Synthesis method of nebivolol and intermediate compound thereof

文档序号：163084 发布日期：2021-10-29 浏览：38次中文

阅读说明：本技术 奈必洛尔的合成方法及其中间体化合物 (Synthesis method of nebivolol and intermediate compound thereof ) 是由郑志国于 2015-05-19 设计创作，主要内容包括：本发明涉及奈必洛尔的合成方法及其中间体化合物。具体而言,涉及用于合成奈必洛尔的方法、其中间体化合物以及制备所述中间体化合物的方法。(The invention relates to a synthetic method of nebivolol and an intermediate compound thereof. In particular, it relates to a process for the synthesis of nebivolol, intermediate compounds thereof and a process for the preparation of said intermediate compounds.)

1. A process for the preparation of a compound of formula VII (S/R),

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

the method comprises the following steps:

3) the trans-compound IV1

Epoxidation under the action of an epoxidizing agent to give an epoxy intermediate V, wherein R is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or a silicon-protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl, but in the formula wherein R is represented by benzyl (Bn) for example,

wherein the compound V is racemic mixture containing equal amount of formula Va and its enantiomer Vb, and its relative configuration is represented by V (2R,3R)

4) Deprotection and cyclization of compound V (2R,3R) provides intermediate compound VII (S/R), wherein R is as defined above, but in the formula below R is shown as for example benzyl (Bn),

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

2. a process for the preparation of a compound of formula VIII (R/R),

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

the method comprises the following steps:

3) cis-Compound IV2

Epoxidation under the action of an epoxidizing agent to give an epoxy intermediate V, wherein R is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or a silicon-protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group such as p-methoxyphenyl or halophenyl, but in the formula wherein R is shown as exemplified by benzyl (Bn),

wherein compound VI is racemic mixture containing equal amount of formula VIa and its enantiomer VIb, and its relative configuration is represented by VI (2R,3S)

4) Deprotection and cyclization of compound VI (2R,3S) provides intermediate compound VIII (R/R), wherein R is as defined above, but in the formula R is shown as benzyl (Bn) for example,

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

3. the process according to claim 1 or 2, wherein in step 3) the epoxidation of trans compound IV1 or cis compound IV2 is carried out using epoxidation methods commonly used in the art, e.g. the epoxidizing agent which may be used is selected from the group consisting of organic peroxy acids such as MCPBA, trifluoroperoxyacetic acid, dimethyl ketone peroxide (DMDO), mixtures of hydrogen peroxide and acetic acid and vo (acac)₂With tert-butanol peroxide, and the mixture,and pyridine-H in the presence of catalytic amounts of Methyltrioxorhenium (MTO)₂O₂The reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, toluene or a mixture of any two or more thereof.

4. A process according to any one of the preceding claims, wherein in step 4) the hydroxy protecting group is removed by methods commonly used in organic chemistry, such as by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, followed by cyclization with a base; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic heterocyclic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reactions can adopt the basic hydrogenolysis condition under the condition of taking Pd/C as the catalyst to simultaneously carry out the benzyl protecting group removal and cyclization reactions so as to directly obtain the cyclization product.

5. The method according to any one of the preceding claims, wherein:

in step 3), the epoxidation reaction of trans compound IV1 or cis compound IV2 may be carried out by an epoxidation method generally used in the art, for example, an epoxidizing agent selected from organic peroxy acids such as MCPBA, trifluoroperacetic acid, dimethyl ketone peroxide (DMDO), a mixture of hydrogen peroxide and acetic acid, and VO (acac)₂Mixture with tert-butyl peroxy-butanol, and pyridine-H in the presence of catalytic amounts of Methyltrioxorhenium (MTO)₂O₂A system in which the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof; and

in step 4), the hydroxyl protecting group can be removed by methods commonly used in the field of organic chemistry, for example, the benzyl protecting group is removed by hydrogenolysis in the presence of a catalyst, and then a base is added for cyclization; the catalyst used in the hydrogenolysis reaction is a palladium catalyst,for example Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic heterocyclic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reactions can adopt the basic hydrogenolysis condition under the condition of taking Pd/C as the catalyst to simultaneously carry out the benzyl protecting group removal and cyclization reactions so as to directly obtain the cyclization product.

6. A process for the preparation of a compound of formula III;

wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, allyl, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

the method comprises the following steps:

step a): reacting a compound of formula XIV, wherein R is a hydroxy protecting group as described above and X is a halogen, with 3-trisubstituted silyl-prop-2-yn-1-lithium to provide a compound of formula XV, wherein R is₁、R₂、R₃Each independently selected from alkyl or aryl groups, such as methyl, t-butyl or phenyl;

step b): removing the silicon protecting group at the alkynyl end of the compound of the formula XV to obtain a compound of the formula XVI, wherein R is as defined above;

step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to provide a compound of formula III, wherein R is as defined above; and

optional step d): adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the compound of formula III obtained in step c), stirring at low temperature such as at 0 to-20 ℃, crystallizing, and filtering to obtain a solid of the compound of formula III.

7. The process according to claim 6, wherein the reaction of step a) is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene.

8. Process according to any one of claims 6 to 7, wherein the reaction of step b) is carried out in the presence of a base, an acid or a fluoride-containing salt, preferably in the presence of a base selected from hydroxides or carbonates of alkali or alkaline earth metals, such as NaOH, KOH, Na₂CO₃、K₂CO₃The solvent used for the reaction is selected from protic solvents such as water, methanol, ethanol or a mixture of any two or more thereof.

9. The process according to any one of claims 6 to 8, wherein the base in step c) is selected from metal hydrides or organic bases, such as NaNH₂Or KNH₂The organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagents such as MeMgX, EtMgX, BuMgX, I-PrMgX, where X is Br, I or Cl, and the reaction solvent used 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.

10. The method according to any one of claims 6-9, wherein:

the reaction of step a) is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene;

the reaction of step b) is carried out in the presence of a base selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as NaOH, KOH, Na, or of fluorine-containing salts, preferably in the presence of a base₂CO₃、K₂CO₃The solvent used for the reaction is selected from protic solvents such as water, methanol, ethanol or a mixture of any two or more thereof; and

the base in step c) is selected from a metal hydride or an organic base, for example, NaNH₂Or KNH₂The organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagents such as MeMgX, EtMgX, BuMgX, I-PrMgX, where X is Br, I or Cl, and the reaction solvent used 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.

Technical Field

The present invention relates to a method for synthesizing a drug and an intermediate compound thereof, and particularly to a method for synthesizing nebivolol, an intermediate compound thereof, and a method for preparing the intermediate compound.

Background

Nebivolol hydrochloride, chemically (+/-) -bis [2- (6-fluorobenzo-dihydropyran-2-yl) -2-hydroxyethyl ] amine (formula I) hydrochloride, is a highly selective third-generation beta-receptor blocker with vasodilation developed by Johnson corporation and is mainly used for treating mild to moderate hypertension, angina pectoris and congestive heart failure. Nebivolol hydrochloride is a mixture of equal amounts of dextro-isomer (formula Ia) and levo-isomer (formula Ib), i.e. its racemate (formula I). The beta-receptor blocking effect of nebivolol hydrochloride is mainly from the dextro isomer, but other effects depend on the coexistence of the levorotatory isomer and the dextro isomer.

The relative configuration of nebivolol is shown below:

wherein I (S R) represents a racemic mixture composed of equimolar dextronebivolol Ia (SRRR) with the configuration shown as the following and enantiomer levonebivolol Ib (RSSS);

both the levorotatory isomer and the dextrorotatory isomer of nebivolol have important biological activity, the levorotatory isomer has endothelial cell dependent vasodilation effect, and the dextrorotatory isomer has strong beta 1 receptor blocking effect. The current clinical application is a mixture of levorotatory and dextrorotatory isomers, which enables the activities of the two isomers to be synergistic, and ensures that the nebivolol has unique advantages except the beta receptor blocker: selectively antagonize the beta 1 receptor by enhancing the release of NO, thereby vasodilating the blood vessel. Does not affect beta 2 receptors and does not cause contraction of bronchial smooth muscle and vascular smooth muscle. Therefore, in view of the important pharmacological value of nebivolol, the development of a method for preparing nebivolol and optical isomers thereof, which is efficient, low in cost and meets the industrial requirements, has great economic and social benefits.

Nebivolol has a molecular structure containing four chiral carbon atoms, labeled as shown below, where the isomers S R are clinically used nebivolol, represented as a racemic mixture containing equal amounts of the absolute configurations SRRR (dextro) and RSSS (levo) enantiomers.

The nebivolol has certain symmetry, the left side and the right side of the molecule respectively have a (6-fluoro-benzopyranyl) ethane-2-alcohol structural unit with different configurations, the hydroxyl on the left side (part A) and the oxygen on the pyran ring are cis-form, the right side (part B) is trans-form, and the middle part of the molecule is connected through a nitrogen atom.

In the prior art, basically, the synthesis of nebivolol is realized by utilizing the symmetry of molecules, separately synthesizing A, B parts, then coupling with benzylamine, and performing separation, purification and deprotection.

Specifically, the existing preparation method of nebivolol mainly includes the following steps:

firstly, a racemic intermediate is adopted as a raw material, fragments with opposite configurations at the left side and the right side of a nebivolol molecule are respectively constructed, and then cross coupling is carried out to prepare the nebivolol compound;

the key to using this method is how to prepare A, B in high diastereomeric purity with the desired configuration, otherwise a mixture containing the ten isomers described above would be obtained after the coupling reaction.

The intermediate obtained by coupling the two fragments with the relative configuration of A, B, which contains two pairs of diastereoisomers, is isolated by recrystallization to obtain the intermediate with the desired configuration:

patent EP145067 to Yanssen (Janssen) disclosesThe synthesis method is characterized by comprising the following steps: chromanal and iodotrimethyl oxysulfate under the action of sodium hydrogen to obtain a pair of diastereoisomers M with different amounts_A(S R) and M_B(R) epoxidation intermediate, epoxy intermediate M_A(S R) and M_B(R) can be used as a key intermediate for synthesizing the nebivolol after chromatographic separation, and then is subjected to cross coupling reaction with benzylamine to obtain a mixture of SRRR/RSSS and SRSS/RSRR, wherein the reaction is as follows:

then separated by multiple fractional recrystallization, and subjected to hydrogenolysis deprotection to obtain S R-nebivolol as shown in the following table:

although the preparation method is a commonly adopted method in the industry at present, the method has the main problems that the key intermediate needs to be separated by chromatographic column chromatography, the application cost in large-scale production is high, in addition, the reaction condition for preparing the epoxide from the unstable chromanal is harsh, the yield is lower and the reagent is expensive.

Second, the cyanation derivative method of patent WO2007/009143(CN101243062)

The method comprises the steps of reacting racemic chromanal with sodium bisulfite and sodium cyanide to obtain a nitrile alcohol intermediate, then separating by column chromatography to obtain a pair of cis-form and trans-form diastereoisomers of nitrile alcohol,

the cis-nitrile alcohol intermediate is acetylated and then catalytically hydrogenated to be converted into corresponding aldehyde, and then the corresponding aldol intermediate is obtained through hydrolysis.

Then catalytically hydrogenating corresponding alcohol amine of the trans-nitrile alcohol intermediate, reacting with benzoyl chloride to obtain amide, reducing to obtain a benzylamine intermediate, condensing with an aldol intermediate to obtain a nebivolol crude product of a pair of diastereoisomers (four isomers), salifying with hydrochloric acid, and recrystallizing for multiple times with ethanol to remove the other pair of isomers to obtain racemic nebivolol.

The method has the problems similar to the previous method, the reaction conditions are harsh, the separation of the key intermediate needs to be separated by chromatographic column chromatography, and the method is difficult to be applied to large-scale industrial production.

And thirdly, respectively synthesizing dextronebivolol and levonebivolol, and then mixing equal amounts of dextro-isomer and levonebivolol to obtain the racemic nebivolol. The following methods are mainly used for the synthesis of nebivolol optical isomers:

patents EP0334429 and US6545040 resolve chromanic acid to obtain corresponding S-chromanic acid and R-chromanic acid, and synthesize levonebivolol through the following steps;

the above process is still the derivation process of the Yanssen (Janssen) patent EP145067, and although the optically pure chromanic acid obtained by manual resolution is used, the subsequent step of the formation of the epoxy intermediate by the action of iodotrimethyloxysulfate on sodium hydrogen still produces unequal amounts of two diastereomers, and the separation by chromatographic column is also necessary to obtain the optically pure two epoxy intermediates.

The literature (Tetrahedron,56, 6339-:

however, the synthetic routes of the methods are long, intermediates are oily substances, column chromatography is needed for separation and purification, and reagents are expensive, so that industrial production is difficult.

In addition, the following multi-step reaction is required to convert the intermediate 1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1R) -1, 2-diol into 1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1R) -1, 2-diol to obtain SRRR-nebivolol of the desired configuration:

the patent CN1834093A and CN1978442 take acetone glyceraldehyde as raw material for synthesis: performing Kabbe condensation reaction on the D-acetonide glyceraldehyde and the 5-fluoro-2-hydroxyacetophenone, and performing column chromatography separation to obtain two isomers of chromandiol (S, R) and (R, R)

The two isomers of chromandiol (S, R) and chromandiol (R, R) are respectively selectively sulfonylated with paratoluensulfonyl chloride, and then amination is carried out to obtain optically active dextro SRRR-nebivolol.

In conclusion, it is found that the synthesis of nebivolol still has major technical drawbacks, according to the prior art documents so far. For example, the method of yanssen (Janssen), although a short synthetic route, requires separation of two diastereomeric epoxy intermediates by preparative HPLC, while other methods generally face more synthetic steps and separation of isomers. Therefore, there is a need to develop a new method for preparing nebivolol and its optical isomers, which is efficient, inexpensive and meets the industrial requirements.

Disclosure of Invention

In the present invention, the following terms have the meanings as described below:

the term "alkyl", alone or in combination with other groups, denotes a radical consisting of carbon anda linear or branched monovalent saturated hydrocarbon group consisting of hydrogen atoms. "C_1-6Alkyl "denotes a branched or straight-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-hexyl.

The term "alkylene" alone or in combination with other groups, denotes a straight-chain or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. "C_1-6The alkylene group "means a branched or straight chain alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, and the like.

The term "alkoxy" alone or in combination with other groups denotes the group R^A-O-wherein R^AIs an alkyl group as described above. "C_1-6Alkoxy "denotes the radical R^A-O-wherein R^AIs C as described above_1-6An alkyl group.

"halogen" means fluorine, chlorine, bromine or iodine.

"haloalkyl" means an alkyl group as defined above substituted with one or more halogens, e.g., trifluoromethyl.

"nitro" means-NO₂。

"aryl" refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms. "C_5-10Aryl "means an aryl group containing 5 to 10 carbon atoms. E.g. C_5-10Aryl may be phenyl or naphthyl.

"substituted aryl" refers to aryl substituted with alkyl, alkoxy, halogen, haloalkyl, and nitro as described above.

"aralkyl" refers to an alkyl group as described above substituted with an aryl group as described above.

"substituted aralkyl" refers to aralkyl substituted with alkyl, alkoxy, halo, haloalkyl, and nitro as described above.

"aralkoxy" refers to an alkoxy group as described above substituted with an aryl group as described above.

"substituted aralkoxy" refers to aralkoxy substituted with alkyl, alkoxy, halo, haloalkyl as described above.

In one aspect, the invention provides a process for the preparation of a compound of formula III

Wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, allyl, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

the method comprises the following steps:

step b): removing the silicon protecting group at the alkynyl end of the compound of the formula XV to obtain a compound of the formula XVI, wherein R is as defined above;

step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to provide a compound of formula III, wherein R is as defined above; and

In a preferred embodiment, the reaction of step a is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene, at a temperature of from-100 ℃ to 60 ℃.

In another preferred embodiment, the reaction of step b is carried out in the presence of a base, an acid or a fluoride-containing salt, preferably in the presence of a base selected from hydroxides or carbonates of alkali or alkaline earth metals, such as NaOH, KOH, Na₂CO₃、K₂CO₃The solvent used for the reaction is selected from protic solvents such as water, methanol, ethanol or a mixture of any two or more thereof, and the reaction temperature is from-100 ℃ to 80 ℃.

In another preferred embodiment, the base in step c is selected from a metal hydride or an organic base, such as NaNH₂Or KNH₂The organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagents, such as MeMgX, EtMgX, BuMgX, I-PrMgX, where X is Br, I or Cl, and the reaction solvent used 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, at a reaction temperature of-100 ℃ to 100 ℃.

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, t-butyl methyl ether or a mixture of any two or more thereof.

In a more preferred embodiment, the reaction of step a is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene;

the reaction of step b is carried out in the presence of a base, an acid or a fluoride-containing salt, preferably in the presence of a base selected from hydroxides or carbonates of alkali metals or alkaline earth metals, for example NaOH, KOH, Na₂CO₃、K₂CO₃The solvent used for the reaction is selected from protic solvents such as water, methanol, ethanol or a mixture of any two or more thereof; and

the base in step c is selected from a metal hydride or an organic base, e.g. NaNH₂Or KNH₂The organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagents such as MeMgX, EtMgX, BuMgX, I-PrMgX, where X is Br, I or Cl, and the reaction solvent used 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.

It will be appreciated by those skilled in the art that in the above method of synthesizing the compound of formula III, compound III may be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps a) to c) or d) as a starting material. For example, compound III can be prepared using a compound of formula (XV) as a starting material and performing steps b) to c) or d) as described above, or using a compound of formula (XVI) as a starting material and performing steps c) or d) as described above.

In another aspect, the invention provides a compound of formula III,

wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, allyl, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halophenyl.

In another aspect, the present invention provides a process for preparing racemic nebivolol of formula I,

wherein I (S R) represents a racemate which is a racemic mixture consisting of dextronebivolol Ia (SRRR) with an equimolar configuration shown as follows and levonebivolol Ib (RSSS) as an enantiomer thereof;

the method comprises the following steps:

1) reducing the compound III by using metal complex hydride to obtain a trans-compound shown as a formula IV 1;

and optionally the steps of: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV1, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV1,

wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

2) carrying out selective catalytic hydrogenation reduction on the compound III to obtain a cis-form compound of a formula IV 2;

and optionally the steps of: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV2, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV2,

wherein R is as defined in 1) above,

3) epoxidizing the trans compound IV1 and the cis compound IV2 under the action of an epoxidizing agent to obtain epoxy intermediates V and VI respectively, wherein R is defined as above,

wherein the compound V is racemic mixture containing equal amount of formula Va and its enantiomer Vb, and its relative configuration is represented by V (2R,3R)

Wherein compound VI is racemic mixture containing equal amount of formula VIa and its enantiomer VIb, and its relative configuration is represented by VI (2R,3S)

4) Deprotection and cyclization of compounds V and VI, respectively, gives intermediate compounds VII (S/R) and VIII (R/R), wherein R is as defined above,

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

5) reacting compounds VII and VIII with compounds of the formula M-SO₂Sulfonylating a sulfonyl halide of X (wherein M is alkyl or substituted or unsubstituted aryl and X is halogen) in the presence of a catalyst and a base to give compounds IX (S/R) and X (R/R),

wherein IX (S/R) is the racemate, being a racemic mixture containing equal amounts of formula IXa (S/R) and its enantiomer IXb (R/S),

wherein X (R/R) is a racemate which is a racemic mixture containing equal amounts of formula Xa (R/R) and its enantiomer Xb (S/S),

6) carrying out amine-alkylation reaction on the compound IX or X and benzylamine to obtain a corresponding compound XI or XII;

wherein XI (S/R) is a racemate which is a racemic mixture containing equal amounts of formula XIa (S/R) and its enantiomer XIb (R/S),

wherein XII (R/R) is a racemate which is a racemic mixture containing equal amounts of formula XIIa (R/R) and its enantiomer XIIb (S/S)

7) Subjecting intermediates IX (S/R) and XII (R/R) or intermediates X (R/R) and XI (S/R) to cross-coupling reaction under basic conditions to give compounds XIII (S R) and XIII' (S R S), wherein R "is as defined for M above,

wherein XIII (S R) is a racemate comprising equal amounts of a racemic mixture of formula XIIIa (SRRR) and its enantiomer XIIIb (RSSS),

XIII ' (S R S) is a racemate comprising equal amounts of a racemic mixture of formula XIII ' a (srss) and its enantiomer XIII ' b (rsrr),

8) salifying and recrystallizing the mixture containing compounds XIII and XIII 'to remove isomer XIII' (S R S) to obtain intermediate XIII (S R),

9) deprotection of intermediate XIII (S R) affords racemic nebivolol of formula I

Wherein I (S R) is the racemate, being a racemic mixture containing equal amounts of formula ia (srrr) and its enantiomer ib (rsss).

In one embodiment, the metal complex hydride reducing agent used in step 1) is LiAlH₄Or sodium dihydrobis (2-methoxyethoxy) aluminate, with the reaction solvent being 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, at a temperature of-100 ℃ to 60 ℃.

In one embodiment, in step 2), the catalyst used for selective catalytic hydrogenation reduction is selected from the group consisting of Lindlar catalyst or P-2 type nickel boride/ethylene diamine catalyst.

In one embodiment, in step 3), the epoxidation reaction of trans compound IV1 and cis compound IV2 may be carried out using epoxidation methods commonly used in the art, for example, the epoxidation reagent that may be used is selected from the group consisting of organic peroxyacids such as MCPBA, trifluoroperoxyacetic acid, dimethyl ketone peroxide (DMDO), mixtures of hydrogen peroxide and acetic acid, and vo (acac)₂Mixture with tert-butyl peroxy-butanol, and pyridine-H in the presence of catalytic amounts of Methyltrioxorhenium (MTO)₂O₂The reaction solvent is organic non-protonic solvent, such as dichloromethane, chloroform, tetrahydrofuran, toluene or their mixture, and the reaction temperature is-50 deg.c to 50 deg.c.

In one embodiment, in step 4), the hydroxyl protecting group may be removed by methods commonly used in the field of organic chemistry, such as hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, followed by addition of a base for cyclization; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reaction is catalyzed by Pd/C under alkaline conditionHydrogenolysis is carried out by the agent, so that the removal of the benzyl protecting group and the cyclization reaction are carried out simultaneously, and the cyclization product is directly obtained.

In one embodiment, in step 5), the sulfonyl halide used for the sulfonylation reaction may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or an alkylsulfonyl chloride such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-halobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride or methylsulfonyl chloride; no catalyst or proper amount of acylation catalyst may be used in the reaction, and the catalyst may be dialkyl tin oxide compound, DMAP, such as dibutyl tin oxide and 2, 2-dibutyl-1, 3, 2-dioxa tin heterocycle pentane; the base used in the reaction may be a commonly used organic base such as pyridine, organic tertiary amine such as triethylamine or diisopropylethylamine, and the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA or a mixture of any two or more thereof, and the reaction temperature is-50 ℃ to 50 ℃.

In one embodiment, in step 6), the amine-alkylation reaction is carried out to react benzylamine with the corresponding sulfonate ester using a charged molar ratio of benzylamine to the corresponding sulfonate ester substrate of from 1/1 to 10/1 and an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof at a temperature of from-25 ℃ to 150 ℃.

In one embodiment, in step 7), the base used in the cross-coupling reaction may be selected from inorganic bases, such as K₂CO₃、Na₂CO₃Or an organic tertiary amine, such as triethylamine or diisopropylethylamine, in an organic protic solvent, such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of the foregoing solvents, at a reaction temperature of-25 ℃ to 150 ℃.

In one embodiment, in step (ii), the step (ii) is performed by9) The catalyst used for the deprotection reaction is a Pd catalyst, such as Pd/C, Pd (OH)₂，Pd(OAc)₂、PdCl₂Pd; the reaction solvent is an alcohol or an ester or an ether, or a mixture of any two or more of the above solvents, such as methanol or ethanol.

In a preferred embodiment, the metal complex hydride reducing agent used in step 1) is LiAlH₄Or sodium dihydrobis (2-methoxyethoxy) aluminate, the reaction solvent being an organic aprotic solvent such as methyltetrahydrofuran, tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof;

in the step 2), the catalyst used for selective catalytic hydrogenation reduction is selected from a Lindlar catalyst or a P-2 type nickel boride/ethylenediamine catalyst;

in step 3), the epoxidation reaction of trans compound IV1 and cis compound IV2 may be carried out by an epoxidation method generally used in the art, for example, an epoxidizing agent selected from organic peroxy acids such as MCPBA, trifluoroperacetic acid, dimethyl ketone peroxide (DMDO), a mixture of hydrogen peroxide and acetic acid, and VO (acac)₂Mixture with tert-butyl peroxy-butanol, and pyridine-H in the presence of catalytic amounts of Methyltrioxorhenium (MTO)₂O₂A system in which the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, toluene or a mixture of any two or more thereof;

in step 4), the hydroxyl protecting group can be removed by methods commonly used in the field of organic chemistry, for example, the benzyl protecting group is removed by hydrogenolysis in the presence of a catalyst, and then a base is added for cyclization; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂，Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or deprotection and cyclization reaction under alkaline condition by adopting PdThe catalyst is subjected to hydrogenolysis, so that the benzyl protecting group removal and the cyclization reaction are carried out simultaneously, and a cyclization product is directly obtained;

in step 5), the sulfonyl halide used in the sulfonylation reaction may be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-halobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride or o-nitrobenzenesulfonyl chloride or methanesulfonyl chloride; no catalyst or proper amount of acylation catalyst may be used in the reaction, and the catalyst may be dialkyl tin oxide compound, DMAP, such as dibutyl tin oxide and 2, 2-dibutyl-1, 3, 2-dioxa tin heterocycle pentane; the base used in the reaction may be a commonly used organic base such as pyridine, an organic tertiary amine such as triethylamine or diisopropylethylamine, and the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, pyridine, toluene, acetonitrile, ethyl acetate, DMF, DMA or a mixture of any two or more thereof;

in step 6), amine-alkylation to benzylamine with the corresponding sulfonic acid ester, the reaction solvent being an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof;

in step 7), the base used in the cross-coupling reaction may be chosen from inorganic bases, such as K₂CO₃、Na₂CO₃Or an organic tertiary amine, such as triethylamine or diisopropylethylamine, the reaction solvent being an organic protic solvent, such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of the foregoing solvents; and

in step 9), the catalyst used for the deprotection reaction is a Pd catalyst, such as Pd/C, Pd (OH)₂，Pd(OAc)₂、PdCl₂Pd, the reaction solvent is an alcohol, ester or ether, or a mixture of any two or more of the above solvents, for example methanol or ethanol.

It will be appreciated by those skilled in the art that in the above method of synthesizing the compound of formula I, the compound of formula I may be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any one of steps 1) to 9) as starting material, for example, the compounds of formula IV1 and IV2 may be used as starting material and carrying out the steps 2) to 9) as described above) to give racemic nebivolol of formula I. Alternatively, the compound of formula IX and XII can be used as starting material and the steps 7) to 9) described can be performed to give racemic nebivolol of formula I.

In another aspect, the present invention provides a process for preparing a compound of formula IV1,

wherein R is a hydroxy protecting group selected from aralkyl, alkoxyalkyl, allyl or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

the method comprises the following steps:

reducing compound III with a metal complex hydride to give a compound of formula IV1, and optionally the following steps: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV1, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV1,

wherein R is as defined above.

In a preferred embodiment, the metal complex hydride reducing agent used in the above method is LiAlH₄Or dihydroSodium bis (2-methoxyethoxy) aluminate, the reaction solvent being an organic aprotic solvent such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof.

In another aspect, the present invention provides a process for preparing a compound of formula IV2,

the method comprises the following steps:

selective catalytic hydrogenation reduction of compound III to give the cis-compound of formula IV2, and optionally the following steps: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV2, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV2,

wherein R is as defined above.

In a preferred embodiment, the catalyst used in the selective catalytic hydrogenation reduction in the above process is selected from the group consisting of Lindlar (Lindlar) catalyst or P-2 type nickel boride/ethylene diamine catalyst.

In another aspect, the invention provides a process for the preparation of a compound of formula VII (S/R),

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

the method comprises the following steps:

3) the trans-compound IV1

Epoxidation under the action of an epoxidizing agent to give an epoxy intermediate V, wherein R is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or a silicon-protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group such as p-methoxyphenyl or halophenyl, but in the formula wherein R is shown as exemplified by benzyl (Bn),

wherein the compound V is racemic mixture containing equal amount of formula Va and its enantiomer Vb, and its relative configuration is represented by V (2R,3R)

4) Deprotection and cyclization of compound V (2R,3R) provides intermediate compound VII (S/R), wherein R is as defined above, but in the formula below R is shown as for example benzyl (Bn),

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

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

In another aspect, the invention provides a process for the preparation of a compound of formula VIII (R/R),

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

the method comprises the following steps:

3) cis-Compound IV2

Epoxidation under the action of an epoxidizing agent to give an epoxy intermediate V, wherein R is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or a silicon-protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted or substituted aryl, e.g. p-methoxyphenyl or halophenyl, but in the formula R is represented by benzyl (Bn)For the purpose of example only,

wherein compound VI is racemic mixture containing equal amount of formula VIa and its enantiomer VIb, and its relative configuration is represented by VI (2R,3S)

4) Deprotection and cyclization of compound VI (2R,3S) provides intermediate compound VIII (R/R), wherein R is as defined above, but in the formula R is shown as benzyl (Bn) for example,

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

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

In another aspect, the present invention provides a process for preparing racemic nebivolol of formula I,

the method comprises the following steps a) to c) or d) and steps 1) to 9):

step a): reacting a compound of formula XIV with 3-trisubstituted silyl-prop-2-yn-1-lithium to provide a compound of formula XV, wherein R₁、R₂、R₃Each independently selected from alkyl or aryl groups, such as methyl, t-butyl or phenyl; r is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halophenyl, X is halogen;

step b): removing the silicon protecting group at the alkynyl end of the compound of the formula XV to obtain a compound of the formula XVI, wherein R is as defined above;

step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to provide a compound of formula III, wherein R is as defined above; (ii) a And

optional step d): adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the compound of formula III obtained in step c), stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to obtain a solid of the compound of formula III

Step 1): reducing compound III with a metal complex hydride to give a trans compound of formula IV1, and optionally the following steps: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV1, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV1,

wherein R is as defined above, and wherein,

step 2): selective catalytic hydrogenation reduction of compound III to give the cis-compound of formula IV2, and optionally the following steps: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV2, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV2,

wherein R is as defined above, and wherein,

step 3): epoxidizing the trans compound IV1 and the cis compound IV2 under the action of an epoxidizing agent to obtain epoxy intermediates V and VI respectively, wherein R is defined as above,

wherein the compound V is racemic mixture containing equal amount of formula Va and its enantiomer Vb, and its relative configuration is represented by V (2R,3R)

Wherein compound VI is racemic mixture containing equal amount of formula VIa and its enantiomer VIb, and its relative configuration is represented by VI (2R,3S)

Step 4): deprotection and cyclization of compounds V and VI, respectively, gives intermediate compounds VII (S/R) and VIII (R/R), wherein R is as defined above,

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

step 5): reacting compounds VII and VIII with compounds of the formula M-SO₂Sulfonylating a sulfonyl halide of X (wherein M is alkyl or substituted or unsubstituted aryl and X is halogen) in the presence of a catalyst and a base to give compounds IX (S/R) and X (R/R),

wherein IX (S/R) is the racemate, being a racemic mixture containing equal amounts of formula IXa (S/R) and its enantiomer IXb (R/S),

wherein X (R/R) is a racemate which is a racemic mixture containing equal amounts of formula Xa (R/R) and its enantiomer Xb (S/S),

step 6): carrying out amine-alkylation reaction on the compound IX or X and benzylamine to obtain a corresponding compound XI or XII;

wherein XI (S/R) is a racemate which is a racemic mixture containing equal amounts of formula XIa (S/R) and its enantiomer XIb (R/S),

wherein XII (R/R) is a racemate which is a racemic mixture containing equal amounts of formula XIIa (R/R) and its enantiomer XIIb (S/S)

Step 7): subjecting intermediates IX (S/R) and XII (R/R) or intermediates X (R/R) and XI (S/R) to cross-coupling reaction under basic conditions to give compounds XIII (S R) and XIII' (S R S), wherein R "is as defined for M above,

wherein XIII (S R) is a racemate comprising equal amounts of a racemic mixture of formula XIIIa (SRRR) and its enantiomer XIIIb (RSSS),

XIII ' (S R S) is a racemate comprising equal amounts of a racemic mixture of formula XIII ' a (srss) and its enantiomer XIII ' b (rsrr),

step 8): salifying and recrystallizing the mixture containing compounds XIII and XIII 'to remove isomer XIII' (S R S) to obtain intermediate XIII (S R),

step 9): deprotection of intermediate XIII to give racemic nebivolol of formula I

Wherein I (S R) is the racemate, being a racemic mixture containing equal amounts of formula ia (srrr) and its enantiomer ib (rsss).

For this process for the preparation of the compound of formula I, the reaction conditions, solvents and reagents used in steps a) to c) and steps 1) to 9), etc. are as described above.

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 fluoride-containing salt, preferably in the presence of a base selected from hydroxides or carbonates of alkali metals or alkaline earth metals, for example NaOH, KOH, Na₂CO₃、K₂CO₃The solvent used for the reaction is selected from protic solvents such as water, methanol, ethanol or a mixture of any two or more thereof;

in step c), the base is selected from a metal hydride or an organic base, such as NaNH₂Or KNH₂SaidThe organometallic reagent of (a) is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagents, such as MeMgX, EtMgX, BuMgX, I-PrMgX, where X is Br, I or Cl, and the reaction solvent used is an organic aprotic solvent, such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene or a mixture of any two or more thereof;

in step 1), the metal complex hydride reducing agent used is LiAlH₄Or sodium dihydrobis (2-methoxyethoxy) aluminate, the reaction solvent being an organic aprotic solvent such as tetrahydrofuran, methyltetrahydrofuran, toluene, dioxane, diethyl ether, isopropyl ether, tert-butyl methyl ether, toluene, or a mixture of any two or more thereof;

in the step 2), the catalyst used for the selective catalytic hydrogenation reduction is selected from a Lindlar (Lindlar) catalyst or a P-2 type nickel boride/ethylene diamine catalyst;

in step 3), the epoxidation reaction of trans compound IV1 and cis compound IV2 may be carried out by an epoxidation method generally used in the art, for example, an epoxidizing agent selected from organic peroxy acids such as MCPBA, trifluoroperacetic acid, dimethyl ketone peroxide (DMDO), a mixture of hydrogen peroxide and acetic acid, and VO (acac)₂Mixture with tert-butyl peroxy-butanol, and pyridine-H in the presence of catalytic amounts of Methyltrioxorhenium (MTO)₂O₂A system in which the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, toluene, or a mixture of any two or more thereof;

in step 4), the hydroxyl protecting group can be removed by methods commonly used in the field of organic chemistry, for example, the benzyl protecting group is removed by hydrogenolysis in the presence of a catalyst, and then a base is added for cyclization; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or deprotection and cyclizationThe method can adopt the alkaline hydrogenolysis condition under the condition of taking Pd/C as a catalyst to simultaneously carry out the benzyl protecting group removal and the cyclization reaction so as to directly obtain a cyclization product;

in step 5), the sulfonyl halide used in the sulfonylation reaction may be arylsulfonyl chloride or substituted arylsulfonyl chloride or alkylsulfonyl chloride such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-halobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride or methanesulfonyl chloride; no catalyst or proper amount of acylation catalyst may be used in the reaction, and the catalyst may be dialkyl tin oxide compound, DMAP, such as dibutyl tin oxide and 2, 2-dibutyl-1, 3, 2-dioxa tin heterocycle pentane; the base used in the reaction may be a commonly used organic base such as pyridine, an organic tertiary amine such as triethylamine or diisopropylethylamine, and the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof;

in step 9), the catalyst used for the deprotection reaction is a Pd catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd, the reaction solvent being an alcohol, ester or ether, or a mixture of any two or more of the above solvents, e.g. methanol orAnd (3) ethanol.

It will be appreciated by those skilled in the art that in the above method of synthesising a compound of formula I, the compound of formula I may be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps a) to 9) as starting material. For example, the steps b) to 9) described can be performed starting with a compound of formula XV or the steps c) to 9) described can be performed starting with a compound of formula XVI, to give racemic nebivolol of formula I.

In another aspect, the present invention provides a method of preparing dexnebivolol (formula Ia),

the method comprises the following steps:

3') asymmetric epoxidation of compounds IV1 and IV2 to give compounds Va and VIa, respectively, wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halophenyl;

4') deprotecting and cyclizing intermediates Va and VIa, respectively, to give intermediates VIIa and VIIIa, wherein R is as defined above,

5') reacting intermediates VIIa and VIIIa with a compound of the formula M-SO₂Sulfonylation of a sulfonyl halide of X (wherein M is alkyl or substituted or unsubstituted aryl and X is halogen) in the presence of a catalyst and a base to giveIntermediates IXa and Xa

6') carrying out amine-alkylation reaction on the intermediate IXa or the intermediate Xa and benzylamine to obtain a corresponding compound XIa or XIIa;

7 ') intermediate IXa and XIIa or intermediate Xa and XIIa are subjected to a cross-coupling reaction under alkaline conditions to give intermediate XIIIa, wherein Ar' is as defined for M above,

and optionally converting intermediate XIIIa into its hydrochloride salt,

8') deprotection of intermediate XIIIa to give dextronebivolol (formula Ia)

Alternatively, the hydrochloride salt of intermediate XIIIa is converted to the free intermediate XIIIa by base neutralization and then deprotected to give d-nebivolol (formula Ia).

In another aspect, the present invention provides a method of preparing levonebivolol (formula Ib),

the method comprises the following steps:

3') subjecting compounds IV1 and IV2 to asymmetric epoxidation reaction to obtain compounds Vb and VIb, wherein R is hydroxyl protecting group selected from alkyl and halogenated protecting groupAlkyl, aralkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

4') deprotection and ring closure of intermediates Vb and VIb, respectively, to give intermediates VIIb and VIIIb, wherein R is as defined above,

5') reacting intermediates VIIb and VIIIb, respectively, with a compound of formula M-SO₂Sulfonylation of X, wherein M is alkyl or substituted or unsubstituted aryl and X is halogen, in the presence of a catalyst and a base to give intermediates IXb and Xb,

6') the intermediate IXb or the intermediate Xb is subjected to an amine-alkylation reaction with benzylamine to obtain the intermediate XIb or XIIb

7 ') the intermediates IXb and XIIb or the intermediates Xb and XIb are subjected to a cross-coupling reaction under basic conditions to give an intermediate XIIIb, wherein Ar' is as defined for M above,

and optionally converting intermediate XIIIb into its hydrochloride salt,

8') deprotection of intermediate XIIIb to afford levonebivolol (formula Ib)

Alternatively, the hydrochloride salt of intermediate XIIIb is converted to the free intermediate XIIIb by base neutralization and then deprotected to afford levonebivolol (formula Ib).

In one embodiment of the preparation of the compound of formula Ia, step 3') is performed using a Sharpless asymmetric epoxidation reaction using a chiral catalyst of diethyl D- (-) -tartrate or diisopropyl D- (-) -tartrate as the reactant, tetraisopropyl titanyl, t-butyl peroxide or cumene hydroperoxide as the reaction solvent, dichloromethane, and a 3A or 4A molecular sieve as the reaction system at a temperature of-45 deg.C to 50 deg.C.

In one embodiment of the preparation of the compound of formula Ib, step 3 ") employs a Sharpless asymmetric epoxidation reaction using L- (+) -diethyl tartrate or L- (+) -diisopropyl tartrate as the chiral catalyst, tetraisopropyl titanyl, t-butyl peroxide or cumene hydroperoxide as the reactant, dichloromethane as the reaction solvent, and a 3A or 4A molecular sieve is added to the reaction system at a temperature of-45 ℃ to 50 ℃.

In the process for preparing the compounds of the formula Ia or Ib, the hydroxyl protecting group can be removed in step 4 ') or step 4') by methods customary in the art of organic chemistry, for example by hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group and then cyclizing with a base; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic heterocyclic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reactions can adopt the basic hydrogenolysis condition under the condition of taking Pd/C as the catalyst to simultaneously carry out the benzyl protecting group removal and cyclization reactions so as to directly obtain the cyclization product.

In the process for preparing the compound of formula Ia or Ib, in step 5') or step 5 ″), the sulfonyl halide used in the sulfonylation reaction may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or an alkylsulfonyl chloride such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-halobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride or methylsulfonyl chloride; no catalyst or acylation catalyst can be used in the reaction, and the catalyst used can be dialkyl tin oxide compounds, DMAP, such as dibutyl tin oxide and 2, 2-dibutyl-1, 3, 2-dioxa tin cyclopentane; the base used in the reaction may be a commonly used organic base such as pyridine, an organic tertiary amine such as triethylamine or diisopropylethylamine, and the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA or a mixture of any two or more thereof, and the reaction temperature is-5 to 50 ℃.

In the process for the preparation of the compound of formula Ia or Ib, in step 6') or 6 ″), the amine-alkylation reaction is carried out with benzylamine and the corresponding sulfonic acid ester in an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA or a mixture of any two or more thereof at a temperature of-25 ℃ to 150 ℃.

In the process for the preparation of the compounds of formula Ia or Ib, in step 7') or step 7 ″), the base used in the cross-coupling reaction can be selected from inorganic bases, such as K₂CO₃、Na₂CO₃Or an organic tertiary amine, such as triethylamine or diisopropylethylamine, in an organic protic solvent, such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of the foregoing solvents, at a reaction temperature of-25 ℃ to 150 ℃.

In the process for the preparation of the compound of formula Ia or Ib, in step 8 ') or step 8'), the catalyst used for the deprotection reaction is Pd-catalyzedAgents, e.g. Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd, the reaction solvent is an alcohol, ester or ether, or a mixture of any two or more of the above solvents, for example methanol or ethanol.

In one embodiment, the step of converting intermediate XIIIa or intermediate XIIIb to its hydrochloride salt is by adding hydrochloric acid, e.g. 1N hydrochloric acid, to the intermediate compound, crystallizing, and filtering to give a hydrochloride salt as a solid.

In a preferred embodiment of the process for preparing the compounds of the formula Ia or Ib, in step 4 ') or 4') the hydroxy-protecting group can be deprotected by methods customary in the art of organic chemistry, for example by hydrogenolysis in the presence of a catalyst to remove the benzyl-protecting group and then cyclizing with further base; the catalyst used in the hydrogenolysis reaction is a Pd catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic heterocyclic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reactions can adopt the basic hydrogenolysis condition under the condition of taking Pd/C as the catalyst to simultaneously carry out the benzyl protecting group removal and cyclization reactions so as to directly obtain a cyclization product;

in step 5') or step 5 ″), the sulfonyl halide used in the sulfonylation reaction may be an arylsulfonyl chloride or a substituted arylsulfonyl chloride or an alkylsulfonyl chloride such as p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-halobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride or methylsulfonyl chloride; the catalyst used in the reaction may be dialkyltin oxide compounds, DMAP, such as dibutyltin oxide and 2, 2-dibutyl-1, 3, 2-dioxastannane; the base used in the reaction may be a commonly used organic base such as pyridine, an organic tertiary amine such as triethylamine or diisopropylethylamine, and the reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof;

in step 6') or step 6 ″), amine-alkylation to benzylamine with the corresponding sulfonic acid ester, the reaction solvent being an organic aprotic solvent such as dichloromethane, chloroform, methyltetrahydrofuran, tetrahydrofuran, pyridine, toluene, ethyl acetate, acetonitrile, DMF, DMA, or a mixture of any two or more thereof;

in step 7 ') or step 7'), the base used in the cross-coupling reaction can be chosen from inorganic bases, such as K₂CO₃、Na₂CO₃Or an organic tertiary amine, such as triethylamine or diisopropylethylamine, the reaction solvent being an organic protic solvent, such as ethanol, propanol, isopropanol, or an organic polar aprotic solvent, such as acetone, butanone, toluene, tetrahydrofuran, dimethylformamide, or a mixture of any two or more of the foregoing solvents;

in step 8 ') or step 8'), the catalyst used for the deprotection reaction is a Pd catalyst, for example Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd, the reaction solvent is an alcohol, ester or ether, or a mixture of any two or more of the above solvents, for example methanol or ethanol.

It will be appreciated by those skilled in the art that in the above methods of synthesizing compounds of formula Ia or Ib, the reaction product obtained in any of the steps described may be used as starting material for the direct subsequent reaction to prepare compounds of formula Ia or Ib. For example, the compounds of formula IXa and XIIa can be used as starting materials and the steps 7 ') to 8') described can be performed to give d-nebivolol of formula Ia. Alternatively, the steps 7 ") to 8") described can be carried out using the compounds of formula IXb and formula XIIb as starting materials to give levonebivolol of formula Ib.

In another aspect, the present invention also provides a mixture of dextronebivolol (formula Ia) and levonebivolol (formula Ib) in any ratio,

wherein d-nebivolol (formula Ia) and l-nebivolol (formula Ib) are prepared according to the methods described above.

In another aspect, the present invention provides a method for preparing a mixture of dextronebivolol (formula Ia) and levonebivolol (formula Ib) in any ratio, comprising:

(1) preparing dextronebivolol (formula Ia) and levonebivolol (formula Ib) according to the methods described in the above steps 3 ') to 8') and steps 3 ") to 8"), respectively, and mixing the two in an arbitrary ratio; or

(2) Preparing a hydrochloride of intermediate XIIIa and a hydrochloride of intermediate XIIIb according to the methods described in the above steps 3 ') to 7 ') and steps 3 ") to 7"), respectively, and mixing them in an arbitrary ratio, neutralizing them with a base, and then performing the deprotection step described in step 8 ') using the resulting mixture; or

(3) The hydrochloride of intermediate XIIIa and the hydrochloride of intermediate XIIIb are prepared according to the methods described in steps 3 ') to 7 ') and steps 3 ") to 7") above, respectively, and are neutralized with a base to give free intermediate XIIIa and free intermediate XIIIb, respectively, which are then mixed in an arbitrary ratio, followed by performing the deprotection step described in step 8 ') using the resulting mixture.

In another aspect, the invention provides a compound of formula IV1

Wherein R is^aIs hydrogen or R^aIs a hydroxy protecting group selected from aralkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted orSubstituted aryl groups, such as p-methoxyphenyl or halophenyl.

In another aspect, the invention provides a compound of formula IV2

Wherein R is^bIs hydrogen or R^bIs a hydroxy protecting group selected from aralkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halophenyl.

In another aspect, the invention provides a compound of formula V' (2R,3R)

Wherein R is^cIs hydrogen or R^cIs a hydroxy protecting group selected from aralkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

wherein compound V 'is a racemate, the relative configuration of which is indicated by V' (2R,3R), and is a racemic mixture containing equal amounts of Va '(2R, 3R) and its enantiomer Vb' (2S,3S), for example of formula wherein R is^cA compound that is benzyl:

in another aspect, the invention provides a compound of formula VI' (2R,3S)

Wherein R is^dIs hydrogen or R^dIs a hydroxy protecting group selected from aralkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

wherein compound VI 'is a racemate, the relative configuration of which is indicated by VI' (2R,3S), and is a racemic mixture containing equal amounts of VIa '(2R, 3S) and its enantiomer VIb' (2S,3R), for example of the formula wherein R is^dA compound that is benzyl:

in another aspect, the invention provides a compound of formula XI':

wherein R' is a substituted or unsubstituted aralkyl group, C_1-6Alkoxycarbonyl or C_5-10Aralkoxycarbonyl, such as substituted or unsubstituted benzyl, tert-butoxycarbonyl, phenoxycarbonyl.

In another aspect, the invention provides a compound of formula XII':

wherein R' is a substituted or unsubstituted aralkyl group, C_1-6Alkoxycarbonyl or C_5-10Aralkoxycarbonyl, such as substituted or unsubstituted benzyl, tert-butoxycarbonyl, phenoxycarbonyl.

In another aspect, the invention provides a compound of formula XVI':

wherein R is^eIs hydrogen or R^eIs a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, benzoyl with substituents on the phenyl ring or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is unsubstituted or substituted aryl, such as p-methoxyphenyl or halophenyl.

In one embodiment, the present invention also provides a specific compound for the synthesis of nebivolol selected from the group consisting of:

1-benzyloxy-2-bromomethyl-4-fluorobenzene,

4- [ (2-benzyloxy-5-fluorophenyl) -butyn-1-yl ] trimethylsilane,

1- (benzyloxy) -2- (butyn-3-yl) -4-fluorobenzene,

5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-yn-1-ol,

trans-5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-en-1-ol,

(2R,3R) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane,

1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-chromen-2-yl ] - (1R) -1, 2-ethanediol,

cis-5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-en-1-ol,

(2R,3S) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane,

1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-chromen-2-yl ] - (1R) -1, 2-ethanediol,

(S, R) - (+/-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(R, R) - (+/-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(S, R) - (+/-) -alpha- [ (benzylamino) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(R, R) - (+/-) -alpha- [ (benzylamino) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(2R,3R) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane,

(2S,3S) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane,

(2R,3S) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane,

(2S,3R) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane,

1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-chromen-2-yl ] - (1R) -1, 2-ethanediol,

1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-chromen-2-yl ] - (1S) -1, 2-ethanediol,

1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-chromen-2-yl ] - (1R) -1, 2-ethanediol,

1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-chromen-2-yl ] - (1S) -1, 2-ethanediol,

(S, R) - (+) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(R, R) - (-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(R, S) - (-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol,

(S, S) - (+) -alpha- [ (p-toluenesulfonyloxy) 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.

Detailed Description

The process of the present invention is further illustrated by the following examples. It should be understood that the following examples are provided only for the purpose of enabling a better understanding of the present invention, and are not intended to limit the scope of the present invention in any way.

Abbreviations used in this application have the following meanings.

Abbreviations:

boc tert-butoxycarbonyl

DEAD azodicarboxylic acid diethyl ester

DIPEA diisopropylethylamine

DMF dimethyl formamide

DMA dimethyl acetamide

EtOAc ethyl acetate

TBAF tetrabutylammonium fluoride

THF tetrahydrofuran

TLC thin layer chromatography

t-Bu(Me)₂Si tert-butyl dimethyl silicon base

TBS tert-butyl dimethylsilyl group

TBSCl tert-butyldimethylsilyl chloride

Example 1: preparation of 1-benzyloxy-2-bromomethyl-4-fluorobenzene (compound XIV, wherein R is benzyl)

The starting material 2-benzyloxy-5-fluorobenzyl alcohol used in this example can be prepared by a known method of 2-hydroxy-5-fluorobenzyl alcohol (Medicinal Chemistry letters,2010, vol.1, #7 p.321-325 reference, Bioorganic & Medicinal Chemistry,2006, vol.14, #6 p.2022-2031).

5.14g (22mmol) of 2-benzyloxy-5-fluorobenzyl alcohol was dissolved in 180mL of anhydrous diethyl ether, and PBr was added dropwise at 0 deg.C₃(2.3mL,24.4mmol) in 20mL dry ether was warmed to room temperature for 2h and TLC indicated complete reaction.

And (3) post-treatment: adding 50mL of water, separating to obtain organic layer, extracting water layer with (50mL x 3) DCM, mixing organic phases, washing with saturated sodium bicarbonate, washing with water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering, concentrating to obtain crude product 6g, and recrystallizing the obtained product (PE/Et)₂O) to obtain 5.9g of crystal product with the total yield of 91.2 percent.

¹H-NMR(400MHz,CDCl₃)δ7.33～7.47(m,5H)，7.06～7.09(dd,J＝7.6,2.8Hz,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)

Example 2: preparation of 4- [ (2-benzyloxy-5-fluorophenyl) -butyn-1-yl ] trimethylsilane (Compound XV, wherein R is benzyl)

2.4mL of 16.1mmol of trimethylsilylpropyne was added to 40mL of anhydrous THF, the mixture was cooled to-23 ℃ and 2.5M n-BuLi 7.7mL (19.3mmol) was added thereto, and after stirring at this temperature for 2 hours until the reaction mixture became orange-red, the mixture was cooled to-100 ℃ and 3.5g (11.9mmol) of Compound XIV (wherein R is benzyl) in 5mL of anhydrous THF was added thereto, and after the addition, the reaction was completed at this temperature for 1 hour, and TLC showed completion.

And (3) post-treatment: stopping reaction with 10% saturated ammonium chloride, separating several layers, extracting water layer (100 mL. times.2) with diethyl ether, mixing organic phases, washing with saturated ammonium chloride, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (PE/Et)₂O100: 1) to obtain 3.79g of a pure product, the yield was 97.6%.

¹H-NMR(400MHz,CDCl₃)δ7.38～7.42(m,5H)，6.93～6.96(dd,J＝8.8,2.4Hz,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)

Example 3: preparation of 1- (benzyloxy) -2- (butyn-3-yl) -4-fluorobenzene (Compound XVI, wherein R is benzyl)

1.15g (3.52mmol) of Compound XV, wherein R is benzyl, are dissolved in 20ml MeOH, 0.5g (3.6mmol) of K are added₂CO₃Stirring at room temperature for 3h, evaporating under reduced pressure to remove solvent, extracting residue with EtOAc, washing with water, washing with saturated NaCl, and washing with anhydrous Na₂SO₄Drying, filtering, evaporating filtrate to drynessTo obtain 0.87g of a colorless oil. Filtration through a short column of silica, eluting with PL/EtOAc (100/2), afforded 0.85g of a colorless oil.

¹H-NMR(400MHz,CDCl₃)δ7.33～7.42(m,5H)，6.93～6.96(dd,J＝9.6,2.8Hz,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)

Example 4: preparation of 5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-yn-1-ol (compound III, wherein R is benzyl)

1.49g (5.6mmol) of Compound XVI (wherein R is benzyl) are dissolved in 20ml THF, cooled to-100 deg.C, 2.9ml 2.4M BuLi (6.9mmol) are added dropwise, stirred at-100 deg.C for 30min, warmed to 0 deg.C, and 0.6g (20mmol) (CH) are added₂O)_nStirring to react at 0 deg.C to room temperature for 2.5h, adding saturated NH4Cl to stop reaction, separating organic layer, and separating water layer with Et₂Extracting twice with O, mixing extractive solutions, washing with water, washing with saturated NaCl, and washing with anhydrous Na₂SO₄Drying, filtration, evaporation of the filtrate to dryness, purification over a short pad of silica gel, washing with petroleum ether/EtOAc (4/1) gave 1.51g of a colourless oil.

¹H-NMR(400MHz,CDCl₃)δ7.33～7.42(m,5H)，6.93～6.96(dd,J＝9.6,2.8Hz,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) calcd for C18H18O2F (M + H) +: 285.1285, found 285.1290.

Example 4': preparation of 5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-yn-1-ol (compound III, wherein R is benzyl)

1.49g (5.6mmol) of Compound XVI (wherein R is benzyl) are dissolved in 20ml THF, cooled to-100 deg.C, 2.9ml 2.4M BuLi (6.9mmol) are added dropwise, and after addition 3.4M BuLi is stirred at-100 deg.C0min, heating to 0 deg.C, adding 0.6g (20mmol) (CH)₂O)_nStirring to react at 0 deg.C to room temperature for 2.5h, adding saturated NH4Cl to stop reaction, separating organic layer, and separating water layer with Et₂Extracting twice with O, mixing extractive solutions, washing with water, washing with saturated NaCl, and washing with anhydrous Na₂SO₄Drying, filtering, and evaporating the filtrate to dryness to obtain oil. 10ml of n-hexane was added to the oily substance, stirred, cooled to-20 ℃ and crystallized, and filtered to obtain 1.2g of a white solid with a purity of 98%.

¹H-NMR(400MHz,CDCl₃)δ7.33～7.42(m,5H)，6.93～6.96(dd,J＝9.6,2.8Hz,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) calcd for C18H18O2F (M + H) +: 285.1285, found 285.1290.

Example 5: preparation of trans-5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-en-1-ol (compound IV-1, wherein R is benzyl)

After 1.05g (3.6mmol) of compound III (wherein R is benzyl) was dissolved in 25ml THF and cooled in an ice bath, 2.1ml of 3.4M (7.1mmol) Red-Al was added dropwise, and after completion of the reaction, the mixture was stirred at room temperature overnight (TLC showed that the Rf value of the product coincided with that of the starting material under PL/EtOA ═ 4/1), saturated sodium potassium tartrate (about 20ml) was added dropwise carefully the next day to stop the reaction, the organic layer was separated, the aqueous layer was extracted with 20ml of x 2EtOAc, the extracts were combined, washed with 1N HCl, water, saturated NaCl, anhydrous Na2SO4, dried, filtered, and the filtrate was evaporated to dryness to obtain 1.0g of the product (pale yellow oil).

¹H-NMR(400MHz,CDCl₃)δ7.32～7.42(m,5H)，6.85～6.87(d,J＝8.4Hz,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) calculated C18H20O2F (M + H)⁺: 287.1448 found 287.1441.

Example 5': preparation of trans-5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-en-1-ol (compound IV-1, wherein R is benzyl)

Dissolving 1.05g (3.6mmol) of compound III (wherein R is benzyl) in 25ml of THF, cooling in an ice bath, adding 2.1ml of 3.4M (7.1mmol) Red-Al dropwise after cooling, stirring at room temperature for reaction overnight (TLC shows that the Rf value of the product coincides with that of the raw material under the condition of PL/EtOA ═ 4/1), stopping the reaction by carefully adding saturated potassium sodium potassium tartrate (about 20ml) dropwise the next day, separating an organic layer, extracting the aqueous layer with 20ml of X2 EtOAc, combining the extracts, washing with 1N HCl, washing with water, washing with saturated NaCl, drying with anhydrous Na2SO4, filtering, evaporating the filtrate to dryness to obtain an oil. 8ml of n-hexane was added to the oily substance, stirred, cooled to-20 ℃, crystallized, and filtered to obtain 0.7g of an off-white solid having a purity of 99%, a melting point: 18-20 ℃.

HR-MS (ESI) calculated C18H20O2F (M + H)⁺: 287.1448 found 287.1441.

Example 6: preparation of (2R,3R) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane (compound V, wherein R is benzyl)

Dissolving 1.06g (4mmol) of compound IV-1 (wherein R is benzyl) in 20ml DMC, adding 1.01g 75% MCPBA (4.4mmol) under stirring, stirring at room temperature for 4h, diluting the reaction solution with DMC, washing with 5% NaOH twice, washing with water, and anhydrous Na₂SO₄And (5) drying. Filtration and evaporation of the filtrate to dryness gave 1.08g (90%) of a pale yellow oil.

¹H-NMR(400MHz,CDCl₃)δ7.32～7.41(m,5H)，6.88～6.90(d,J＝8.4Hz,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).

Example 7: preparation of 1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1R) -1, 2-ethanediol (Compound VII)

The method comprises the following steps:

1.08g of Compound V (wherein R is benzyl) was dissolved in 20ml of EtOAc, 0.2g of 10% Pd/C was added, the mixture was hydrogenated at room temperature under normal pressure overnight, filtered, the filtrate was evaporated to dryness to obtain 0.85g of an oil, which was dissolved in 20ml of DMC, cooled in ice bath, 10ml of 10% NaOH-NaCl solution was added, stirred in ice bath for 30min, warmed to room temperature and stirred for reaction for 3h, the organic layer was separated, the aqueous layer was extracted with 10ml of DMC again, the extracts were combined, washed with water, dried over anhydrous Na2SO4, purified by silica gel short column, and eluted with PL/EtOAc (1/1) to obtain 0.71g (95%) of a white solid.

The second method comprises the following steps:

adding 1.5g of compound V (wherein R is benzyl) into 25ml of absolute ethanol, 200mg of 10% Pd/C and 100mg of anhydrous Na₂CO₃The reaction was hydrogenated at atmospheric pressure until no hydrogen absorption occurred (about 1.5 h). Then heating and stirring are carried out for 2.5 hours at the temperature of 60 ℃, filtering is carried out, filtrate is evaporated to dryness, and 0.95g of white solid is obtained.

¹H-NMR(400MHz,CDCl₃)δ6.70～6.80(m,3H)，3.99～4.02(dd,J＝10.4,3.6Hz,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) calculated value C₁₁H₁₃O₃F(M)⁺: calculated value 212.0849, found value 212.0851

Example 8: preparation of cis-5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-en-1-ol (compound IV-2, wherein R is benzyl)

250 mL round bottom flask containing (420 mg,1.7mmol) Ni (OAc)₂·4H₂O, vacuumizing, introducing argon, adding 20mL of 95% ethanol with air discharged, adding (100mg,2.6mmol) sodium borohydride under argon stirring, stirring for 15min, wherein the reaction solution is black, adding ethylenediamine (0.5mL,7.5mmol), stirring for 5min, adding air-discharged NaOH (2M, 60 uL, 0.1mmol), dissolving compound III (wherein R is benzyl) (3.2g,11.3mmol) in 10mL of 95% ethanol, dropwise adding the reaction solution, replacing the argon in the reaction solution with hydrogen, reacting at room temperature for 18h, and TLC showing that the reaction is complete.

And (3) post-treatment: and replacing the hydrogen with argon again, removing the hydrogen, filtering the reaction solution by using kieselguhr, washing a filter cake by using 100mL of ethyl acetate, (3X 20mL) of water, drying the organic phase by using anhydrous sodium sulfate, filtering, and evaporating the filtrate to dryness to obtain a product of 3.15g with the yield of 97%.

¹HNMR(400MHz,CDCl₃)δ7.34～7.43(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) calcd for C18H20O2F (M + H) +: 287.1448 found 287.1441.

Example 8': preparation of cis-5- [2- (benzyloxy) -5-fluorophenyl ] pent-2-en-1-ol (compound IV-2, wherein R is benzyl)

250 mL round bottom flask containing (420 mg,1.7mmol) Ni (OAc)₂·4H₂O, vacuumizing, introducing argon, adding 20mL of 95% ethanol with air discharged, adding (100mg,2.6mmol) sodium borohydride under stirring argon, stirring for 15min until the reaction solution is black, adding ethylenediamine (0.5mL,7.5mmol), and stirringAfter 5min, further air-purged NaOH (2M, 60. mu.L, 0.1mmol) was added, and Compound III (wherein R is benzyl) (3.2g,11.3mmol) was dissolved in 10mL of 95% ethanol, and the above reaction solution was added dropwise, after which argon in the reaction solution was replaced with hydrogen gas and reacted at room temperature for 18h, and TLC showed completion of the reaction.

And (3) post-treatment: the hydrogen was replaced again with argon, after removal of the hydrogen, the reaction was filtered through celite, the filter cake was washed with 100mL ethyl acetate, (3 × 20mL) water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give an oil. Adding n-hexane 30ml into the oily substance, stirring, cooling to-20 deg.C, crystallizing, and filtering to obtain white solid 2.7g, purity 99%, melting point: 32-34 ℃.

¹HNMR(400MHz,CDCl₃)δ7.34～7.43(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) calcd for C18H20O2F (M + H) +: 287.1448 found 287.1441.

Example 9: preparation of (2R,3S) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane (compound VI, where R is benzyl)

Compound VI can be obtained in a similar manner to example 6 starting from compound IV-2, wherein R is benzyl.

¹H-NMR(400MHz,CDCl₃)δ7.34～7.41(m,5H)，6.88～6.90(d,J＝8.4Hz,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).

Example 10: preparation of 1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1R) -1, 2-ethanediol (Compound VIII)

Compound VIII was obtained in the same manner as in example 7 using Compound VI (wherein R is benzyl) as a starting material.

¹H-NMR(400MHz,CDCl₃)δ6.73～6.81(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) calculated value C₁₁H₁₃O₃F(M)⁺: calculated value 212.0849, found value 212.0844

Example 11: preparation of (S, R) - (+/-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound IX)

4.24g (20mmol) of the compound VII are suspended in 100ml of toluene, and 0.5g (2mmol) of dibutyltin oxide (Bu)₂SnO) was stirred at room temperature for 1 hour, then diisopropylethylamine (3.95ml,24mmol)) and 3.99g (21mmol) of p-toluenesulfonyl chloride (TsCl) were added, and the reaction was stirred at room temperature overnight. The next 2N HCl wash, water wash, dry Na2SO4, short column of silica gel, eluting with PL/EtOAc (3/1) afforded 6.89g (94%) of a white solid.

¹H-NMR(400MHz,CDCl₃)δ7.80～7.82(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) calculated value C₁₈H₁₉O₅FNaS(M+Na)⁺Found value of 389.0829 found value 389.0822

Example 12: preparation of (R, R) - (+/-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound X)

Suspending 4.24g (20mmol) of Compound VIII in 100ml of toluene, 0.5g (2mmol) of dibutyltin oxide (Bu) are added₂SnO) was stirred at room temperature for 1 hour, then diisopropylethylamine (3.95ml,24mmol) and 3.99g (21mmol) of p-toluenesulfonyl chloride (TsCl) were added, and the reaction was stirred at room temperature overnight. Washed with 2N HCl, water, dried over anhydrous Na2SO4, purified over a short column of silica, eluting with PL/EtOAc (3/1) to give 7.07 (98%) as a colorless syrup.

¹H-NMR(400MHz,CDCl₃)δ7.80～7.82(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) calculated value C₁₈H₁₉O₅FNaS(M+Na)⁺Found value of 389.0829 found value 389.0823

Example 13: preparation of (S, R) - (+/-) -alpha- [ (benzylamino) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound XI)

1.83g (5mmol) of Compound IX in 20ml THF, 2.72ml benzylamine, heating under reflux for 16h (TLC showed disappearance of the starting spot), evaporating to dryness under reduced pressure, adding 10% Na to the residue₂CO₃Extracted three times with EtOAc, the extracts combined, 10% Na₂CO₃Washing, water washing, saturated NaCl washing, anhydrous Na2SO4 drying, filtering, vacuum evaporation of the filtrate to remove EtOAc, residue with 20ml cyclohexane, precipitation of white crystal, filtering to obtain white solid 1.25 g.

¹H-NMR(400MHz,CDCl₃)δ7.28～7.36(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) calculated value C₁₈H₂₁O₂FN(M+H)⁺: calculated value 302.1550 found value 302.1546

Example 14: preparation of (R, R) - (+/-) -alpha- [ (benzylamino) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound XII)

1.95g (5.3mmol) of Compound X in 20ml of THF, 2.72ml of benzylamine added and the reaction heated under reflux for 16h (TLC showed disappearance of the starting spot); evaporating to dryness under reduced pressure, adding 10% Na into the residue₂CO₃Extracted three times with EtOAc, the extracts combined, 10% Na₂CO₃Washing, water washing, saturated NaCl washing, drying with anhydrous Na2SO4, filtering, evaporating the filtrate under reduced pressure to remove EtOAc, adding 20ml cyclohexane to the residue, and precipitating white crystal 0.91 g.

¹H-NMR(400MHz,CDCl₃)δ7.28～7.38(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)

Example 15: preparation of N-benzyl- (+/-) -nebivolol (Compound XIII)

Dissolving 1.19g (3.2mmol) of compound IX and 0.94g (3.12mmol) of compound XII in 15ml of EtOH, adding 0.5g of solid anhydrous sodium carbonate, heating, stirring, refluxing for 16h, evaporating under reduced pressure, adding 50ml of water to the residue, extracting twice with EtOAc, combining the extracts, washing with saturated NaCl, drying with anhydrous Na2SO4, filtering, and evaporating the filtrate under reduced pressure to obtain 1.59g of syrup. Dissolving the above product in 25ml isopropanol, adding 0.5g oxalic acid (FW ═ 126), heating and stirring for 20min, cooling, standing at room temperature for 5h, filtering, and oven drying to obtain 1.59g white solid. The product was recrystallized twice from ethanol to give 0.69g of the oxalate salt of Compound XIII. The above product was suspended in 20ml of dichloromethane, 10ml of 10% sodium carbonate was added, stirred at room temperature for 25 minutes, the organic layer was separated, washed with water, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to dryness to obtain 0.58g of free base (compound XIII).

¹HNMR(500MHz,CDCl₃)δ7.27～7.34(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) calculated value C₂₉H₃₁O₄F₂N(M+H)⁺: calculated value 496.2293 found value 496.2287

Example 16: preparation of (2R,3R) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane (Compound Va, where R is benzyl)

2g of a 4A molecular sieve in the form of a powder in 25ml of anhydrous dichloromethane were cooled to-25 ℃ and 1.85g D- (-) -DIPT (7.9mmol) and 2.06g (7.2mmol) of Ti (OPr-i) were added in that order₄After the addition was completed, stirring was carried out at-25 ℃ for 20min, then 6.7ml of 3.2N TBHP (19.8mmol) (toluene solution) was added dropwise, after the addition was completed, stirring was carried out at-25 ℃ for 20min, then 1.89g (6.6mmol) of Compound IV1 (where R is benzyl) in 20ml of dichloromethane (added over about 15 min) was added dropwise, and the reaction was stirred at-25 to-22 ℃ for 6h (disappearance of S spots on the starting material).

And (3) post-treatment: pouring the reaction solution into newly prepared FeSO₄Tartaric acid/H₂In O solution (2.5g FeSO4+1.0g tartaric acid +20ml H2O), stirring at room temperature for 1H, filtering with diatomaceous earth, separating the organic layer from the filtrate, extracting the aqueous layer twice with dichloromethane, combining the extracts, washing with water, drying with anhydrous Na2SO4, and evaporating under reduced pressure to obtain 4.0g of oily substance.

Dissolving the product in 40ml of DCM, dropwise adding 20ml of 30% NaOH saturated NaCl solution under ice bath cooling, stirring and reacting at room temperature for 1h after the addition is finished, separating an organic layer, extracting a water layer twice with DCM, combining extract liquor, washing with water, drying with anhydrous Na2SO4, filtering, evaporating filtrate to dryness, loading on a silica gel column, and eluting with PL/EtOAc (3/1) to obtain 1.54g of colorless oily matter.

HR-MS (ESI) calculated value C₁₈H₁₉O₃FNa(M+Na)⁺: 325.1210 found 325.1201

[α]_D ²⁰；+22.9(CHCl₃,C 1.0)

Example 17: preparation of (2S,3S) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane (compound Vb, where R is benzyl)

Compound Vb can be obtained by a similar method to that of Experimental example 16, starting from compound IV1 and using L- (+) -diisopropyl tartrate as a chiral inducer.

[α]_D ²⁰；-23.1(CHCl₃,C 1.0)

Example 18: preparation of (2R,3S) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane (compound VIa, where R is benzyl)

2g of a 4A molecular sieve in the form of a powder in 25ml of anhydrous dichloromethane were cooled to-25 ℃ and 1.85g D- (-) -DIPT and 2.06g Ti (OPr-i) were added in that order₄After the addition is completed, stirring at-25 ℃ for 20min, then dropwise adding 6.7ml of 3.2N TBHP (toluene solution), after the addition is completed, stirring at-25 ℃ for 20min, then dropwise adding 1.92g (6.7mmol) of compound IV2 (wherein R is benzyl) in 20ml of dichloromethane solution (adding within about 15 min), after the addition is completed, stirring at-25 to-22 ℃ for reaction for 6h, and pouring the reaction solution into newly prepared FeSO₄Tartaric acid/H₂In O solution (2.5g FeSO)₄+1.0g tartaric acid +20ml H₂O), stirring at room temperature for 1h, filtering with diatomaceous earth, separating organic layer from filtrate, extracting water layer with dichloromethane twice, mixing extractive solutions, washing with water, drying with anhydrous Na2SO4, and reducingEvaporating to dryness under reduced pressure to obtain oily substance.

The product is dissolved in 40ml Et₂And O, dropwise adding 20ml of a saturated NaCl solution of 30% NaOH under ice-bath cooling, stirring at room temperature for 1h after adding, separating an organic layer, extracting the water layer twice with DCM, combining extract liquor, washing with water, drying with anhydrous Na2SO4, filtering, evaporating filtrate to dryness, loading on a silica gel column, and eluting with PL/EtOAc (3/1) to obtain 1.63g of colorless oily matter.

¹H-NMR(400MHz,CDCl₃)δ7.34～7.41(m,5H)，6.88～6.90(d,J＝8.4Hz,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)

Example 19: preparation of (2S,3R) -3- [2- (benzyloxy) -5-fluorophenethyl ] -2-hydroxymethyl-oxirane (compound VIb, where R is benzyl)

Compound VIb was obtained in a similar manner to experimental example 16 starting from compound IV2 (where R is benzyl) and using L- (+) -diisopropyl tartrate as the chiral inducer.

[α]_D ²⁰；+1.6(CHCl₃,c 2.0)

Example 20: preparation of 1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1R) -1, 2-ethanediol (Compound VIIa)

1.09g of Compound Va, wherein R is benzyl, is dissolved in 25ml of EtOH, 0.25g of 10% Pd-C and 0.075g of anhydrous sodium carbonate are added and the reaction is hydrogenated at atmospheric pressure (about 1h), the hydrogenation is stopped, the mixture is stirred in an oil bath at 60 ℃ for 2h, Pd/C is removed by filtration, the filter residue is washed with EtOH, and the filtrate is evaporated to dryness to give 0.75g of a white solid.

¹H-NMR(400MHz,CDCl₃)δ6.70～6.80(m,3H)，3.99～4.02(dd,J＝10.4,3.6Hz,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)

Example 21: preparation of 1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1S) -1, 2-ethanediol (Compound VIIb)

Compound VIIb can be obtained in a similar manner to Experimental example 20, starting from compound Vb (wherein R is benzyl)

[α]_D ²⁰；-87.9(CH₃OH,c 1.0)

Example 22: preparation of 1- [ 6-fluoro- (2R) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1R) -1, 2-ethanediol (Compound VIIIa)

Dissolving 1.3g of compound VIa (wherein R is benzyl) in 25ml of EtOH, adding 0.2g of 10% Pd-C and 0.1g of anhydrous sodium carbonate, carrying out hydrogenation reaction under normal pressure until hydrogen is not absorbed any more, stopping hydrogenation, stirring in an oil bath at 60 ℃ for 2h, filtering to remove Pd/C, washing filter residues with EtOH, and evaporating filtrate to dryness to obtain 0.88g of white solid.

¹H-NMR(400MHz,CDCl₃)δ6.73～6.81(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)

Example 23: preparation of 1- [ 6-fluoro- (2S) -3, 4-dihydro-2H-benzopyran-2-yl ] - (1S) -1, 2-ethanediol (Compound VIIIb)

Compound VIIIb, a white solid, was obtained in a similar manner to experimental example 22 starting from compound VIb (where R is benzyl); [ alpha ] to]_D ²⁰；+95.6(CH₃Cl,c 0.045)。

Example 24: preparation of (S, R) - (+) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound IXa)

Compound IXa can be obtained in a similar manner to that in Experimental example 11 starting from compound VIIa.

[α]_D ²⁰；+82.1(CHCl₃,c 0.56)

Example 25: preparation of (R, R) - (-) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound Xa)

Compound Xa can be obtained in a similar manner to that described in example 11 starting from compound VIIIa.

HR-MS (ESI) calculated value C₁₈H₁₉O₅FNaS(M+Na)⁺Found value of 389.0829 found value 389.0823

[α]_D ²⁰；-48.4(CH₃Cl,c 0.68)

Example 26: preparation of (R, S) - (-) - α - [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol (compound IXb)

Compound IXb can be obtained in a similar manner to Experimental example 11 starting from compound VIIb.

[α]_D ²⁰；-80.3(CHCl₃,c 0.85)

Example 27: preparation of (S, S) - (+) -alpha- [ (p-toluenesulfonyloxy) methyl ] - (6-fluoro-2-chromanyl) -methanol (compound Xb)

Compound Xb can be obtained by a similar method to that of Experimental example 11, starting from compound VIIIa.

[α]_D ²⁰；+50.3(CH₃Cl,c 0.50)

Example 28: preparation of (S, R) - [ (benzylamino) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound XIa)

Compound XIa can be obtained by a method similar to that of Experimental example 13, starting from compound IXa.

Compound XIa is a white solid, [ alpha ]]_D ²⁰；+82.1(CHCl₃,c 0.56)

Example 29: preparation of (R, S) - [ (benzylamino) methyl ] - (6-fluoro-2-chromanyl) -methanol (Compound XIb)

Compound XIb can be obtained by using compound IXb as a starting material in a similar manner to example 13.

[α]_D ²⁰；-79.3(CHCl₃,c 0.45)

Example 30: preparation of N-benzyl-D-nebivolol (Compound XIIIa)

287mg (0.95mmol) of compound XIa and 350mg (0.95mmol) of compound Xa are dissolved in 5ml of ethanol, 150mg of anhydrous Na are added₂CO₃The reaction was heated and refluxed for 16 hours.

Evaporating to dryness under reduced pressure, adding 10ml water into residue, extracting with EtOAc twice, mixing extractive solutions, washing with saturated NaCl, drying with anhydrous Na2SO4, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain syrup 453 mg. Recrystallization from ethanol/water gave 373mg (79%) of a white solid.

Example 30': preparation of N-benzyl-D-nebivolol hydrochloride (Compound XIIIa hydrochloride)

287mg (0.95mmol) of compound XIa and 350mg (0.95mmol) of compound Xa are dissolved in 5ml of ethanol, 150mg of anhydrous Na are added₂CO₃The reaction was heated and refluxed for 16 hours.

Evaporating to dryness under reduced pressure, adding 10ml of water into residue, extracting with EtOAc twice, mixing extractive solutions, adding 1N hydrochloric acid 2ml, stirring for crystallization, and filtering to obtain white solid 390mg with purity of 99.5%.

Example 30 ": preparation of N-benzyl-D-nebivolol (Compound XIIIa)

390mg of compound XIIIa hydrochloride was added to 10ml dichloromethane, stirred, neutralized with aqueous sodium bicarbonate solution, the layers were separated, the organic layer was dried and concentrated to give 355mg of white solid with a purity of 99.7%.

Example 31: preparation of N-benzyl-L-nebivolol (Compound XIIIb)

Compound XIIIb can be obtained by a similar manner to that of example 30, starting from compound XIb and Xb.

Example 31': preparation of N-benzyl-L-nebivolol hydrochloride (Compound XIIIb hydrochloride)

Compound XIIIb hydrochloride was obtained in 99.6% purity in a similar manner to example 30' starting from compound XIb and Xb.

Example 31 ": preparation of N-benzyl-L-nebivolol (Compound XIIIb)

Compound XIIIb is obtained in a purity of 99.8% in a similar manner to example 30 ".

Example 32: preparation of DL-nebivolol (Compound I) hydrochloride

Dissolving 200mg (0.4mmol) of compound I in 5ml of ethanol, adding 50mg of 10% Pd-C, carrying out hydrogenation reaction at room temperature under normal pressure for 18h, filtering, washing filter residues with ethanol, introducing hydrogen chloride gas into the filtrate, then distilling under reduced pressure to remove ethanol to obtain a white solid, adding anhydrous ether, stirring, and filtering to obtain 160mg (89%) of a product.

¹H-NMR(500MHz,DMSO-d₆)δ8.81(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⁺) Calculated value C₂₂H₂₆F₂NO₄ S(M+1-HCl)⁺: calculated value 406.1829 found value 406.1825

Example 32': preparation of DL-nebivolol (Compound I) hydrochloride

Adding 100mg of compound XIIIa 'and 100mg of compound XIIIb' into 15ml of dichloromethane, adding an aqueous solution of sodium bicarbonate for neutralization, then carrying out layering, concentrating an organic layer to dryness, adding 50ml of methanol and 50mg of 10% Pd-C, carrying out hydrogenation reaction at room temperature and normal pressure for 18h, filtering, washing filter residues with methanol, adding 2ml of 1N hydrochloric acid into filtrate, crystallizing, filtering, washing, and drying to obtain 100mg of white solid with the purity of 99.9%.

HR-MS(FAB⁺) Calculated value C₂₂H₂₆F₂NO₄ S(M+1-HCl)⁺: calculated value 406.1829 found value 406.1825

Example 32 ": preparation of DL-nebivolol (Compound I) hydrochloride

100mg of the compound XIIIa obtained in example 30 "and 100mg of the compound XIIIb obtained in example 31" are added to 50ml of methanol, 50mg of 10% Pd-C are then added, the reaction is hydrogenated at room temperature and pressure for 18h, the mixture is filtered, the residue is washed with methanol, 2ml of 1N hydrochloric acid is added to the filtrate, and the white solid 105mg with a purity of 99.9% is obtained by crystallization, filtration, washing and drying.

HR-MS(FAB⁺) Calculated value C₂₂H₂₆F₂NO₄ S(M+1-HCl)⁺: calculated value 406.1829 found value 406.1825

Example 33 a: preparation of D-nebivolol (Compound Ia) hydrochloride

Compound Ia hydrochloride was obtained by similar method to example 32 starting from compound XIIIa. [ alpha ] to]_D ²⁰；+22.0(CH₃OH,C 0.5)

Example 33 b: preparation of L-nebivolol (compound Ib) hydrochloride

Compound Ib hydrochloride can be obtained by a similar method to that of example 32 starting from compound XIIIb. [ alpha ] to]_D ²⁰；-21.2(CH₃OH,C 0.4)

In conclusion, the novel method provided by the invention has high stereoselectivity, the preparation of the key intermediate can avoid column chromatography separation, the reaction condition is mild, and no special reagent is needed. Compared with the prior art, the cost for preparing the nebivolol by using the method is greatly reduced, and the method is very suitable for industrial production. Particularly, the intermediate and the product quality are greatly improved by the crystallization purification of the intermediates of the formulas III, IV1 and IV2, so that the product quality is controllable, the yield is improved, and the production cost is obviously reduced. Moreover, the compounds of the formulas XIIIa and XIIIb are purified by salifying crystallization, so that the product quality is greatly improved, and the purity of the final product can reach more than 99.9%.

While some embodiments of the present invention and specific examples thereof have been provided above, it will be understood by those skilled in the art that these embodiments and examples are merely illustrative of the present invention and that other modifications and variations may be made thereto without departing from the spirit of the invention.

Detailed description of the preferred embodiments：

1. A process for the preparation of a compound of formula VII (S/R),

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

the method comprises the following steps:

3) the trans-compound IV1

Epoxidizing under the action of an epoxidizing reagent to obtain an epoxy intermediate V, wherein R is a hydroxyl protecting group selected from alkyl, halogenated alkyl and arylAlkyl, alkoxyalkyl, allyl or silicon protecting groups, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl, but in the formula wherein R is represented by benzyl (Bn) for example,

wherein the compound V is racemic mixture containing equal amount of formula Va and its enantiomer Vb, and its relative configuration is represented by V (2R,3R)

4) Deprotection and cyclization of compound V (2R,3R) provides intermediate compound VII (S/R), wherein R is as defined above, but in the formula below R is shown as for example benzyl (Bn),

wherein VII (S/R) is a racemate comprising equal amounts of a racemic mixture of formula VIIa (S/R) and its enantiomer VIIb (R/S),

2. a process for the preparation of a compound of formula VIII (R/R),

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

the method comprises the following steps:

3) cis-Compound IV2

Epoxidation under the action of an epoxidizing agent to give an epoxy intermediate V, wherein R is a hydroxy-protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl or a silicon-protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group such as p-methoxyphenyl or halophenyl, but in the formula wherein R is shown as exemplified by benzyl (Bn),

wherein compound VI is racemic mixture containing equal amount of formula VIa and its enantiomer VIb, and its relative configuration is represented by VI (2R,3S)

4) Deprotection and cyclization of compound VI (2R,3S) provides intermediate compound VIII (R/R), wherein R is as defined above, but in the formula R is shown as benzyl (Bn) for example,

wherein VIII (R/R) is a racemate, being a racemic mixture containing equal amounts of formula VIIIa (R/R) and its enantiomer VIIIb (S/S),

3. the method according to embodiment 1 or 2, wherein in step 3), the epoxidation reaction of trans compound IV1 or cis compound IV2 may be carried out using epoxidation methods commonly used in the art, for example, the epoxidation reagent which may be used is selected from the group consisting of organic peroxyacids such as MCPBA, trifluoroperacetic acid, dimethyl ketone peroxide (DMDO), a mixture of hydrogen peroxide and acetic acid, and vo (acac)₂Mixture with tert-butyl peroxy-butanol, and pyridine-H in the presence of catalytic amounts of Methyltrioxorhenium (MTO)₂O₂The reaction solvent is an organic aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, toluene or a mixture of any two or more thereof.

4. The process according to any of the above embodiments, wherein in step 4), the hydroxyl protecting group can be removed by methods commonly used in the field of organic chemistry, such as hydrogenolysis in the presence of a catalyst to remove the benzyl protecting group, followed by addition of a base for cyclization; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic heterocyclic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reactions can adopt the basic hydrogenolysis condition under the condition of taking Pd/C as the catalyst to simultaneously carry out the benzyl protecting group removal and cyclization reactions so as to directly obtain the cyclization product.

5. The method according to any of the above embodiments, wherein:

in step 4), the hydroxyl protecting group can be removed by methods commonly used in the field of organic chemistry, for example, the benzyl protecting group is removed by hydrogenolysis in the presence of a catalyst, and then a base is added for cyclization; the catalyst used in the hydrogenolysis reaction is a palladium catalyst, such as Pd/C, Pd (OH)₂、Pd(OAc)₂、PdCl₂Pd; the base used in the cyclization reaction is selected from hydroxides or carbonates of alkali metals and alkaline earth metals, alkoxides or organic heterocyclic bases, e.g. NaOH, KOH, K₂CO₃NaOMe, DBU; or the deprotection and cyclization reactions can adopt the basic hydrogenolysis condition under the condition of taking Pd/C as the catalyst to simultaneously carry out the benzyl protecting group removal and cyclization reactions so as to directly obtain the cyclization product.

6. A process for the preparation of a compound of formula III;

the method comprises the following steps:

step a): reacting a compound of formula XIV, wherein R is a hydroxy protecting group as described above and X is halogen, with 3-trisubstituted silyl-propan-2-Reaction of alkyne-1-lithium to give the compound of formula XV, wherein R₁、R₂、R₃Each independently selected from alkyl or aryl groups, such as methyl, t-butyl or phenyl;

step b): removing the silicon protecting group at the alkynyl end of the compound of the formula XV to obtain a compound of the formula XVI, wherein R is as defined above;

step c): reacting a compound of formula XVI with paraformaldehyde in the presence of a base or an organometallic reagent to provide a compound of formula III, wherein R is as defined above; and

7. The process according to embodiment 6, wherein the reaction of step a) is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene.

8. The process according to any of embodiments 6 to 7, wherein the reaction of step b) is carried out in the presence of a base, an acid or a fluoride-containing salt, preferably in the presence of a base selected from hydroxides or carbonates of alkali or alkaline earth metals, such as NaOH, KOH, Na₂CO₃、K₂CO₃The solvent used for the reaction is selected from protic solvents such as water, methanol, ethanol or a mixture of any two or more thereof.

9. The process according to any of embodiments 6 to 8, wherein the base in step c) is selected from a metal hydride or an organic base, such as NaNH₂Or KNH₂The organometallic reagent is selected from BuLi, t-BuLi, s-BuLi, LDA or Grignard reagents, such as MeMgX, EtMgX, BuMgX, I-PrMgX, where X is Br, I or Cl, and the reaction solvent used 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。

10. The method according to any one of embodiments 6-9, wherein:

the reaction of step a) is carried out in an organic aprotic solvent, such as methyltetrahydrofuran, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether or toluene;

11. A process for preparing a compound of formula IV1,

the method comprises the following steps:

reduction of compound III with a metal hydride affords a compound of formula IV1,

wherein R is as defined above;

and optionally the steps of: to the resulting compound of formula IV1 is added a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof, stirred at low temperature, e.g. at 0 to-20 ℃, crystallized, filtered to give a solid of the compound of formula IV 1.

12. The method according to embodiment 11, wherein the metal complex hydride reducing agent used is LiAlH₄Or sodium dihydrobis (2-methoxyethoxy) aluminate, the reaction solvent being 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.

13. A process for preparing a compound of formula IV2,

the method comprises the following steps:

the compound III is subjected to selective catalytic hydrogenation reduction to obtain a cis-compound of a formula IV2,

wherein R is as defined above;

and optionally the steps of: to the resulting compound of formula IV2 is added a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof, stirred at low temperature, e.g. at 0 to-20 ℃, crystallized, filtered to give a solid of the compound of formula IV 2.

14. The process according to embodiment 13, wherein the catalyst used for the selective catalytic hydrogenation reduction is selected from the group consisting of Lindlar (Lindlar) catalyst or P-2 type nickel boride/ethylenediamine catalyst.

15. A process for the preparation of racemic nebivolol of formula I,

the method comprises the following steps:

1) reducing compound III with a metal complex hydride to give a trans compound of formula IV1, and optionally the following steps: adding nonpolar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or mixture of any two or more thereof to the obtained compound of formula IV1, stirring at low temperature such as 0-20 deg.C, crystallizing, filtering to obtain solid of compound of formula IV1,

wherein R is a hydroxy protecting group selected from alkyl, haloalkyl, aralkyl, alkoxyalkyl, allyl, or a silicon protecting group, e.g. t-BuMe₂Si、t-BuPh₂Si、(i-Pr)₃Si、Et₃Si, methoxymethyl, benzyl or-CH₂Ar, wherein Ar is an unsubstituted or substituted aryl group, such as p-methoxyphenyl or halophenyl,

2) selective catalytic hydrogenation reduction of compound III to give the cis-compound of formula IV2, and optionally the following steps: adding a non-polar organic solvent such as n-hexane, n-heptane, petroleum ether, diethyl ether, isopropyl ether or tert-butyl methyl ether or a mixture of any two or more thereof to the resulting compound of formula IV2, stirring at low temperature such as 0 to-20 deg.C, crystallizing, filtering to give a solid of the compound of formula IV2,