acid (0.100 g / mmol) in water (1 mL / mmol). The biphasic mixture was stirred for 45 min, then the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic phases were concentrated to 1/3 volume and used in the next step of the synthesis.

Step 2. Base-catalyzed intramolecular cyclization:

The solution of epoxides from step 1 was cooled to 0 ° C. under N ₂ . 30% NaOH in sat. NaCl solution (2.9 ml / mmol) [100 ml of 30% NaOH in NaCl solution prepared by addition of 5 g of NaCl to a solution of NaOH (30 g) in water (90 ml)] was added. The color of the reaction mixture changed from pale yellow to violet, after 10 minutes the mixture became colorless. After a further 60 min stirring at 0 ° C was warmed to room temperature. The phases were separated and the aqueous phase extracted with CH ₂ Cl ₂ (3x). It was dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo. The crude product was purified by flash chromatography on SiO ₂ (eluent: Et ₂ O / MeOH 96: 4 to 92: 8). The chromadiols were obtained as a white solid.

1-chroman-2-yl-ethane-1,2-diol (3a);

• ¹ H NMR (400 MHz, CDCl _3): δ = 7:10 to 7:01 (m, 2H); 6.90-6.81 (t, J = 8.33 Hz, 1H); 6.81-6.74 (d, J = 8.33 Hz, 1H); 4.07-3.95 (m, 1H); 3.92-3.76 (m, 3H); 3.36-3.08 (br, OH); 2.88-2.72 (m, 2H); 2.16-2.08 (m, 1H); 1.91-1.77 (m, 1H); ¹³ C NMR (100 MHz, CDCl _3): δ = 154.27, 129.68, 127.35, 122.18, 120.61, 116.72, 76.42, 73.39, 63.48, 24.35, 23:32.

1-chroman-2-yl-ethane-1,2-diol (3b);

• ¹ H NMR (400 MHz, CDCl _3): δ = 7:12 to 7:01 (m, 2H); 6.89-6.81 (t, J = 7.46 Hz, 1H); 6.81-6.73 (d, J = 8.46 Hz, 1H); 4.10-3.96 (m, 1H); 3.92-3.77 (m, 3H); 3.04-2.64 (br, 4H); 2.17-2.07 (m, 1H); 2.16-2.08 (m, 1H); 1.92-1.78 (m, 1H). ¹³ C NMR (100 MHz, CDCl _3): δ = 154.29, 129.70, 127.38, 122.20, 120.65, 116.75, 76.56, 73.35, 63.48, 24.40, 23:36.

Mitsunobu inversion of chroman diols 3a and 3b to diols 3c and 3d - General rule:

Step 1: Chromanediol bis-4-nitrobenzoates:

Diisopropyl azo dicarboxylate (DIAD) (6.00 eq) was dissolved in THF (7.14 ml / mmol) and the solution cooled to -20 ° C under N ₂ . A solution of PPh ₃ (6.00 eq) in THF (7.14 ml / mmol) was added dropwise. A solution of the chromanediol 3a or 3b (1.00 eq) in THF (2.9 ml / mmol) was then added dropwise as well, followed by p-nitrobenzoic acid (6.00 eq) in THF (6 ml / mmol). After 5 h at -20 ° C was warmed to room temperature. The solvent was distilled off and MTBE was added to the remaining oil to precipitate PPh ₃ O. The combined organic phases were concentrated in vacuo and the crude products purified by flash chromatography on SiO ₂ (eluent: Et ₂ O / MeOH 20: 1 to 9 :1).

Step 2: Saponification of the bis-4-nitrobenzoate:

The diester 13c or 13d (1.00 eq) - dissolved in MeOH and NaOMe (95%, 3, 100 eq) - was added at room temperature. After stirring at RT for 16 h, the solvent was removed in vacuo. CH ₂ Cl ₂ was added followed by saturated NH ₄ Cl solution. After phase separation, the aqueous phase was extracted with CH ₂ Cl ₂ (3x). The combined organic phases were washed with H ₂ O and sat. NaCl Solution. After drying over Na ₂ SO ₄ and filtration, the solvent was removed. Flash chromatography on SiO ₂ (eluent: 100% MTBE to MTBE / MeOH 9: 1) afforded the chroman diols in 38% to 42% yield.

1-chroman-2-yl-ethane-1,2-diol bis (4-nitrobenzene ester) (13c);

• ¹ H NMR (400 MHz, CDCl _3): δ = 8:37 to 8:30 (m, 4H); 7.92-7.80 (m, 4H); 7.13 (dd, J = 9.28 Hz, 1.94 Hz, 1 H); 7.06 (d, J = 7.34 Hz, 1H); 6.93-6.83 (m, 2H); 5.84-5.75 (ddd, J = 8.63 Hz, 5.61 Hz, 3.45 Hz, 1H); 4.96 (dddd, J = 18.97 Hz, 18.91 Hz, 12.55 Hz, 6.36 Hz, 2H); 4.91-4.84 (d, J = 5.72 Hz, 2H); 4.46-4.39 (m, 1H); 3.02-2.77 (m, 2H); 2.16-1.90 (m, 2H).

1-chroman-2-yl-ethane-1,2-diol (3c);

• ¹ H NMR (400 MHz, CDCl _3): δ = 7:18 to 7:00 (m, 2H); 6.92-6.75 (m, 2H); 4.13-4.03 (m, 2H); 3.85-3.67 (m, 3H); 2.95-2.82 (m, 1H); 2.82-2.73 (m, 1H); 2.56-2.39 (br, 2 OH); 2.05-1.86 (m, 2H); ¹³ C NMR (100 MHz, _CDCl3).

Tosylation of Chromane Diols 3a to 3d - General Procedure

At room temperature, under N ₂ , pyridine (2.42 eq) was added to a solution of the chromanediol (1.00 eq) in CH ₂ Cl ₂ (3 ml / mmol). After cooling to 0 ° C, p-tosyl chloride (1.11 eq) - dissolved CH ₂ Cl ₂ (1 mL / mmol) - was added dropwise. The mixture was warmed to room temperature and stirred until complete reaction. The reaction was washed with sat. CuSO ₄ solution (3.7 ml / mmol) and stirred vigorously at room temperature. The phases were separated and then the aqueous phase extracted with CH ₂ Cl ₂ (3x). The combined organic phases were dried over Na ₂ SO ₄ . After distilling off the solvent was purified by flash chromatography on SiO ₂ (eluent: hexane / MTBE 6: 1 to 4: 1). The tosylates were obtained in 56% to 93% yield.

Toluene-4-sulfonic acid 2-chroman-2-yl-2-hydroxyethyl ester (12a);

• ¹ H NMR (400 MHz, CDCl _3): δ = 7.81 (d, J = 7.99 Hz, 2H); 7.34 (d, J = 7.99 Hz, 2H); 7.08-6.86 (m, 2H); 6.87-6.75 (m, 1H); 6.83 (dt, J = 7.73 Hz, 1.26 Hz, 1H); 6.66 (d, J = 8.15 Hz, 1H); 4.38 (dd, J = 10.54 Hz, 2.95 Hz, 1H); 4.25-4.18 (dd, J = 10.74 Hz, 5.62 Hz, 1H); 3.98-3.89 (m, 2H); 2.84-2.70 (m, 2H); 2.44 (s, 3H); 2.21-2.14 (m, 1H); 1.84-1.72 (m, 1H).

Toluene-4-sulfonic acid 2-chroman-2-yl-2-hydroxy-ethyl ester (12b);

• ¹ H NMR (400 MHz, CDCl _3): δ = 7.81 (d, J = 7.71 Hz, 2H); 7.34 (d, J = 8.48 Hz, 2H); 7.15-6.97 (m, 2H); 7.15-6.97 (m, 2H); 6.89-6.79 (m, 1H); 6.72-6.61 (d, J = 7.71 Hz, 1H); 4.42-4.36 (dd, 4.38 (dd, J = 10.79 Hz, 3.08 Hz, 1H); 4.25-4.19 (dd, J = 10.02 Hz, 6.16 Hz, 1H); 3.97-3.87 (m, 2H); 2.85-2.70 (m, 2H); 2.44 (s, 3H); 2.22-2.14 (m, 1H); 1.84-1.72 (m, 1H).

Toluene-4-sulfonic acid 2-chroman-2-yl-2-hydroxy-ethyl ester (12c);

• ¹ H NMR (400 MHz, CDCl _3): δ = 7.81 (d, J = 8.69 Hz, 2H); 7.33 (d, J = 8.07 Hz, 2H); 7.10-7.01 (m, 2H); 6.90-6.81 (m, 1H), 6.71 (d, J = 8.69 Hz, 1H); 4.25-4.20 (dd, J = 5.89 Hz, 1.57 Hz, 1H); 4.06-3.99 (m, 1H); 3.98-3.89 (m, 1H); 2.43 (s, 3H): 2.92-2.71 (m, 2H); 2.00-1.99 (m, 2H); ¹³ C NMR (100 MHz, CDCl3) (14): □ 154.07, 145.23, 132.70, 130.06, 129.76, 128.14, 127.41, 121.90, 120.96, 116.84, 76.83, 74.89, 71.29, 70.10, 24.67, 23.64, 21.79.

Preparation of Chroman Epoxides 1a to 1d from Tosylates - General Procedure:

Under N ₂ , NaOMe (95%, 1.10 eq) was added in small portions at room temperature to a solution of tosylate (1.00 eq) in isopropanol (1.15 ml / mmol). The mixture was stirred for 60 minutes and treated with a solution of acetic acid (0.13 eq) in isopropanol (0.2 ml / mmol). The reaction mixture was filtered over dicalite and the filter cake washed thoroughly with isopropanol. Distilling off the solvent yielded the pure chroman epoxides.

Preparation of the N-benzylamino-chroman alcohols 7a to 7d from the chroman epoxides 1a to 1d:

Benzylamine (5 eq) was dissolved in isopropanol (0.6 ml / mmol) and heated to reflux. The corresponding chroman epoxide (1.00 eq) - dissolved in isopropanol (2 ml / mmol) - was added dropwise over 2 h. After a further 2 h at reflux, the reaction mixture was slowly cooled to 0 ° C. The crystallization was initiated with isopropanol. The solids were isolated by filtration and dried in vacuo.

Coupling of Chroman Epoxides 1a to 1d to the N-Benzyl-Nebivolol Derivatives - General Procedure:

The corresponding chroman epoxides (1.10 eq) and N-benzylamino-alcohol (1.00 eq) were dissolved in isopropanol (3.6 ml / mmol) and heated under reflux until complete reaction. The solvent was removed and the crude product purified by flash chromatography on SiO ₂ (eluent: CH ₂ Cl ₂ / MeOH 15: 1). The products were obtained as a white solid in 89-100% yield.

General procedure for the debenzylation of the protected nebivolol derivatives 14:

N-Benzyl-Desfluoro Nebivolol 14 (1.00 eq) in THF / H ₂ O (6: 1) (5.6 ml / mmol) was treated with conc. HCl (1.12 eq), Pd / C (10%) and cyclohexene (10 eq) heated to reflux. Upon completion of the reaction, it was filtered through dicalite and the filter cake thoroughly washed with THF (3x). The filtrates were concentrated and the residue was added with EtOAc (2 mL / mmol) to facilitate crystallization of the hydrochlorides. The desfluoro-nebivolol hydrochloride salts were isolated in 72% to 95% yield as a white solid.

1-Chroman-2-yl-2- [2- (6-fluorochroman-2-yl) -2-hydroxy-ethylamino] -ethanol hydrochloride 15a ';

• ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.84 (br s, NH ₂ ); 7.09-7.03 (m, 2H); 6.95-6.87 (m, 2H); 6.85-6.79 (m, 1H); 6.78-6.73 (m, 2H); 5.99 (d, J = 5.6 Hz, OH); 5.81 (d, J = 5.6 Hz, OH); 4.16-4.08 (m, 1H); 4.07-3.96 (m, 2H); 3.95-3.88 (m, 1H); 3.42-3.34 (br, 1H); 3.28-3.13 (m, 2H); 3.12-3.02 (m, 1H); 2.88-2.65 (m, 4H); 2.18-2.09 (m, 1H); 1.98-1.89 (m, 1H); 1.84-1.64 (m, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 155.9 (d, ¹ J _CF = 236 Hz), 153.8, 150.5 (d, J = 1.2 Hz), 129.6, 127.0, 123.7 (d, J = 7.5 Hz), 122.2, 120.2, 117.4 (d, J = 8.2 Hz), 116.3, 115.3 (d, J = 22.5 Hz), 113.6 (d, J = 23.0 Hz), 77.0, 76.8, 67.6, 67.3, 50.0, 49.5 , 24.1, 23.4, 22.8, 22.2 ppm

2- (2-Chroman-2-yl-2-hydroxy-ethylamino-1- (6-fluorochroman-2-yl) -ethanol hydrochloride 15b ';

• ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.99-8.59 (br, NH ₂ ); 7.11-7.03 (m, 2H); 6.98-6.87 (m, 2H); 6.82 (t, J = 7.72 Hz, 1.29 Hz, 1H); 6.79-6.71 (m, 2H); 5.97 (d, J = 5.57 Hz, OH); 5.78 (d, J = 5.57 Hz, OH); 4.15-4.06 (m, 1H); 4.06-3.95 (m, 2H); 3.94-3.85 (m, 1H); 3.43-3.34 (br, 1H); 3.28-3.13 (m, 2H); 3.12-2.99 (m, 1H); 2.89-2.63 (m, 4H); 2.19-2.06 (m, 1H); 1.99-1.86 (m, 1H); 1.84-1.62 (m, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 155.89 (d, J = 235.78 Hz, CF), 153.86, 150.49, 129.60, 127.09, 123.71 (d, J = 8.49 Hz), 122.19, 120.26, 117.40 (d, J = 8.49 Hz), 116.32, 115.33 (d, J = 22.44 Hz), 113.68 (d, J = 23.04 Hz), 76.02, 76.79, 67.58, 67.33, 49.95, 49.48, 24.16, 23.44, 22.79, 22.21 ,

1-Chroman-2-yl-2 [2- (6-fluorochroman-2-yl) -2-hydroxy-ethylamino] -ethanol hydrochloride 15a '':

• ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.98-8.44 (br, NH.HCl); 7.12-7.02 (m, 2H); 7.00-6.86 (m, 2H); 6.86-6.66 (m, 3H); 6.08-5.88 (br, OH); 5.86-5.84 (br, OH); 4.17-4.06 (m, 1H); 4.06-3.95 (m, 2H); 3.94-3.84 (m, 1H); 3.34 (br, 1H); 3.28-3.12 (m, 3H); 3.05 (dd, J = 12.32 Hz, 9.93 Hz, 1H); 2.90-2.62 (m, 4H); 2.18-2.05 (m, 1H); 2.00-1.88 (m, 1H); 1.86-1.59 (m, 2H); ¹³ C NMR (400 MHz, DMSO-d ₆ ): □ 155.63 (d, J = 234.67 Hz, CF), 154.86, 154.27, 150.12 (d, J = 1.69 Hz), 129.54, 127.05, 123.79 (d, J = 6.94 Hz), 122.15, 120.15, 117.42 (d, J = 8.44 Hz), 117.38, 116.34, 115.38 (d, J = 22.34 Hz), 113.75 (d, J = 22.84 Hz), 77.11, 76.71, 67.55, 67.45, 49.92, 49.53, 24.09, 23.58, 22.57, 22.41.

1-Chroman-2-yl-2- [2- (6-fluorochroman-2-yl) -2-hydroxy-ethylamino] -ethanol hydrochloride 15b '':

• ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.84 (br s, NH ₂ ); 7.09-7.03 (m, 2H); 6.96-6.87 (m, 2H); 6.81 (dt, J = 7.4 Hz, 1.1 Hz, 1H); 6.79-6.73 (m, 2H); 6.00 (d, J = 5.6 Hz, OH); 5.97 (d, J = 5.6 Hz, OH); 4.16-4.09 (m, 1H); 4.07-3.98 (m, 2H); 3.93-3.86 (m, 1H); 3.38 (br s, 1H); 3.29-3.13 (m, 2H); 3.12-3.00 (m, 1H); 2.89-2.65 (m, 4H); 2.16-2.07 (m, 1H); 1.99-1.90 (m, 1H); 1.85-1.63 (m, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 156.0 (d, J = 236 Hz, CF), 154.2, 150.1 (d, J = 1.6 Hz), 129.5, 127.0, 123.8 (d, J = 7.5 Hz), 122.1, 120.0, 117.4 (d, J = 8.2 Hz), 116.3, 115.3 (d, J = 22.6 Hz), 113.7 (d, J = 23.2 Hz), 77.1, 76.7, 67.5, 67.3, 49.9, 49.5 , 24.1, 23.6, 22.5, 22.4.

1-Chroman-2-yl-2 [2- (chroman-2-yl-2-hydroxy-ethylamino] -ethanol hydrochloride 15a '':

• ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 9.01-8.52 (br, NH ₂ ); 7.18-7.01 (m, 4H); 6.94-6.67 (m, 4H); 5.97 (d, J = 5.62 Hz, OH); 5.78 (d, J = 5.87 Hz, OH); 4.20-4.07 (m, 1H); 4.07-3.96 (m, 2H); 3.96-3.82 (m, 1H); 3.29-3.14 (m, 2H); 3.34 (br, 1H); 3.14-2.94 (m, 1H); 2.89-2.65 (m, 4H); 2.20-2.04 (m, 1H); 1.99-1.89 (m, 1H); 1.86-1.64 (m, 2H); ¹³ C NMR (100 MHz, CDCl _3): δ = 154.27, 153.87, 129.60, 129.53, 127.09, 127.04, 122.20, 122.15, 120.26, 120.14, 116.34, 116.34, 77.02, 76.71, 67.60, 67.40, 49.96, 49.52, 24.08 , 23.43, 22.80, 22.55.

1-Chroman-2-yl-2- (2-chroman-2-yl) -2-hydroxy-ethylamino) -ethanol hydrochloride 15b '':

• ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.81 (br s, NH ₂ ); 7.09-7.04 (m, 4H); 6.85-6.79 (m, 2H); 6.78-6.74 (m, 2H); 5.99 (d, J = 5.6 Hz, OH); 5.79 (d, J = 5.6 Hz, OH); 4.16-4.08 (m, 1H); 4.07-3.97 (m, 2H); 3.95-3.88 (m, 1H); 3.43-3.35 (m, 1H); 3.29-3.14 (m, 2H); 3.12-3.02 (m, 1H); 2.88-2.65 (m, 4H); 2.18-2.09 (m, 1H); 1.98-1.90 (m, 1H); 1.85-1.65 (m, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 154.3, 153.9, 129.6, 129.5, 127.1, 127.0, 122.2, 122.1, 120.2, 120.1, 116.3 (x 2), 77.0, 76.7, 67.6, 67.4, 50.0 , 49.5, 24.1, 23.5, 22.8, 22.6.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0145067 [0002, 0002, 0010]
• US 4654326 [0002]
• EP 0334429 [0002, 0010]
• WO 96/19987 [0003]
• US 4654362 A [0005]
• EP 0334429 A1 [0005]
• WO 2004/041805 A1 [0005]
• WO 2006/016376 A1 [0005]
• WO 2007/083318 A1 [0005]
• WO 2006/025070 A2 [0005]
• WO 2008/010022 A2 [0005]
• WO 2008/064826 A2 [0005]
• WO 2008/064827 A2 [0005]
• WO 2009/082913 A1 [0005]
• CN 101463024 A [0005]
• WO 2010/049455 [0005, 0008, 0008, 0008]
• WO 2010/089764 A1 [0005]
• EP 14155300 [0008, 0056]
• US 4654362 [0010]
• WO 2011/091968 [0012]

Cited non-patent literature

• Mol. Pharmacol. 34 (1988), 843; J. Cardiovasc. Pharmacol. 11 (1988) 552 [0002]
• Clin. Drug Invest. 3 (1), 1991, 25-30 [0003]
• PGM Wuts, "Greene's Protective Groups in Organic Synthesis," 4th ed. (2006, Wiley; ISBN 978-0-471-69754-1; 5th edition June 2013 Wiley-Blackwell) [0020]
• Tsutomu Katsuki, K. Barry Sharpless: The first practical method for asymmetric epoxidation. In: Journal of the American Chemical Society. 102, No. 18, 1980, p. 5974-5976 [0022]
• Synthesis 2009, 1886-1896; Tetrahedron 2000, 56, 6339-6344 [0029]
• Tsutomu Katsuki, K. Barry Sharpless: The first practical method for asymmetric epoxidation. In: Journal of the American Chemical Society. 102, No. 18, 1980, p. 5974-5976 [0035]
• PGM Wuts, "Greene's Protective Groups in Organic Synthesis," 4th ed. (2006, Wiley; ISBN 978-0-471-69754-1; 5th edition June 2013 Wiley-Blackwell [0052]

Claims (10)

A process for the preparation of epoxides of the formula 1a to 1d,

comprising the steps i. Reaction of an E-allyl alcohol of the formula 2

to a dialcohol of formula 3a to 3d

and converting the primary alcohol of the dialcohols of the formula 3a to 3d into a leaving group and subsequent treatment with a base; or ii. Reaction of an epoxide of the formula 4a to 4d

wherein PG is a hydroxy-protecting group or H and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F, is by means of a conversion of the primary alcohol of the epoxides of the formula 4a to 4d in a leaving group, optionally deprotecting, and performing an intramolecular cyclization. The process of claim 1, wherein the dialkols of formula 3a and 3b are synthesized by Sharpless epoxidation of the E-allyl alcohol of formula 2 and opening of the epoxides formed thereby. The process of claim 1, wherein the dialkols of formula 3c and 3d are synthesized by reacting the E-allyl alcohol of formula 2 by Sharpless epoxidation and opening the resulting epoxides to the dialcohols of formula 3a and 3b and then inversion of the dialcohols of the formula 3a and 3b by means of a Mitsunobu inversion to form a diester and subsequent reduction of the diester to the desired dialcohols of the formula 3c and 3d. The process of claim 3, wherein the Mitsunobu reaction is carried out in the presence of 4-nitrobenzoic acid (PNB), the diesters of formula 13c and 13d

which are subsequently reduced to the desired dialcohols of the formula 3c and 3d, wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F. The process of any one of the preceding claims wherein the E-allyl alcohol of Formula 2 is prepared from a reduction of a propargyl alcohol of Formula 5

is synthesized, wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F. The process of claim 1 wherein the epoxide of formula 4a to 4d is prepared by asymmetric Sharpless epoxidation of the allyl alcohols of formula 6a and 6b

wherein PG is a hydroxy-protecting group or H, and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F. The process of claim 6, wherein the allyl alcohols of formula 6a and 6b are prepared by Wittig olefination of derivatives of chroman-2-ol of formula 9

be synthesized, wherein R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F. A process for the preparation of amino alcohols of the formula 7a to 7d,

by reacting the epoxides of formulas 1a to 1d, which are synthesized by a process according to any one of claims 1 to 7, with an amine of the formula H ₂ NP, wherein P is an amine protecting group and R is selected from the group of F, Cl , Br, I or H, in particular from the group of H or F. A process for the preparation of nebivolol derivatives of formula 15,

or their salts, in particular their hydrochlorides, where * denotes a stereocenter, which may have an E or Z configuration, and R is selected from the group of F, Cl, Br, I or H, in particular from the group of H or F. , is by means of a coupling reaction of a. in each case an epoxide selected from the group of the compounds represented by the formulas 1a to 1d,

which are synthesized by a method according to any one of claims 1 to 7, b. in each case with an aminal alcohol selected from the group of the compounds represented by those of the formulas 7a to 7d,

which are synthesized in particular by a process according to claim 8, wherein P is an amine-protecting group, and then removing the protective group, in particular by means of transfer hydrogenation. The method of any one of claims 1 to 9, wherein R is H.