Nebivolol synthesis method and intermediate compound 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] This invention relates to a method for synthesizing pharmaceuticals and intermediate compounds thereof. Specifically, this invention relates to a method for synthesizing nebibolol, an intermediate compound thereof, and a method for preparing the intermediate compound. [Background technology]

[0002] Nebiborol hydrochloride, chemical name (+ / -)-di[2-(6-fluoro-dihydrobenzopyran-2-yl)-2-hydroxyethyl]amine (formula I) hydrochloride, is a third-generation highly selective β-receptor blocker developed by Johnson & Johnson, and also possesses vasodilatory effects. Nebiborol hydrochloride is primarily used to treat mild to moderate hypertension, angina pectoris, and congestive heart failure. Clinically used nebiborol hydrochloride is an equimolar mixture of the dextrorotatory isomer (formula Ia) and the levorotatory isomer (formula Ib), i.e., its racemic mixture (formula I). ​​The effect of nebiborol hydrochloride as a β-receptor blocker is mainly due to the dextrorotatory isomer, but other effects are due to the presence of both the dextrorotatory and levorotatory isomers.

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

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

[0005] [ka]

[0006] Both the levorotatory and dextrorotatory isomers of nebibolol possess significant biological activity; the levorotatory isomer exhibits endothelial cell-dependent vasodilatory effects, while the dextrorotatory isomer has potent β1 receptor blocking effects. Mixtures of the levorotatory and dextrorotatory isomers are currently used clinically, resulting in synergistic activity between the two isomers. In addition to the aforementioned β receptor blocking effect, this ensures that nebibolol possesses the unique advantage of selectively antagonizing β1 receptors by promoting NO release and resulting in vasodilation. Nebibolol does not affect β2 receptors and does not constrict bronchial or vascular smooth muscle. Therefore, from the perspective of nebibolol's important pharmacological value, developing a highly efficient, low-cost method for preparing nebibolol and its optical isomers that meets industrialization requirements would be of great economic and social benefit.

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

[0008] [ka]

[0009] Nebibolol is structurally characterized by a specific symmetry. The left and right parts of the molecule each contain structural units of (6-fluorobenzopyranyl)ethane-2-ol in different configurations. In the left part (part A), the hydroxyl group and the oxygen in the pyran ring are in the cis configuration, while in the right part (part B), they are in the trans configuration, and these two parts are linked by a nitrogen atom.

[0010] In prior art documents, the synthesis of nebivolol is mainly based on the symmetry of its molecule, where part A and part B are synthesized separately and then bonded with benzylamine. After separation, purification, and deprotection, nebivolol is obtained.

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

[0012] (1) Using a racemic intermediate as a raw material, constructing the left and right part fragments with relative configurations within the nebivolol molecule respectively, and then performing a cross-coupling reaction to prepare the desired product.

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

[0014]

Chemical formula

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

[0016]

Chemical formula

[0017] In European Patent No. 145067 of Janssen, chroman aldehyde and trimethylsulfoxonium iodide are reacted in the presence of sodium hydride to obtain a pair of non-equivalent diastereoisomers, namely the epoxide intermediate M A (S * [[ID=4))R * ) and M B (R * R *The following synthesis method is disclosed, characterized by obtaining ) as follows: Epoxy intermediate M A (S * R * ) and M B (R * R * When ) is separated by chromatography, it becomes an important intermediate for the synthesis of nebibolol, and subsequently, a cross-coupling reaction with benzylamide can yield mixtures of SRRR / RSSS and SRSS / RSRR.

[0018] [ka] Next, these are separated by repeated fractional crystallization as follows, and then deprotected by hydrogenolysis, resulting in S * R * R * R * - Nebibolol is obtained.

[0019] [ka]

[0020] Although the above-described preparation method is currently widely used in industry, its main problem is that it requires the separation of key intermediates by column chromatography, making it costly for large-scale production. Furthermore, the reaction conditions for preparing epoxides from unstable chromanaldehydes are stringent, yields are low, and the reagents used are expensive.

[0021] (2) Method for producing cyanide derivatives as described in International Publication No. WO2007 / 009143 (Chinese Patent No. 101243062) The method involves reacting racemocromaldehyde with sodium bisulfite and sodium cyanide to obtain a nitrile alcohol intermediate, which is then separated by column chromatography to obtain a pair of cis- and trans-nitrile alcohol diastereomers.

[0022] [ka]

[0023] The cis-nitrile alcohol intermediate is acetylated, then catalytically hydrogenated to convert it to the corresponding aldehyde, and then hydrolyzed to obtain the corresponding aldol intermediate.

[0024] Next, the trans-nitrile alcohol intermediate is catalytically hydrogenated to the corresponding alcoholamine, and this is reacted with benzoyl chloride to obtain an amide. Subsequently, reduction yields a benzylamine intermediate, which is finally condensed with the aldol intermediate to obtain a pair of diastereoisomers (four isomers) as crude nebibolol. Then, the crude nebibolol is converted to a salt with hydrochloric acid. After repeated recrystallization from ethanol and removal of another pair of isomers, a nebibolol racemic mixture is obtained.

[0025] [ka]

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

[0027] (3) D-nebibolol and L-nebibolol are synthesized separately, and when the D-isomer and L-isomer are mixed in equal amounts, a nebibolol racemate is obtained. Methods for synthesizing optical isomers of nebibolol mainly include the following.

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

[0029] [ka]

[0030] The above method is still the method described in Janssen's European Patent No. 145067. Although optically pure chromancarboxylic acid obtained by chiral separation is used, in the subsequent step of forming an epoxide intermediate using trimethylsulfoxonium iodide in the presence of sodium hydride, two unequal amounts of diastereoisomers are still produced, 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 an important intermediate has been reported, utilizing the Sharpless asymmetric epoxidation reaction. The synthetic route is as follows:

[0032] [ka]

[0033] However, these methods involve lengthy synthesis pathways, produce oily intermediates, require column chromatography for separation and purification, and employ expensive reagents; therefore, applying these methods to industrial production is difficult.

[0034] Furthermore, the following multi-step reaction also requires converting 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 SRRR-nevibolol in the desired configuration.

[0035] [ka]

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

[0037] [ka]

[0038] Optically active dextrorotatory SRRR-nebibolol can be obtained by selectively sulfonyling two chromandiol (S,R) and (R,R) isomers with p-toluenesulfonyl chloride, 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 [Overview of the Initiative] [Problems that the invention aims to solve]

[0041] In summary, prior art literature reveals that nebibolol synthesis still suffers from numerous technical drawbacks. For example, Janssen's method, while having a short synthesis pathway, requires the separation of two diastereomer epoxide intermediates by preparative HPLC, while other methods often involve multiple synthesis steps and the problem of isomer separation. Therefore, there is a need to develop a novel, highly efficient, and low-cost method for preparing nebibolol and its optical isomers that meets industrial requirements. [Modes for carrying out the invention]

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

[0043] The term "alkyl," whether used alone or in combination with other groups, refers to a monovalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, either linear or branched. 1~6 "Alkyl" refers to linear or branched alkyl groups having 1 to 6 carbon atoms, such as 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 straight-chain or branched divalent saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms. 1~6"Alkylene" refers to linear or branched alkylenes having 1 to 6 carbon atoms, such as methylene and ethylene.

[0045] The term "alkoxy" is used both alone and in combination with other groups. A -O- represents the group, where R A This represents an alkyl group as defined above. 1~6 "alkoxy" is R A -O- represents the group, where R A C as defined above 1~6 Represents alkyl.

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

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

[0048] "Nitro" represents -NO2.

[0049] "Aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms. 5~10 "Aryl" refers to an aryl molecule that has 5 to 10 carbon atoms. For example, C 5~10 The aryl group may be phenyl or naphthyl.

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

[0051] "Aralkyl" represents an alkyl group as defined above, which is substituted with an aryl group as defined above.

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

[0053] "Aralkoxy" represents an alkoxy as defined above, which is substituted with an aryl as defined above.

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

[0055] In one embodiment, the present invention relates to Formula III

[0056] [ka] A method for preparing [wherein R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, for example t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, for example p-methoxyphenyl or halogen-substituted phenyl], The following steps:

[0057] [ka] Step a): A step of reacting a compound of formula XIV [wherein R is a hydroxyl-protecting group as described above, and X is a halogen] with 3-(trisubstituted silyl)-propa-2-in-1-lithium to obtain a compound of formula XV [wherein R1, R2, and R3 are independently selected from alkyl or aryl groups, such as methyl, tert-butyl, or phenyl], Step b): A step of removing the silyl protecting group from the alkynyl terminus of the compound of formula XV to obtain the compound of formula XVI [wherein R is defined above], Step c): A step of reacting the compound of formula XVI with paraformaldehyde in the presence of a base or organometallic reagent to obtain the compound of formula III [wherein R is defined as above], Optionally, step d): Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the compound of formula III obtained in step c), stir at a low temperature, for example, 0°C to -20°C, then crystallize, filter, and obtain the compound of formula III as a solid. This provides a method that includes [something].

[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-butylmethyl ether, or toluene, at a reaction temperature of -100°C to 60°C.

[0059] In another preferred embodiment, the reaction in step b) is carried out in the presence of a base, an acid, or a fluorine-containing salt, preferably a base, wherein the base is selected from alkali metal or alkaline earth metal hydroxides or carbonates, 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 two or more of these; 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, NaNH2 or KNH2, 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 two or more of these, 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 two or more of these.

[0062] In a more 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. The reaction in 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 alkali metal or alkaline earth metal hydroxides or carbonates, such as NaOH, KOH, Na2CO3, and K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of two or more of these, and The base in step c) is selected from a metal hydride or an organic base, e.g., NaNH2 or KNH2; the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or a Grignard reagent, e.g., MeMgX, EtMgX, BuMgX, i-PrMgX [wherein X is Br, I, or Cl]; and the solvent used in the reaction is an organic aprotic solvent, e.g., tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of two or more of these.

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

[0064] In another embodiment, the present invention relates to compounds of formula III.

[0065] [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, for example, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, for example, p-methoxyphenyl or halogen-substituted phenyl].

[0066] In another embodiment, the present invention relates to the nevibolol racemic mixture of formula I.

[0067] [ka] [where I(S * R * R * R * ) represents a racemic mixture, which is arranged as follows:

[0068] [ka] This is a racemic mixture consisting of equimolar amounts of D-nebibolol Ia (SRRR) and its enantiomer L-nebibolol Ib (RSSS). A method for preparing, The following steps: 1) A step of reducing the compound of formula III with a metal composite hydride to obtain the compound of formula IV1 in a trans configuration, Optionally, the following steps may be taken: Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV1; stir at a low temperature, for example, 0°C to -20°C; then crystallize; filter; and obtain the compound of formula IV1 as a solid. [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] and,

[0069] 2) A step of reducing the compound of formula III by selective catalytic hydrogenation to obtain the compound of formula IV2 in the cis configuration, Optionally, the following steps may be taken: Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV2; stir at a low temperature, for example, 0°C to -20°C; then crystallize; filter; and obtain the compound of formula IV2 as a solid. [ka] [In the formula, R is defined as in 1) above] and,

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

[0071] [ka] Here, compound V is a racemic mixture, consisting of equimolar amounts of compound Va and enantiomer Vb.

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

[0073] [ka] Here, compound VI is a racemic mixture, consisting of equimolar amounts of compound VIa and enantiomer VIb.

[0074] [ka] It is a racemic mixture consisting of VI(2R), and its relative configuration is VI(2R * ,3S * ) is expressed as and, 4) Deprotect the compound of formula V and the compound of formula VI, and then carry out a cyclization reaction to obtain the compound of formula VII(S * / R * ) and formula VIII(R * / R * The process of obtaining each of the intermediate compounds. [In the formula, R is defined as above]

[0075] [ka] Here, VII(S * / R* ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S).

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

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

[0078] [ka] It is a racemic mixture consisting of, and, 5) Compounds of formulas VII and VIII are sulfonallylated with a halogenated sulfonyl 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 obtain compound IX (S * / R * ) and X(R * / R * The process of obtaining each of the following:

[0079] [ka] Here, IX(S * / R * ) is a racemic mixture, and it consists of equimolar amounts of the compound IXa(S / R) and the enantiomer IXb(R / S).

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

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

[0082] [Chemistry] and, and 6) Reacting a compound of formula IX or X with benzylamine to effect alkylation of the amine to obtain the corresponding compound XI or XII

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

[0084] [Chemistry] and,

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

[0086] [Chemistry] and, and 7) Under basic conditions, intermediate compounds IX(S * / R * ) and XII(R * / R *) or intermediate compound X(R * / R * ) and XI(S * / R * ) are subjected to a cross-coupling reaction to obtain compounds XIII(S * R * R * R * ) and XIII'(S * R * S * S * ) [wherein the definition of R" is the same as the definition of M above]

[0087]

Chemical formula

[0088]

Chemical formula

[0089]

Chemical formula

[0090]

Chemical formula

[0091] In certain embodiments, in step 1), the metal complex hydride used as the reducing agent is LiAlH4 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, and the reaction temperature is -100°C to 60°C.

[0092] In certain embodiments, in step 2), the catalyst used in the selective catalytic hydrogenation is selected from a Lindlar catalyst or a P-2 nickel boride / ethylenediamine catalyst.

[0093] In one embodiment, in step 3), the epoxidation of the trans-configured compound of formula IV1 or the cis-configured compound of formula IV2 can be carried out using epoxidation methods commonly used in the art. For example, the epoxidizing reagents that can be used in the reaction are selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, as well as the pyridine-H2O2 system in the presence of a catalytic amount of methylrhenium trioxide (MTO). The solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, tetrahydrofuran, toluene, or a mixture of two or more of these, and the reaction temperature is -50°C to 50°C.

[0094] In one embodiment, in step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, the catalyst used for hydrolysis being a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, the base used for cyclization being selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis 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 one embodiment, in step 5), the halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or alkylsulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and the reaction may be carried out without a catalyst or with an appropriate amount of acylation catalyst, and the catalyst may be dialkyltin oxide, DMAP, For example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane can be used, 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 chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these, and the reaction temperature is -50°C to 50°C.

[0096] In one embodiment, in step 6), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, the molar ratio of benzylamine to the corresponding sulfonate substrate used is 1 / 1 to 10 / 1, the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these, 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 an inorganic base, such as K2CO3, Na2CO3, or an organic tertiary amine, 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 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)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, ester, or ether, or a mixture of 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 a reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydrogenate, 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 two or more of these. In step 2), the catalyst used for selective catalytic hydrogenation is selected from either the Lindlar catalyst or the P-2 nickel boride / ethylenediamine catalyst. In step 3), the epoxidation of the trans-configured compound of formula IV1 or the cis-configured compound of formula IV2 can be carried out using epoxidation methods commonly used in the art. For example, the epoxidizing reagents that can be used in the reaction are selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the 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 chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, toluene, or a mixture of two or more of these. In step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, the catalyst used for hydrolysis being a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, the base used for cyclization being selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and perform cyclization to directly obtain the cyclized product. In step 5), the halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or alkylsulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, or o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride. The reaction may be carried out without a catalyst or with an appropriate amount of acylation catalyst, and the catalyst may be a dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane. The base used in the reaction may be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine. The solvent in the reaction may be an organic aprotic solvent, for example, methylene dichloride, chloroform, tetrahydrofuran, methyltetrahydrofuran, pyridine, toluene, acetonitrile, ethyl acetate, DMF, DMA, or a mixture of two or more of these. In step 6), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. 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, 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 two or more of these solvents. In step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, ester, or ether, or a mixture of two or more of these solvents, such as methanol or ethanol.

[0100] Those skilled in the art will understand that in the above 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 IV2 can be used as a starting material for carrying out steps 2) to 9) above to obtain the nebibolol racemate of formula I, or the compounds of formula IX and XII can be used as a starting material for carrying out steps 7) to 9) above to obtain the nebibolol racemate of formula I.

[0101] In another embodiment, the present invention is formulated by formula IV1

[0102] [ka] [In the formula, R is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] A method for preparing, The following steps: The process involves reducing the compound of formula III with a metal composite hydride to obtain the compound of formula IV1, and optionally, the following steps: adding a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV1, stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization, filtration, and obtaining the compound of formula IV1 as a solid.

[0103] [ka] [In the formula, R is defined as above] and This provides a method that includes [something].

[0104] In a preferred embodiment, the metal complex hydride used as a reducing agent in the above method is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydrogenate, 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 two or more of these.

[0105] In another embodiment, the present invention is based on formula IV2

[0106] [ka] [In the formula, R is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] A method for preparing, The following steps: The process involves reducing the compound of formula III by selective catalytic hydrogenation to obtain the compound of formula IV2 in a cis configuration, and optionally, the following steps: adding a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV2, stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization, filtration, and obtaining the compound of formula IV2 as a solid.

[0107] [ka] [In the formula, R is defined as above] and This provides a method that includes [something].

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

[0109] In another embodiment, the present invention is based on formula VII(S * / R * ) compounds

[0110] [ka] [where VII(S * / R * ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S).

[0111] [ka] It is a racemic mixture consisting of the following: A method for preparing, The following steps: 3) Compounds of formula IV1 in trans configuration

[0112] [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but as an example, R in the following formula is represented by benzyl (Bn)] The process involves epoxidizing the product in the presence of an epoxidizing reagent to obtain an epoxide intermediate V.

[0113] [ka] Here, compound V is a racemic mixture, consisting of equimolar amounts of compound Va and enantiomer Vb.

[0114] [ka] It is a racemic mixture consisting of V(2R * ,3R * ) is expressed as and, 4) Formula V(2R * ,3R * The compound of ) is deprotected, followed by a cyclization reaction, and then formula VII(S * / R * The process of obtaining an intermediate compound of ) [In the formula, R is defined as above, but as an example, R shown in the following formula is represented by benzyl (Bn).]

[0115] [ka] Here, VII(S * / R * ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S).

[0116] [ka] It is a racemic mixture consisting of, and This provides a method that includes [something].

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

[0118] In another embodiment, the present invention is based on formula VIII(R * / R * ) compounds

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

[0120] [ka] It is a racemic mixture consisting of the following: A method for preparing, The following steps: 3) Compounds of formula IV2 in cis configuration

[0121] [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but as an example, R in the following formula is represented by benzyl (Bn)] The process involves epoxidizing the intermediate VI in the presence of an epoxidizing reagent.

[0122] [ka] Here, compound VI is a racemic mixture, consisting of equimolar amounts of compound VIa and enantiomer VIb.

[0123] [ka] It is a racemic mixture consisting of VI(2R), and its relative configuration is VI(2R * ,3S * ) is expressed as and, 4) Equation VI(2R * ,3S * The compound of formula VIII(R) is deprotected, followed by a cyclization reaction. * / R * The process of obtaining an intermediate compound of ) [In the formula, R is defined as above, but as an example, R shown in the following formula is represented by benzyl (Bn).]

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

[0125] [ka] It is a racemic mixture consisting of, and This provides a method that includes [something].

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

[0127] In another embodiment, the present invention relates to the nevibolol racemic mixture of formula I.

[0128] [ka] [where I(S * R * R * R * ) represents a racemic mixture, which is arranged as follows:

[0129] [ka] This is a racemic mixture consisting of equimolar amounts of D-nebibolol Ia (SRRR) and its enantiomer L-nebibolol Ib (RSSS). A method for preparing, The following steps a) to c) or d) and steps 1) to 9):

[0130] [ka] Step a): A step of reacting the compound of formula XIV with 3-(trisubstituted silyl)-propa-2-in-1-lithium to obtain the compound of formula XV [wherein each R1, R2, and R3 is independently selected from alkyl or aryl groups, e.g., methyl, tert-butyl, or phenyl, and R is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, e.g., t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl group, e.g., p-methoxyphenyl or halogen-substituted phenyl, and X is a halogen], Step b): The step of removing the silyl protecting group from the alkynyl terminus of the compound of formula XV to obtain the compound of formula XVI [wherein R is defined as above], Step c): A step of reacting the compound of formula XVI with paraformaldehyde in the presence of a base or organometallic reagent to obtain the compound of formula III [wherein R is defined as above], Optionally, step d): Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the compound of formula III obtained in step c), stir at a low temperature, for example, 0°C to -20°C, then crystallize, filter, and obtain the compound of formula III as a solid. Step 1): A step of reducing the compound of formula III with a metal composite hydride to obtain the trans-configured compound of formula IV1, and optionally the following step: Adding a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV1, stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization, filtration, and obtaining the compound of formula IV1 as a solid.

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

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

[0133] [ka] Here, compound V is a racemic mixture, consisting of equimolar amounts of compound Va and enantiomer Vb.

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

[0135] [ka] Here, compound VI is a racemic mixture, consisting of equimolar amounts of compound VIa and enantiomer VIb.

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

[0137] [ka] Here, VII(S * / R* ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S).

[0138] [ka] It is a racemic mixture consisting of the following:

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

[0140] [ka] It is a racemic mixture consisting of, and, Step 5): Compounds of formulas VII and VIII are sulfonallylated with a halogenated sulfonyl 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 form compound IX (S * / R * ) and X(R * / R * The process of obtaining each of the following:

[0141] [ka] Here, IX(S * / R * ) is a racemic mixture, and it consists of equimolar amounts of the compound IXa(S / R) and the enantiomer IXb(R / S).

[0142] [ka] It is a racemic mixture consisting of the following:

[0143] [ka] Here, X(R * / R * ) is a racemic mixture, which consists of equimolar amounts of the compound Xa(R / R) and the enantiomer Xb(S / S).

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

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

[0146] [ka] It is a racemic mixture consisting of the following:

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

[0148] [ka] It 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 * The cross-coupling reaction of compound XIII(S) was carried out, and compound XIII(S) * R * R * R * ) and XIII'(S * R * S * S * ) process to obtain [In the formula, the definition of R" is the same as the definition of M above.]

[0149] [ka] JPEG2023109863000081.jpg49155 Here, XIII(S * R * R * R *) It is a racemic mixture, and it consists of equimolar amounts of the compound of formula XIIIa (SRRR) and the enantiomer XIIIb (RSSS).

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

[0151] [ka] It is a racemic mixture consisting of, and, Step 8): Form a salt of the mixture of compounds of formula XIII and formula XIII', purify it by recrystallization, and obtain the isomer XIII'(S * R * S *S * Remove the intermediate compound XIII(S * R * R * R * The process of obtaining ) Step 9): Deprotecting intermediate compound XIII to obtain the nevibolol racemate of formula I.

[0152] [ka] Here, I(S * R * R * R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula Ia(SRRR) and its enantiomer Ib(RSSS). and This provides a method that includes [something].

[0153] Regarding this method for preparing the compound 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 more 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, and K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of two or more of these. In step c), the base is selected from a metal hydride or an organic base, for example, NaNH2 or KNH2; the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or Grignard reagents, for example, MeMgX, EtMgX, BuMgX, i-PrMgX [wherein X is Br, I, or Cl]; and 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 two or more of these. In step 1), the metal complex hydride used as a reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydrogenate, 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 two or more of these. In step 2), the catalyst used for selective catalytic hydrogenation is selected from either the Lindlar catalyst or the P-2 nickel boride / ethylenediamine catalyst. In step 3), the epoxidation of the trans-configured compound of formula IV1 or the cis-configured compound of formula IV2 can be carried out using epoxidation methods commonly used in the art. For example, the epoxidizing reagents that can be used in the reaction are selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, as well as the 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 chloride, chloroform, tetrahydrofuran, toluene, or a mixture of two or more of these. In step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, the catalyst used for hydrolysis being a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, the base used for cyclization being selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and perform cyclization to directly obtain the cyclized product. In step 5), the halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or alkylsulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride. The reaction may be carried out without a catalyst or with an appropriate amount of acylation catalyst, and the catalyst may be a dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane. The base used in the reaction may be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine. The solvent in the reaction may be an organic aprotic solvent, for example, methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. In step 6), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. 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, 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 two or more of these solvents. In step 9), the catalyst used in the deprotection reaction is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, ester, or ether, or a mixture of two or more of these solvents, such as methanol or ethanol.

[0155] Those skilled in the art will understand that in the above method for preparing the 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 the compound of formula I. For example, the compound of formula XV can be used as a starting material for carrying out steps b) to 9) above to obtain the nebibolol racemate of formula I, or the compound of formula XVI can be used as a starting material for carrying out steps c) to 9) above to obtain the nebibolol racemate of formula I.

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

[0157] [ka] 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. [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.]

[0158] [ka] and, 4') A step of deprotecting intermediate compounds Va and VIa, followed by cyclization to obtain intermediate compounds VIIa and VIIIa, respectively. [In the formula, R is defined as above]

[0159] [ka] and, 5') A step to obtain intermediate compounds IXa and Xa by sulfonating intermediate compounds VIIa and VIIIa with a sulfonyl halogen 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.

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

[0161] [ka] and, 7') A step in which intermediate compounds IXa and XIIa, or intermediate compounds Xa and XIa, are cross-coupled under basic conditions to obtain intermediate compound XIIIa. [In the formula, the definition of Ar' is the same as the definition of M above.]

[0162] [ka] and, Optionally, a step is taken to convert intermediate compound XIIIa to its hydrochloride salt, 8') Steps to deprotect intermediate compound XIIIa to obtain D-nebibolol (formula Ia)

[0163] [ka] Alternatively, the hydrochloride salt of intermediate compound XIIIa is neutralized with a base to convert it to the free form of intermediate compound XIIIa, followed by deprotection to obtain D-nebibolol (formula Ia). This provides a method that includes [something].

[0164] In another embodiment, the present invention relates to L-nebibolol (formula Ib)

[0165] [ka] A method for preparing, The following steps: 3) The process of asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to obtain intermediate compounds Vb and VIb, respectively. [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.]

[0166] [ka] and, 4") A step of deprotecting intermediate compounds Vb and VIb, followed by cyclization to obtain intermediate compounds VIIb and VIIIb. [In the formula, R is defined as above]

[0167] [ka] and, 5") The intermediate compounds VIIb and VIIIb are sulfonated with a halogenated sulfonyl 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 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 and obtain intermediate compound XIb or XIIb.

[0169] [ka] and, A step to obtain intermediate compound XIIIb by carrying out a cross-coupling reaction of intermediate compounds IXb and XIIb, or intermediate compounds Xb and XIb, under 7" basic conditions. [In the formula, the definition of Ar' is the same as the definition of M above.]

[0170] [ka] and, Optionally, a step is taken to convert intermediate compound XIIIb to its hydrochloride salt, 8") Step of deprotecting intermediate compound XIIIb to obtain L-nebibolol (formula Ib)

[0171] [ka] Alternatively, the hydrochloride salt of intermediate compound XIIIb is neutralized with a base to convert it to the free form of intermediate compound XIIIb, followed by deprotection to obtain L-nebibolol (formula Ib). This provides a method that includes [something].

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

[0174] In a method for preparing a compound of formula Ia or Ib, in step 4') or step 4"), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, wherein the catalyst used for hydrolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization can be selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis 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 a method for preparing a compound of formula Ia or Ib, in step 5') or step 5"), the halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride or a 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 may be performed without a catalyst or with an acylation catalyst, and the catalyst used may be a dialkyl The reaction can use tin oxides, DMAPs, such as dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane, 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 chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these, and the reaction temperature is -5 to 50°C.

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

[0177] In a 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 an inorganic base, such as K2CO3, Na2CO3, or an organic tertiary amine, 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 two or more of these solvents; and the reaction temperature is -25°C to 150°C.

[0178] In a 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)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, ester, or ether, or a mixture of two or more of these solvents, such as methanol or ethanol.

[0179] In one embodiment, 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, filtration, and obtaining the hydrochloride salt as a solid.

[0180] In a preferred embodiment for preparing a compound of formula Ia or formula Ib, in step 4') or step 4"), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, wherein the catalyst used for hydrolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis 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 halogenated sulfonyl used in sulfonylation may be an aryl sulfonyl chloride or a substituted aryl sulfonyl chloride or alkyl sulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and the catalyst used in the reaction may be a dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane, the base used in the reaction may be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine, and the solvent in the reaction may be an organic aprotic solvent, for example, methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. In step 6') or step 6"), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. 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 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 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, PdCl2, or Pd, and the solvent in the reaction is an alcohol, ester, or ether, or a mixture of two or more of these solvents, such as methanol or ethanol.

[0181] In one embodiment, 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, filtration, and obtaining the hydrochloride salt as a solid.

[0182] Those skilled in the art will understand that in the above method for preparing a compound of formula Ia or formula Ib, the reaction product of any one of the above steps can be used as a starting material for carrying out the subsequent steps described above to prepare a compound of formula Ia or formula Ib. For example, compounds of formula IXa and formula XIIa can be used as a starting material for carrying out steps 7') to 8') above to obtain D-nebibolol of formula Ia, or compounds of formula IXb and formula XIIb can be used as a starting material for carrying out steps 7") to 8") above to obtain L-nebibolol of formula Ib.

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

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

[0185] In another embodiment, the present invention also provides a method for preparing a mixture of D-nebibolol (formula Ia) and L-nebibolol (formula Ib) in any proportion, (1) Prepare D-nebibolol (formula Ia) and L-nebibolol (formula Ib) respectively according to the methods described in steps 3') to 8') and steps 3) to 8) above, and mix them in any proportion; or (2) Prepare the hydrochloride salt of intermediate compound XIIIa and the hydrochloride salt of intermediate compound XIIIb respectively according to the methods described in steps 3') to 7') and steps 3) to 7) above, mix them in any proportion, neutralize with a base, and deprotect the mixture obtained according to the method described in step 8'); or (3) Prepare the hydrochloride salt of intermediate compound XIIIa and the hydrochloride salt of intermediate compound XIIIb according to the methods described in steps 3') to 7') and steps 3) to 7) above, neutralize them with a base to obtain free intermediate compound XIIIa and free intermediate compound XIIIb, mix the two free intermediate compounds in any proportion, and deprotect the mixture obtained according to the method described in step 8'). This provides a method that includes [something].

[0186] In another embodiment, the present invention relates to compounds of formula IV1'.

[0187] [ka] [In the formula, R a is hydrogen, or R a [The protecting group is a hydroxyl group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] To provide.

[0188] In another embodiment, the present invention relates to compounds of formula IV2'.

[0189] [ka] [In the formula, R b is hydrogen, or R b [The protecting group is a hydroxyl group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] To provide.

[0190] In another embodiment, the present invention is based on the formula V'(2R * ,3R * ) compounds

[0191] [ka] [In the formula, R c is hydrogen, or R c This is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl. Here, compound V' is a racemic mixture, and its relative configuration is V'(2R * ,3R * This is represented by ), which is an equimolar amount of Va'(2R,3R) and the enantiomer Vb'(2S,3S), for example R c Compounds having the following formula, wherein benzyl

[0192] [ka] It is a racemic mixture consisting of the following: To provide.

[0193] In another embodiment, the present invention is based on formula VI'(2R * ,3S * ) compounds

[0194] [ka] [In the formula, R d is hydrogen, or R dThis is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl. Here, compound VI' is a racemate, and its relative configuration is VI'(2R * ,3S * ) is represented as, which is equivalent to equimolar amounts of VIa'(2R,3S) and the enantiomer VIb'(2S,3R), for example R d Compounds having the following formula, wherein benzyl

[0195] [ka] It is a racemic mixture consisting of the following: To provide.

[0196] In another embodiment, the present invention relates to compounds of formula XI'.

[0197] [ka] [In the formula, R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10 Aralcoxycarbonyls, for example, substituted or unsubstituted benzyls, tert-butyloxycarbonyls, and benzyloxycarbonyls. To provide.

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

[0199] [ka] [In the formula, R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10Aralcoxycarbonyls, for example, substituted or unsubstituted benzyls, tert-butyloxycarbonyls, and benzyloxycarbonyls. To provide.

[0200] In another embodiment, the present invention relates to compounds of formula XVI'.

[0201] [ka] [In the formula, R e is hydrogen, or R e The hydroxyl protecting group is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl, benzoyl having substituents (multiple substituents) on the phenyl ring, or silyl protecting groups, for example, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, for example, p-methoxyphenyl or halogen-substituted phenyl. To provide.

[0202] In one embodiment, the present invention also provides the following for use in the synthesis of nebibolol: 1-benzyloxy-2-bromomethyl-4-fluorobenzene, 4-[(2-benzyloxy-5-fluorophenyl)-butyne-1-yl]trimethylsilane, 1-(benzyloxy)-2-(buty-3-yl)-4-fluorobenzene, 5-[2-(benzyloxy)-5-fluorophenyl]penta-2-in-1-ol, trans-5-[2-(benzyloxy)-5-fluorophenyl]penta-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]penta-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-chromanil)-methanol, (R * ,R * )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanil)-methanol, (S * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-methanol, (R * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-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-chromanil)-methanol, (R,S)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanil)-methanol, (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-methanol, or The present invention provides specific compounds selected from (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-methanol. [Examples]

[0203] The methods of the present invention are further illustrated by the following embodiments. It should be understood that these embodiments are provided to further aid in understanding the present invention and are not intended to limit the scope of the invention in any way.

[0204] The abbreviations used in this invention have the following meanings. Abbreviation: Boc tert-butyloxycarbonyl DEAD Diethyl Azodicarboxylate DIPEA Diisopropylethylamine DMF Dimethylformamide DMA (dimethylacetamide) HCl 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 at 0°C. The temperature was raised to room temperature, and the reaction was carried out for 2 hours. TLC indicated that the reaction was complete.

[0208] Workup: 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 x 3). The organic phases were combined and washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The resulting organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6 g of crude product. The obtained crude product was recrystallized from PE / Et2O to obtain 5.9 g of the desired product as crystals. The overall yield was 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)-butyne-1-yl]trimethylsilane (compound XV, where R is benzyl)

[0210] [ka] 2.4 mL (16.1 mmol) of trimethylsilylpropine 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. After the addition, the solution was stirred at this temperature for 2 hours until the reaction solution turned orange-red. The temperature was then reduced to below -100°C. A solution of compound XIV (where R is benzyl) 3.5 g (11.9 mmol) in 5 mL of anhydrous THF was added. The reaction was then carried out for 1 hour. TLC indicated that the reaction was complete.

[0211] Workup: The reaction was completed with a 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. Column chromatography (PE / Et2O = 100:1) yielded 3.79 g of pure product. 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-(buty-3-yl)-4-fluorobenzene (compound XVI, where R is benzyl)

[0213] [ka] Compound XV (wherein R is benzyl) 1.15 g (3.52 mmol) was dissolved in 20 ml of MeOH, and 0.5 g (3.6 mmol) of K2CO3 was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure. The residue was extracted with toluene, washed with water and saturated NaCl solution, dried over anhydrous Na2SO4, and filtered. After evaporation of the filtrate to dryness, 0.87 g of a colorless oil was obtained. After filtration on a short silica gel column and elution with PL / toluene (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]penta-2-in-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, cooled to -100°C, and 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 (CH2O) was added. n 0.6 g (20 mmol) was added. After the addition was complete, the reaction mixture was stirred at 0°C to room temperature for 2.5 hours. A saturated NH4Cl solution was added to complete the reaction. The organic phase was separated, and the aqueous layer was extracted twice with Et2O. The extracts were combined, washed with water, washed with a saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness. After purification by elution with petroleum ether / siRNA(4 / 1) on a short silica gel column, 1.51 g of a colorless oily substance 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 value for C18H18O2F (M+H)+: 285.1285, measured value: 285.1290.

[0216] [Example 4'] Preparation of 5-[2-(benzyloxy)-5-fluorophenyl]penta-2-in-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, cooled to -100°C, and 2.9 ml (6.9 mmol) of 2.4 M BuLi was added. After the addition was complete, the solution was stirred at -100°C for 30 minutes, then heated to 0°C, and (CH2O) was added. n 0.6 g (20 mmol) 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 extracts were combined, washed with water, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain an oily substance. 10 ml of n-hexane was added to the oily substance. The resulting 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 value for C18H18O2F (M+H)+: 285.1285, measured value: 285.1290.

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

[0219] [ka] 1.05 g (3.6 mmol) of compound III (wherein 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 then added. After the addition was complete, the reaction mixture was stirred overnight at room temperature (TLC showed that under PL / EtOA = 4 / 1 conditions, the Rf value of the product was the same as that of the starting material). The following day, approximately 20 ml of saturated potassium sodium tartrate solution was carefully added dropwise to complete the reaction. The organic phase was separated, and the aqueous layer was extracted with 20 ml x 2 of ethyl acetate. The extracts were combined, washed with 1 N HCl, washed with water, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain 1.0 g of the product (a pale yellow oily substance). 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]penta-2-en-1-ol (compound IV-1, where R is benzyl)

[0221] [ka] 1.05 g (3.6 mmol) of compound III (wherein 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 then added. After the addition was complete, the reaction mixture was stirred overnight at room temperature (TLC showed that under PL / EtOA = 4 / 1 conditions, the Rf value of the product was the same as that of the starting material). The following day, approximately 20 ml of saturated potassium sodium tartrate solution was carefully added dropwise to complete the reaction. The organic phase was separated, and the aqueous layer was extracted with 20 ml x 2 of ethyl phosphate. The extracts were combined, washed with 1 N HCl, washed with water, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain an oily substance. 8 ml of n-hexane was added to the oily substance. The resulting mixture was stirred and cooled to -20°C. Crystals precipitated. After filtration, 0.7 g of an off-white solid with 99% purity was obtained. 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 (wherein R is benzyl) was dissolved in 20 ml of DMC, and 1.01 g of 75% MCPBA (4.4 mmol) was added while stirring. After the addition was complete, the reaction mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with DMC, washed twice continuously with 5% NaOH, washed with water, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness to obtain 1.08 g of a pale yellow oily substance (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) Method 1

[0225] [ka] 1.08 g of compound V (wherein R is benzyl) was dissolved in 20 ml of ethyl acetate, and 0.2 g of 10% Pd / C was added. 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 oily substance. The oily substance was dissolved in 20 ml of DMC and cooled in an ice bath, to which 10 ml of 10% NaOH-NaCl solution was added. The resulting solution was stirred in an ice bath for 30 minutes. The reaction mixture was heated 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 extracts were combined, washed with water, and dried over anhydrous Na2SO4. After purification by elution with PL / ethyl acetate (1 / 1) on a short silica gel column, 0.71 g of a white solid (95%) was obtained.

[0226] Method 2

[0227] [ka] 1.5 g of compound V (wherein R is benzyl) was mixed with 25 ml of anhydrous ethanol, 200 mg of 10% Pd / C, and 100 mg of anhydrous Na2CO3. The reaction mixture was hydrogenated under atmospheric pressure until no more hydrogen was absorbed (approximately 1.5 hours), and then stirred at 60°C for 2.5 hours. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain 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: 212.0849, Measured value: 212.0851

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

[0229] [ka] 420 mg, 1.7 mmol of Ni(OAc)2·4H2O was placed in a 250 ml round-bottom flask, the flask was evacuated to create a vacuum, and argon was introduced. 20 ml of degassed 95% ethanol was added. 100 mg, 2.6 mmol of sodium borohydride was added to the reaction mixture under argon while stirring. The reaction mixture was stirred for 15 minutes until it turned black. Next, 0.5 ml, 7.5 mmol of ethylenediamine was added. The reaction mixture was stirred for 5 minutes, and degassed NaOH solution (2 M, 60 μL, 0.1 mmol) was added. Compound III (wherein 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 carried out at room temperature for 18 hours. TLC showed that the reaction was complete.

[0230] Workup: The hydrogen used in the reaction was replaced with argon. After removing the hydrogen, the reaction mixture was filtered through Celite. The filtrate was washed with 100 ml of ethyl acetate and water (3 × 20 ml). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain 3.15 g of 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 value for C18H20O2F (M+H)+: 287.1448, measured value: 287.1441.

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

[0232] [ka] Ni(OAc)2·4H2O (420 mg, 1.7 mmol) was placed in a 250 ml round-bottom flask, evacuated to create a vacuum, and argon was introduced. 20 ml of degassed 95% ethanol was added. Sodium borohydride (100 mg, 2.6 mmol) was added to the reaction mixture under argon while stirring. The reaction mixture was stirred for 15 minutes, at which point it turned black. Next, ethylenediamine (0.5 ml, 7.5 mmol) was added. The reaction mixture was stirred for 5 minutes, and degassed NaOH solution (2 M, 60 μL, 0.1 mmol) was added. Compound III (wherein 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 carried out at room temperature for 18 hours. TLC showed that the reaction was complete.

[0233] Workup: The hydrogen used in the reaction was replaced with argon. After removing the hydrogen, the reaction mixture was filtered through Celite. The filtrate was washed with 100 ml of ethyl acetate and water (3 × 20 ml). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the resulting filtrate was evaporated to dryness to obtain an oily substance. 30 ml of n-hexane was added to the oily substance. 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 value for C18H20O2F (M+H)+: 287.1448, measured value: 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] Compound VI was obtained using compound IV-2 (wherein R is benzyl) as a starting material, following the same method as in Example 6. 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] Compound VIII was obtained using compound VI (wherein R is benzyl) as a starting material, following a similar method to the two methods of Example 7. 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: 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] Compound VII was suspended in 100 ml of toluene, and 0.5 g (2 mmol) of dibutyltin oxide (Bu₂SnO) was added. The mixture was stirred at room temperature for 1 hour, and then diisopropylethylamine (3.95 ml, 24 mmol) and p-methylphenylsulfonyl chloride (TsCl) (3.99 g, 21 mmol) were added to the mixture. The reaction mixture was stirred at room temperature overnight. The following day, the reaction mixture was washed with 2N HCl, washed with water, and dried over anhydrous Na₂SO₄. After purification by elution with PL / siRNA(3 / 1) on a short silica gel column, 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] Compound VIII 4.24 g (20 mmol) was suspended in 100 ml of toluene, and dibutyltin oxide (Bu₂SnO) 0.5 g (2 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then diisopropylethylamine (3.95 ml, 24 mmol) and p-methylphenylsulfonyl chloride (TsCl) 3.99 g (21 mmol) were added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with 2N HCl, washed with water, and dried over anhydrous Na₂SO₄. After purification by elution with PL / siRNA(3 / 1) on a short silica gel column, 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: 389.0829, Measured value: 389.0823

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

[0243] [ka] 1.83 g (5 mmol) of compound IX was dissolved in 20 ml of THF, and 2.72 ml of benzylamine was added. The reaction mixture was heated under reflux for 16 hours (TLC showed that the spots of the starting material had disappeared), and evaporated to dryness under reduced pressure. 10% Na2CO3 was added to the residue, and the resulting solution was extracted three times with siRNA. The extracts were combined, 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 siRNA. When 20 ml of cyclohexane was added to the residue, 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: 302.1550, Measured value: 302.1546

[0244] [Example 14] (R * ,R * Preparation of )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-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. The reaction mixture was heated under reflux for 16 hours (TLC showed that the spots of the starting material had disappeared), and evaporated to dryness under reduced pressure. 10% Na2CO3 was added to the residue, and the resulting solution was extracted three times with siRNA. The extracts were combined, 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 siRNA. When 20 ml of cyclohexane was added to the residue, 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-(+ / -)-nebibolol (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 under reflux for 16 hours with stirring, and evaporated to dryness under reduced pressure. 50 ml of water was added to the residue, and the resulting solution was extracted twice with ELISA. The extracts were combined, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain 1.59 g of the product as a syrup. 25 ml of isopropanol was added to the product, and the mixture was heated to dissolve the product. 0.5 g of oxalic acid (FW=126) was added. The resulting solution was heated for 20 minutes with stirring, cooled, left at room temperature for 5 hours, filtered, and oven-dried to obtain 1.59 g of a white solid. The obtained product was recrystallized twice from ethanol to obtain 0.69 g of compound XIII as an oxalate. The obtained product was suspended in 20 ml of methylene chloride, and 10 ml of 10% sodium carbonate was added. The mixture was stirred at room temperature for 25 minutes, 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 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: 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] 2 g of powdered 4A molecular sieve was cooled to -25°C in 25 ml of anhydrous methylene chloride, and 1.85 g (7.9 mmol) of D-(-)-DIPT and 42.06 g (7.2 mmol) of Ti(OPr-i) were added successively. After the additions were 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 additions were complete, the mixture was stirred at -25°C for 20 minutes, and then 1.89 g (6.6 mmol) of compound IV1 (where R is benzyl) in 20 ml of methylene chloride was added dropwise (within approximately 15 minutes). After the additions were complete, the reaction mixture was stirred at -25 to -22°C for 6 hours (until the spots of the starting material disappeared).

[0250] Workup: The reaction mixture was poured into a fresh solution of FeSO4 / tartaric acid / H2O (FeSO4 2.5g + tartaric acid 1.0g + H2O 20ml). 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 chloride. The extracts were combined, washed with water, dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to obtain 4.0g of oily substance.

[0251] The oily substance was dissolved in 40 ml of DCM, and 20 ml of a 30% NaOH solution in saturated NaCl 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 extracts were combined, washed with water, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness. The residue was loaded onto a silica gel column and eluted with PL / siRNA(3 / 1) to obtain 1.54 g of a colorless oily substance. 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] Compound Vb was obtained using compound IV1 as a starting material and L-(+)-diisopropyl tartrate as a chiral derivative, following the same method as in Example 16. [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] 2 g of powdered 4A molecular sieve was cooled to -25°C in 25 ml of anhydrous methylene chloride, and 1.85 g (7.9 mmol) of D-(-)-DIPT and 42.06 g (7.2 mmol) of Ti(OPr-i) were added successively. After the additions were 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 additions were complete, the mixture was stirred at -25°C for 20 minutes, and then 1.92 g (6.7 mmol) of compound IV2 (wherein R is benzyl) in 20 ml of methylene chloride was added dropwise (within approximately 15 minutes). After the additions were 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 / H2O (FeSO4 2.5g + tartaric acid 1.0g + H2O 20ml). 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 chloride. The extracts were combined, washed with water, dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to obtain an oily substance.

[0256] The oily substance was dissolved in 40 ml of Et2O, and 20 ml of a 30% NaOH solution in saturated NaCl 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 extracts were combined, washed with water, and dried over anhydrous Na2SO4. The mixture was filtered, and the resulting filtrate was evaporated to dryness. The residue was loaded onto a silica gel column and eluted with PL / siRNA(3 / 1) to obtain 1.63 g of a colorless oily substance. 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] Compound VIb was obtained using compound IV2 (wherein R is benzyl) as a starting material and L-(+)-diisopropyl tartrate as a chiral derivative, following the same method as in Example 16. [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 (where 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. Hydrogenation was carried out at atmospheric pressure (for about 1 hour). Hydrogenation was stopped. The reaction mixture was stirred in an oil bath at 60°C for 2 hours, filtered, and 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] Compound VIIb was obtained using compound Vb (wherein R is benzyl) as a starting material, following the same method as in Example 20. [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. Hydrogenation was carried out under atmospheric pressure until no more hydrogen was absorbed. Hydrogenation was stopped. The reaction mixture was stirred in an oil bath at 60°C for 2 hours, filtered, and Pd / C was removed. 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] Compound VIIIb was obtained as a white solid by using compound VIb (wherein R is benzyl) as a starting material, following the same method as in Example 22. [α] D 20 :+95.6 (CH3Cl, c0.045).

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

[0268] [ka] Compound IXa was obtained using compound VIIa as a starting material, following the same method as in Example 11. 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-chromanil)-methanol (compound Xa)

[0270] [ka] Compound Xa was obtained using compound VIIIa as a starting material, following the same method as in Example 11. 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: 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-chromanil)-methanol (compound IXb)

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

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

[0274] [ka] Compound Xb was obtained using compound VIIIb as a starting material, following the same method as in Example 11. [α] D 20 :+50.3(CH3Cl, c0.50)

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

[0276] [ka] Compound XIa was obtained using compound IXa as a starting material, following the same method as in Example 13.

[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-chromanil)-methanol (compound XIb)

[0279] [ka] Compound XIb was obtained using compound IXb as a starting material, following the same method as in Example 13. [α] D 20 :-79.3 (CHCl3, c0.45)

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

[0281] [ka] Compound XIa 287 mg (0.95 mmol) and compound Xa 350 mg (0.95 mmol) were dissolved in 5 ml of ethanol, and 150 mg of anhydrous sodium 2CO3 was added. The reaction mixture was heated under reflux for 16 hours with stirring.

[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 siRNA. The extracts were combined, washed with saturated NaCl solution, and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated to dryness under reduced pressure to obtain 453 mg of the product as a syrup, which was then recrystallized from ethanol / water to obtain 373 mg of a white solid (79%).

[0283] [Example 30'] Preparation of N-benzyl-D-nebiborol hydrochloride (compound XIIIa hydrochloride) Compound XIa 287 mg (0.95 mmol) and compound Xa 350 mg (0.95 mmol) were dissolved in 5 ml of ethanol, and 150 mg of anhydrous sodium 2CO3 was added. The reaction mixture was heated under reflux for 16 hours with stirring.

[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 ELISA. The extracts were combined, and 2 ml of 1N hydrochloric acid was added. When the resulting mixture was stirred, crystals precipitated. After filtration, 390 mg of a white solid with a purity of 99.5% was obtained.

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

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

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

[0288] [Example 31'] Preparation of N-benzyl-L-nebiborol hydrochloride (compound XIIIb hydrochloride) Compound XIIIb hydrochloride with a purity of 99.6% was obtained using compounds XIb and Xb as starting materials, following the same method as in Example 30'.

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

[0290] [Example 32] Preparation of DL-Nebivolol (Compound I) Hydrochloride Compound I (0.4 mmol) was dissolved in 5 ml of ethanol, and 50 mg of 10% Pd-C was added. Hydrogenation was carried out at atmospheric pressure and room temperature 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 the ethanol and obtain a white solid, to which anhydrous diethyl ether was added. The resulting mixture was stirred and filtered to obtain 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: 406.1829, Measured value: 406.1825

[0291] [Example 32'] Preparation of DL-Nebivolol (Compound I) Hydrochloride Compound XIIIa' 100 mg and Compound XIIIb' 100 mg were added to 15 ml of methylene chloride. The resulting solution was neutralized by adding an aqueous sodium bicarbonate solution. Different layers appeared. The organic layer was concentrated and allowed to dry. 50 ml of methanol and 50 mg of 10% Pd-C were added to the residue. Hydrogenation was carried out at atmospheric pressure and 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 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: 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 at atmospheric pressure and 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: 406.1829, Measured value: 406.1825

[0293] [Example 33a] Preparation of D-nebiborol (compound Ia) hydrochloride Compound Ia was obtained as the hydrochloride salt using compound XIIIa as a starting material, following the same method as in Example 32. [α] D 20 :+22.0 (CH3OH, C0.5)

[0294] [Example 33b] Preparation of L-nebiborol (compound Ib) hydrochloride Compound Ib was obtained as the hydrochloride salt using compound XIIIb as a starting material, following the same method as in Example 32. [α] D 20 :-21.2 (CH3OH, C0.4).

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

[0296] While several embodiments and specific examples of the present invention are provided herein, those skilled in the art will understand that these embodiments and examples are merely examples of the present invention, and that other modifications and changes can be made without departing from the spirit of the invention.

[0297] Examples of embodiments of the present invention include the following. [Embodiment 1] Formula VII(S * / R * ) compounds [ka] [where VII(S * / R * ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S). [ka] It is a racemic mixture consisting of the following: A method for preparing, The following steps: 3) Compounds of formula IV1 in trans configuration [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but as an example, R in the following formula is represented by benzyl (Bn)] The process involves epoxidizing the product in the presence of an epoxidizing reagent to obtain an epoxide intermediate V. [ka] Here, compound V is a racemic mixture, consisting of equimolar amounts of compound Va and enantiomer Vb. [ka] It is a racemic mixture consisting of V(2R * ,3R * ) is expressed as and, 4) Formula V(2R * ,3R * The compound of ) is deprotected, followed by a cyclization reaction, and then formula VII(S * / R * The process of obtaining an intermediate compound of ) [In the formula, R is defined as above, but as an example, R shown in the following formula is represented by benzyl (Bn).] [ka] Here, VII(S * / R * ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S). [ka] It is a racemic mixture consisting of, and A method that includes this. [Embodiment 2] Formula VIII(R * / R * ) compounds [ka] [In the formula, VIII(R * / R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula VIIIa(R / R) and the enantiomer VIIIb(S / S). [ka] It is a racemic mixture consisting of the following: A method for preparing, The following steps: 3) Compounds of formula IV2 in cis configuration [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl, but as an example, R in the following formula is represented by benzyl (Bn)] The process involves epoxidizing the intermediate VI in the presence of an epoxidizing reagent. [ka] Here, compound VI is a racemic mixture, consisting of equimolar amounts of compound VIa and enantiomer VIb. [ka] It is a racemic mixture consisting of VI(2R), and its relative configuration is VI(2R * ,3S * ) is expressed as and, 4) Equation VI(2R* ,3S * The compound of formula VIII(R) is deprotected, followed by a cyclization reaction. * / R * The process of obtaining an intermediate compound of ) [In the formula, R is defined as above, but as an example, R shown in the following formula is represented by benzyl (Bn).] [ka] Here, VIII(R * / R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula VIIIa(R / R) and the enantiomer VIIIb(S / S). [ka] It is a racemic mixture consisting of, and A method that includes this. [Embodiment 3] The method according to Embodiment 1 or 2, wherein in step 3), the epoxidation of the trans-configured compound of formula IV1 or the cis-configured compound of formula IV2 can be carried out by using an epoxidation method commonly used in the art, for example, the epoxidizing reagent that can be used in the reaction is selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, 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 chloride, chloroform, tetrahydrofuran, toluene, or a mixture of two or more of these. [Embodiment 4] The method according to any one of Embodiments 1 to 3, wherein in step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example by hydrolysis 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 for hydrolysis being a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization are carried out by hydrolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and perform cyclization to directly obtain the cyclized product. [Embodiment 5] In step 3), the epoxidation of the trans-configured compound of formula IV1 or the cis-configured compound of formula IV2 can be carried out by using epoxidation methods commonly used in the art, for example, the epoxidizing reagent that can be used in the reaction is selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the 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 chloride, chloroform, tetrahydrofuran, toluene, or a mixture of two or more of these, and The method according to any one of Embodiments 1 to 4, wherein in step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl 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 for hydrogenolysis being a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic 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. [Embodiment 6] Formula III [ka] A method for preparing [wherein R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, for example t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, for example p-methoxyphenyl or halogen-substituted phenyl], The following steps: [ka] Step a): A step of reacting a compound of formula XIV [wherein R is a hydroxyl-protecting group as described above, and X is a halogen] with 3-(trisubstituted silyl)-propa-2-in-1-lithium to obtain a compound of formula XV [wherein R1, R2, and R3 are independently selected from alkyl or aryl groups, such as methyl, tert-butyl, or phenyl], Step b): A step of removing the silyl protecting group from the alkynyl terminus of the compound of formula XV to obtain the compound of formula XVI [wherein R is defined above], Step c): A step of reacting the compound of formula XVI with paraformaldehyde in the presence of a base or organometallic reagent to obtain the compound of formula III [wherein R is defined as above], Optionally, step d): Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the compound of formula III obtained in step c), stir at a low temperature, for example, 0°C to -20°C, then crystallize, filter, and obtain the compound of formula III as a solid. A method that includes this. [Embodiment 7] The method according to 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] The method according to any one 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, the base is selected from alkali metal or alkaline earth metal hydroxides or carbonates, such as NaOH, KOH, Na2CO3, and K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of two or more of these. [Embodiment 9] The method according to any one of Embodiments 6 to 8, wherein in step c), the base is selected from a metal hydride or an organic base, for example, NaNH2 or KNH2, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or Grignard reagents, for example, MeMgX, EtMgX, BuMgX, i-PrMgX [wherein X is Br, I, or Cl], and 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 two or more of these. [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 alkali metal or alkaline earth metal hydroxides or carbonates, such as NaOH, KOH, Na2CO3, and K2CO3, and the solvent used in the reaction is selected from protic solvents, such as water, methanol, ethanol, or a mixture of two or more of these, and The method according to any one of Embodiments 6 to 9, wherein in step c), the base is selected from a metal hydride or an organic base, for example, NaNH2 or KNH2, the organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA, or Grignard reagents, for example, MeMgX, EtMgX, BuMgX, i-PrMgX [wherein X is Br, I, or Cl], and 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 two or more of these. [Embodiment 11] Compound of formula IV1 [ka] [In the formula, R is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] A method for preparing, The following steps: The process involves reducing the compound of formula III with a metal hydride to obtain the compound of formula IV1. [ka] [In the formula, R is defined as above] and, Optionally, the following steps may be taken: Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV1; stir at a low temperature, for example, 0°C to -20°C; subsequently crystallize; filter; and obtain the compound of formula IV1 as a solid. A method that includes this. [Embodiment 12] The method according to Embodiment 11, wherein the metal hydride used as a reducing agent is LiAlH4 or sodium bis(2-methoxyethoxy)aluminum dihydrogenate, 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 two or more of these. [Embodiment 13] Compound of formula IV2 [ka] [In the formula, R is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] A method for preparing, The following steps: A step to obtain the compound of formula IV2 in cis configuration by selective catalytic hydrogenation of the compound of formula III. [ka] [In the formula, R is defined as above] and, Optionally, the following steps may be taken: Add a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV2; stir at a low temperature, for example, 0°C to -20°C; subsequently crystallize; filter; and obtain the compound of formula IV2 as a solid. A method that includes this. [Embodiment 14] The method according to Embodiment 13, wherein the catalyst used in selective catalytic hydrogenation is selected from a Lindlar catalyst or a P-2 nickel boride / ethylenediamine catalyst. [Embodiment 15] Nevibolol racemic mixture of formula I [ka] [where I(S * R * R * R * ) represents a racemic mixture, which is arranged as follows: [ka] This is a racemic mixture consisting of equimolar amounts of D-nebibolol Ia (SRRR) and its enantiomer L-nebibolol Ib (RSSS). A method for preparing, The following steps: 1) A step of reducing the compound of formula III with a metal composite hydride to obtain the trans-configured compound of formula IV1, and optionally the following step: Adding a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV1, stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization, filtration, and obtaining the compound of formula IV1 as a solid. [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] and, 2) A step of reducing the compound of formula III by selective catalytic hydrogenation to obtain the compound of formula IV2 in cis configuration, and optionally the following step: adding a nonpolar organic solvent, such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether, or tert-butyl methyl ether, or a mixture of two or more of these, to the obtained compound of formula IV2, stirring at a low temperature, for example, 0°C to -20°C, followed by crystallization, filtration, and obtaining the compound of formula IV2 as a solid. [ka] [In the formula, R is defined as in 1) above] and, 3) The step of epoxidizing the trans-configured compound of formula IV1 and the cis-configured compound of formula IV2 in the presence of an epoxidizing reagent to obtain epoxide intermediates V and VI, respectively. [In the formula, R is defined as above] [ka] Here, compound V is a racemic mixture, consisting of equimolar amounts of compound Va and enantiomer Vb. [ka] It is a racemic mixture consisting of V(2R * ,3R * ) is expressed as, [ka] Here, compound VI is a racemic mixture, consisting of equimolar amounts of compound VIa and enantiomer VIb. [ka] It is a racemic mixture consisting of VI(2R), and its relative configuration is VI(2R * ,3S * ) is expressed as and, 4) Deprotect the compound of formula V and the compound of formula VI, and then carry out a cyclization reaction to obtain the compound of formula VII(S * / R * ) and formula VIII(R * / R * The process of obtaining each of the intermediate compounds. [In the formula, R is defined as above] [ka] Here, VII(S * / R * ) is a racemic mixture, and this is equivalent to equimolar amounts of the compound of formula VIIa(S / R) and the enantiomer VIIb(R / S). [ka] It is a racemic mixture consisting of the following: [ka] Here, VIII(R * / R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula VIIIa(R / R) and the enantiomer VIIIb(S / S). [ka] It is a racemic mixture consisting of, and, 5) Compounds of formulas VII and VIII are sulfonallylated with a halogenated sulfonyl 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 obtain compound IX (S * / R *) and X(R * / R * The process of obtaining each of the following: [ka] Here, IX(S * / R * ) is a racemic mixture, and it consists of equimolar amounts of the compound IXa(S / R) and the enantiomer IXb(R / S). [ka] It is a racemic mixture consisting of the following: [ka] Here, X(R * / R * ) is a racemic mixture, which consists of equimolar amounts of the compound Xa(R / R) and the enantiomer Xb(S / S). [ka] It is a racemic mixture consisting of, and, 6) A step of reacting a compound of formula IX or X with benzylamine to alkylate the amine and obtain the corresponding compound XI or XII. [ka] Here, XI(S * / R * ) is a racemic mixture, and it consists of equimolar amounts of the compound of formula XIa(S / R) and the enantiomer XIb(R / S). [ka] It is a racemic mixture consisting of the following: [ka] Here, XII(R * / R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula XIIa(R / R) and the enantiomer XIIb(S / S). [ka] It 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 * The cross-coupling reaction of compound XIII(S) was carried out, and compound XIII(S) * R * R * R * ) and XIII'(S * R * S * S * ) process to obtain [In the formula, the definition of R" is the same as the definition of M above.] [ka] Here, XIII(S * R * R * R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula XIIIa(SRRR) and the enantiomer XIIIb(RSSS). [ka] It is a racemic mixture consisting of the following: XIII'(S * R * S * S * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula XIII'a(SRSS) and the enantiomer XIII'b(RSRR). [ka] It is a racemic mixture consisting of, and, 8) Form a salt of a mixture of compounds of formula XIII and formula XIII', purify it by recrystallization, and obtain the isomer XIII'(S * R * S * S * Remove the intermediate compound XIII(S * R * R * R * The process of obtaining ) 9) Intermediate compound XIII(S * R * R * R * The process of deprotecting ) to obtain the nevibolol racemic mixture of formula I. [ka] Here, I(S * R * R * R * ) is a racemic mixture, which consists of equimolar amounts of the compound of formula Ia(SRRR) and its enantiomer Ib(RSSS). and A method that includes this. [Embodiment 16] The method according to Embodiment 15, wherein in step 1), the metal complex hydride used as a reducing agent is LiAlH4 or bis(2-methoxyethoxy)aluminum sodium dihydrogenate, 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 two or more of these. [Embodiment 17] The method according to any one of embodiments 15 to 16, wherein in step 2), the catalyst used for selective catalytic hydrogenation is selected from a Lindlar catalyst or a 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 trans-configured compound of formula IV1 and the cis-configured compound of formula IV2 can be carried out by using epoxidation methods commonly used in the art, for example, the epoxidizing reagent that can be used in the reaction is selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, and a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the 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 chloride, chloroform, tetrahydrofuran, toluene, or a mixture of two or more of these. [Embodiment 19] The method according to any one of Embodiments 15 to 18, wherein in step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization is carried out in the presence of a base, wherein the catalyst used for hydrolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization are carried out by hydrolysis 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 halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or alkylsulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and the reaction may be carried out without a catalyst or with an appropriate amount of acylation catalyst, and the catalyst used may be a dialkyltin oxide, DMAP, for example, di The method according to any one of Embodiments 15 to 19, wherein the reaction may use butyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane, the base used in the reaction may be a conventional organic base, such as pyridine, an organic tertiary amine, such as triethylamine or diisopropylethylamine, and the solvent in the reaction may be an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. [Embodiment 21] The method according to any one of Embodiments 15 to 20, wherein in step 6), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. [Embodiment 22] The method according to any one of Embodiments 15 to 21, wherein in step 7), the base used in the cross-coupling reaction can be selected from an inorganic base, for example K2CO3, Na2CO3, or an organic tertiary amine, for example triethylamine or diisopropylethylamine, and the solvent in the reaction is an organic protic solvent, for example ethanol, propanol, isopropanol, or an organic polar aprotic solvent, for example acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of two or more of these solvents. [Embodiment 23] The method according to any one of Embodiments 15 to 22, wherein in step 9), the catalyst used in the deprotection reaction is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of two or more of these solvents, for example, methanol or ethanol. [Embodiment 24] In step 1), the metal complex hydride used as a reducing agent is LiAlH4 or bis(2-methoxyethoxy)aluminum sodium dihydrogenate, 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 two or more of these. In step 2), the catalyst used for selective catalytic hydrogenation is selected from either a Lindlar catalyst or a P-2 nickel boride / ethylenediamine catalyst. In step 3), the epoxidation of the trans-configured compound of formula IV1 and the cis-configured compound of formula IV2 can be carried out by using epoxidation methods commonly used in the art, for example, the epoxidizing reagents that can be used in the reaction are selected from organic peroxy acids, such as MCPBA, trifluoroperacetic acid, dimethyldioxirane (DMDO), a mixture of hydrogen peroxide and acetic acid, a mixture of VO(acac)2 and tert-butyl hydroperoxide, and the 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 chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, toluene, or a mixture of two or more of these. In step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, wherein the catalyst used for hydrolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization can be selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis using Pd / C as a catalyst under basic conditions to simultaneously remove the benzyl protecting group and perform cyclization to directly obtain the cyclized product. In step 5), the halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or alkylsulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride; the reaction may be carried out without a catalyst or with an appropriate amount of acylation catalyst, and the catalyst may be a dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane; the base used in the reaction may be a conventional organic base, for example, pyridine; an organic tertiary amine, for example, triethylamine or diisopropylethylamine; and the solvent in the reaction may be an organic aprotic solvent, for example, methylene dichloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. In step 6), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. 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, and the solvent in the reaction can be 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 two or more of these solvents. The method according to 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)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of two or more of these solvents, such as methanol or ethanol. [Embodiment 25] The method according to any one of Embodiments 15 to 24, wherein compounds of formula IV1 and formula IV2 are used as starting materials to obtain the nevibolol racemic mixture of formula I by carrying out steps 2) to 9). [Embodiment 26] The method according to any one of Embodiments 15 to 24, wherein compounds of formula IX and formula XII are used as starting materials to obtain the nevibolol racemic mixture of formula I by carrying out steps 7) to 9). [Embodiment 27] D-Nebibolol (Formula Ia) [ka] 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. [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] [ka] and, 4') A step of deprotecting intermediate compounds Va and VIa, followed by cyclization to obtain intermediate compounds VIIa and VIIIa, respectively. [In the formula, R is defined as above] [ka] and, 5') A step in which intermediate compounds VIIa and VIIIa are sulfonated with a sulfonyl halogen 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 obtain intermediate compounds IXa and Xa, respectively. [ka] and, 6') A step of reacting intermediate compound IXa or intermediate compound Xa with benzylamine to alkylate the amine and obtain the corresponding compound XIa or XIIa. [ka] and, 7') A step in which intermediate compounds IXa and XIIa, or intermediate compounds Xa and XIa, are cross-coupled under basic conditions to obtain intermediate compound XIIIa. [In the formula, the definition of Ar' is the same as the definition of M above.] [ka] and, Optionally, a step is taken to convert intermediate compound XIIIa to its hydrochloride salt, 8') Steps to deprotect intermediate compound XIIIa to obtain D-nebibolol (formula Ia) [ka] Alternatively, the hydrochloride salt of intermediate compound XIIIa is neutralized with a base to convert it to the free form of intermediate compound XIIIa, followed by deprotection to obtain D-nebibolol (formula Ia). A method that includes this. [Embodiment 28] L-Nebiborol (Formula Ib) [ka] A method for preparing, The following steps: 3) The process of asymmetric epoxidation of the compound of formula IV1 and the compound of formula IV2 to obtain intermediate compounds Vb and VIb, respectively. [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] [ka] and, 4") A step of deprotecting intermediate compounds Vb and VIb, followed by cyclization to obtain intermediate compounds VIIb and VIIIb, respectively. [In the formula, R is defined as above] [ka] and, 5") Intermediate compounds VIIb and VIIIb are sulfonated with a sulfonyl halogen of the 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 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 and obtain intermediate compound XIb or XIIb. [ka] and, A step to obtain intermediate compound XIIIb by carrying out a cross-coupling reaction of intermediate compounds IXb and XIIb, or intermediate compounds Xb and XIb, under 7" basic conditions. [In the formula, the definition of Ar' is the same as the definition of M above.] [ka] and, Optionally, a step is taken to convert intermediate compound XIIIb to its hydrochloride salt, 8") Step of deprotecting intermediate compound XIIIb to obtain L-nebibolol (formula Ib) [ka] Alternatively, the hydrochloride salt of intermediate compound XIIIb is neutralized with a base to convert it to the free form of intermediate compound XIIIb, followed by deprotection to obtain L-nebibolol (formula Ib). A method that includes this. [Embodiment 29] The method according to Embodiment 27, wherein in step 3'), Sharpless asymmetric epoxidation is used, 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 chloride, and molecular sieves of 3A or 4A are added to the reaction system. [Embodiment 30] The method according to Embodiment 28, wherein in step 3"), Sharpless asymmetric epoxidation is used, the chiral catalyst used in the reaction is L-(+)-diethyl tartrate or L-(+)-diisopropyl tartrate, the reagent in the reaction is titanium tetraisopropoxide, tert-butyl hydroperoxide, or cumene hydroperoxide, the solvent in the reaction is methylene chloride, and molecular sieves of 3A or 4A are added to the reaction system. [Embodiment 31] The method according to Embodiment 29 or 30, wherein in step 4') or step 4"), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization is carried out in the presence of a base, wherein the catalyst used for hydrolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization are carried out by hydrolysis 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 halogenated sulfonyl used in sulfonylation may be an arylsulfonyl chloride, 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. The reaction may be carried out without a catalyst or with an acylation catalyst, and the catalyst used may be dialkyltin oxide or DMAP. The method according to Embodiment 31, wherein, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane may be used, the base used in the reaction may be a conventional organic base, such as pyridine, an organic tertiary amine, such as triethylamine or diisopropylethylamine, and the solvent in the reaction may be an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. [Embodiment 33] The method according to Embodiment 31 or 32, wherein in step 6') or step 6"), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. [Embodiment 34] The method according to any one 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, for example K2CO3, Na2CO3, or an organic tertiary amine, for example triethylamine or diisopropylethylamine, and the solvent in the reaction is an organic protic solvent, for example ethanol, propanol, isopropanol, or an organic polar aprotic solvent, for example acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of two or more of these solvents. [Embodiment 35] The method according to any one of Embodiments 31 to 34, wherein in step 8') or step 8"), the catalyst used in the deprotection reaction is a Pd catalyst, for example, Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the solvent in the reaction is an alcohol, an ester, or an ether, or a mixture of two or more of these solvents, for example, methanol or ethanol. [Embodiment 36] In step 4') or step 4), deprotection can be carried out by conventional methods in the field of organic chemistry for removing the hydroxyl protecting group, for example, by hydrolysis in the presence of a catalyst to remove the benzyl protecting group, and cyclization can be carried out in the presence of a base, wherein the catalyst used for hydrolysis is a Pd catalyst, such as Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, or Pd, and the base used for cyclization can be selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organoheterocyclic bases, such as NaOH, KOH, K2CO3, NaOMe, or DBU, or deprotection and cyclization can be carried out by hydrolysis 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 halogenated sulfonyl used in sulfonylation may be an aryl sulfonyl chloride or a substituted aryl sulfonyl chloride or alkyl sulfonyl chloride, for example, p-toluenesulfonyl chloride, phenylsulfonyl chloride, p-halophenylsulfonyl chloride, p-nitrophenylsulfonyl chloride, o-nitrophenylsulfonyl chloride, or methylsulfonyl chloride, and the catalyst used in the reaction may be a dialkyltin oxide, DMAP, for example, dibutyltin oxide and 2,2-dibutyl-1,3,2-dioxastanolane, and the base used in the reaction may be a conventional organic base, for example, pyridine, an organic tertiary amine, for example, triethylamine or diisopropylethylamine, and the solvent in the reaction may be an organic aprotic solvent, for example, methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. In step 6') or step 6"), the alkylation of the amine is carried out by the reaction of benzylamine with the corresponding sulfonate, and the solvent in the reaction is an organic aprotic solvent, such as methylene chloride, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of two or more of these. In step 7') or step 7"), the base used in the cross-coupling reaction can be selected from inorganic bases, e.g., K2CO3, Na2CO3, or organic tertiary amines, e.g., triethylamine or diisopropylethylamine, and the solvent in the reaction can be an organic protic solvent, e.g., ethanol, propanol, isopropanol, or an organic polar aprotic solvent, e.g., acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of 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, PdCl2, or Pd, and the solvent in the reaction is an alcohol, ester, or ether, or a mixture of two or more of these solvents, such as methanol or ethanol. The method according to any one of embodiments 31 to 35. [Embodiment 37] The method according to any one of embodiments 27 to 36, wherein 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, filtration, and obtaining the hydrochloride salt as a solid. [Embodiment 38] The method according to any one 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-nebibolol of formula Ia. [Embodiment 39] The method according to any one of embodiments 31 to 37, wherein compounds of formula IXb and formula XIIb are used as starting materials for steps 7") to 8") to obtain L-nebibolol of formula Ib. [Embodiment 40] A mixture of D-nebibolol (formula Ia) and L-nebibolol (formula Ib) in any proportion. [ka] And, A mixture comprising D-nebibolol (formula Ia) and L-nebibolol (formula Ib) prepared by the method described in any of embodiments 31 to 39. [Embodiment 41] A method for preparing a mixture of D-nebibolol (formula Ia) and L-nebibolol (formula Ib) in any proportion described in Embodiment 40, (1) A step of preparing D-nebibolol (formula Ia) and L-nebibolol (formula Ib) respectively according to the method described in any of embodiments 27 to 39, and mixing them in any proportion, or (2) A step of 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 proportion, neutralizing with a base, and deprotecting the mixture obtained according to the deprotection step described in embodiment 35, or (3) A step of 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, neutralizing them with a base to obtain free intermediate compound XIIIa and free intermediate compound XIIIb, mixing the two free intermediate compounds in any proportion, and deprotecting the mixture obtained according to the deprotection step described in embodiment 35. A method that includes this. [Embodiment 42] Compounds of formula III. [ka] [In the formula, R is a hydroxyl protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, for example, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, for example, p-methoxyphenyl or halogen-substituted phenyl] [Embodiment 43] Compound of formula IV1'. [ka] [In the formula, R a is hydrogen, or R a [The protecting group is a hydroxyl group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] [Embodiment 44] The compound of formula IV2'. [ka] [In the formula, R b is hydrogen, or R b [The protecting group is a hydroxyl group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl.] [Embodiment 45] Formula V'(2R * ,3R * A compound of ). [ka] [In the formula, R c is hydrogen, or R cThis is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl. Here, compound V' is a racemic mixture, and its relative configuration is V'(2R * ,3R * This is represented by ), which is an equimolar amount of Va'(2R,3R) and the enantiomer Vb'(2S,3S), for example R c Compounds having the following formula, wherein benzyl [ka] It is a racemic mixture consisting of the following: [Embodiment 46] Formula VI'(2R * ,3S * A compound of ). [ka] [In the formula, R d is hydrogen, or R d This is a hydroxyl protecting group selected from aralkyl, alkoxyalkyl, allyl, or silyl protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, such as p-methoxyphenyl or halogen-substituted phenyl. Here, compound VI' is a racemate, and its relative configuration is VI'(2R * ,3S * ) is represented as, which is equivalent to equimolar amounts of VIa'(2R,3S) and the enantiomer VIb'(2S,3R), for example R d Compounds having the following formula, wherein benzyl [ka] It is a racemic mixture consisting of the following: [Embodiment 47] Compound of formula XI'. [ka] [In the formula, R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10 Aralcoxycarbonyls, for example, substituted or unsubstituted benzyls, tert-butyloxycarbonyls, and benzyloxycarbonyls. [Embodiment 48] Compound of formula XII'. [ka] [In the formula, R' is a substituted or unsubstituted aralkyl, C 1~6 Alkoxycarbonyl or C 5~10 Aralcoxycarbonyls, for example, substituted or unsubstituted benzyls, tert-butyloxycarbonyls, and benzyloxycarbonyls. [Embodiment 49] Compound of formula XVI'. [ka] [In the formula, R e is hydrogen, or R e The hydroxyl protecting group is selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl, benzoyl having substituents (multiple substituents) on the phenyl ring, or silyl protecting groups, for example, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is an unsubstituted or substituted aryl, for example, p-methoxyphenyl or halogen-substituted phenyl. [Embodiment 50] 1-benzyloxy-2-bromomethyl-4-fluorobenzene, 4-[(2-benzyloxy-5-fluorophenyl)-butyne-1-yl]trimethylsilane, 1-(benzyloxy)-2-(buty-3-yl)-4-fluorobenzene, 5-[2-(benzyloxy)-5-fluorophenyl]penta-2-in-1-ol, trans-5-[2-(benzyloxy)-5-fluorophenyl]penta-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]penta-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-chromanil)-methanol, (R * ,R * )-(+ / -)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanil)-methanol, (S * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-methanol, (R * ,R * )-(+ / -)-α-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-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-chromanil)-methanol, (R,S)-(-)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanyl)-methanol, (S,S)-(+)-α-[(p-tolylsulfonyloxy)methyl]-(6-fluoro-2-chromanil)-methanol, (S,R)-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-methanol, or (R,S)-[(benzylamino)methyl]-(6-fluoro-2-chromanil)-methanol A compound selected from the following.

Claims

1. Formula VI'(2R * ,3S * ) compound. [Formula 1] [In the formula, R d is a hydroxy protecting group selected from allyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, 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 the enantiomer VIb' (2S,3R) [chemical 2] is a racemic mixture consisting of

2. Equimolar amounts of [C3] 2. The compound of claim 1 which is a racemic mixture consisting of:

3. Formula VI(2R * ,3S * ) Compound [C4] A method for preparing The following steps: 2) reducing the compound of formula III by selective catalytic hydrogenation to obtain a compound of formula IV2 in the cis configuration; Optionally, the following steps are performed: 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 between 0° C. and −20° C., followed by crystallization and filtration to obtain the compound of formula IV2 as a solid. [C5] wherein R is a hydroxy protecting group selected from allyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, 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 agent to obtain an epoxide intermediate VI, where R is defined as above. [C6] wherein compound VI is racemic, which is a mixture of equimolar amounts of compound of formula VIa and enantiomer VIb [C7] It is a racemic mixture consisting of VI(2R * ,3S * ), and The method includes:

4. The method according to claim 3, wherein in step 3), the epoxidation of the compound of formula IV2 in cis configuration can be carried out by using an epoxidation reagent selected from 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 selected from methylene dichloride, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more of them.

5. 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 25. The method according to claim 3 or 4, wherein the Pd catalyst is selected from Pd, and the base used in cyclization is selected from alkali metal and alkaline earth metal hydroxides or carbonates, alkoxides, or organic heterocyclic bases, or the deprotection and cyclization is carried out by hydrogenolysis using Pd / C as catalyst under basic conditions to simultaneously remove the benzyl protecting group and cyclize to directly obtain the cyclized product.

6. The method according to claim 5, wherein in step 4), the base used in the cyclization is selected from NaOH, KOH, K2CO3, NaOMe, and DBU.

7. Formula VIII(R * / R * ) Compound [C8] [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) [C9] is a racemic mixture consisting of 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 [C10] wherein R is a hydroxy protecting group selected from allyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is p-methoxyphenyl or halogen substituted phenyl. wherein compound VI is a racemate, that is a racemic mixture consisting of equimolar amounts of the compound of formula VIa and the enantiomer VIb, the relative configuration of which is represented as VI(2R*,3S*); [C11] The method includes:

8. The method of claim 7, wherein R is benzyl.

9. A compound of formula III. [C12] wherein R is a hydroxy protecting group selected from t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, allyl, methoxymethyl, benzyl, or -CH2Ar, where Ar is p-methoxyphenyl or halogen substituted phenyl.

10. Compound of formula IV2'. [C13] [In the formula, R b is a hydroxy protecting group selected from allyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, methoxymethyl, benzyl, or -CH2Ar, where Ar is p-methoxyphenyl or halogen-substituted phenyl.

11. 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, (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 (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:

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