Method for synthesizing nebivolol and intermediate compounds thereof

Abstract

To provide a method for preparing new nebivolol and its optical isomer in high efficiency at a low cost.SOLUTION: There is provided a method for preparing a racemic mixture consisting of equimolar amounts of a compound of formula VIIIa(R / R) and an enantiomer VIIIb(S / S) represented by following formulae, the method comprising: reducing a compound of following formula III by a selective catalytic hydrogenation to yield a compound of formula IV2 in cis-configuration; epoxidizing the compound of formula IV2 in cis-configuration in the presence of an epoxidizing reagent to yield an epoxide intermediate VI (compound VI is a racemate); and deprotecting the compound VI and carrying out a cyclization reaction to yield an intermediate compound.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for synthesizing a pharmaceutical product and an intermediate compound thereof. Specifically, the present invention relates to a method for synthesizing nebivolol, an intermediate compound thereof, and a method for preparing the intermediate compound. [Background technology]

[0002] Nebivolol hydrochloride, chemically named (+ / -)-di[2-(6-fluoro-dihydrobenzopyran-2-yl)-2-hydroxyethyl]amine (Formula I) hydrochloride, is a third-generation, highly selective beta-receptor blocker developed by Johnson & Johnson and also possesses vasodilatory effects. Nebivolol hydrochloride is primarily used to treat mild to moderate hypertension, angina pectoris, and congestive heart failure. Clinically used nebivolol hydrochloride is an equal mixture of dextrorotatory isomers (Formula Ia) and levorotatory isomers (Formula Ib), i.e., its racemate (Formula I). ​​The effect of nebivolol hydrochloride as a beta-receptor blocker is primarily due to the dextrorotatory isomer, while other effects are due to the presence of both dextrorotatory and levorotatory isomers.

[0003] The relative configuration of nebivolol is as follows:

[0004] [ka] Here, I(S * R * R * R * ) represents the racemate, which is a racemic mixture of equimolar amounts of D-nebivolol Ia (SRRR) and its enantiomer L-nebivolol Ib (RSSS) as shown below.

[0005] [ka]

[0006] Both the levorotatory and dextrorotatory isomers of nebivolol have important biological activities, with the levorotatory isomer having an endothelial cell-dependent vasodilatory effect and the dextrorotatory isomer having a strong β1 receptor-blocking effect. A mixture of the levorotatory and dextrorotatory isomers is currently used clinically, which synergizes the activities of the two isomers. In addition to the β1 receptor-blocking effect, nebivolol also has the unique advantage of selectively antagonizing β1 receptors by promoting NO release and resulting in vasodilation. Nebivolol does not affect β2 receptors and does not constrict bronchial or vascular smooth muscle. Therefore, in view of the important pharmacological value of nebivolol, developing a highly efficient, low-cost method for preparing nebivolol and its optical isomers that meets the requirements for industrialization would be of great economic and social benefit.

[0007] The molecular structure of nebivolol contains four chiral carbon atoms, as shown below, where the isomer S * R * R * R * is the clinically used nebivolol, which is expressed as a racemic mixture containing equimolar amounts of the D-isomer with absolute configuration SRRR and its enantiomeric L-isomer with absolute configuration RSSS.

[0008] [ka]

[0009] Nebivolol is structurally characterized by a particular symmetry. The left and right parts of the molecule each have a different arrangement of (6-fluoro-benzopyranyl)ethan-2-ol structural units. In the left part (part A), the hydroxyl group and the oxygen in the pyran ring are in cis configuration, while in the right part (part B), they are in trans configuration, and the units of the two parts are linked by a nitrogen atom.

[0010] In the prior art, the synthesis of nebivolol is primarily based on the symmetry of the molecule, with the A and B moieties synthesized separately and then coupled with benzylamine. After separation, purification, and deprotection, nebivolol is obtained.

[0011] Specifically, the existing methods for preparing nebivolol mainly include:

[0012] (1) Using a racemic intermediate as the starting material, left and right fragments having the relative configuration within the nebivolol molecule are constructed, respectively, and then cross-coupling reactions are carried out to prepare the desired product.

[0013] The key to this method is how to prepare the two fragments A and B in the desired configuration with high diastereomeric purity; otherwise, a mixture containing the above 10 isomers will be obtained after the coupling reaction.

[0014] [ka]

[0015] The intermediate compound obtained by coupling two fragments A and B with the desired configuration contains two pairs of diastereoisomers, which must be isolated by recrystallization to obtain the intermediate with the desired configuration.

[0016] [ka]

[0017] Janssen, European Patent No. 145067, reacts chromanaldehyde and trimethylsulfoxonium iodide in the presence of sodium hydride to give a pair of unequal diastereoisomers, namely, the epoxide intermediate M A (S * R * ) and M B (R * R *The following synthesis method is disclosed, which is characterized by obtaining an epoxide intermediate M A (S * R * ) and M B (R * R * ) can then be separated by chromatography to serve as a key intermediate for the synthesis of nebivolol, which can then be cross-coupled with benzylamide to afford mixtures of SRRR / RSSS and SRSS / RSRR.

[0018] [ka] These are then separated by repeated fractional crystallization and deprotected by hydrogenolysis to give S * R * R * R * -Nebivolol is obtained.

[0019] [ka]

[0020] Although the above-mentioned preparation method is currently widely used in industry, the main problem of this method is that the key intermediates need to be separated by column chromatography, which makes it expensive to use in large-scale production. Moreover, the reaction conditions for preparing epoxides from unstable chromanaldehydes are harsh, the yields are low, and the reagents used are expensive.

[0021] (2) Cyanide derivative method of International Publication No. WO2007 / 009143 (Chinese Patent No. 101243062) The method is carried out by reacting racemic chromanaldehyde with sodium bisulfite and sodium cyanide to give a nitrile alcohol intermediate, which is then separated by column chromatography to give a pair of cis- and trans-nitrile alcohol diastereomers.

[0022] [ka]

[0023] The cis-nitrile alcohol intermediate is acetylated and then converted by catalytic hydrogenation to the corresponding aldehyde, which is then hydrolyzed to give the corresponding aldol intermediate.

[0024] The trans-nitrile alcohol intermediate is then catalytically hydrogenated to the corresponding alcohol amine, which is reacted with benzoyl chloride to give the amide, which is subsequently reduced to give the benzylamine intermediate, which is finally condensed with the aldol intermediate to give crude nebivolol as a pair of diastereoisomers (four isomers). The crude nebivolol is then converted to a salt with hydrochloric acid. After repeated recrystallization from ethanol to remove the other pair of isomers, nebivolol racemate is obtained.

[0025] [ka]

[0026] The problems with this method are similar to those of the previously mentioned method, namely, the reaction conditions are harsh and column chromatography is required to separate the key intermediates, making it difficult to apply this method to large-scale industrial production.

[0027] (3) D-nebivolol and L-nebivolol are synthesized separately, and then the D- and L-isomers are mixed in equal amounts to obtain nebivolol racemate. Methods for synthesizing the optical isomers of nebivolol mainly include the following:

[0028] European Patent No. 0334429 and U.S. Patent No. 6,545,040 disclose the synthesis of L-nebivolol by resolving chromancarboxylic acids into the corresponding S-chromancarboxylic acids and R-chromancarboxylic acids using the following procedure:

[0029] [ka]

[0030] The above process is still according to Janssen, European Patent No. 145067. Although it uses optically pure chromancarboxylic acids obtained by chiral separation, the subsequent step of forming an epoxide intermediate using trimethylsulfoxonium iodide in the presence of sodium hydride still produces unequal amounts of two diastereoisomers, and therefore chromatographic separation is also required to obtain two optically pure epoxide intermediates.

[0031] In the literature (Tetrahedron, 56, pp. 6339-6344, 2000 and Chinese Journal of Organic Chemistry, 28, pp. 511-514, 2008), a synthesis using 1-(6-fluoro-benzopyranyl)ethane-1,2-diol as a key intermediate has been reported, in which a Sharpless asymmetric epoxidation reaction is utilized. The synthetic route is as follows:

[0032] [ka]

[0033] However, these methods require long synthetic routes, the intermediates are oily, column chromatography is required for separation and purification, and the reagents are expensive, making it difficult to apply these methods to industrial production.

[0034] Additionally, the following multi-step reaction also requires the conversion of the intermediate 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-diol to 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-diol to obtain the desired configuration of SRRR-nebivolol.

[0035] [ka]

[0036] CN Patent No. 1834093A and CN Patent No. 1978442 disclose a synthesis using glyceraldehyde acetonide as raw material, in which D-glyceraldehyde acetonide is reacted with 5-fluoro-2-hydroxyacetophenone using Kabbe condensation, followed by separation by column chromatography to obtain two chromanediol isomers (S,R) and (R,R).

[0037] [ka]

[0038] Optically active dextrorotatory SRRR-nebivolol can be obtained by selective sulfonylation of the two chromanediol (S,R) and (R,R) isomers with p-toluenesulfonyl chloride, respectively, followed by amination. [Prior art documents] [Patent documents]

[0039] [Patent Document 1] European Patent No. 145067 [Patent Document 2] International Publication No. WO2007 / 009143 [Patent Document 3] European Patent No. 0334429 [Patent Document 4] U.S. Patent No. 6,545,040 [Patent Document 5] Chinese Patent No. 1834093A [Patent Document 6] Chinese Patent No. 1978442 [Non-patent literature]

[0040] [Non-Patent Document 1] Tetrahedron, 56, pp. 6339-6344, 2000 [Non-patent document 2] Chinese Journal of Organic Chemistry 28, pp. 511-514, 2008 Summary of the Invention [Problem to be solved by the invention]

[0041] In summary, according to the prior art literature, it can be seen that the synthesis of nebivolol still has many technical shortcomings. For example, Janssen's method has a short synthetic route but requires the separation of two diastereomeric epoxide intermediates by preparative HPLC, while other methods often involve multiple synthetic steps and the problem of separating isomers. Therefore, it is necessary to develop a novel, highly efficient, and low-cost method for preparing nebivolol and its optical isomers that meets the requirements of industrialization. DETAILED DESCRIPTION OF THE INVENTION

[0042] Throughout this invention, the following terms have the meanings indicated below.

[0043] The term "alkyl", whether used alone or in combination with other groups, refers to a linear or branched monovalent saturated hydrocarbon radical consisting of carbon and hydrogen atoms. 1~6 "Alkyl" refers to straight or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and n-hexyl.

[0044] The term "alkylene," whether used alone or in combination with other groups, refers to a linear or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. 1~6"Alkylene" refers to straight or branched chain alkylene having 1 to 6 carbon atoms, for example, methylene, ethylene, and the like.

[0045] The term "alkoxy", whether used alone or in combination with other groups, refers to R A represents an —O— group, where R A represents alkyl as defined above. 1~6 "Alkoxy" is R A represents an —O— group, where R A is C as defined above 1~6 Represents alkyl.

[0046] "Halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0047] "Haloalkyl" refers to alkyl as defined above that is substituted with one or more halogens, such as trifluoromethyl.

[0048] "Nitro" refers to -NO2.

[0049] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms. 5~10 "Aryl" refers to an aryl having 5 to 10 carbon atoms. For example, C 5~10 Aryl can be phenyl or naphthyl.

[0050] "Substituted aryl" refers to aryl substituted with alkyl, alkoxy, halo, haloalkyl, or nitro, as defined above.

[0051] "Aralkyl" refers to an alkyl, as defined above, substituted with an aryl, as defined above.

[0052] "Substituted aralkyl" refers to aralkyl, as defined above, substituted with alkyl, alkoxy, halo, haloalkyl, or nitro.

[0053] "Aralkoxy" refers to an alkoxy, as defined above, substituted with an aryl, as defined above.

[0054] "Substituted aralkoxy" refers to aralkoxy substituted with alkyl, alkoxy, halo, haloalkyl, or nitro, as defined above.

[0055] In one embodiment, the present invention provides a compound of formula III

[0056] [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, allyl, methoxymethyl, benzyl, or -CHAr, and Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl, comprising the steps of: The following steps:

[0057] [ka] Step a): reacting a compound of formula XIV, wherein R is a hydroxy-protecting group as described above and X is a halogen, with 3-(trisubstituted silyl)-prop-2-yne-1-lithium to obtain a compound of formula XV, wherein each R, R, and R is independently selected from alkyl or aryl, e.g., methyl, tert-butyl, or phenyl; Step b): Removal of the silyl protecting group at the alkynyl terminus of a compound of formula XV to give a compound of formula XVI, wherein R is defined as above; Step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to obtain a compound of formula III, wherein R is defined as above; Optionally, step d): adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the compound of formula III obtained by step c), stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula III as a solid; The present invention provides a method comprising:

[0058] In a preferred embodiment, the reaction in step a) is carried out in an organic aprotic solvent such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, or toluene, and the reaction temperature is -100°C to 60°C.

[0059] In another preferred embodiment, the reaction of step b) is carried out in the presence of a base, an acid, or a fluorine-containing salt, preferably in the presence of a base, wherein the base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as NaOH, KOH, Na2CO3, and K2CO3, the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of any two or more thereof, and the reaction temperature is −100° C. to 80° C.

[0060] In another preferred embodiment, the base in step c) is selected from a metal hydride or an organic base, for example, NaNH or KNH; the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or a Grignard reagent, for example, MeMgX, EtMgX, BuMgX, i-PrMgX, wherein X is Br, I, or Cl; the solvent used in the reaction is an organic aprotic solvent, for example, tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof; and the reaction temperature is −100° C. to 100° C.

[0061] In another preferred embodiment, the organic solvent in step d) is an organic aprotic solvent, such as n-heptane, n-hexane, petroleum ether, diethyl ether, isopropyl ether, tert-butyl methyl ether, or a mixture of any two or more thereof.

[0062] In a further preferred embodiment, the reaction of step a) is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, or toluene; The reaction of step b) is carried out in the presence of a base, an acid, or a fluorine-containing salt, preferably in the presence of a base, wherein the base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as NaOH, KOH, Na2CO3, K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of any two or more thereof; and The base in step c) is selected from a metal hydride or an organic base, such as NaNH or KNH, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or a Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, where X is Br, I, or Cl, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof.

[0063] In the above method for preparing a compound of formula III, it will be understood by those skilled in the art that the reaction product of any one of steps a) to c) or d) can be used as a starting material for preparing a compound of formula III by carrying out the subsequent steps described above. For example, a compound of formula (XV) can be used as a starting material for preparing a compound of formula III by carrying out the above-mentioned steps b) to c) or d), or a compound of formula (XVI) can be used as a starting material for preparing a compound of formula III by carrying out the above-mentioned step c) or d).

[0064] In another aspect, the present invention provides a compound of formula III

[0065] [ka] wherein R is a hydroxy protecting group selected from an alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, allyl, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl.

[0066] In another embodiment, the present invention provides racemic nebivolol of formula I

[0067] [ka] [where I(S * R * R * R * ) represents the racemic form, which has the following configuration:

[0068] [ka] and its enantiomer L-nebivolol Ib (RSSS) in equimolar amounts. 1. A method for preparing The following steps: 1) reducing a compound of formula III with a metal complex hydride to obtain a compound of formula IV1 in the trans configuration; Optionally, the following step: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV1, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV1 as a solid. [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. and,

[0069] 2) reducing the compound of formula III by selective catalytic hydrogenation to obtain the compound of formula IV2 in the cis configuration; Optionally, the following step: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV2, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV2 as a solid. [ka] [wherein R is defined as in 1) above] and,

[0070] 3) epoxidizing the compound of formula IV1 in the trans configuration and the compound of formula IV2 in the cis configuration in the presence of an epoxidizing reagent to obtain epoxide intermediates V and VI, respectively. wherein R is defined as above.

[0071] [ka] wherein compound V is a racemate, which is a mixture of equimolar amounts of a compound of formula Va and enantiomer Vb

[0072] [ka] It is a racemic mixture consisting of V(2R * ,3R * ) and

[0073] [ka] wherein compound VI is racemic, which is a mixture of equimolar amounts of the compound of formula VIa and the enantiomer VIb

[0074] [ka] It is a racemic mixture consisting of VI(2R * ,3S * ), and, 4) Deprotection of the compound of formula V and the compound of formula VI, followed by cyclization, to give the compound of formula VII(S * / R * ) and formula VIII(R * / R * ) a step of obtaining each of the intermediate compounds wherein R is defined as above.

[0075] [ka] Here, VII(S * / R* ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S)

[0076] [ka] is a racemic mixture consisting of

[0077] [ka] where VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S)

[0078] [ka] is a racemic mixture consisting of and, 5) Sulfonylation of the compounds of formula VII and formula VIII with a sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, and X is halogen) in the presence of a catalyst and a base to give compounds IX (S * / R * ) and X(R * / R * ) respectively

[0079] [ka] Here, IX(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula IXa (S / R) and the enantiomer IXb (R / S)

[0080] [ka] is a racemic mixture consisting of

[0081] [ka] where X(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula Xa(R / R) and the enantiomer Xb(S / S)

[0082] [ka] is a racemic mixture consisting of and, 6) reacting a compound of formula IX or X with benzylamine to effect alkylation of the amine to give the corresponding compound XI or XII.

[0083] [ka] Here, XI(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIa (S / R) and the enantiomer XIb (R / S)

[0084] [ka] is a racemic mixture consisting of

[0085] [ka] where XII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIIa (R / R) and the enantiomer XIIb (S / S)

[0086] [ka] is a racemic mixture consisting of and, 7) Under basic conditions, intermediate compound IX(S * / R * ) and XII(R * / R *), or intermediate compound X(R * / R * ) and XI(S * / R * ) to carry out a cross-coupling reaction to give compound XIII(S * R * R * R * ) and XIII'(S * R * S * S * ) to obtain wherein R″ is defined as M above.

[0087] [ka] Here, XIII(S * R * R * R * ) is a racemate, which is composed of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS)

[0088] [ka] is a racemic mixture consisting of XIII'(S * R * S * S * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIII'a (SRSS) and the enantiomer XIII'b (RSRR)

[0089] [ka] is a racemic mixture consisting of and, 8) Forming a salt of a mixture of compounds of formula XIII and formula XIII' and purifying it by recrystallization to obtain isomer XIII' (S * R * S * S * ) was removed, and intermediate compound XIII (S * R *R * R * ) and 9) Intermediate compound XIII(S * R * R * R * ) to obtain the racemic nebivolol of formula I.

[0090] [ka] Here, I(S * R * R * R * ) is a racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Ia (SRRR) and the enantiomer Ib (RSSS), and The present invention provides a method comprising:

[0091] In one embodiment, in step 1), the metal complex hydride used as the reducing agent is LiAlH or sodium bis(2-methoxyethoxy)aluminum dihydride, the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof, and the reaction temperature is -100°C to 60°C.

[0092] In one embodiment, in step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst.

[0093] In one embodiment, in step 3), the epoxidation of the compound of formula IV1 in a trans configuration or the compound of formula IV2 in a cis configuration can be carried out by using an epoxidation method commonly used in the art. For example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac) and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO). The solvent used in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof. The reaction temperature is -50°C to 50°C.

[0094] In one embodiment, in step 4), the deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and the cyclization is carried out in the presence of a base, where the catalyst used in the hydrogenolysis is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, or Pd, and the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, such as NaOH, KOH, KCO, NaOMe, and DBU, or the deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product.

[0095] In some embodiments, in step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and no catalyst is used in the reaction or an appropriate amount of an acylation catalyst is used, and the catalyst is dialkyltin oxide, DMAP, For example, the bases used in the reaction may be conventional organic bases such as pyridine, organic tertiary amines such as triethylamine or diisopropylethylamine, the solvent used in the reaction may be an organic aprotic solvent such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof, and the reaction temperature is -50°C to 50°C.

[0096] In one embodiment, in step 6), the alkylation of amine is carried out by reacting benzylamine with a corresponding sulfonate, the molar ratio of benzylamine to the corresponding sulfonate substrate used is 1 / 1 to 10 / 1, the solvent used in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof, and the reaction temperature is −25° C. to 150° C.

[0097] In one embodiment, in step 7), the base used in the cross-coupling reaction can be selected from inorganic bases such as KCO, NaCO, or organic tertiary amines such as triethylamine or diisopropylethylamine; the solvent used in the reaction is an organic protic solvent such as ethanol, propanol, or isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; and the reaction temperature is −25° C. to 150° C.

[0098] In one embodiment, in step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.

[0099] In a preferred embodiment, in step 1), the metal complex hydride used as the reducing agent is LiAlH or sodium bis(2-methoxyethoxy)aluminum dihydride, and the solvent used in the reaction is an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof; In step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst; In step 3), the epoxidation of the compound of formula IV1 in trans configuration or the compound of formula IV2 in cis configuration can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac) and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, toluene, or a mixture of any two or more thereof; In step 4), deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl-protecting group, and cyclization is carried out in the presence of a base, the catalyst used in hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, for example, NaOH, KOH, K2CO3, NaOMe, DBU, or deprotection and cyclization can be carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl-protecting group and cyclize, thereby directly obtaining the cyclized product; In step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, or o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride; no catalyst is used in the reaction or an appropriate amount of an acylation catalyst is used, and the catalyst can be dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolan; the base used in the reaction can be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine; the solvent in the reaction can be an organic aprotic solvent, for example, methylene dichloride, chloroform, tetrahydrofuran, methyltetrahydrofuran, pyridine, toluene, acetonitrile, ethyl acetate, DMF, DMA, or a mixture of any two or more thereof; In step 6), the alkylation of the amine is carried out by reacting benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 7), the base used in the cross-coupling reaction can be selected from inorganic bases such as K2CO3, Na2CO3, or organic tertiary amines such as triethylamine or diisopropylethylamine; the solvent in the reaction is an organic protic solvent such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; and In step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.

[0100] It will be understood by those skilled in the art that in the above-described method for preparing the compound of formula I, the reaction product of any one of steps 1) to 9) can be used as a starting material for carrying out the subsequent steps described above to prepare the compound of formula I. For example, the compounds of formula IV1 and formula IV2 can be used as starting materials for carrying out the above-described steps 2) to 9) to obtain the racemic nebivolol of formula I, or the compounds of formula IX and formula XII can be used as starting materials for carrying out the above-described steps 7) to 9) to obtain the racemic nebivolol of formula I.

[0101] In another embodiment, the present invention provides a compound of formula IV1

[0102] [ka] wherein R is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. 1. A method for preparing The following steps: reducing the compound of formula III with a metal complex hydride to obtain a compound of formula IV1; and optionally, adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV1, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV1 as a solid.

[0103] [ka] wherein R is defined as above. and The present invention provides a method comprising:

[0104] In a preferred embodiment, in the above method, the metal complex hydride used as the reducing agent is LiAlH or sodium bis(2-methoxyethoxy)aluminum dihydride, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof.

[0105] In another embodiment, the present invention provides a compound of formula IV2

[0106] [ka] wherein R is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. 1. A method for preparing The following steps: reducing the compound of formula III by selective catalytic hydrogenation to obtain a compound of formula IV2 in the cis configuration; and optionally, adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV2, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV2 as a solid.

[0107] [ka] wherein R is defined as above. and The present invention provides a method comprising:

[0108] In a preferred embodiment, in the above process, the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst.

[0109] In another embodiment, the present invention provides a compound of formula VII(S * / R * ) compounds

[0110] [ka] [where VII(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S)

[0111] [ka] a racemic mixture consisting of 1. A method for preparing The following steps: 3) Compound of formula IV1 in the trans configuration

[0112] [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl, although, as an example, R shown in the formula below is represented by benzyl (Bn). in the presence of an epoxidizing reagent to obtain an epoxide intermediate V.

[0113] [ka] wherein compound V is a racemate, which is a mixture of equimolar amounts of a compound of formula Va and enantiomer Vb

[0114] [ka] It is a racemic mixture consisting of V(2R * ,3R * ), and, 4) Formula V(2R * ,3R * ) is deprotected and then subjected to a cyclization reaction to give a compound of formula VII(S * / R * ) a step of obtaining an intermediate compound of [wherein R is defined as above, but as an example, R shown in the formula below is represented by benzyl (Bn)]

[0115] [ka] Here, VII(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S)

[0116] [ka] is a racemic mixture consisting of and The present invention provides a method comprising:

[0117] In a preferred embodiment, the reaction conditions, solvents, etc. in steps 3) and 4) are as described above.

[0118] In another embodiment, the present invention provides a compound of formula VIII (R * / R * ) compounds

[0119] [ka] [In the formula, VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S)

[0120] [ka] a racemic mixture consisting of 1. A method for preparing The following steps: 3) Compound of formula IV2 in cis configuration

[0121] [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl, although, as an example, R shown in the formula below is represented by benzyl (Bn). in the presence of an epoxidizing reagent to obtain an epoxide intermediate VI.

[0122] [ka] wherein compound VI is racemic, which is a mixture of equimolar amounts of the compound of formula VIa and the enantiomer VIb

[0123] [ka] It is a racemic mixture consisting of VI(2R * ,3S * ), and, 4) Equation VI(2R * ,3S * ) is deprotected, followed by cyclization to give a compound of formula VIII (R * / R * ) a step of obtaining an intermediate compound of [wherein R is defined as above, but as an example, R shown in the formula below is represented by benzyl (Bn)]

[0124] [ka] where VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S)

[0125] [ka] is a racemic mixture consisting of and The present invention provides a method comprising:

[0126] In a preferred embodiment, the reaction conditions, solvents, etc. in steps 3) and 4) are as described above.

[0127] In another embodiment, the present invention provides racemic nebivolol of formula I

[0128] [ka] [where I(S * R * R * R * ) represents the racemic form, which has the following configuration:

[0129] [ka] and its enantiomer L-nebivolol Ib (RSSS) in equimolar amounts. 1. A method for preparing The following steps a) to c) or d) and steps 1) to 9):

[0130] [ka] Step a): reacting a compound of formula XIV with 3-(trisubstituted silyl)-prop-2-yne-1-lithium to obtain a compound of formula XV, wherein each R, R, and R is independently selected from alkyl or aryl, e.g., methyl, tert-butyl, or phenyl; R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or —CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl; and X is halogen. Step b): Removal of the silyl protecting group at the alkynyl terminus of a compound of formula XV to give a compound of formula XVI, wherein R is defined as above; Step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to obtain a compound of formula III, wherein R is defined as above; Optionally, step d): adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the compound of formula III obtained by step c), stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula III as a solid; Step 1): reducing a compound of formula III with a metal complex hydride to obtain a compound of formula IV1 in a trans configuration, and optionally the following step: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV1, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV1 as a solid.

[0131] [ka] wherein R is defined as above. and, Step 2): reducing the compound of formula III by selective catalytic hydrogenation to obtain a compound of formula IV2 in the cis configuration, and optionally the following step: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV2, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV2 as a solid.

[0132] [ka] wherein R is defined as above. and, Step 3): epoxidizing the compound of formula IV1 in the trans configuration and the compound of formula IV2 in the cis configuration in the presence of an epoxidizing reagent to obtain epoxide intermediates V and VI, respectively. wherein R is defined as above.

[0133] [ka] wherein compound V is a racemate, which is a mixture of equimolar amounts of a compound of formula Va and enantiomer Vb

[0134] [ka] It is a racemic mixture consisting of V(2R * ,3R * ) and

[0135] [ka] wherein compound VI is racemic, which is a mixture of equimolar amounts of the compound of formula VIa and the enantiomer VIb

[0136] [ka] It is a racemic mixture consisting of VI(2R * ,3S * ) and, Step 4): The compound of formula V and the compound of formula VI are deprotected, followed by a cyclization reaction to give the compound of formula VII(S * / R * ) and formula VIII(R * / R * ) a step of obtaining each of the intermediate compounds wherein R is defined as above.

[0137] [ka] Here, VII(S * / R* ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S)

[0138] [ka] is a racemic mixture consisting of

[0139] [ka] where VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S)

[0140] [ka] is a racemic mixture consisting of and, Step 5): The compounds of formula VII and formula VIII are sulfonylated with a sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, and X is halogen) in the presence of a catalyst and a base to give compounds IX (S * / R * ) and X(R * / R * ) respectively

[0141] [ka] Here, IX(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula IXa (S / R) and the enantiomer IXb (R / S)

[0142] [ka] is a racemic mixture consisting of

[0143] [ka] where X(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula Xa(R / R) and the enantiomer Xb(S / S)

[0144] [ka] is a racemic mixture consisting of and, Step 6): Reacting a compound of formula IX or X with benzylamine to alkylate the amine to obtain the corresponding compound XI or XII.

[0145] [ka] Here, XI(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIa (S / R) and the enantiomer XIb (R / S)

[0146] [ka] is a racemic mixture consisting of

[0147] [ka] where XII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIIa (R / R) and the enantiomer XIIb (S / S)

[0148] [ka] is a racemic mixture consisting of and, Step 7): Under basic conditions, intermediate compound IX (S * / R * ) and XII(R* / R * ), or intermediate compound X(R * / R * ) and XI(S * / R * ) to carry out a cross-coupling reaction to give compound XIII(S * R * R * R * ) and XIII'(S * R * S * S * ) to obtain wherein R″ is defined as M above.

[0149] [ka] JPEG0007744945000081.jpg49155Here, XIII(S * R * R * R *) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS)

[0150] [ka] is a racemic mixture consisting of XIII'(S * R * S * S * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIII'a (SRSS) and the enantiomer XIII'b (RSRR)

[0151] [ka] is a racemic mixture consisting of and, Step 8): Form a salt of a mixture of compounds of formula XIII and formula XIII' and purify it by recrystallization to obtain isomer XIII' (S * R * S *S * ) was removed, and intermediate compound XIII (S * R * R * R * ) and Step 9): Deprotecting intermediate compound XIII to obtain racemic nebivolol of formula I

[0152] [ka] Here, I(S * R * R * R * ) is a racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Ia (SRRR) and the enantiomer Ib (RSSS), and The present invention provides a method comprising:

[0153] For this method of preparing compounds of formula I, the reaction conditions, solvents, and reagents used in steps a) to c) and steps 1) to 9) are as described above.

[0154] In a further preferred embodiment, in step a), the reaction is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, or toluene, In step b), the reaction is carried out in the presence of a base, an acid, or a fluorine-containing salt, preferably in the presence of a base, wherein the base is selected from alkali metal or alkaline earth metal hydroxides or carbonates, such as NaOH, KOH, Na2CO3, K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of any two or more thereof; In step c), the base is selected from a metal hydride or an organic base, such as NaNH or KNH, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or a Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, where X is Br, I, or Cl, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof; In step 1), the metal complex hydride used as a reducing agent is LiAlH or sodium dihydride bis(2-methoxyethoxy)aluminum, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof; In step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst; In step 3), the epoxidation of the compound of formula IV1 in trans configuration or the compound of formula IV2 in cis configuration can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac) and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof; In step 4), deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl-protecting group, and cyclization is carried out in the presence of a base, the catalyst used in hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, for example, NaOH, KOH, K2CO3, NaOMe, DBU, or deprotection and cyclization can be carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl-protecting group and cyclize, thereby directly obtaining the cyclized product; In step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride; no catalyst is used in the reaction or an appropriate amount of an acylation catalyst is used, and the catalyst can be dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolan; the base used in the reaction can be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine; the solvent in the reaction can be an organic aprotic solvent, for example, methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 6), the alkylation of the amine is carried out by reacting benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 7), the base used in the cross-coupling reaction can be selected from inorganic bases such as K2CO3, Na2CO3, or organic tertiary amines such as triethylamine or diisopropylethylamine; the solvent in the reaction is an organic protic solvent such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; and In step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.

[0155] It will be understood by those skilled in the art that in the above-described method for preparing a compound of formula I, the reaction product of any one of steps a) to 9) can be used as a starting material for carrying out the subsequent steps described above to prepare a compound of formula I. For example, a compound of formula XV can be used as a starting material for carrying out the above-described steps b) to 9) to obtain racemic nebivolol of formula I, or a compound of formula XVI can be used as a starting material for carrying out the above-described steps c) to 9) to obtain racemic nebivolol of formula I.

[0156] In another embodiment, the present invention provides D-nebivolol (formula Ia)

[0157] [ka] 1. A method for preparing The following steps: 3') asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to obtain intermediate compounds Va and VIa, respectively wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl.

[0158] [ka] and, 4') Deprotection and subsequent cyclization of intermediate compounds Va and VIa to obtain intermediate compounds VIIa and VIIIa, respectively. wherein R is defined as above.

[0159] [ka] and, 5') sulfonation of intermediate compounds VIIa and VIIIa with a sulfonyl halide of formula M-SO2X, in the presence of a catalyst and a base, where M is alkyl or substituted or unsubstituted aryl and X is halogen, to give intermediate compounds IXa and Xa.

[0160] [ka] and, 6') reacting intermediate compound IXa or intermediate compound Xa with benzylamine to alkylate the amine, thereby obtaining the corresponding compound XIa or XIIa.

[0161] [ka] and, 7') A step of cross-coupling intermediate compounds IXa and XIIa, or intermediate compounds Xa and XIa, under basic conditions to obtain intermediate compound XIIIa. wherein Ar' is defined as M above.

[0162] [ka] and, Optionally, converting intermediate compound XIIIa into its hydrochloride salt; 8') Deprotecting intermediate compound XIIIa to obtain D-nebivolol (formula Ia)

[0163] [ka] or converting the hydrochloride salt of intermediate compound XIIIa into the free form of intermediate compound XIIIa by neutralizing it with a base, followed by deprotection to obtain D-nebivolol (formula Ia). The present invention provides a method comprising:

[0164] In another embodiment, the present invention provides L-nebivolol (formula Ib)

[0165] [ka] 1. A method for preparing The following steps: 3") Asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to obtain intermediate compounds Vb and VIb, respectively. wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl.

[0166] [ka] and, 4") Deprotection and subsequent cyclization of intermediate compounds Vb and VIb to give intermediate compounds VIIb and VIIIb. wherein R is defined as above.

[0167] [ka] and, 5") sulfonation of intermediate compounds VIIb and VIIIb with a sulfonyl halide of formula M-SO2X, where M is alkyl or substituted or unsubstituted aryl, and X is halogen, in the presence of a catalyst and a base to obtain intermediate compounds IXb and Xb.

[0168] [ka] and, 6") A step of reacting intermediate compound IXb or intermediate compound Xb with benzylamine to alkylate the amine, thereby obtaining intermediate compound XIb or XIIb.

[0169] [ka] and, 7") A step of cross-coupling intermediate compounds IXb and XIIb, or intermediate compounds Xb and XIb, under basic conditions to obtain intermediate compound XIIIb. wherein Ar' is defined as M above.

[0170] [ka] and, Optionally, converting intermediate compound XIIIb into its hydrochloride salt; 8") Deprotection of intermediate compound XIIIb to obtain L-nebivolol (formula Ib)

[0171] [ka] or converting the hydrochloride salt of intermediate compound XIIIb into the free form of intermediate compound XIIIb by neutralizing with a base, followed by deprotection to obtain L-nebivolol (formula Ib). The present invention provides a method comprising:

[0172] In an embodiment for preparing the compound of formula Ia, in step 3'), Sharpless asymmetric epoxidation is used, the chiral catalyst used in the reaction is D-(-)-diethyl tartrate or D-(-)-diisopropyl tartrate, the reagent used in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide, or cumene hydroperoxide, the solvent used in the reaction is methylene dichloride, 3A or 4A molecular sieves are added to the reaction system, and the reaction temperature is -45°C to 50°C.

[0173] In an embodiment for preparing the compound of Formula Ib, in step 3", Sharpless asymmetric epoxidation is used, the chiral catalyst used in the reaction is diethyl L-(+)-tartrate or diisopropyl L-(+)-tartrate, the reagent used in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide, or cumene hydroperoxide, the solvent used in the reaction is methylene dichloride, 3A or 4A molecular sieves are added to the reaction system, and the reaction temperature is -45°C to 50°C.

[0174] In the method for preparing the compound of Formula Ia or Ib, in step 4') or step 4", deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization is carried out in the presence of a base, where the catalyst used in hydrogenolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product.

[0175] In the method for preparing the compound of formula Ia or Ib, in step 5') or step 5", the sulfonyl halide used in the sulfonylation can be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or an alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and the reaction can be either without a catalyst or with an acylation catalyst, and the catalyst used can be a dialkylsulfonyl chloride. The base used in the reaction can be a conventional organic base, such as pyridine, an organic tertiary amine, such as triethylamine or diisopropylethylamine, the solvent in the reaction can be an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof, and the reaction temperature is −5 to 50° C.

[0176] In the method for preparing the compound of formula Ia or Ib, in step 6') or step 6", the alkylation of amine is carried out by reacting benzylamine with the corresponding sulfonate, the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof, and the reaction temperature is -25°C to 150°C.

[0177] In the method for preparing a compound of Formula Ia or Ib, in step 7') or step 7", the base used in the cross-coupling reaction can be selected from inorganic bases such as K2CO3, Na2CO3, or organic tertiary amines such as triethylamine or diisopropylethylamine, the solvent in the reaction is an organic protic solvent such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents, and the reaction temperature is -25°C to 150°C.

[0178] In the method for preparing a compound of formula Ia or Ib, in step 8') or step 8", the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.

[0179] In certain embodiments, the step of converting intermediate compound XIIIa or intermediate compound XIIIb to their hydrochloride salts is carried out by adding hydrochloric acid, for example 1N hydrochloric acid, to the intermediate compound, followed by crystallization and filtration to obtain the hydrochloride salt as a solid.

[0180] In a preferred embodiment of preparing a compound of formula Ia or formula Ib, in step 4') or step 4", deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization is carried out in the presence of a base, the catalyst used in hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, for example, NaOH, KOH, K2CO3, NaOMe, DBU, or deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product; In step 5') or step 5", the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride; the catalyst used in the reaction can be dialkyltin oxide, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolan; the base used in the reaction can be a conventional organic base, such as pyridine, an organic tertiary amine, such as triethylamine or diisopropylethylamine; the solvent in the reaction can be an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 6') or step 6", alkylation of amine is carried out by reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 7') or step 7", the base used in the cross-coupling reaction can be selected from inorganic bases such as K2CO3, Na2CO3, or organic tertiary amines such as triethylamine or diisopropylethylamine, and the solvent used in the reaction is an organic protic solvent such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; In step 8') or step 8", the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, or Pd, and the solvent used in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol.

[0181] In certain embodiments, the step of converting intermediate compound XIIIa or intermediate compound XIIIb to their hydrochloride salts is carried out by adding hydrochloric acid, for example 1N hydrochloric acid, to the intermediate compound, followed by crystallization and filtration to obtain the hydrochloride salt as a solid.

[0182] Those skilled in the art will appreciate that in the above-described methods for preparing compounds of Formula Ia or Formula Ib, the reaction product of any one of the above steps can be used as a starting material for preparing compounds of Formula Ia or Formula Ib by carrying out the subsequent steps described above. For example, compounds of Formula IXa and Formula XIIa can be used as starting materials for obtaining D-nebivolol of Formula Ia by carrying out steps 7') to 8') described above, or compounds of Formula IXb and Formula XIIb can be used as starting materials for obtaining L-nebivolol of Formula Ib by carrying out steps 7" to 8" described above.

[0183] In another embodiment, the present invention also provides a mixture of D-nebivolol (formula Ia) and L-nebivolol (formula Ib) in any proportion.

[0184] [ka] And, D-nebivolol (formula Ia) and L-nebivolol (formula Ib) are provided as mixtures prepared according to the methods described above.

[0185] In another aspect, the present invention also provides a method for preparing a mixture of D-nebivolol (formula Ia) and L-nebivolol (formula Ib) in any ratio, comprising: (1) preparing D-nebivolol (formula Ia) and L-nebivolol (formula Ib) according to the methods described in steps 3') to 8') and steps 3" to 8") above, and mixing them in any ratio; or (2) preparing the hydrochloride salts of intermediate compounds XIIIa and XIIIb according to the methods described in steps 3') to 7') and steps 3" to 7") above, and mixing them in any ratio, neutralizing with a base, and deprotecting the resulting mixture according to the method described in step 8'); or (3) preparing the hydrochloride of intermediate compound XIIIa and the hydrochloride of intermediate compound XIIIb according to the methods described in steps 3') to 7') and steps 3" to 7") above, respectively, neutralizing them with a base to obtain free intermediate compound XIIIa and free intermediate compound XIIIb, respectively, mixing the two free intermediate compounds in any ratio, and deprotecting the resulting mixture according to the method described in step 8'). The present invention provides a method comprising:

[0186] In another embodiment, the present invention provides a compound of formula IV1'

[0187] [ka] [In the formula, R a is hydrogen, or R a is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. to provide.

[0188] In another embodiment, the present invention provides a compound of formula IV2'

[0189] [ka] [In the formula, R b is hydrogen, or R b is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. to provide.

[0190] In another embodiment, the present invention provides a compound of formula V'(2R * ,3R * ) compounds

[0191] [ka] [In the formula, R c is hydrogen, or R c is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or —CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl; Here, compound V' is a racemate, and its relative configuration is V'(2R * ,3R * ), which is represented by equimolar amounts of Va' (2R,3R) and enantiomer Vb' (2S,3S), e.g., R c A compound having the formula:

[0192] [ka] a racemic mixture consisting of to provide.

[0193] In another embodiment, the present invention provides a compound of formula VI'(2R * ,3S * ) compounds

[0194] [ka] [In the formula, R d is hydrogen, or R dis a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or —CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl; Here, compound VI' is a racemate, and its relative configuration is VI'(2R * ,3S * ), which is represented by equimolar amounts of VIa' (2R,3S) and enantiomer VIb' (2S,3R), e.g., R d A compound having the formula:

[0195] [ka] a racemic mixture consisting of to provide.

[0196] In another embodiment, the present invention provides a compound of formula XI'

[0197] [ka] wherein R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10 aralkoxycarbonyl, for example, substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl] to provide.

[0198] In another embodiment, the present invention provides a compound of formula XII'

[0199] [ka] wherein R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10aralkoxycarbonyl, for example, substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl] to provide.

[0200] In another embodiment, the present invention provides a compound of formula XVI'

[0201] [ka] [In the formula, R e is hydrogen, or R e is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl, benzoyl where the phenyl ring has one or more substituents, or silyl protecting groups, such as t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl. to provide.

[0202] In one embodiment, the present invention also provides the following compounds for use in the synthesis of nebivolol: 1-benzyloxy-2-bromomethyl-4-fluorobenzene, 4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane, 1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene, 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yn-1-ol, trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol, (2R * ,3R * )-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2S *)-3,4-dihydro-2H-benzopyran-2-yl]-(1R * )-1,2-ethylene glycol, cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol, (2R * ,3S * )-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2R * )-3,4-dihydro-2H-benzopyran-2-yl]-(1R * )-1,2-ethylene glycol, (S * ,R * )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R * ,R * )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, (R * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, (2R,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2S,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2R,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2S,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol, 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol, 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol, 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol, (S,R)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R,R)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R,S)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, or A specific compound selected from (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol is provided. [Example]

[0203] The method of the present invention is further illustrated by the following examples, which are provided to aid in further understanding of the invention and are not intended to limit the scope of the invention in any manner.

[0204] The abbreviations used in this invention have the following meanings: Abbreviation: Boc tert-butyloxycarbonyl DEAD Diethyl azodicarboxylate DIPEA Diisopropylethylamine DMF Dimethylformamide DMA Dimethylacetamide EtOAc ethyl acetate TBAF Tetrabutylammonium Fluoride THF tetrahydrofuran TLC thin layer chromatography t-Bu(Me)2Si tert-butyldimethylsilyl TBS tert-butyldimethylsilyl TBSCl tert-butyldimethylchlorosilane

[0205] [Example 1] Preparation of 1-benzyloxy-2-bromomethyl-4-fluorobenzene (compound XIV, where R is benzyl)

[0206] [ka] The starting material used in this example, 2-benzyloxy-5-fluorobenzene-methanol, can be prepared from the known compound 2-hydroxy-5-fluorobenzenemethanol (Medicinal Chemistry Letters, 2010, Vol. 1, No. 7, pp. 321-325; References, Bioorganic & Medicinal Chemistry, 2006, Vol. 14, No. 6, pp. 2022-2031).

[0207] 5.14 g (22 mmol) of 2-benzyloxy-5-fluorobenzene-methanol was dissolved in 180 mL of anhydrous diethyl ether, and a solution of PBr3 (2.3 mL, 24.4 mmol) in 20 mL of anhydrous diethyl ether was added dropwise thereto at 0 °C. The temperature was allowed to warm to room temperature, and the reaction was carried out for 2 hours. TLC showed that the reaction was complete.

[0208] Workup (post-treatment): 50 mL of water was added. After the appearance of different layers, the organic layer was removed. The aqueous layer was extracted with DCM (50 mL × 3). The organic phases were combined and washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 6 g of crude product. The resulting crude product was recrystallized from PE / Et2O to give 5.9 g of the desired product as a crystalline mass. The overall yield is 91.2%. 1 H-NMR (400MHz, CDCl3) δ 7.33~7.47 (m, 5H), 7.06~7.09 (dd, J = 7.6, 2.8 Hz, 1H), 6.91~6.96 (m, 1H), 6.82~6.86 (dd, J=8.8, 4.4Hz, 1H), 5.11 (s, 2H), 4.53 (s, 2H)

[0209] [Example 2] Preparation of 4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane (Compound XV, where R is benzyl)

[0210] [ka] 2.4 mL (16.1 mmol) of trimethylsilylpropyne was added to 40 mL of anhydrous THF. The mixture was cooled to -23°C, and 7.7 mL (19.3 mmol) of 2.5 M n-BuLi was added dropwise thereto. After the addition, the solution was stirred at this temperature for 2 hours until the reaction solution turned orange-red. Then, the temperature was lowered to below -100°C. A solution of 3.5 g (11.9 mmol) of compound XIV (wherein R is benzyl) in 5 mL of anhydrous THF was added. The reaction was then carried out for 1 hour. TLC showed that the reaction was complete.

[0211] Workup: The reaction was quenched with 10% saturated ammonium chloride solution. After the appearance of different layers, the aqueous layer was extracted with diethyl ether (100 mL x 2). The organic phases were combined, washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. After column chromatography (PE / Et2O = 100:1), 3.79 g of pure product was obtained. The yield was 97.6%. 1 H-NMR (400MHz, CDCl3) δ 7.38~7.42 (m,5H), 6.93~6.96(dd, J = 8.8, 2.4 Hz, 1H), 6.78~6.85(m,2H), 5.05(s, 2H), 2.86~2.90(t,J=7.2Hz,2H), 2.50~2.53 (t,J=7.2Hz,2H), 1.96(s, 1H), 0.15(s, 9H)

[0212] [Example 3] Preparation of 1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene (compound XVI, where R is benzyl)

[0213] [ka] 1.15 g (3.52 mmol) of compound XV (wherein R is benzyl) was dissolved in 20 ml of MeOH, and 0.5 g (3.6 mmol) of K2CO3 was added thereto. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was extracted with EtOAc, washed with water and saturated NaCl solution, dried over anhydrous Na2SO4, and filtered. After evaporating the filtrate to dryness, 0.87 g of a colorless oil was obtained. After filtration through a short silica gel column and elution with HCl / EtOAc (100 / 2), 0.85 g of a colorless oil was obtained. 1H-NMR (400MHz, CDCl3) δ 7.33~7.42 (m,5H), 6.93~6.96 (dd, J = 9.6, 2.8 Hz, 1H), 6.81~6.86 (m,2H), 5.05 (s, 2H), 2.86~2.90 (t,J=7.2Hz,2H), 2.47~2.51 (t,J=7.2Hz,2H), 1.96 (s, 1H)

[0214] [Example 4] Preparation of 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yn-1-ol (Compound III, where R is benzyl)

[0215] [ka] 1.49 g (5.6 mmol) of compound XVI (wherein R is benzyl) was dissolved in 20 ml of THF and cooled to -100°C, to which 2.9 ml (6.9 mmol) of 2.4 M BuLi was added dropwise. After the addition was complete, the mixture was stirred at -100°C for 30 minutes, warmed to 0°C, and then (CHO) n 0.6 g (20 mmol) of HCl was added. After the addition was complete, the reaction mixture was stirred at 0 °C to room temperature for 2.5 h. Saturated NH₄Cl solution was added to complete the reaction. The organic phase was separated, and the aqueous layer was extracted twice with Et₂O. The combined extracts were washed with water, saturated NaCl solution, and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was evaporated to dryness. After purification on a short silica gel column eluted with petroleum ether / EtOAc (4 / 1), 1.51 g of a colorless oil was obtained. 1 H-NMR (400MHz, CDCl3) δ 7.33~7.42 (m,5H), 6.93~6.96 (dd, J = 9.6, 2.8 Hz, 1H), 6.81~ 6.86 (m,2H), 5.05 (s, 2H), 2.86~ 2.90 (t,J=7.2Hz,2H), 2.47~2.51 (t,J=7.2Hz,2H), 1.96 (s, 1H) HR-MS (ESI) calculated for C18H18O2F (M+H)+: 285.1285, found 285.1290.

[0216] [Example 4'] Preparation of 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yn-1-ol (Compound III, where R is benzyl)

[0217] [ka] 1.49 g (5.6 mmol) of compound XVI (wherein R is benzyl) was dissolved in 20 ml of THF and cooled to -100°C, and 2.9 ml (6.9 mmol) of 2.4 M BuLi was added thereto. After the addition was completed, the solution was stirred at -100°C for 30 minutes, then warmed to 0°C, and (CHO) n 0.6 g (20 mmol) of HCl was added. After the addition was complete, the reaction mixture was stirred at 0°C to room temperature for 2.5 hours. Saturated NH4Cl solution was added to complete the reaction. The organic phase was separated, and the aqueous layer was extracted twice with Et2O. The combined extracts were washed with water, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was evaporated to dryness to obtain an oil. 10 ml of n-hexane was added to the oil. The mixture was stirred and cooled to -20°C. Crystals precipitated. After filtration, 1.2 g of a white solid with a purity of 98% was obtained. 1 H-NMR (400MHz, CDCl3) δ 7.33~7.42 (m,5H), 6.93~6.96 (dd, J = 9.6, 2.8 Hz, 1H), 6.81~ 6.86 (m,2H), 5.05 (s, 2H), 2.86~ 2.90 (t,J=7.2Hz,2H), 2.47~2.51 (t,J=7.2Hz,2H), 1.96 (s, 1H) HR-MS (ESI) calculated for C18H18O2F (M+H)+: 285.1285, found 285.1290.

[0218] [Example 5] Preparation of trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol (Compound IV-1, where R is benzyl)

[0219] [ka] 1.05 g (3.6 mmol) of compound III (where R is benzyl) was dissolved in 25 ml of THF and cooled in an ice bath. 2.1 ml (7.1 mmol) of 3.4 M Red-Al was added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. (TLC showed that the Rf value of the product was the same as that of the starting material under the conditions of PL / EtOA = 4 / 1). The next day, saturated potassium sodium tartrate solution (approximately 20 ml) was carefully added dropwise to complete the reaction. The organic phase was separated, and the aqueous layer was extracted with 20 ml of EtOAc twice. The combined extracts were washed with 1 N HCl, water, and saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness to give 1.0 g of the product (a pale yellow oil). 1 H-NMR (400MHz, CDCl3) δ 7.32~7.42 (m, 5H), 6.85~6.87 (d, J = 8.4 Hz, 1H), 6.81~6.83 (m, 2H), 5.61~5.74 (m, 2H), 5.04 (s, 2H), 4.05~4.07 (d, J=5.6Hz, 2H), 2.71~2.75 (t,J=7.6Hz,2H), 2.33~ 2.38 (q, 2H), 1.39 (s, 2H). HR-MS (ESI) C18H20O2F (M+H) + Calculated value: 287.1448, measured value 287.1441.

[0220] [Example 5'] Preparation of trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol (Compound IV-1, where R is benzyl)

[0221] [ka] 1.05 g (3.6 mmol) of compound III (where R is benzyl) was dissolved in 25 ml of THF and cooled in an ice bath. 2.1 ml (7.1 mmol) of 3.4 M Red-Al was added. After the addition was complete, the reaction mixture was stirred overnight at room temperature. (TLC showed that the Rf value of the product was the same as that of the starting material under the conditions of PL / EtOA = 4 / 1). The next day, saturated potassium sodium tartrate solution (approximately 20 ml) was carefully added dropwise to complete the reaction. The organic phase was separated, and the aqueous layer was extracted with 20 ml of EtOAc twice. The combined extracts were washed with 1 N HCl, water, and saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain an oil. 8 ml of n-hexane was added to the oil. The resulting mixture was stirred and cooled to -20 °C. Crystals precipitated. After filtration, 0.7 g of an off-white solid was obtained with a purity of 99%. Melting point: 18-20°C. 1 H-NMR (400MHz, CDCl3) δ 7.32~7.42 (m, 5H), 6.85~6.87 (d, J = 8.4 Hz, 1H), 6.81~6.83 (m, 2H), 5.61~5.74 (m, 2H), 5.04 (s, 2H), 4.05~4.07 (d, J=5.6Hz, 2H), 2.71~2.75 (t,J=7.6Hz, 2H), 2.33~ 2.38 (q, 2H), 1.39 (s, 2H). HR-MS (ESI) C18H20O2F (M+H) + Calculated value: 287.1448, measured value: 287.1441.

[0222] [Example 6] (2R * ,3R * Preparation of )-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (Compound V, where R is benzyl)

[0223] [ka] 1.06 g (4 mmol) of compound IV-1 (where R is benzyl) was dissolved in 20 ml of DMC, and 1.01 g of 75% MCPBA (4.4 mmol) was added with stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with DMC and washed successively with 5% NaOH twice, water, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness to give 1.08 g of a pale yellow oil (90%). 1 H-NMR (400MHz, CDCl3) δ 7.32~7.41 (m, 5H), 6.88~6.90 (d, J = 8.4 Hz, 1H), 6.83~6.85 (m, 2H), 5.04 (s, 2H), 3.80~3.83 (d, J=12.5Hz, 1H), 3.51~3.57 (m, 1H), 2.97~2.99 (t, J=5.6Hz, 1H), 2.75~2.85 (m, 3H), 1.84~1.91 (m, 2H).

[0224] [Example 7] 1-[6-fluoro-(2S * )-3,4-dihydro-2H-benzopyran-2-yl]-(1R * Preparation of )-1,2-ethylene glycol (Compound VII) First Method

[0225] [ka] 1.08 g of compound V (where R is benzyl) was dissolved in 20 ml of EtOAc, and 0.2 g of 10% Pd / C was added thereto. The reaction mixture was hydrogenated overnight at room temperature under atmospheric pressure. After filtration, the filtrate was evaporated to dryness to obtain 0.85 g of an oil. The oil was dissolved in 20 ml of DMC and cooled in an ice bath, and 10 ml of 10% NaOH-NaCl solution was added thereto. The resulting solution was stirred in the ice bath for 30 minutes. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. The organic phase was separated, and the aqueous layer was extracted with 10 ml of DMC. The extract solutions were combined, washed with water, and dried over anhydrous Na2SO4. After purification on a short silica gel column eluted with P / EtOAc (1 / 1), 0.71 g of a white solid (95%) was obtained.

[0226] Second Method

[0227] [ka] To 1.5 g of compound V (wherein R is benzyl) were added 25 ml of absolute ethanol, 200 mg of 10% Pd / C, and 100 mg of anhydrous Na2CO3. The reaction mixture was hydrogenated under atmospheric pressure until hydrogen absorption ceased (approximately 1.5 hours), and then stirred at 60°C for 2.5 hours. The mixture was filtered, and the filtrate was evaporated to dryness to give 0.95 g of a white solid. 1 H-NMR (400MHz, CDCl3) δ 6.70~ 6.80 (m, 3H), 3.99~4.02 (dd, J = 10.4,3.6 Hz, 1H), 3.82~3.89 (m, 3H), 2.75~2.85 (m, 2H), 2.11~2.16 (m, 1H), 1.82~1.90 (m, 1H) HR-MS (EI) C 11 H 13 O3F (M) + Calculated value: Calculated value 212.0849, Measured value 212.0851

[0228] [Example 8] Preparation of cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol (Compound IV-2, where R is benzyl)

[0229] [ka] A 250 mL round-bottom flask was charged with Ni(OAc)2·4H2O (420 mg, 1.7 mmol), evacuated to a vacuum, and charged with argon. 20 mL of degassed 95% ethanol was added. Sodium borohydride (100 mg, 2.6 mmol) was added to the reaction mixture while stirring under argon. The reaction mixture was stirred for 15 minutes, at which point the reaction mixture turned black. Ethylenediamine (0.5 mL, 7.5 mmol) was then added. The reaction mixture was stirred for 5 minutes, and degassed NaOH solution (2 M, 60 μL, 0.1 mmol) was added. Compound III (where R is benzyl) (3.2 g, 11.3 mmol) was dissolved in 10 mL of 95% ethanol, and the resulting solution was added dropwise to the reaction mixture. The argon used in the reaction was then replaced with hydrogen, and the reaction was allowed to proceed at room temperature for 18 hours. TLC indicated the reaction was complete.

[0230] Post-treatment: The hydrogen used in the reaction was replaced with argon. After removing the hydrogen, the reaction mixture was filtered through Celite. The filter cake was washed with 100 ml of ethyl acetate and 3 x 20 ml of water. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the obtained filtrate was evaporated to dryness to obtain 3.15 g of the product. The yield was 97%. 1 HNMR (400MHz, CDCl3) δ 7.34~7.43 (m, 5H), 6.80~6.86 (m, 3H), 5.53~5.62 (m, 2H), 5.04(s, 2H), 3.97~4.00 (d, J=12Hz,2H), 2.63~2.68 (t,J=8Hz, 2H), 2.35~2.40(q, 2H), 1.27(bs,1H). HR-MS (ESI) calculated for C18H20O2F (M+H)+: 287.1448, found 287.1441.

[0231] [Example 8'] Preparation of cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol (Compound IV-2, where R is benzyl)

[0232] [ka] A 250 mL round-bottom flask was charged with Ni(OAc)2·4H2O (420 mg, 1.7 mmol), evacuated to a vacuum, and charged with argon. 20 mL of degassed 95% ethanol was added. Sodium borohydride (100 mg, 2.6 mmol) was added to the reaction mixture while stirring under argon. The reaction mixture was stirred for 15 minutes, at which point the reaction mixture turned black. Ethylenediamine (0.5 mL, 7.5 mmol) was then added. The reaction mixture was stirred for 5 minutes, and degassed NaOH solution (2 M, 60 μL, 0.1 mmol) was added. Compound III (where R is benzyl) (3.2 g, 11.3 mmol) was dissolved in 10 mL of 95% ethanol, and the resulting solution was added dropwise to the reaction mixture. The argon used in the reaction was then replaced with hydrogen, and the reaction was allowed to proceed at room temperature for 18 hours. TLC indicated the reaction was complete.

[0233] Post-treatment: The hydrogen used in the reaction was replaced with argon. After removing the hydrogen, the reaction mixture was filtered through Celite. The filter cake was washed with 100 ml of ethyl acetate and water (3 x 20 ml). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the obtained filtrate was evaporated to dryness to obtain an oil. To the oil, 30 ml of n-hexane was added. The resulting mixture was stirred and cooled to -20°C. Crystals precipitated. After filtration, 2.7 g of an off-white solid with a purity of 99% was obtained. Melting point: 32-34°C. 1HNMR (400MHz, CDCl3) δ 7.34~7.43 (m, 5H), 6.80~6.86 (m, 3H), 5.53~5.62 (m, 2H), 5.04 (s, 2H), 3.97~4.00 (d, J=12Hz,2H), 2.63~2.68 (t,J=8Hz, 2H), 2.35~2.40 (q, 2H), 1.27 (bs,1H). HR-MS (ESI) calculated for C18H20O2F (M+H)+: 287.1448, found 287.1441.

[0234] [Example 9] (2R * ,3S * Preparation of )-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (Compound VI, where R is benzyl)

[0235] [ka] Following the same method as in Example 6, compound IV-2 (wherein R is benzyl) was used as the starting material to obtain compound VI. 1 H-NMR (400MHz, CDCl3) δ 7.34~7.41 (m, 5H), 6.88~6.90 (d, J = 8.4 Hz, 1H), 6.84~6.86 (m, 2H), 5.03 (s, 2H), 3.48~3.56 (m, 2H), 3.03~3.09 (m, 2H), 2.71~2.87 (m, 2H), 1.89~1.96 (m, 1H), 1.75~1.83 (m, 1H).

[0236] [Example 10] 1-[6-fluoro-(2R * )-3,4-dihydro-2H-benzopyran-2-yl]-(1R * Preparation of )-1,2-ethylene glycol (compound VIII)

[0237] [ka] Following the same procedures as in the two methods of Example 7, compound VI (wherein R is benzyl) was used as the starting material to obtain compound VIII. 1 H-NMR (400MHz, CDCl3) δ 6.73~ 6.81 (m, 3H), 4.04~4.07 (m, 1H),3.81~ 3.85 (m, 2H), 3.76~3.76 (m, 1H) 2.84~2.86 (m, 1H), 2.74~2.79 (m, 1H), 1.78~2.02 (m, 2H), 2.04(bs,2H) HR-MS (EI) C 11 H 13 O3F (M) + Calculated value: Calculated value 212.0849, Measured value 212.0844

[0238] [Example 11] (S * ,R * Preparation of )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound IX)

[0239] [ka] 4.24 g (20 mmol) of compound VII was suspended in 100 ml of toluene, and 0.5 g (2 mmol) of dibutyltin oxide (BuSnO) was added thereto. The mixture was stirred at room temperature for 1 hour, and then 3.95 ml (24 mmol) of diisopropylethylamine and 3.99 g (21 mmol) of p-methylphenylsulfonyl chloride (TsCl) were added thereto. The reaction mixture was stirred at room temperature overnight. The next day, the reaction mixture was washed with 2 N HCl, washed with water, and dried over anhydrous NaSO. After purification on a short silica gel column eluted with HCl / EtOAc (3 / 1), 6.89 g of a white solid (94%) was obtained. 1H-NMR (400MHz, CDCl3) δ 7.80~7.82 (d, J=7.6Hz, 2H), 7.34~7.35 (d, J=7.6Hz, 2H), 6.7 (s, 2H), 6.58~6.61 (m, 1H), 4.36~4.39 (d, J=10.4Hz, 1H), 4.21~4.23 (m, 1H), 3.91 (s, 2H), 2.75~2.8 (m, 2H), 2.45 (s, 3H), 2.16~2.19 (m, 1H), 1.75~1.79 (m, 1H) HR-MS (ESI) C 18 H 19 O5FNaS(M+Na) + Calculated value: Calculated value 389.0829, Measured value 389.0822

[0240] [Example 12] (R * ,R * Preparation of )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound X)

[0241] [ka] 4.24 g (20 mmol) of compound VIII was suspended in 100 ml of toluene, and 0.5 g (2 mmol) of dibutyltin oxide (BuSnO) was added. The mixture was stirred at room temperature for 1 hour, and then 3.95 ml (24 mmol) of diisopropylethylamine and 3.99 g (21 mmol) of p-methylphenylsulfonyl chloride (TsCl) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 2 N HCl, washed with water, and dried over anhydrous NaSO. After purification on a short silica gel column eluted with HCl / EtOAc (3 / 1), 7.07 g of the product (98%) was obtained as a colorless syrup. 1H-NMR (400MHz, CDCl3) δ 7.80~7.82 (d, J=8.0Hz, 2H), 7.33~7.35 (d, J=8.0Hz,2H), 6.73~6.79 (m, 2H), 6.64~6.67 (m, 1H), 4.21~4.22 (d, J=5.6Hz, 2H), 4.0~4.02 (m, 1H), 3.91~3.95 (m, 1H), 2.72~2.87 (m, 2H), 2.44 (s, 3H), 1.93~1.95 (m, 2H) HR-MS (ESI) C 18 H 19 O5FNaS(M+Na) + Calculated value: Calculated value 389.0829, Measured value 389.0823

[0242] [Example 13] (S * ,R * Preparation of )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound XI)

[0243] [ka] Compound IX (1.83 g, 5 mmol) was dissolved in 20 ml of THF, and 2.72 ml of benzylamine was added thereto. The reaction mixture was heated under reflux for 16 hours (TLC showed that the starting material spot had disappeared), and then evaporated to dryness under reduced pressure. 10% Na2CO3 was added to the residue, and the resulting solution was extracted three times with EtOAc. The combined extract solution was washed with 10% Na2CO3, washed with water, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure to remove EtOAc. 20 ml of cyclohexane was added to the residue, and white crystals precipitated. After filtration, 1.25 g of a white solid was obtained. 1H-NMR (400MHz, CDCl3) δ 7.28~7.36 (m, 5H), 6.6~6.8 (m, 3H), 3.85~3.89 (m, 3H), 3.74~3.81 (m, 1H), 2.98~3.02 (dd, J=4,12Hz, 1H), 2.73~2.86 (m, 3H), 2.12~2.15 (m, 1H), 1.76~1.86 (m, 1H) HR-MS (ESI) C 18 H 21 O2FN (M+H) + Calculated value: Calculated value 302.1550, Measured value 302.1546

[0244] [Example 14] (R * ,R * Preparation of )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound XII)

[0245] [ka] 1.95 g (5.3 mmol) of compound X was dissolved in 20 ml of THF, and 2.72 ml of benzylamine was added thereto. The reaction mixture was heated under reflux for 16 hours (TLC showed that the starting material spot had disappeared), and then evaporated to dryness under reduced pressure. 10% Na2CO3 was added to the residue, and the resulting solution was extracted three times with EtOAc. The combined extract solution was washed with 10% Na2CO3, washed with water, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated under reduced pressure to remove EtOAc. 20 ml of cyclohexane was added to the residue, and 0.91 g of white crystals precipitated. 1 H-NMR (400MHz, CDCl3) δ 7.28~7.38 (m, 5H), 6.7~6.8 (m, 3H), 3.86~3.95 (m, 4H), 2.91~2.92 (d, J=5.6Hz, 2H), 2.75~2.84 (m, 2H), 1.91~1.94 (m, 2H)

[0246] [Example 15] Preparation of N-benzyl-(+ / -)-nebivolol (compound XIII)

[0247] [ka] 1.19 g (3.2 mmol) of compound IX and 0.94 g (3.12 mmol) of compound XII were dissolved in 15 ml of EtOH, and 0.5 g of solid anhydrous sodium carbonate was added. The reaction mixture was heated to reflux with stirring for 16 hours and evaporated to dryness under reduced pressure. 50 ml of water was added to the residue, and the resulting solution was extracted twice with EtOAc. The combined extracts were washed with saturated NaCl solution and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness under reduced pressure to give 1.59 g of the product as a syrup. 25 ml of isopropanol was added to the product and heated to dissolve the product. 0.5 g of oxalic acid (FW=126) was added. The resulting solution was heated with stirring for 20 minutes, cooled, left at room temperature for 5 hours, filtered, and oven-dried to give 1.59 g of a white solid. The resulting product was recrystallized twice from ethanol to give 0.69 g of compound XIII as the oxalate salt. The resulting product was suspended in 20 ml of methylene dichloride, to which 10 ml of 10% sodium carbonate was added. The mixture was stirred at room temperature for 25 minutes, and the organic phase was separated, washed with water, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain 0.58 g of the free base (Compound XIII). 1 HNMR (500MHz, CDCl3) δ 7.27~7.34 (m, 5H), 6.67~6.78 (m, 6H), 3.94~3.97 (d, J=15Hz, 1H), 3.82~3.86 (m, 4H), 3.69~3.71 (d, J=15Hz, 1H), 2.98~3.01 (m, 1H), 2.90~2.92 (m, 1H), 2.68~2.83 (m, 7H), 2.11~2.14 (m, 1H), 1.78~1.86 (m, 3H) HR-MS (ESI) C 29 H 31 O4F2N (M+H)+ Calculated value: Calculated value 496.2293, Measured value 496.2287

[0248] [Example 16] Preparation of (2R,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (Compound Va, where R is benzyl)

[0249] [ka] To 2 g of powdered 4A molecular sieves in 25 mL of anhydrous methylene dichloride was cooled to −25°C, 1.85 g (7.9 mmol) of D-(−)-DIPT and 2.06 g (7.2 mmol) of Ti(OPr-i) were added sequentially. After the addition was complete, the mixture was stirred at −25°C for 20 minutes, and then 6.7 mL (19.8 mmol) of 3.2 N TBHP (solution in toluene) was added dropwise. After the addition was complete, the mixture was stirred at −25°C for 20 minutes, and then 1.89 g (6.6 mmol) of compound IV1 (wherein R is benzyl) in 20 mL of methylene dichloride was added dropwise (within approximately 15 minutes). After the addition was complete, the reaction mixture was stirred at −25 to −22°C for 6 hours (until the starting material spot disappeared).

[0250] Workup: The reaction mixture was poured into a fresh solution of FeSO4 / tartaric acid / HO (2.5 g FeSO4 + 1.0 g tartaric acid + 20 ml HO). The resulting mixture was stirred at room temperature for 1 hour and filtered through Celite. The organic layer was separated from the filtrate, and the aqueous layer was extracted twice with methylene dichloride. The extract solutions were combined, washed with water, dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to give 4.0 g of an oil.

[0251] The oil was dissolved in 40 ml of DCM, and 20 ml of a 30% solution of NaOH in saturated NaCl solution was added dropwise while cooling in an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined extracts were washed with water and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was loaded onto a silica gel column and eluted with PEG / EtOAc (3 / 1) to give 1.54 g of a colorless oil. 1 H-NMR (400MHz, CDCl3) δ 7.32~7.41 (m, 5H), 6.88~6.90 (d, J = 8.4 Hz, 1H), 6.83~6.85 (m, 2H), 5.04 (s, 2H), 3.80~3.83 (d, J=12.5Hz, 1H), 3.51~3.57 (m, 1H), 2.97~2.99 (t, J=5.6Hz, 1H), 2.75~2.85 (m, 3H), 1.84~1.91 (m, 2H). HR-MS (ESI) C 18 H 19 O3FNa (M+Na) + Calculated value: 325.1210, measured value: 325.1201 [α] D 20 +22.9 (CHCl3, C 1.0)

[0252] [Example 17] Preparation of (2S,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (compound Vb, where R is benzyl)

[0253] [ka] Following the same method as in Example 16, compound IV1 was used as the starting material and diisopropyl L-(+)-tartrate was used as the chiral inducer to obtain compound Vb. [α] D 20 :-23.1(CHCl3, C1.0)

[0254] [Example 18] Preparation of (2R,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (Compound VIa, where R is benzyl)

[0255] [ka] To 2 g of powdered 4A molecular sieves in 25 mL of anhydrous methylene dichloride was cooled to −25°C, 1.85 g (7.9 mmol) of D-(−)-DIPT and 2.06 g (7.2 mmol) of Ti(OPr-i) were added sequentially. After the addition was complete, the mixture was stirred at −25°C for 20 minutes, and then 6.7 mL (19.8 mmol) of 3.2 N TBHP (solution in toluene) was added dropwise. After the addition was complete, the mixture was stirred at −25°C for 20 minutes, and then a solution of 1.92 g (6.7 mmol) of compound IV2 (wherein R is benzyl) in 20 mL of methylene dichloride was added dropwise (within approximately 15 minutes). After the addition was complete, the reaction mixture was stirred at −25 to −22°C for 6 hours. The reaction mixture was poured into a fresh solution of FeSO4 / tartaric acid / HO (2.5 g FeSO4 + 1.0 g tartaric acid + 20 ml HO). The resulting mixture was stirred at room temperature for 1 hour and filtered through Celite. The organic layer was separated from the filtrate, and the aqueous layer was extracted twice with methylene dichloride. The extract solutions were combined, washed with water, dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to give an oil.

[0256] The oil was dissolved in 40 ml of Et2O, and 20 ml of a 30% solution of NaOH in saturated NaCl solution was added dropwise while cooling in an ice bath. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined extracts were washed with water and dried over anhydrous Na2SO4. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was loaded onto a silica gel column and eluted with DI / EtOAc (3 / 1) to give 1.63 g of a colorless oil. 1H-NMR (400MHz, CDCl3) δ 7.34~7.41 (m, 5H), 6.88~6.90 (d, J = 8.4 Hz, 1H), 6.84~6.86 (m, 2H), 5.03 (s, 2H), 3.48~3.56 (m, 2H), 3.03~3.09 (m, 2H), 2.71~2.87 (m, 2H), 1.89~1.96 (m, 1H), 1.75~1.83 (m, 1H). [α] D 20 ; -1.5 (CHCl3, c 1.0)

[0257] [Example 19] Preparation of (2S,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane (Compound VIb, where R is benzyl)

[0258] [ka] Following the same method as in Example 16, compound IV2 (wherein R is benzyl) was used as the starting material and diisopropyl L-(+)-tartrate was used as the chiral inducer to give compound VIb. [α] D 20 :+1.6(CHCl3, c2.0)

[0259] [Example 20] Preparation of 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol (Compound VIIa)

[0260] [ka] 1.09 g of compound Va (wherein R is benzyl) was dissolved in 25 ml of EtOH, and 0.25 g of 10% Pd / C and 0.075 g of anhydrous sodium carbonate were added thereto, followed by hydrogenation at atmospheric pressure (approximately 1 hour). The hydrogenation was stopped. The reaction mixture was stirred in an oil bath at 60°C for 2 hours, filtered, and the Pd / C was removed. The residue was washed with EtOH. The filtrate was evaporated to dryness to obtain 0.75 g of a white solid. 1 H-NMR (400MHz, CDCl3) δ 6.70~6.80 (m, 3H), 3.99~4.02(dd, J = 10.4, 3.6 Hz, 1H), 3.82~3.89 (m, 3H), 2.75~2.85 (m, 2H), 2.11~2.16 (m, 1H), 1.82~1.90 (m, 1H) [α] D 20 ; +89.6 (CH3OH, c 1.0)

[0261] [Example 21] Preparation of 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol (Compound VIIb)

[0262] [ka] Following the same method as in Example 20, compound VIIb was obtained using compound Vb (wherein R is benzyl) as the starting material. [α] D 20 :-87.9(CH3OH, c1.0)

[0263] [Example 22] Preparation of 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol (Compound VIIIa)

[0264] [ka] 1.3 g of compound VIa (wherein R is benzyl) was dissolved in 25 ml of EtOH, and 0.2 g of 10% Pd-C and 0.1 g of anhydrous sodium carbonate were added thereto. Hydrogenation was carried out under atmospheric pressure until hydrogen was no longer absorbed. The hydrogenation was stopped. The reaction mixture was stirred in an oil bath at 60°C for 2 hours and filtered to remove Pd / C. The residue was washed with EtOH. The filtrate was evaporated to dryness to obtain 0.88 g of a white solid. 1 H-NMR (400MHz, CDCl3) δ 6.73~6.81 (m, 3H), 4.04~4.07 (m, 1H), 3.81~ 3.85 (m, 2H), 3.76~ 3.76 (m, 1H) 2.84~2.86 (m, 1H), 2.74~2.79 (m, 1H), 1.78~2.02 (m, 2H), 2.04(bs,2H) [α] D 20 -113.1 (CH3OH, c 1.0), [α] D 20 -112.0 (CH3Cl, c 0.1)

[0265] [Example 23] Preparation of 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol (Compound VIIIb)

[0266] [ka] Following the same procedure as in Example 22, compound VIb (wherein R is benzyl) was used as the starting material to obtain compound VIIIb as a white solid. D 20 :+95.6(CH3Cl, c0.045).

[0267] [Example 24] Preparation of (S,R)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound IXa)

[0268] [ka] Following the same method as in Example 11, compound IXa was obtained using compound VIIa as the starting material. 1 H-NMR (400MHz, CDCl3) δ 7.80~7.82 (d, J=7.6Hz, 2H), 7.34~7.35 (d, J=7.6Hz,2H), 6.7 (s, 2H), 6.58~6.61 (m, 1H), 4.36~4.39 (d, J=10.4Hz, 1H), 4.21~4.23 (m, 1H), 3.91 (s, 2H), 2.75~2.8 (m, 2H), 2.45(s, 3H), 2.16~2.19 (m, 1H), 1.75~1.79 (m, 1H) [α] D 20 +82.1 (CHCl3, c 0.56)

[0269] [Example 25] Preparation of (R,R)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound Xa)

[0270] [ka] Following the same method as in Example 11, compound VIIIa was used as the starting material to obtain compound Xa. 1 H-NMR (400MHz, CDCl3) δ 7.80~7.82 (d, J=8.0Hz, 2H), 7.33~7.35 (d, J=8.0Hz,2H), 6.73~6.79 (m, 2H), 6.64~6.67 (m, 1H), 4.21~4.22 (d, J=5.6Hz,2H), 4.0~4.02 (m, 1H), 3.91~3.95 (m, 1H), 2.72~2.87 (m, 2H), 2.44 (s, 3H), 1.93~1.95 (m, 2H) HR-MS (ESI) C 18 H 19O5FNaS(M+Na) + Calculated value: Calculated value 389.0829, Measured value 389.0823 [α] D 20 ; -48.4 (CH3Cl, c 0.68)

[0271] [Example 26] Preparation of (R,S)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound IXb)

[0272] [ka] Following the same method as in Example 11, compound IXb was obtained using compound VIIb as the starting material. [α] D 20 :-80.3(CHCl3, c0.85)

[0273] [Example 27] Preparation of (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol (Compound Xb)

[0274] [ka] Following the same method as in Example 11, compound VIIIb was used as the starting material to obtain compound Xb. [α] D 20 :+50.3(CH3Cl, c0.50)

[0275] [Example 28] Preparation of (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (compound XIa)

[0276] [ka] Following the same method as in Example 13, compound IXa was used as the starting material to obtain compound XIa.

[0277] Compound XIa is a white solid. [α] D 20 :+82.1(CHCl3, c0.56)

[0278] [Example 29] Preparation of (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol (compound XIb)

[0279] [ka] Following the same method as in Example 13, compound IXb was used as the starting material to obtain compound XIb. [α] D 20 :-79.3(CHCl3, c0.45)

[0280] [Example 30] Preparation of N-benzyl-D-nebivolol (compound XIIIa)

[0281] [ka] 287 mg (0.95 mmol) of compound XIa and 350 mg (0.95 mmol) of compound Xa were dissolved in 5 ml of ethanol, and 150 mg of anhydrous Na2CO3 was added thereto, and the reaction mixture was heated under reflux with stirring for 16 hours.

[0282] The reaction mixture was evaporated to dryness under reduced pressure. 10 ml of water was added to the residue, and the resulting mixture was extracted twice with EtOAc. The extract solutions were combined, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness under reduced pressure to give 453 mg of product as a syrup, which was then recrystallized from ethanol / water to give 373 mg of a white solid (79%).

[0283] [Example 30'] Preparation of N-benzyl-D-nebivolol hydrochloride (compound XIIIa hydrochloride) 287 mg (0.95 mmol) of compound XIa and 350 mg (0.95 mmol) of compound Xa were dissolved in 5 ml of ethanol, and 150 mg of anhydrous Na2CO3 was added thereto, and the reaction mixture was heated under reflux with stirring for 16 hours.

[0284] The reaction mixture was evaporated to dryness under reduced pressure. 10 ml of water was added to the residue, and the resulting mixture was extracted twice with EtOAc. The extracted solutions were combined, and 2 ml of 1N hydrochloric acid was added thereto. The resulting mixture was stirred, causing precipitation of crystals. After filtration, 390 mg of a white solid with a purity of 99.5% was obtained.

[0285] [Example 30] Preparation of N-benzyl-D-nebivolol (compound XIIIa) 390 mg of compound XIIIa hydrochloride was added to 10 ml of methylene dichloride. The resulting mixture was stirred and neutralized by adding aqueous sodium bicarbonate solution. Different layers appeared. The organic layer was dried and concentrated to give 355 mg of a white solid with a purity of 99.7%.

[0286] [Example 31] Preparation of N-benzyl-L-nebivolol (compound XIIIb)

[0287] [ka] Following the same method as in Example 30, compound XIIIb was obtained using compounds XIb and Xb as starting materials.

[0288] [Example 31'] Preparation of N-benzyl-L-nebivolol hydrochloride (compound XIIIb hydrochloride) Following the same method as in Example 30', Compounds XIb and Xb were used as starting materials to obtain Compound XIIIb hydrochloride with a purity of 99.6%.

[0289] [Example 31] Preparation of N-benzyl-L-nebivolol (compound XIIIb) According to the same method as in Example 30", compound XIIIb with a purity of 99.8% was obtained.

[0290] [Example 32] Preparation of DL-nebivolol (Compound I) hydrochloride 200 mg (0.4 mmol) of compound I was dissolved in 5 ml of ethanol, and 50 mg of 10% Pd-C was added thereto. Hydrogenation was carried out at room temperature under atmospheric pressure for 18 hours. After filtration, the residue was washed with ethanol. Hydrogen chloride gas was introduced into the filtrate. The solution was then evaporated under reduced pressure to remove ethanol, yielding a white solid, to which anhydrous diethyl ether was added. The resulting mixture was stirred and filtered to yield 160 mg of the product (89%). 1 H-NMR (500MHz, DMSO-d6) δ 8.81 (bs,2H), 6.90~6.94 (m, 4H), 6.75~6.76 (dd,2H), 5.99 (bs,1H), 5.80 (bs,1H), 4.11 (m, 1H), 3.98~4.02 (m, 2H), 3.89~3.91 (m, 1H), 3.17~3.22 (m, 2H), 3.05~3.07 (m, 1H), 2.74~2.82 (m, 4H), 2.10~2.13 (m, 1H), 1.92~1.94 (m, 1H), 1.75~1.80 (m, 1H), 1.67~1.71 (m, 1H) HR-MS (FAB + ) C 22 H 26 F2NO4S (M+1-HCl) + Calculated value: Calculated value 406.1829, Measured value 406.1825

[0291] [Example 32'] Preparation of DL-nebivolol (Compound I) hydrochloride 100 mg of compound XIIIa' and 100 mg of compound XIIIb' were added to 15 ml of methylene dichloride. The resulting solution was neutralized by adding aqueous sodium bicarbonate solution. Different layers appeared. The organic layer was concentrated to dryness. 50 ml of methanol and 50 mg of 10% Pd-C were added to the residue. Hydrogenation was carried out at room temperature under atmospheric pressure for 18 hours. After filtration, the residue was washed with methanol. 2 ml of 1N hydrochloric acid was added to the filtrate. Crystals precipitated. The mixture was filtered. The resulting solid was washed and dried to give 100 mg of a white solid with a purity of 99.9%. 1 H-NMR (500MHz, DMSO-d6) δ 8.81 (bs,2H), 6.90~6.94 (m, 4H), 6.75~6.76 (dd,2H), 5.99 (bs,1H), 5.80 (bs,1H), 4.11 (m, 1H), 3.98~4.02 (m, 2H), 3.89~3.91 (m, 1H), 3.17~3.22 (m, 2H), 3.05~3.07 (m, 1H), 2.74~2.82 (m, 4H), 2.10~2.13 (m, 1H), 1.92~1.94 (m, 1H), 1.75~1.80 (m, 1H), 1.67~1.71 (m, 1H) HR-MS (FAB + ) C 22 H 26 F2NO4S(M+1-HCl) + Calculated value: Calculated value 406.1829, Measured value 406.1825

[0292] [Example 32] Preparation of DL-nebivolol (Compound I) hydrochloride 100 mg of compound XIIIa obtained according to Example 30" and 100 mg of compound XIIIb obtained according to Example 31" were added to 50 ml of methanol, and 50 mg of 10% Pd-C was added thereto. Hydrogenation was carried out under atmospheric pressure at room temperature for 18 hours. After filtration, the residue was washed with methanol. 2 ml of 1N hydrochloric acid was added to the filtrate. Crystals precipitated. The mixture was filtered. The obtained solid was washed and dried to obtain 105 mg of a white solid with a purity of 99.9%. 1 H-NMR (500MHz, DMSO-d6) δ 8.81 (bs,2H), 6.90~6.94 (m, 4H), 6.75~6.76 (dd,2H), 5.99 (bs,1H), 5.80 (bs,1H), 4.11 (m, 1H), 3.98~4.02 (m, 2H), 3.89~3.91 (m, 1H), 3.17~3.22 (m, 2H), 3.05~3.07 (m, 1H), 2.74~2.82 (m, 4H), 2.10~2.13 (m, 1H), 1.92~1.94 (m, 1H), 1.75~1.80 (m, 1H), 1.67~1.71 (m, 1H) HR-MS (FAB + ) C 22 H 26 F2NO4S (M+1-HCl) + Calculated value: Calculated value 406.1829, Measured value 406.1825

[0293] Example 33a Preparation of D-nebivolol (compound Ia) hydrochloride Following the same procedure as in Example 32, compound XIIIa was used as the starting material to obtain compound Ia as the hydrochloride salt. D 20 :+22.0(CH3OH, C0.5)

[0294] Example 33b Preparation of L-nebivolol (compound Ib) hydrochloride Following the same procedure as in Example 32, compound XIIIb was used as the starting material to obtain compound Ib as the hydrochloride salt. D 20 :-21.2(CH3OH, C0.4).

[0295] In view of the above, the novel method provided by the present invention has high stereoselectivity, can avoid separation by column chromatography by preparing key intermediates, and the reaction conditions are mild and do not require special reagents. Compared with the prior art, the method for preparing nebivolol according to the present invention is significantly less costly and highly suitable for industrial production. In particular, the purification by crystallization of the intermediate compounds of formulas III, IV1, and IV2 greatly improves the quality of the intermediate compounds and the product, resulting in controllable product quality, improved yield, and significantly reduced production costs. Furthermore, the compounds of formulas XIIIa and XIIIb can be purified by salt formation and crystallization, which greatly improves product quality and allows the purity of the final product to be 99.9% or more.

[0296] Although several embodiments and specific examples of the present invention are provided herein, it will be understood by those skilled in the art that these embodiments and examples are merely illustrative of the present invention, and further that other variations and modifications can be made without departing from the spirit of the present invention.

[0297] The following are examples of embodiments of the present invention. [Embodiment 1] Formula VII(S * / R * ) compounds [ka] [where VII(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S) [ka] a racemic mixture consisting of 1. A method for preparing The following steps: 3) Compound of formula IV1 in the trans configuration [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl, although, as an example, R shown in the formula below is represented by benzyl (Bn). in the presence of an epoxidizing reagent to obtain an epoxide intermediate V. [ka] wherein compound V is a racemate, which is a mixture of equimolar amounts of a compound of formula Va and enantiomer Vb [ka] It is a racemic mixture consisting of V(2R * ,3R * ), and, 4) Formula V(2R * ,3R * ) is deprotected and then subjected to a cyclization reaction to give a compound of formula VII(S * / R * ) a step of obtaining an intermediate compound of [wherein R is defined as above, but as an example, R shown in the formula below is represented by benzyl (Bn)] [ka] Here, VII(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S) [ka] is a racemic mixture consisting of and A method comprising: [Embodiment 2] Formula VIII(R * / R * ) compounds [ka] [In the formula, VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S) [ka] a racemic mixture consisting of 1. A method for preparing The following steps: 3) Compound of formula IV2 in cis configuration [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl, although, as an example, R shown in the formula below is represented by benzyl (Bn). in the presence of an epoxidizing reagent to obtain an epoxide intermediate VI. [ka] wherein compound VI is racemic, which is a mixture of equimolar amounts of the compound of formula VIa and the enantiomer VIb [ka] It is a racemic mixture consisting of VI(2R * ,3S * ), and, 4) Equation VI(2R* ,3S * ) is deprotected, followed by cyclization to give a compound of formula VIII (R * / R * ) a step of obtaining an intermediate compound of [wherein R is defined as above, but as an example, R shown in the formula below is represented by benzyl (Bn)] [ka] where VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S) [ka] is a racemic mixture consisting of and A method comprising: [Embodiment 3] The method according to embodiment 1 or 2, wherein in step 3, the epoxidation of the compound of formula IV1 in trans configuration or the compound of formula IV2 in cis configuration can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof. [Embodiment 4] The method according to any one of embodiments 1 to 3, wherein in step 4), the deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and the cyclization is carried out in the presence of a base, wherein the catalyst used in the hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, for example, NaOH, KOH, KCO, NaOMe, DBU, or the deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product. [Embodiment 5] In step 3), the epoxidation of the compound of formula IV1 in trans configuration or the compound of formula IV2 in cis configuration can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac) and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof, and The method according to any one of embodiments 1 to 4, wherein in step 4), the deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and the cyclization is carried out in the presence of a base, wherein the catalyst used in the hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, for example, NaOH, KOH, KCO, NaOMe, DBU, or the deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product. [Embodiment 6] Formula III [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, allyl, methoxymethyl, benzyl, or -CHAr, and Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl, comprising the steps of: The following steps: [ka] Step a): reacting a compound of formula XIV, wherein R is a hydroxy-protecting group as described above and X is a halogen, with 3-(trisubstituted silyl)-prop-2-yne-1-lithium to obtain a compound of formula XV, wherein each R, R, and R is independently selected from alkyl or aryl, e.g., methyl, tert-butyl, or phenyl; Step b): Removal of the silyl protecting group at the alkynyl terminus of a compound of formula XV to give a compound of formula XVI, wherein R is defined as above; Step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to obtain a compound of formula III, wherein R is defined as above; Optionally, step d): adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the compound of formula III obtained by step c), stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula III as a solid; A method comprising: [Embodiment 7] 7. The method of embodiment 6, wherein in step a), the reaction is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, or toluene. [Embodiment 8] 8. The method according to any of embodiments 6 to 7, wherein in step b), the reaction is carried out in the presence of a base, an acid, or a fluorine-containing salt, preferably in the presence of a base, and the base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as NaOH, KOH, Na2CO3, K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of any two or more thereof. [Embodiment 9] 9. The method of any of embodiments 6 to 8, wherein in step c), the base is selected from a metal hydride or an organic base, such as NaNH or KNH; the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or a Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, where X is Br, I, or Cl; and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof. [Embodiment 10] In step a), the reaction is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, or toluene, In step b), the reaction is carried out in the presence of a base, an acid, or a fluorine-containing salt, preferably in the presence of a base, wherein the base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as NaOH, KOH, Na2CO3, K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of any two or more thereof; and 10. The method of any of embodiments 6 to 9, wherein in step c), the base is selected from a metal hydride or an organic base, such as NaNH or KNH; the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or a Grignard reagent, such as MeMgX, EtMgX, BuMgX, i-PrMgX, where X is Br, I, or Cl; and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof. [Embodiment 11] Compound of Formula IV1 [ka] wherein R is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. 1. A method for preparing The following steps: reducing the compound of formula III with a metal hydride to obtain a compound of formula IV1; [ka] wherein R is defined as above. and, Optionally, the following steps are performed: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV1, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV1 as a solid; A method comprising: [Embodiment 12] 12. The method of embodiment 11, wherein the metal hydride used as the reducing agent is LiAlH or sodium bis(2-methoxyethoxy)aluminum dihydride, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof. [Embodiment 13] Compound of Formula IV2 [ka] wherein R is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. 1. A method for preparing The following steps: reducing the compound of formula III by selective catalytic hydrogenation to give the compound of formula IV2 in the cis configuration; [ka] wherein R is defined as above. and, Optionally, the following step is performed: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV2, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV2 as a solid; A method comprising: [Embodiment 14] 14. The process of embodiment 13, wherein the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst. [Embodiment 15] Nebivolol racemate of formula I [ka] [where I(S * R * R * R * ) represents the racemic form, which has the following configuration: [ka] and its enantiomer L-nebivolol Ib (RSSS) in equimolar amounts. 1. A method for preparing The following steps: 1) reducing a compound of formula III with a metal complex hydride to obtain a compound of formula IV1 in a trans configuration, and optionally the following steps: adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV1, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV1 as a solid. [ka] wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. and, 2) reducing the compound of formula III by selective catalytic hydrogenation to obtain a compound of formula IV2 in the cis configuration, and optionally, adding a non-polar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV2, stirring at a low temperature, such as 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV2 as a solid. [ka] [wherein R is defined as in 1) above] and, 3) epoxidizing the compound of formula IV1 in the trans configuration and the compound of formula IV2 in the cis configuration in the presence of an epoxidizing reagent to obtain epoxide intermediates V and VI, respectively. wherein R is defined as above. [ka] wherein compound V is a racemate, which is a mixture of equimolar amounts of a compound of formula Va and enantiomer Vb [ka] It is a racemic mixture consisting of V(2R * ,3R * ) and [ka] wherein compound VI is racemic, which is a mixture of equimolar amounts of the compound of formula VIa and the enantiomer VIb [ka] It is a racemic mixture consisting of VI(2R * ,3S * ), and, 4) Deprotection of the compound of formula V and the compound of formula VI, followed by cyclization, to give the compound of formula VII(S * / R * ) and formula VIII(R * / R * ) a step of obtaining each of the intermediate compounds wherein R is defined as above. [ka] Here, VII(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIa (S / R) and the enantiomer VIIb (R / S) [ka] is a racemic mixture consisting of [ka] where VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S) [ka] is a racemic mixture consisting of and, 5) Sulfonylation of the compounds of formula VII and formula VIII with a sulfonyl halide of formula M-SO2X (wherein M is alkyl or substituted or unsubstituted aryl, and X is halogen) in the presence of a catalyst and a base to give compounds IX (S * / R *) and X(R * / R * ) respectively [ka] Here, IX(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula IXa (S / R) and the enantiomer IXb (R / S) [ka] is a racemic mixture consisting of [ka] where X(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula Xa(R / R) and the enantiomer Xb(S / S) [ka] is a racemic mixture consisting of and, 6) reacting a compound of formula IX or X with benzylamine to effect alkylation of the amine to give the corresponding compound XI or XII. [ka] Here, XI(S * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIa (S / R) and the enantiomer XIb (R / S) [ka] is a racemic mixture consisting of [ka] where XII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIIa (R / R) and the enantiomer XIIb (S / S) [ka] is a racemic mixture consisting of and, 7) Under basic conditions, intermediate compound IX(S * / R * ) and XII(R * / R * ), or intermediate compound X(R * / R * ) and XI(S * / R * ) to carry out a cross-coupling reaction to give compound XIII(S * R * R * R * ) and XIII'(S * R * S * S * ) to obtain wherein R″ is defined as M above. [ka] Here, XIII(S * R * R * R * ) is a racemate, which is composed of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS) [ka] is a racemic mixture consisting of XIII'(S * R * S * S * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula XIII'a (SRSS) and the enantiomer XIII'b (RSRR) [ka] is a racemic mixture consisting of and, 8) Forming a salt of a mixture of compounds of formula XIII and formula XIII' and purifying it by recrystallization to obtain isomer XIII' (S * R * S * S * ) was removed, and intermediate compound XIII (S * R * R * R * ) and 9) Intermediate compound XIII(S * R * R * R * ) to obtain the racemic nebivolol of formula I. [ka] Here, I(S * R * R * R * ) is a racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula Ia (SRRR) and the enantiomer Ib (RSSS), and A method comprising: [Embodiment 16] 16. The method of embodiment 15, wherein in step 1), the metal complex hydride used as the reducing agent is LiAlH or sodium bis(2-methoxyethoxy)aluminum dihydride, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof. [Embodiment 17] 17. The method of any of embodiments 15 to 16, wherein in step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst. [Embodiment 18] The method according to any one of embodiments 15 to 17, wherein in step 3, the epoxidation of the compound of formula IV1 in trans configuration and the compound of formula IV2 in cis configuration can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac) and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof. [Embodiment 19] The method according to any one of embodiments 15 to 18, wherein in step 4), the deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and the cyclization is carried out in the presence of a base, wherein the catalyst used in the hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, for example, NaOH, KOH, KCO, NaOMe, DBU, or the deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product. [Embodiment 20] In step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and no catalyst is used in the reaction or an appropriate amount of an acylation catalyst is used, and the catalyst used can be dialkyltin oxide, DMAP, for example, di butyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane, the base used in the reaction can be a conventional organic base, such as pyridine, an organic tertiary amine, such as triethylamine or diisopropylethylamine, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof. [Embodiment 21] 21. The method of any of embodiments 15 to 20, wherein in step 6), the alkylation of the amine is carried out by reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof. [Embodiment 22] 22. The method of any of embodiments 15 to 21, wherein in step 7), the base used in the cross-coupling reaction can be selected from an inorganic base, such as KCO, NaCO, or an organic tertiary amine, such as triethylamine or diisopropylethylamine, and the solvent in the reaction is an organic protic solvent, such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents. [Embodiment 23] 23. The method of any of embodiments 15 to 22, wherein in step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol. [Embodiment 24] In step 1), the metal complex hydride used as a reducing agent is LiAlH or sodium bis(2-methoxyethoxy)aluminum dihydride, and the solvent used in the reaction is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more of them; In step 2), the catalyst used in the selective catalytic hydrogenation is selected from Lindlar's catalyst or P-2 nickel boride / ethylenediamine catalyst; In step 3), the epoxidation of the compound of formula IV1 in trans configuration and the compound of formula IV2 in cis configuration can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidation reagent that can be used in the reaction is selected from organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac) and tert-butylhydroperoxide, and a pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO), and the solvent in the reaction is an organic aprotic solvent such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, toluene, or a mixture of any two or more thereof; In step 4), deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl-protecting group, and cyclization can be carried out in the presence of a base, where the catalyst used in hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, for example, NaOH, KOH, K2CO3, NaOMe, DBU, or deprotection and cyclization can be carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl-protecting group and cyclize, thereby directly obtaining the cyclized product; In step 5), the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride; no catalyst is used in the reaction or an appropriate amount of an acylation catalyst is used, and the catalyst can be dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolan; the base used in the reaction can be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine; the solvent in the reaction is an organic aprotic solvent, for example, methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 6), alkylation of the amine is carried out by reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 7), the base used in the cross-coupling reaction can be selected from inorganic bases such as KCO, NaCO, or organic tertiary amines such as triethylamine or diisopropylethylamine; the solvent in the reaction is an organic protic solvent such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; 24. The method of any one of embodiments 15 to 23, wherein in step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol. [Embodiment 25] The method according to any of embodiments 15 to 24, wherein the compounds of formula IV1 and formula IV2 are used as starting materials for carrying out steps 2) to 9) to obtain nebivolol racemate of formula I. [Embodiment 26] 25. The method of any of embodiments 15 to 24, wherein the compounds of formula IX and formula XII are used as starting materials to carry out steps 7) to 9) to obtain nebivolol racemate of formula I. [Embodiment 27] D-Nebivolol (Formula Ia) [ka] 1. A method for preparing The following steps: 3') asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to obtain intermediate compounds Va and VIa, respectively wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. [ka] and, 4') Deprotection and subsequent cyclization of intermediate compounds Va and VIa to obtain intermediate compounds VIIa and VIIIa, respectively. wherein R is defined as above. [ka] and, 5') sulfonation of intermediate compounds VIIa and VIIIa with a sulfonyl halide of formula M-SO2X, in the presence of a catalyst and a base, where M is alkyl or substituted or unsubstituted aryl, and X is halogen, to obtain intermediate compounds IXa and Xa, respectively. [ka] and, 6') reacting intermediate compound IXa or intermediate compound Xa with benzylamine to alkylate the amine, thereby obtaining the corresponding compound XIa or XIIa. [ka] and, 7') A step of cross-coupling intermediate compounds IXa and XIIa, or intermediate compounds Xa and XIa, under basic conditions to obtain intermediate compound XIIIa. wherein Ar' is defined as M above. [ka] and, Optionally, converting intermediate compound XIIIa into its hydrochloride salt; 8') Deprotecting intermediate compound XIIIa to obtain D-nebivolol (formula Ia) [ka] or converting the hydrochloride salt of intermediate compound XIIIa into the free form of intermediate compound XIIIa by neutralizing it with a base, followed by deprotection to obtain D-nebivolol (formula Ia). A method comprising: [Embodiment 28] L-Nebivolol (Formula Ib) [ka] 1. A method for preparing The following steps: 3") Asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to obtain intermediate compounds Vb and VIb, respectively. wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. [ka] and, 4") Deprotection and subsequent cyclization of intermediate compounds Vb and VIb to give intermediate compounds VIIb and VIIIb, respectively. wherein R is defined as above. [ka] and, 5") sulfonation of intermediate compounds VIIb and VIIIb with a sulfonyl halide of formula M-SO2X, where M is alkyl or substituted or unsubstituted aryl, and X is halogen, in the presence of a catalyst and a base to obtain intermediate compounds IXb and Xb, respectively. [ka] and, 6") A step of reacting intermediate compound IXb or intermediate compound Xb with benzylamine to alkylate the amine, thereby obtaining intermediate compound XIb or XIIb. [ka] and, 7") A step of cross-coupling intermediate compounds IXb and XIIb, or intermediate compounds Xb and XIb, under basic conditions to obtain intermediate compound XIIIb. wherein Ar' is defined as M above. [ka] and, Optionally, converting intermediate compound XIIIb into its hydrochloride salt; 8") Deprotection of intermediate compound XIIIb to obtain L-nebivolol (formula Ib) [ka] or converting the hydrochloride salt of intermediate compound XIIIb into the free form of intermediate compound XIIIb by neutralizing with a base, followed by deprotection to obtain L-nebivolol (formula Ib). A method comprising: [Embodiment 29] 28. The method according to embodiment 27, wherein in step 3'), Sharpless asymmetric epoxidation is used, and the chiral catalyst used in the reaction is diethyl D-(-)-tartrate or diisopropyl D-(-)-tartrate, the reagent in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide, or cumene hydroperoxide, the solvent in the reaction is methylene dichloride, and 3A or 4A molecular sieves are added to the reaction system. [Embodiment 30] 29. The method of embodiment 28, wherein in step 3", Sharpless asymmetric epoxidation is used, and the chiral catalyst used in the reaction is diethyl L-(+)-tartrate or diisopropyl L-(+)-tartrate, the reagent in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide, or cumene hydroperoxide, the solvent in the reaction is methylene dichloride, and 3A or 4A molecular sieves are added to the reaction system. [Embodiment 31] The method of embodiment 29 or 30, wherein in step 4′) or step 4″, the deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and the cyclization is carried out in the presence of a base, wherein the catalyst used in the hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the base used in the cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, for example, NaOH, KOH, KCO, NaOMe, DBU, or the deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize, thereby directly obtaining the cyclized product. [Embodiment 32] In step 5') or step 5", the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and the reaction can be performed without using a catalyst or with an acylation catalyst, and the catalyst used can be dialkyltin oxide, DMAP, or the like. , for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolane; the base used in the reaction can be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine; and the solvent in the reaction is an organic aprotic solvent, for example, methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof. [Embodiment 33] 33. The method of embodiment 31 or 32, wherein in step 6') or step 6", the alkylation of the amine is carried out by reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof. [Embodiment 34] 34. The method of any of embodiments 31 to 33, wherein in step 7') or step 7", the base used in the cross-coupling reaction can be selected from an inorganic base, such as KCO, NaCO, or an organic tertiary amine, such as triethylamine or diisopropylethylamine, and the solvent in the reaction is an organic protic solvent, such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents. [Embodiment 35] The method of any of embodiments 31 to 34, wherein in step 8') or step 8", the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH), Pd(OAc), PdCl, Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol. [Embodiment 36] In step 4') or step 4", deprotection can be carried out by a conventional method in the field of organic chemistry for removing a hydroxy-protecting group, for example, by hydrogenolysis in the presence of a catalyst to remove the benzyl-protecting group, and cyclization is carried out in the presence of a base, the catalyst used in hydrogenolysis is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, for example, NaOH, KOH, K2CO3, NaOMe, DBU, or deprotection and cyclization are carried out by hydrogenolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl-protecting group and cyclize, thereby directly obtaining the cyclized product; In step 5') or step 5", the sulfonyl halide used in the sulfonylation can be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride, such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride; the catalyst used in the reaction can be dialkyltin oxide, DMAP, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastannolan; the base used in the reaction can be a conventional organic base, such as pyridine, an organic tertiary amine, such as triethylamine or diisopropylethylamine; the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 6') or step 6", alkylation of amine is carried out by reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof; In step 7') or step 7", the base used in the cross-coupling reaction can be selected from inorganic bases such as K2CO3, Na2CO3, or organic tertiary amines such as triethylamine or diisopropylethylamine; the solvent in the reaction is an organic protic solvent such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of these solvents; In step 8') or step 8", the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , or Pd, and the solvent used in the reaction is an alcohol, an ester, or an ether, or a mixture of any two or more of these solvents, such as methanol or ethanol; 36. The method of any one of embodiments 31 to 35. [Embodiment 37] 37. The method of any of embodiments 27 to 36, wherein the step of converting intermediate compound XIIIa or intermediate compound XIIIb into their hydrochloride salts is carried out by adding hydrochloric acid, for example 1 N hydrochloric acid, to the intermediate compound, followed by crystallization and filtration to obtain the hydrochloride salt as a solid. [Embodiment 38] The method of any of embodiments 31 to 37, wherein the compounds of formula IXa and formula XIIa are used as starting materials to carry out steps 7') to 8') to obtain D-nebivolol of formula Ia. [Embodiment 39] The method of any of embodiments 31-37, wherein the compounds of formula IXb and formula XIIb are used as starting materials for carrying out steps 7"-8" to obtain L-nebivolol of formula Ib. [Embodiment 40] A mixture of D-nebivolol (formula Ia) and L-nebivolol (formula Ib) in any proportion [ka] And, A mixture of D-nebivolol (Formula Ia) and L-nebivolol (Formula Ib) prepared by the method of any of embodiments 31 to 39. [Embodiment 41] 41. A method for preparing a mixture of D-nebivolol (formula Ia) and L-nebivolol (formula Ib) in any proportion according to embodiment 40, comprising: (1) preparing D-nebivolol (formula Ia) and L-nebivolol (formula Ib) according to any of the methods of embodiments 27 to 39, and mixing them in any ratio; or (2) preparing the hydrochloride salt of intermediate compound XIIIa and the hydrochloride salt of intermediate compound XIIIb according to the method of any one of embodiments 27 to 37, mixing them in any ratio, neutralizing them with a base, and deprotecting the resulting mixture according to the deprotection step of embodiment 35; or (3) preparing the hydrochloride salt of intermediate compound XIIIa and the hydrochloride salt of intermediate compound XIIIb according to the method of any one of embodiments 27 to 37, respectively neutralizing them with a base to obtain free intermediate compound XIIIa and free intermediate compound XIIIb, respectively, mixing the two free intermediate compounds in any ratio, and deprotecting the resulting mixture according to the deprotection step described in embodiment 35. A method comprising: [Embodiment 42] A compound of formula III. [ka] wherein R is a hydroxy protecting group selected from an alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, allyl, methoxymethyl, benzyl, or —CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. Compound of formula IV1'. [ka] [In the formula, R a is hydrogen, or R a is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. [Embodiment 44] Compound of formula IV2'. [ka] [In the formula, R b is hydrogen, or R b is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl. [Embodiment 45] Formula V'(2R * ,3R * ) compound. [ka] [In the formula, R c is hydrogen, or R cis a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or —CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl; Here, compound V' is a racemate, and its relative configuration is V'(2R * ,3R * ), which is represented by equimolar amounts of Va' (2R,3R) and enantiomer Vb' (2S,3S), e.g., R c A compound having the formula: [ka] a racemic mixture consisting of [Embodiment 46] Formula VI'(2R * ,3S * ) compound. [ka] [In the formula, R d is hydrogen, or R d is a hydroxy protecting group selected from an aralkyl, alkoxyalkyl, allyl, or silyl protecting group, e.g., t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or —CHAr, where Ar is unsubstituted or substituted aryl, e.g., p-methoxyphenyl or halogen-substituted phenyl; Here, compound VI' is a racemate, and its relative configuration is VI'(2R * ,3S * ), which is represented by equimolar amounts of VIa' (2R,3S) and enantiomer VIb' (2S,3R), e.g., R d A compound having the formula: [ka] a racemic mixture consisting of [Embodiment 47] Compound of formula XI'. [ka] wherein R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10 aralkoxycarbonyl, for example, substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl] [Embodiment 48] Compound of formula XII'. [ka] wherein R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10 aralkoxycarbonyl, for example, substituted or unsubstituted benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl] [Embodiment 49] Compound of formula XVI'. [ka] [In the formula, R e is hydrogen, or R e is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl, benzoyl where the phenyl ring has one or more substituents, or silyl protecting groups, such as t-BuMeSi, t-BuPhSi, (i-Pr)Si, EtSi, methoxymethyl, benzyl, or -CHAr, where Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl. [Embodiment 50] 1-benzyloxy-2-bromomethyl-4-fluorobenzene, 4-[(2-benzyloxy-5-fluorophenyl)-butyn-1-yl]trimethylsilane, 1-(benzyloxy)-2-(butyn-3-yl)-4-fluorobenzene, 5-[2-(benzyloxy)-5-fluorophenyl]pent-2-yn-1-ol, trans-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol, (2R * ,3R * )-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2S * )-3,4-dihydro-2H-benzopyran-2-yl]-(1R * )-1,2-ethylene glycol, cis-5-[2-(benzyloxy)-5-fluorophenyl]pent-2-en-1-ol, (2R * ,3S * )-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2R * )-3,4-dihydro-2H-benzopyran-2-yl]-(1R * )-1,2-ethylene glycol, (S * ,R * )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R * ,R * )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, (R * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, (2R,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2S,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2R,3S)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, (2S,3R)-3-[2-(benzyloxy)-5-fluorophenethyl]-2-hydroxymethyl-oxacyclopropane, 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol, 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol, 1-[6-fluoro-(2R)-3,4-dihydro-2H-benzopyran-2-yl]-(1R)-1,2-ethylene glycol, 1-[6-fluoro-(2S)-3,4-dihydro-2H-benzopyran-2-yl]-(1S)-1,2-ethylene glycol, (S,R)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R,R)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (R,S)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol, or (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanyl)-methanol A compound selected from:

Claims

1. Formula VI'(2R * ,3S * ) compound. 【Chemical 1】 [In the formula, R d is benzyl or -CH 2 a hydroxy-protecting group selected from Ar, where Ar is p-methoxyphenyl or halogen-substituted phenyl; Here, compound VI' is a racemate, and its relative configuration is VI'(2R * ,3S * ), which is represented by equimolar amounts of VIa' (2R,3S) and enantiomer VIb' (2S,3R) 【Chemistry 2】 is a racemic mixture consisting of

2. Equimolar amounts 【Chemistry 3】 2. The compound of claim 1, which is a racemic mixture consisting of:

3. Formula VI(2R * ,3S * ) compounds 【Chemistry 4】 1. A method for preparing The following steps: 2) reducing the compound of formula III by selective catalytic hydrogenation to obtain the compound of formula IV2 in the cis configuration; Optionally, the following step: adding a non-polar organic solvent selected from n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of any two or more thereof, to the obtained compound of formula IV2, stirring at a temperature of 0°C to -20°C, followed by crystallization and filtration to obtain the compound of formula IV2 as a solid. 【Chemistry 5】 wherein R is benzyl or -CH 2 Ar is a hydroxy-protecting group selected from Ar, where Ar is p-methoxyphenyl or halogen-substituted phenyl. and, 3) epoxidizing the compound of formula IV2 in the cis configuration in the presence of an epoxidizing reagent to obtain the epoxide intermediate VI, where R is defined as above. 【Chemistry 6】 wherein compound VI is racemic, which is a mixture of equimolar amounts of the compound of formula VIa and the enantiomer VIb 【Chemistry 7】 It is a racemic mixture consisting of VI(2R * ,3S * ), and A method comprising:

4. In step 3), the epoxidation of the compound of formula IV2 in the cis configuration is carried out using MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and VO(acac) 2 and tert-butyl hydroperoxide, and pyridine-H in the presence of a catalytic amount of methylrhenium trioxide (MTO). 2 O 2 The method according to claim 3, wherein the reaction can be carried out by using an epoxidizing reagent selected from the group consisting of methylene dichloride, chloroform, tetrahydrofuran, toluene, and a mixture of any two or more thereof.

5. Formula VIII(R * / R * ) compounds 【Chemistry 8】 [In the formula, VIII(R * / R * ) is a racemate, which is a mixture of equimolar amounts of the compound of formula VIIIa (R / R) and the enantiomer VIIIb (S / S) 【Chemistry 9】 is a racemic mixture consisting of 1. A method for preparing The following steps: 4) Equation VI(2R * ,3S * ) is deprotected, followed by cyclization to give a compound of formula VIII (R * / R * ) a step of obtaining an intermediate compound of 【Chemistry 10】 wherein R is benzyl or -CH 2 Ar is a hydroxy-protecting group selected from Ar, where Ar is p-methoxyphenyl or halogen-substituted phenyl. wherein compound VI is a racemate, which is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is VI(2R * ,3S * ), 【Chemistry 11】 A method comprising:

6. 6. The method of claim 5, wherein R is benzyl.

7. In step 4), deprotection can be carried out by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, and the catalyst used in hydrogenolysis is Pd / C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 7. The method according to claim 5 or 6, wherein the Pd catalyst is selected from the group consisting of Pd, Pd, and the base used in the cyclization is selected from the group consisting of alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, or the deprotection and cyclization are carried out by hydrogenolysis under basic conditions using Pd / C as a catalyst to simultaneously remove the benzyl protecting group and cyclize the compound, thereby directly obtaining the cyclized product.

8. In step 4), the base used in the cyclization is NaOH, KOH, K 2 CO 3 8. The method of claim 7, wherein the hydroxybenzoate is selected from the group consisting of NaOMe, DBU, and HCl.

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