CN108203434B - A kind of asymmetric synthesis method for preparing solifenacin - Google Patents

Abstract

The invention relates to an asymmetric synthesis method for preparing solifenacin. The method comprises the steps of taking ortho-substituted aldehyde as a raw material, and obtaining a key intermediate of high enantioselectivity addition under the catalysis of rhodium and a chiral thiolene ligand; the intermediate is further transformed with functional groups and cyclized to give solifenacin. The method has the advantages of simple operation, mild reaction conditions, high efficiency and high selectivity.

Description

A kind of asymmetric synthesis method for preparing solifenacin

technical field

The invention belongs to the technical field of preparation of bulk drugs, in particular to an asymmetric synthesis method for preparing solifenacin.

Background technique

Overactive bladder (OAB) is one of the common clinical manifestations of voiding dysfunction. Urinary urgency with or without urge incontinence, often accompanied by frequent urination and nocturia. At present, the incidence of OAB is relatively high. According to statistics, about 1/6 of the European population over the age of 40 suffers from OAB, and the incidence of OAB in the United States has also reached 17%. The incidence of incontinence ranges from 18% to 53%, and the incidence of elderly women is as high as 70%. Now countries spend a lot of money on the treatment of OAB every year. In 2000, the United States spent 12.02 billion U.S. dollars on this item alone, accounting for 2% of the national health and economic expenditure, and many OAB patients suffer from repeated frequent urination Urinary urgency and urinary incontinence lead to embarrassment and embarrassment, which seriously affects the normal daily life and social activities of patients. Therefore, the current research on the treatment of OAB has become one of the hot spots at home and abroad.

Solifenacin succinate (trade name: Weixikang) is a highly selective cholinergic receptor (M3) blocker, developed by Japan's Astellas Company, and firstly listed in Europe in 2004. It was approved by the US FDA in 2006, landed in Japan in 2006-2007, and approved for import in China in 2009. From 2013 to 2014, the number of prescriptions in the United States was 3,873,046, ranking 38th, and the sales in the United States in 2013 were 912 million US dollars, ranking 49th in the TOP100, ranking first in the treatment of ADHD. The drug targets the M3 receptor in the human bladder, and has high safety and efficacy for urinary incontinence and/or urinary frequency and urgency in patients with overactive bladder. Its structural formula is:

Solifenacin is an important intermediate for the preparation of solifenacin succinate, and its preparation method mainly includes the following two:

1) Optically pure (S)-1 is obtained by the resolution of the racemate 1-phenyl-1,2,3,4-tetrahydroisoquinoline, which is the currently adopted process synthesis method, but causes Great waste of the other half of the (R)-configurational isomer;

2) It is synthesized by the asymmetric hydrogenation of imine 2 catalyzed by transition metals. The literature Chang, M.; Li, Wei.; Zhang, X.Angew.Chem.Int.Ed.2011,50,10679 reported Ir/ (S,S)-(f)-binaphane-catalyzed asymmetric hydrogenation reaction, but the enantioselectivity control is still not ideal, the ee value is 95%, and it cannot meet the optical purity requirements of chiral drugs. The synthesis of chiral ligands is more complicated and less stable.

Analysis of the existing preparation methods of solifenacin shows that there is a waste of one of the (R)-enantiomers in the splitting route, and the use of asymmetric catalytic reaction is the most efficient and practical method. The symmetric catalytic hydrogenation method still needs to be improved in the stereoselectivity control of the key intermediate (S)-1. Therefore, it is of great significance to develop more efficient and practical catalytic asymmetric methods.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a new method for preparing the precursor of solifenacin succinate, a drug for hyperactivity of the bladder, which is simple in operation, low in cost and mild and controllable in reaction conditions, aiming at the deficiencies of the prior art.

A first aspect of the present invention provides a preparation method of solifenacin, comprising the steps:

A-1: in an inert solvent, the compound of formula a is reacted with N,N-dimethylsulfonamide, thereby forming the compound of formula I;

A: Under the catalysis of transition metal Rh(I) and chiral thiolene ligand L, in a mixed system of alkaline aqueous solution and organic solvent, the compound of formula I reacts with organoboron reagent Ph-[B], thereby forming formula II compound;

Described chiral thioene ligand L has the following structural formula:

wherein, R ³ is phenyl, substituted phenyl, naphthyl, substituted naphthyl, isopropyl, tert-butyl or adamantyl; n=0 or 1, wherein the substitution refers to being selected from the following Substituted by group of substituents: C1-4 alkyl, halogen, nitro, methoxy or N,N-dimethyl;

B-1: in an amine solvent, the compound of formula II is subjected to the reaction of removing the sulfonyl protecting group, thereby forming the compound of formula III;

B-2: in an inert solvent, the compound of formula III is reacted with a chloroformate (R ² OC(=O)Cl) to form a compound of formula IV;

B-3: in an inert solvent, the compound of formula IV is carried out to remove the reaction of the hydroxyl protecting group, thereby forming the compound of formula V;

C: in an inert solvent, in the presence of Mitsunobu reagent, the compound of formula V is subjected to ring-closure reaction, thereby forming the compound of formula VI;

D: in an inert solvent, under basic conditions, the compound of formula VI is carried out transesterification with (R)-(-)-3-quinic alcohol, thereby forming solifenacin;

In the above formulas, R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl; R ² is C1- 6 alkyl or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl.

In another preferred example, R ² is methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.

In another preferred example, in step A, the molar ratio of the compound of formula I to the organoboron reagent is 1:0.33-3.

In another preferred example, in step A, the molar ratio of the compound of formula I to the organoboron reagent is 1:0.5-2.

In another preferred example, in step A, the organoboron reagent is phenylboronic acid, phenylboronic anhydride, potassium phenyltrifluoroborate, phenylboronic acid pinacol boron ester or sodium tetraphenylboron; and/or the The alkaline aqueous solution is potassium hydroxide aqueous solution, potassium carbonate aqueous solution or potassium phosphate aqueous solution.

In another preferred example, in step A, the molar ratio of the compound of formula I to the organoboron reagent is 1:0.5-2.

In another preferred example, in step A, the transition metal Rh(I) is [Rh(coe) ₂ Cl] ₂ or [Rh(C ₂ H ₄ ) ₂ Cl] ₂ .

In another preferred example, in step A, the organic solvent is selected from the group consisting of toluene, ortho-xylene, meta-xylene, para-xylene, 1,2-dichloroethane, or a combination thereof.

In another preferred example, in step A, the temperature of the reaction is 40-100°C.

In another preferred example, in step A, the temperature of the reaction is 40-70°C.

In another preferred example, in step B-1, the amine solvent is selected from the group consisting of n-butylamine, 1,3-propanediamine, ethylenediamine, or a combination thereof.

In another preferred example, in step B-1, the temperature of the reaction for removing the sulfonyl protecting group is 80-140°C.

In another preferred example, in step B-1, the reaction of removing the sulfonyl protecting group is carried out in a microwave or an oil bath.

In another preferred example, in step B-1, the temperature of the reaction for removing the sulfonyl protecting group is microwave 110-125° C. or oil bath reflux.

In another preferred example, in step B-2, the chloroformate is methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate or butyl chloroformate.

In another preferred example, in step B-2, the reaction of removing the hydroxyl protecting group is carried out under the action of tetrabutylammonium fluoride.

In another preferred example, in step C, the Mitsunobu reaction reagent is an equimolar ratio of diisopropyl azodicarboxylate or diethyl azodicarboxylate to triphenylphosphine (diisopropyl azodicarboxylate) propyl ester or diethyl azodicarboxylate: triphenylphosphine) combination.

In another preferred example, in step C, the molar ratio of the compound of formula V to the Mitsunobu reagent is 1:1-5.

In another preferred example, in step C, the compound of formula V and the Mitsunobu reaction reagent (when the Mitsunobu reaction reagent contains multiple substances, the moles of the Mitsunobu reaction reagent here are calculated by the moles of any of the substances) ) in a molar ratio of 1:1 to 3.

In another preferred example, in step C, the temperature of the ring-closing reaction is 20-70°C.

In another preferred example, in step C, the temperature of the ring-closure reaction is 20-60°C.

The second aspect of the present invention provides an intermediate compound whose structure is as follows:

in,

R is hydrogen, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl;

R' is hydrogen or phenyl; and when R' is hydrogen, the carbon-nitrogen bond connected to it is a double bond, and R"' is no; when R' is phenyl; the carbon-nitrogen bond connected to it is a single bond, and R"' is hydrogen;

其中，R²为C1-6烷基或取代的C1-6烷基或苯基，其中，所述取代是指被选自下组的取代基所取代：C1-4烷基、卤素、苯基。R" is

wherein, R ² is C1-6 alkyl or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl .

In another preferred embodiment, the intermediate compound is a compound represented by the following structural formula:

Wherein, R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl; R ² is C1-6 alkyl Or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl.

In another preferred example, R ² is methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.

A third aspect of the present invention provides a chiral thioene ligand, which has the following structural formula:

n＝0或1。wherein, R ³ is isopropyl or

n=0 or 1.

It should be understood that, within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After extensive and in-depth research, the inventors have unexpectedly discovered a new preparation method of solifenacin with simple operation, mild reaction conditions and better economy. The method saves the tedious chiral separation step, avoids the waste of the other half of the enantiomer, is beneficial to reduce the production cost, and has a good industrial application prospect. On this basis, the inventors have completed the present invention.

As used herein, "C1-6 alkyl" refers to a straight or branched chain alkyl group having 1-6 carbon atoms; for example, it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, n-pentyl, n-hexyl and similar groups.

As used herein, "halogen" refers to fluorine, chlorine, bromine, iodine.

Ligand

The ligand used in the present invention is a chiral thioene ligand L, which has the following structural formula:

Wherein, R ³ is phenyl, substituted phenyl, naphthyl, substituted naphthyl, isopropyl, tert-butyl or adamantyl; n=0 or 1, wherein, the substitution refers to being selected from the group Substituents substituted by: C1-4 alkyl, halogen, nitro, methoxy or N,N-dimethyl.

In another preferred example, the structural formula of the chiral thioene ligand L is as follows:

In another preferred example, the chiral thioene ligand L is a chiral thioene ligand in which R ³ is a tert-butyl group.

The preparation method of solifenacin

The present invention provides a new preparation method of solifenacin. The method can use ortho-substituted aldimine I as a raw material, use chiral thiolene L as a ligand, under the catalysis of rhodium (I), through manual The product II is obtained by sexual addition, and the compound of formula VI, the key precursor of solifenacin, is further obtained through a series of reactions, thereby further preparing solifenacin.

The preparation method of the present invention can be as follows:

Wherein, R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl; R ² is C1-6 alkyl Or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl.

Specifically, it can mainly include the following steps:

A-1: in an inert solvent, the compound of formula a is reacted with N,N-dimethylsulfonamide, thereby forming the compound of formula I;

A: Under nitrogen protection, under the catalysis of transition metal rhodium (I) and chiral thiolene ligand L, in a mixed solution of alkaline aqueous solution and organic solvent, aldimine I and organoboron reagent are reacted, thereby to form the addition product of formula II;

In this step, the organic boron reagent is phenylboronic acid, phenylboronic anhydride, potassium phenyltrifluoroborate, phenylboronic acid pinacol boron ester or sodium tetraphenylboron, preferably phenylboronic anhydride. The molar ratio of the compound of formula I to the organoboron reagent is 1:0.33-3, preferably 1:1. The transition metal rhodium (I) is [Rh(coe) ₂ Cl] ₂ or [Rh(C ₂ H ₄ ) ₂ Cl] ₂ , preferably [Rh(coe) ₂ Cl] ₂ . The alkaline aqueous solution is potassium hydroxide aqueous solution, potassium carbonate aqueous solution or potassium phosphate aqueous solution, preferably potassium hydroxide aqueous solution. The organic solvent is toluene, o-xylene, m-xylene, p-xylene, 1,2-dichloroethane, or a combination thereof; toluene is preferred. The reaction time is 1 to 12 hours, preferably 6 hours. The reaction temperature is 40 to 100°C, preferably 60°C. The amount of [Rh(coe) ₂ Cl] ₂ is 1-5 mol% (calculated according to the compound of formula I), preferably 3.3 mol% (calculated according to the compound of formula I). The amount of chiral thioene ligand used is 1-5.5 mol% (calculated according to the compound of formula I), preferably 3.3 mol% (calculated according to the compound of formula I).

B-1: in an amine solvent, the compound of formula II is subjected to the reaction of removing the sulfonyl protecting group, thereby forming the compound of formula III;

In this step, the amine solvent is n-butylamine, 1,3-propanediamine, ethylenediamine, or a combination thereof; preferably 1,3-propanediamine. The temperature of the reaction for removing the sulfonyl protecting group is 80-140°C, preferably 120°C. The reaction of removing the sulfonyl protecting group is carried out in microwave or oil bath. The temperature of the reaction for removing the sulfonyl protecting group is microwave 110-125° C. or oil bath reflux.

B-2: in an inert solvent, the compound of formula III is reacted with a chloroformate (R ² OC(=O)Cl) to form a compound of formula IV;

In this step, the chloroformate is methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, and butyl chloroformate; preferably ethyl chloroformate. The inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or a combination thereof.

B-3: in an inert solvent, the compound of formula IV is carried out to remove the reaction of the hydroxyl protecting group, thereby forming the compound of formula V;

In this step, the reaction of removing the hydroxyl protecting group is carried out under the action of tetrabutylammonium fluoride. The inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or a combination thereof.

C: in an inert solvent, in the presence of Mitsunobu reagent, the compound of formula V obtained in the above steps is subjected to ring-closure reaction, thereby forming the compound of formula VI;

In this step, the Mitsunobu reaction reagent is an equimolar ratio combination of diisopropyl azodicarboxylate or diethyl azodicarboxylate and triphenylphosphine, preferably diisopropyl azodicarboxylate and triphenylphosphine An equimolar combination of phosphines. The molar ratio of the compound of formula V to the Mitsunobu reagent is 1:1 to 5, preferably 1:2. The reaction temperature is 20 to 70°C, preferably 25°C. The inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or a combination thereof.

D: in an inert solvent, under basic conditions, the compound of formula VI obtained in the above steps is subjected to transesterification with (R)-(-)-3-quinic alcohol, thereby obtaining solifenacin;

In this step, the alkali is NaH, potassium tert-butoxide, sodium methoxide, sodium ethoxide, or a combination thereof; preferably NaH. The temperature of the transesterification reaction is 80-150°C, preferably 120°C. The inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, ortho-xylene, meta-xylene, para-xylene, DMF, DMSO, or a combination thereof; preferably toluene.

The solifenacin prepared by the preparation method of the present invention can be directly used for synthesizing solifenacin succinate.

Intermediate

The present invention also provides an intermediate compound whose structure is shown below for the preparation of solifenacin:

in,

R is hydrogen, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl;

R' is hydrogen or phenyl; and when R' is hydrogen, the carbon-nitrogen bond connected to it is a double bond, and R"' is no; when R' is phenyl; the carbon-nitrogen bond connected to it is a single bond, and R"' is hydrogen;

其中，R²为C1-6烷基或取代的C1-6烷基或苯基，其中，所述取代是指被选自下组的取代基所取代：C1-4烷基、卤素、苯基。R" is

wherein, R ² is C1-6 alkyl or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl .

In another preferred embodiment, the intermediate compound is a compound represented by the following structural formula:

Wherein, R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl; R ² is C1-6 alkyl Or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl.

In another preferred example, R ² is methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.

The present invention provides a method for preparing a compound represented by formula I, comprising the steps of: in an inert solvent (such as tetrahydrofuran, etc.), at a certain temperature (such as reflux), mixing the compound of formula a with N,N-dimethylsulfonic acid The amide is reacted for a period of time (eg, 1-36 hours, or 5-24 hours) to form the compound of formula I;

Wherein, R ¹ is as defined above.

The invention provides a method for preparing a compound represented by formula II, comprising the steps of: under the catalysis of transition metal Rh(I) and chiral thioene ligand L, in a mixed system of an alkaline aqueous solution and an organic solvent, formula Compound I reacts with the organoboron reagent Ph-[B] to form compound of formula II;

Described chiral thioene ligand L has the following structural formula:

Wherein, R ¹ and R ³ are as defined above.

In this step, the organic boron reagent is phenylboronic acid, phenylboronic anhydride, potassium phenyltrifluoroborate, phenylboronic acid pinacol boron ester or sodium tetraphenylboron, preferably phenylboronic anhydride. The molar ratio of the compound of formula I to the organoboron reagent is 1:0.33-3, preferably 1:1. The transition metal rhodium (I) is [Rh(coe) ₂ Cl] ₂ or [Rh(C ₂ H ₄ ) ₂ Cl] ₂ , preferably [Rh(coe) ₂ Cl] ₂ . The alkaline aqueous solution is potassium hydroxide aqueous solution, potassium carbonate aqueous solution or potassium phosphate aqueous solution, preferably potassium hydroxide aqueous solution. The organic solvent is toluene, o-xylene, m-xylene, p-xylene, 1,2-dichloroethane, or a combination thereof; toluene is preferred. The reaction time is 1 to 12 hours, preferably 6 hours. The reaction temperature is 40 to 100°C, preferably 60°C. The amount of [Rh(coe) ₂ Cl] ₂ is 1-5 mol% (calculated according to the compound of formula I), preferably 3.3 mol% (calculated according to the compound of formula I). The amount of chiral thioene ligand used is 1-5.5 mol% (calculated according to the compound of formula I), preferably 3.3 mol% (calculated according to the compound of formula I).

The invention provides a preparation method of a compound represented by formula III, comprising the steps of: in an amine solvent, the compound of formula II is subjected to a reaction of removing a sulfonyl protecting group, thereby forming a compound of formula III;

Wherein, R ¹ is as defined above.

In this step, the amine solvent is n-butylamine, 1,3-propanediamine, ethylenediamine, or a combination thereof; preferably 1,3-propanediamine. The temperature of the reaction for removing the sulfonyl protecting group is 80-140°C, preferably 120°C. The reaction of removing the sulfonyl protecting group is carried out in microwave or oil bath. The temperature of the reaction for removing the sulfonyl protecting group is microwave 110-125° C. or oil bath reflux.

The invention provides a preparation method of a compound represented by formula IV, comprising the steps of: reacting the compound of formula III with chloroformate in an inert solvent to form the compound of formula IV;

Wherein, R ¹ and R ² are as defined above.

In this step, the chloroformate is methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, and butyl chloroformate; preferably ethyl chloroformate. The inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or a combination thereof.

The invention provides a preparation method of a compound represented by formula V, comprising the steps of: in an inert solvent, the compound of formula IV is subjected to a reaction of removing a hydroxyl protecting group, thereby forming a compound of formula V;

Wherein, R ¹ and R ² are as defined above.

In this step, the reaction of removing the hydroxyl protecting group is carried out under the action of tetrabutylammonium fluoride. The inert solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, DMF, DMSO, or a combination thereof.

The main advantages of the present invention include:

The invention provides a preparation method of solifenacin with simple operation, mild reaction conditions and better economy. The method uses ortho-substituted aldehydes as raw materials, under the catalysis of transition metal rhodium (I), takes chiral thioenes as ligands, and obtains the drug solifenacin succinate through cyclization and transesterification of asymmetric reaction products. The method saves the tedious chiral separation step, avoids the waste of the other half of the enantiomer, is beneficial to reduce the production cost, and has a certain industrial application prospect.

The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. The raw materials or instruments used in the examples of the present invention are commercially available unless otherwise specified.

Preparation Example 1

A 100mL round bottom flask was weighed A (1g, 3.8mmol), N,N-dimethylsulfonamide (470mg, 3.8mmol, 1eq) was added, 25mL of anhydrous tetrahydrofuran was dissolved, and tetraethyl titanate (1.6mL, 7.6 mmol, 2 equiv), refluxed (reflux) in an oil bath for 12 hours, cooled to room temperature, added with saturated brine to precipitate a precipitate, filtered through celite, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and subjected to flash column chromatography. 1.22 g of white solid 1a were obtained.

白色固体，产率87％.¹H NMR(300MHz,CDCl₃)δ9.21(s,1H),8.07(d,J＝8.0Hz,1H),7.52(t,J＝6.9Hz,1H),7.34(t,J＝7.7Hz,2H),3.82(t,J＝6.4Hz,2H),3.14(t,J＝6.4Hz,2H),2.87(s,6H),0.79(s,9H),-0.09(s,6H).

White solid, 87% yield. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.21 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.52 (t, J=6.9 Hz, 1H), 7.34(t,J＝7.7Hz,2H),3.82(t,J＝6.4Hz,2H),3.14(t,J＝6.4Hz,2H),2.87(s,6H),0.79(s,9H), -0.09(s,6H).

A 100 mL round-bottomed flask was weighed B (3.6 g, 9.2 mmol), N,N-dimethylsulfonamide (1.14 g, 9.2 mmol, 1 equiv.) was added, dissolved in 25 mL of anhydrous tetrahydrofuran, and tetraethyl titanate (3.84 g) was added. mL, 18.32 mmol, 2 equiv), refluxed (reflux) in an oil bath for 12 hours, cooled to room temperature, added saturated brine to precipitate a precipitate, filtered through celite, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and flash column layer After precipitation, 3.52 g of white solid 1b was obtained.

白色固体，产率78％。¹H NMR(300MHz,CDCl₃)δ9.19(s,1H),8.07(d,J＝7.9Hz,1H),7.60-7.28(m,13H),3.87(t,J＝6.2Hz,2H),3.23(t,J＝6.2Hz,2H),2.77(s,6H),0.98(s,9H).

White solid, 78% yield. ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.19 (s, 1H), 8.07 (d, J=7.9 Hz, 1H), 7.60-7.28 (m, 13H), 3.87 (t, J=6.2 Hz, 2H) ,3.23(t,J＝6.2Hz,2H),2.77(s,6H),0.98(s,9H).

Preparation Example 2

50mL round bottom flask, add 218mg compound α, β-unsaturated aldehyde, 121mg (R)-tert-butanesulfinamide, dissolve in 25mL anhydrous tetrahydrofuran, add 0.42mL tetraethyl titanate, put it in an oil bath to reflux (reflux ) After reacting for 6 hours, cooled to room temperature, adding solid sodium borohydride, reacting for 1 hour, slowly adding methanol until no bubbles were formed, adding saturated brine to precipitate the precipitate, filtering through celite, extracting with ethyl acetate, drying over anhydrous sodium sulfate, column Chromatography gave 272 mg of L1 as a white solid.

白色固体，产率88％。¹H NMR(300MHz,CDCl₃)δ5.14(s,1H),4.82(s,1H),3.80-3.69(m,1H),3.64(d,J＝7.9Hz,1H),3.21(s,1H),2.94(m,1H),1.95(s,3H),1.85(d,J＝6.0Hz,1H),1.75-1.60(m,5H),1.49(s,5H),1.25(s,9H),0.94(d,J＝6.0Hz,1H).

White solid, 88% yield. ¹ H NMR (300MHz, CDCl ₃ ) δ 5.14(s, 1H), 4.82(s, 1H), 3.80-3.69(m, 1H), 3.64(d, J=7.9Hz, 1H), 3.21(s, 1H), 2.94(m, 1H), 1.95(s, 3H), 1.85(d, J＝6.0Hz, 1H), 1.75-1.60(m, 5H), 1.49(s, 5H), 1.25(s, 9H ),0.94(d,J=6.0Hz,1H).

Example 1

A Schlenk flask was charged with aldimine 1a (148 mg, 0.4 mmol, 1 equiv), phenylboronic anhydride (125 mg, 0.4 mmol, 1 equiv), [Rh(coe) ₂ Cl] ₂ (4.4 mg, 3 mol %) and chiral branch Thiene ligand L2 (3.1 mg, 3.3 mol%) was replaced with nitrogen, 4 mL of toluene was added, stirred at room temperature for 30 min, and then 0.8 mL of potassium hydroxide aqueous solution (1.5 M) was added to the system, and the reaction was carried out at 60 °C for 6 h. The solvent was spin-dried, and column chromatography (petroleum ether/ethyl acetate=5/1) gave the addition product 2a (yield: 82%; 99% ee).

白色固体，产率(yield)82％，99％ee.[α]²⁵ _D＝+24.6(c 0.71,CHCl₃).¹H NMR(300MHz,CDCl₃)δ7.39-7.22(m,9H),5.87(d,J＝6.0Hz,1H),5.18(d,J＝6.0Hz,1H),3.72(dd,J＝13.9,7.0Hz,2H),2.86(t,J＝7.0Hz,2H),2.54(s,6H),0.82(s,9H),-0.04(s,6H).¹³C NMR(150MHz,CDCl₃)δ141.3,139.1,136.9,131.0,128.7,127.8,127.79,127.77,127.74,126.6,63.8,58.3,37.6,35.6,26.0,18.4,-5.4.HRMS(ESI):C₂₃H₃₆N₂O₃NaSiS[M+Na]⁺:calcd 471.2114,found 471.2119.HPLC:Chiralpak AD-H柱(250mm)；检测波长:224nm；己烷/异丙醇＝97/3；流速＝0.4mL/min；保留时间:18.6min(主峰),22.0min.

White solid, 82% yield, 99% ee. [α] ²⁵ _D = +24.6 (c 0.71, CHCl ₃ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39-7.22 (m, 9H) ,5.87(d,J＝6.0Hz,1H),5.18(d,J＝6.0Hz,1H),3.72(dd,J＝13.9,7.0Hz,2H),2.86(t,J＝7.0Hz,2H) , 2.54(s, 6H), 0.82(s, 9H), -0.04(s, 6H). ¹³ C NMR(150MHz, CDCl ₃ )δ141.3,139.1,136.9,131.0,128.7,127.8,127.79,127.77,127.74, 126.6, 63.8, 58.3, 37.6, 35.6, 26.0, 18.4, -5.4. HRMS (ESI): C ₂₃ H ₃₆ N ₂ O ₃ NaSiS [M+Na] ⁺ : calcd 471.2114, found 471.2119. HPLC: Chiralpak AD-H Column (250mm); detection wavelength: 224nm; hexane/isopropanol=97/3; flow rate=0.4mL/min; retention time: 18.6min (main peak), 22.0min.

Example 2

Compound 2a (101 mg, 0.226 mmol, 99% ee) was added to a 10 mL microwave reaction tube, then 2 mL of 1,3-diaminopropane was added to dissolve, and the reaction was carried out in a microwave at 120 °C for 30 min or oil bath reflux for 2 h, and cooled. After reaching room temperature, 10 mL of water was added, extracted with DCM, dried over anhydrous sodium sulfate, and concentrated to obtain the product 3a with the sulfonyl group removed, which was directly put into the next step; under nitrogen protection, 2 mL of anhydrous dichloromethane was added, triethylamine (34.3 mg, 0.339 mmol, 47 μL), ethyl chloroformate (27 mg, 0.248 mmol, 47 μL) was added dropwise in an ice-water bath, transferred to room temperature for 12 h, quenched by adding water, extracted with dichloromethane, dried over anhydrous Na ₂ SO ₄ , The organic phase was concentrated to obtain the carbamate compound 4a, then 2 mL of tetrahydrofuran was added, 1M TBAF tetrahydrofuran solution was added dropwise under an ice-water bath, and the reaction was carried out at room temperature for 12 h. After treatment, column chromatography (petroleum ether/ethyl acetate=1/ 1) to obtain the product 5a with the TBS protecting group removed (52 mg, three-step yield 77%, 99% ee).

无色液体，收率77％，99％ee.¹H NMR(300MHz,CDCl₃)δ7.31-7.18(m,9H),6.26(d,J＝7.3Hz,1H),5.67(d,J＝6.4Hz,1H),4.22-3.94(m,2H),3.79(t,J＝6.2Hz,2H),2.95-2.73(m,2H),2.65(s,1H),1.20(t,J＝6.7Hz,3H).¹³C NMR(100MHz,CDCl₃)δ156.1,141.3,140.2,137.2,130.6,128.6,127.8,127.5,127.3,127.0,55.5,35.8,14.6.HRMS(ESI):C₁₈H₂₁NO₃Na[M+Na]⁺:calcd322.1419,found322.1410.HPLC:ChiralpakAD-H柱(250mm)；检测波长：224nm；己烷/异丙醇＝90/10；流速＝0.7mL/min；保留时间:16.3min(主峰),25.0min.

Colorless liquid, yield 77%, 99% ee. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.31-7.18 (m, 9H), 6.26 (d, J=7.3 Hz, 1H), 5.67 (d, J =6.4Hz,1H),4.22-3.94(m,2H),3.79(t,J=6.2Hz,2H),2.95-2.73(m,2H),2.65(s,1H),1.20(t,J= 6.7Hz, 3H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 156.1, 141.3, 140.2, 137.2, 130.6, 128.6, 127.8, 127.5, 127.3, 127.0, 55.5, 35.8, 14.6.HRMS (ESI): C ₁₈ H ₂₁ NO ₃ Na[M+Na] ⁺ : calcd322.1419, found322.1410.HPLC: Chiralpak AD-H column (250mm); detection wavelength: 224nm; hexane/isopropanol=90/10; flow rate=0.7mL/min ; Retention time: 16.3min (main peak), 25.0min.

Example 3

Under the protection of _N2 , compound 5a (42 mg, 0.14 mmol) and _PPh3 (73.4 mg, 0.28 mmol, 2 equiv.) were dissolved in 1.0 mL of THF, and DIAD (55 μL, 0.28 mmol, 2 equiv.) was slowly added under an ice-water bath, The reaction was stirred at room temperature for 12 hours. After concentrating the solvent, column chromatography (petroleum ether/ethyl acetate=20/1) gave the cyclized product 6a (28 mg, yield 71%, 99% ee).

无色液体，收率71％，99％ee.¹H NMR(300MHz,CDCl₃)δ7.25-7.15(m,8H),7.04(d,J＝6.9Hz,1H),6.37(brs,1H),4.22-4.04(m,3H),3.29-3.23(m,1H),2.97-2.95(m,1H),2.75-2.71(m,1H),1.28(t,J＝6.5Hz,3H)；LR-MS(ESI):m/z 304.3[M+Na]⁺.HPLC:Chiralpak AD-H柱(250mm)；检测波长：224nm；己烷/异丙醇＝90/10；流速＝0.7mL/min；保留时间:10.7min,18.5min(主峰).

Colorless liquid, yield 71%, 99% ee. ¹ H NMR (300MHz, CDCl ₃ ) δ 7.25-7.15 (m, 8H), 7.04 (d, J=6.9Hz, 1H), 6.37 (brs, 1H) ), 4.22-4.04(m, 3H), 3.29-3.23(m, 1H), 2.97-2.95(m, 1H), 2.75-2.71(m, 1H), 1.28(t, J=6.5Hz, 3H); LR-MS (ESI): m/z 304.3 [M+Na] ⁺ .HPLC: Chiralpak AD-H column (250mm); detection wavelength: 224nm; hexane/isopropanol=90/10; flow rate=0.7mL/ min; retention time: 10.7min, 18.5min (main peak).

Example 4

A Schlenk flask was charged with aldimine 1b (198 mg, 0.4 mmol, 1 equiv), phenylboronic anhydride (125 mg, 0.4 mmol, 1 equiv), [Rh(coe) ₂ Cl] ₂ (4.4 mg, 3 mol %) and chiral branch Thiene ligand L2 (3.1 mg, 3.3 mol%) was replaced with nitrogen, 4 mL of toluene was added, stirred at room temperature for 30 min, and then 0.8 mL of potassium hydroxide aqueous solution (1.5 M) was added to the system, and the reaction was carried out at 60 °C for 6 h. The solvent was spun dry, and column chromatography (petroleum ether/ethyl acetate=5/1) gave the addition product 2b (yield: 99%; 99% ee).

白色固体，收率(yield)99％，99％ee.¹H NMR(300MHz,CDCl₃)δ7.55(dd,J＝11.5,7.2Hz,4H),7.42-7.13(m,15H),5.81(d,J＝6.3Hz,1H),4.93(d,J＝6.2Hz,1H),3.73(dd,J＝8.7,5.6Hz,2H),3.09-2.82(m,2H),2.45(s,6H),1.00(s,9H).¹³C NMR(125MHz,CDCl₃)δ140.6,138.6,136.1,135.1,133.2,133.1,130.7,129.12,129.10,128.15,127.18,127.17,126.2,63.6,57.3,37.0,35.1,26.4,18.7.HPLC:Chiralpak AY-H柱(250mm)；检测波长：224nm；己烷/异丙醇＝90/10；流速＝0.7mL/min；保留时间:11.6min(主峰),17.8min.

White solid, yield 99%, 99% ee. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55 (dd, J=11.5, 7.2 Hz, 4H), 7.42-7.13 (m, 15H), 5.81 (d, J＝6.3Hz, 1H), 4.93(d, J＝6.2Hz, 1H), 3.73(dd, J＝8.7, 5.6Hz, 2H), 3.09-2.82(m, 2H), 2.45(s, 6H), 1.00(s, 9H). ¹³ C NMR (125MHz, CDCl ₃ )δ140.6, 138.6, 136.1, 135.1, 133.2, 133.1, 130.7, 129.12, 129.10, 128.15, 127.18, 127.17, 126.2, 63.6, 57.3 , 35.1, 26.4, 18.7.HPLC: Chiralpak AY-H column (250mm); detection wavelength: 224nm; hexane/isopropanol=90/10; flow rate=0.7mL/min; retention time: 11.6min (main peak), 17.8min.

Example 5

Compound 2b (63 mg, 0.134 mmol, 99% ee) was added to a 10 mL microwave reaction tube, then 2 mL of 1,3-diaminopropane was added to dissolve, and the reaction was carried out at 120°C in a microwave for 30 min or oil bath reflux for 2 h, and cooled. At room temperature, 10 mL of water was added, extracted with DCM, dried over anhydrous sodium sulfate, and concentrated to obtain the product 3b with the sulfonyl group removed, which was directly put into the next step; under nitrogen protection, 1 mL of anhydrous dichloromethane was added, triethylamine (20 mg, 0.201 mmol, 28 μL), methyl chloroformate (14 mg, 0.148 mmol, 12 μL) was added dropwise in an ice-water bath, transferred to room temperature for 12 h, quenched by adding water, extracted with dichloromethane, dried over anhydrous Na ₂ SO ₄ , organic The phase was concentrated to obtain the carbamate compound 4b; then 2 mL of tetrahydrofuran was added, 1M TBAF tetrahydrofuran solution was added dropwise under an ice-water bath, and the reaction was carried out at room temperature for 12 h, followed by post-treatment, column chromatography (petroleum ether/ethyl acetate=3/1 ) to obtain the product 5b (42 mg, three-step yield 87%, 99% ee) with the TBDPS protecting group removed.

无色液体，收率87％，99％ee.¹H NMR(300MHz,CDCl₃)δ7.35-7.17(m,9H),6.27(s,1H),5.60(s,1H),3.86(t,J＝6.1Hz,2H),3.68(s,3H),3.01-2.73(m,2H),2.29(s,1H).HPLC:Chiralpak AD-H柱(250mm)；检测波长：224nm；己烷/异丙醇＝90/10；流速＝0.7mL/min；保留时间s:15.4min(主峰),21.8min.

Colorless liquid, yield 87%, 99% ee. ¹ H NMR (300MHz, CDCl ₃ )δ7.35-7.17(m, 9H), 6.27(s, 1H), 5.60(s, 1H), 3.86(t , J=6.1Hz, 2H), 3.68 (s, 3H), 3.01-2.73 (m, 2H), 2.29 (s, 1H). HPLC: Chiralpak AD-H column (250mm); detection wavelength: 224nm; hexane /isopropanol=90/10; flow rate=0.7mL/min; retention time s: 15.4min (main peak), 21.8min.

Example 6

Under the protection of _N2 , compound 5b (14 mg, 0.05 mmol) and _PPh3 (39 mg, 0.15 mmol, 3 equiv.) were dissolved in 1.0 mL of THF, DIAD (30 μL, 0.15 mmol, 3 equiv.) was slowly added under an ice-water bath, and the temperature was turned to room temperature. The reaction was stirred for 12 hours, and after the solvent was concentrated, column chromatography (petroleum ether/ethyl acetate=30/1) gave the cyclized product 6b (11 mg, 79% yield, 99% ee).

无色液体，79％产率,99％ee.¹H NMR(300MHz,CDCl₃)δ7.24-7.12(m,8H),7.05(d,J＝7.6Hz,1H),6.43(s,1H),4.01(s,1H),3.77(s,3H),3.24(d,J＝9.4Hz,1H),3.07-2.90(m,1H),2.83-2.68(m,1H).LR-MS(ESI):m/z 267[M+Na]⁺.HPLC:ChiralpakAD-H柱(250mm)；检测波长：224nm；己烷/异丙醇＝90/10；流速＝0.7mL/min；保留时间s:13.7min,22.8min(主峰).

Colorless liquid, 79% yield, 99% ee. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.24-7.12 (m, 8H), 7.05 (d, J=7.6 Hz, 1H), 6.43 (s, 1H) ),4.01(s,1H),3.77(s,3H),3.24(d,J=9.4Hz,1H),3.07-2.90(m,1H),2.83-2.68(m,1H).LR-MS( ESI): m/z 267 [M+Na] ⁺ .HPLC: Chiralpak AD-H column (250 mm); detection wavelength: 224 nm; hexane/isopropanol=90/10; flow rate=0.7 mL/min; retention time s : 13.7min, 22.8min (main peak).

Example 7

To a suspension of 60% w/w NaH (36 mg, 0.888 mmol) in dry toluene at 0°C was added a solution of (R)-(-)-3-quininol (35 mg, 0.272 mmol) in toluene , and the reaction was stirred for 15 minutes at this temperature, and then a toluene solution of compound 6a (25 mg, 0.088 mmol) was added. Subsequently, the reaction mixture was transferred to an oil bath at 120° C. to react for 12 hours, and ethanol was separated from a water separator. After the reaction was completed, it was cooled to room temperature, 50 mL of brine was added, followed by extraction with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Column chromatography of the crude product (petroleum ether/ethyl acetate=30/1) gave the product (+)-sorlifenacin (27 mg, yield 85%) as a colorless liquid.

无色液体。¹H NMR(400MHz,CDCl₃)δ7.26-7.14(m,8H),7.07(d,J＝7.1Hz,1H),6.32(s,1H),4.83-4.81(m,1H),4.08-3.97(m,1H),3.39-3.22(m,2H),2.88-2.70(m,7H),2.04(s,1H),1.84-1.82(m,1H),1.72-1.65(m,1H),1.59-1.55(m,1H),1.44-1.37(m,1H)；¹³C NMR(100MHz,CDCl₃,60℃)δ155.4,143.0,135.7,135.1,129.0,128.6,128.4,128.2,127.5,127.2,126.3,72.4,58.3,56.1,47.7,46.7,38.9,28.6,25.8,24.8,20.1.

Colorless liquid. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.26-7.14(m, 8H), 7.07(d, J=7.1Hz, 1H), 6.32(s, 1H), 4.83-4.81(m, 1H), 4.08- 3.97(m,1H),3.39-3.22(m,2H),2.88-2.70(m,7H),2.04(s,1H),1.84-1.82(m,1H),1.72-1.65(m,1H), 1.59-1.55 (m, 1H), 1.44-1.37 (m, 1H); ¹³ C NMR (100MHz, CDCl ₃ , 60°C) δ 155.4, 143.0, 135.7, 135.1, 129.0, 128.6, 128.4, 128.2, 127.5, 127.2, 126.3,72.4,58.3,56.1,47.7,46.7,38.9,28.6,25.8,24.8,20.1.

Example 8

A Schlenk flask was charged with aldimine 1a (148 mg, 0.4 mmol, 1 equiv), phenylboronic anhydride (125 mg, 0.4 mmol, 1 equiv), [Rh(coe) ₂ Cl] ₂ (4.4 mg, 3 mol %) and chiral branch Thiene ligand L1 (3.1 mg, 3.3 mol%) was replaced with nitrogen, 4 mL of toluene was added, stirred at room temperature for 30 min, and then 0.8 mL of potassium hydroxide aqueous solution (1.5 M) was added to the system, and the reaction was carried out at 60 °C for 6 h. The solvent was spin-dried, and column chromatography (petroleum ether/ethyl acetate=5/1) gave the addition product 2a (yield: 85%; 99% ee).

白色固体，产率(yield)85％，99％ee.[α]²⁵ _D＝+24.6(c 0.71,CHCl₃).¹H NMR(300MHz,CDCl₃)δ7.39-7.22(m,9H),5.87(d,J＝6.0Hz,1H),5.18(d,J＝6.0Hz,1H),3.72(dd,J＝13.9,7.0Hz,2H),2.86(t,J＝7.0Hz,2H),2.54(s,6H),0.82(s,9H),-0.04(s,6H).¹³C NMR(150MHz,CDCl₃)δ141.3,139.1,136.9,131.0,128.7,127.8,127.79,127.77,127.74,126.6,63.8,58.3,37.6,35.6,26.0,18.4,-5.4.HRMS(ESI):C₂₃H₃₆N₂O₃NaSiS[M+Na]⁺:calcd 471.2114,found471.2119.HPLC:Chiralpak AD-H柱(250mm)；检测波长:224nm；己烷/异丙醇＝97/3；流速＝0.4mL/min；保留时间:18.6min(主峰),22.0min.

White solid, 85% yield, 99% ee. [α] ²⁵ _D = +24.6 (c 0.71, CHCl ₃ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39-7.22 (m, 9H) ,5.87(d,J＝6.0Hz,1H),5.18(d,J＝6.0Hz,1H),3.72(dd,J＝13.9,7.0Hz,2H),2.86(t,J＝7.0Hz,2H) , 2.54(s, 6H), 0.82(s, 9H), -0.04(s, 6H). ¹³ C NMR(150MHz, CDCl ₃ )δ141.3,139.1,136.9,131.0,128.7,127.8,127.79,127.77,127.74, 126.6, 63.8, 58.3, 37.6, 35.6, 26.0, 18.4, -5.4. HRMS (ESI): C ₂₃ H ₃₆ N ₂ O ₃ NaSiS[M+Na] ⁺ : calcd 471.2114, found471.2119. HPLC: Chiralpak AD- H column (250mm); detection wavelength: 224nm; hexane/isopropanol=97/3; flow rate=0.4mL/min; retention time: 18.6min (main peak), 22.0min.

In addition, experiments have proved that if the chiral thioene ligand in Example 1 is replaced with other ligands of the present invention, the ee of the obtained products (ie, the compound of formula II) is all greater than 85%.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (11)

1. a preparation method of solifenacin, is characterized in that, comprises the steps: A-1: in an inert solvent, the compound of formula a is reacted with N,N-dimethylsulfonamide, thereby forming the compound of formula I;

A: Under the catalysis of transition metal Rh(I) and chiral thiolene ligand L, in a mixed system of alkaline aqueous solution and organic solvent, the compound of formula I reacts with organoboron reagent Ph-[B], thereby forming formula II compound;

Described chiral thioene ligand L has the following structural formula:

Wherein, R ³ is tert-butyl or adamantyl; n=1; B-1: in an amine solvent, the compound of formula II is subjected to the reaction of removing the sulfonyl protecting group, thereby forming the compound of formula III;

B-2: in an inert solvent, the compound of formula III is reacted with R ² OC(=0)Cl, thereby forming the compound of formula IV;

B-3: in an inert solvent, the compound of formula IV is carried out to remove the reaction of the hydroxyl protecting group, thereby forming the compound of formula V;

C: in an inert solvent, in the presence of Mitsunobu reagent, the compound of formula V is subjected to ring-closure reaction, thereby forming the compound of formula VI;

D: in an inert solvent, under basic conditions, the compound of formula VI is carried out transesterification with (R)-(-)-3-quinic alcohol, thereby forming solifenacin;

In the above formulas, R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl; R ² is C1- 6 alkyl or substituted C1-6 alkyl or phenyl, wherein the substitution refers to being substituted by a substituent selected from the group consisting of C1-4 alkyl, halogen, phenyl. 2 . The preparation method according to claim 1 , wherein in step A, the molar ratio of the compound of formula I to the organoboron reagent is 1:0.33-3. 3 . 3. preparation method as claimed in claim 1 is characterized in that, in step A, described organoboron reagent is phenylboronic acid, phenylboronic anhydride, phenylboronic potassium trifluoroborate, phenylboronic acid pinacol boron ester or tetrakis Sodium phenylboron; and/or the alkaline aqueous solution is an aqueous potassium hydroxide solution, an aqueous potassium carbonate solution or an aqueous potassium phosphate solution. 4. The preparation method of claim 1, wherein in step A, the transition metal Rh(I) is [Rh(coe) ₂ Cl] ₂ or [Rh(C ₂ H ₄ ) ₂ Cl ] ₂ . 5. preparation method as claimed in claim 1 is characterized in that, in step A, described organic solvent is selected from following group: toluene, ortho-xylene, meta-xylene, para-xylene, 1,2-dichloro Ethane, or a combination thereof. 6. The preparation method of claim 1, wherein in step B-1, the amine solvent is selected from the group consisting of n-butylamine, 1,3-propanediamine, ethylenediamine, or its combination. 7. preparation method according to claim 1 is characterized in that, in step C, described Mitsunobu reagent is the equimolar ratio of diisopropyl azodicarboxylate or diethyl azodicarboxylate and triphenylphosphine than the combination. 8 . The preparation method of claim 1 , wherein in step C, the molar ratio of the compound of formula V to the Mitsunobu reagent is 1:1 to 5. 9 . 9. a preparation method of formula II compound, is characterized in that, comprises the steps: A: Under the catalysis of transition metal Rh(I) and chiral thiolene ligand L, in a mixed system of alkaline aqueous solution and organic solvent, the compound of formula I reacts with organoboron reagent Ph-[B], thereby forming formula II compound;

Described chiral thioene ligand L has the following structural formula:

Wherein, R ³ is tert-butyl or adamantyl; n=1; R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl. 10. The method of claim 9, wherein the method further comprises the steps of: A-1: in an inert solvent, the compound of formula a is reacted with N,N-dimethylsulfonamide, thereby forming the compound of formula I;

Wherein, R ¹ is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl. 11. A chiral thioene ligand having the following structural formula:

where ^R3 is

n=1.