TW201910336A - Preparation method of imidazoisoindole derivatives - Google Patents

Abstract

The present invention relates to preparation method for imidazo isoindole derivative. Specifically, the present invention relates to preparation method for imidazo isoindole derivative of formula (I), comprising resolving compound of formula (II) to obtain high optical purity compound of formula (III). Then reacting compound of formula (III) as raw material to obtain the final product. The final product has high optical purity, low cost, more economical and more suitable for industrial production.

Description

   Preparation method of imidazoisoindole derivatives   

The invention belongs to the field of medicine and relates to a method for preparing imidazoisoindole derivatives.

Indoleamine-pyrrole-2,3-dioxygenase (IDO) is a heme-containing monomeric protein. A large number of studies have shown that IDO is highly expressed in leukemia cells. Suppresses local T cell proliferation, suppresses T-cell-mediated immune response, blocks T-cell activation signal transduction, and thereby mediates tumor cells to escape the attack of the immune system. Most human tumors have been found to constitutively express IDO. Therefore, IDO is a promising target for cancer immunotherapy.

IDO inhibitors have good application prospects as pharmaceuticals in the pharmaceutical industry. WO2016169421 discloses a new IDO inhibitor, the compound structure of which is shown in formula (I),

This compound showed excellent IDO inhibitory effect. At present, the synthesis method of these compounds is mainly obtained by the reaction of halophenylpyrazole with piperidylimidazoisoindole, and then by chiral analysis.

During the preparation process, we found that the yield of the chiral analysis in the last step is very low, especially when the chiral column analysis is used, because the racemate and the product are not highly soluble in the eluent, it is easy to precipitate during the preparation process. The chiral tubing is blocked, which seriously affects the analysis efficiency.

In order to overcome the shortcomings of the prior art, the object of the present invention is to provide a new method for preparing imidazoisoindole derivatives.

One aspect of the present invention provides a novel reaction intermediate, such as a compound represented by Formula III, A compound represented by formula IV,

Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO ₂ R, R is a C ₁ to C ₆ alkyl group; preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy.

A compound represented by formula VII,

Wherein R2 is selected from a hydroxyl protecting group; and a compound represented by formula d,

Another aspect of the present invention provides a method for preparing a compound represented by Formula III, including a step of chiral analysis of a compound represented by Formula II,

Methods for this chiral analysis can be chemical analysis, membrane analysis, chromatographic analysis, capillary electrophoresis analysis, and biological analysis.

In some embodiments, the method of chiral analysis is chromatographic analysis.

In some embodiments, the method of chiral resolution is chemical resolution. The resolving agent used may be an organic acid and the like, such as L-tartaric acid, D-tartaric acid, benzophenone-L-tartaric acid (L-DBTA), benzophenone-D-tartaric acid (D-DBTA), xylene Formamidine-L-tartaric acid (L-DTTA) or dimethyl p-toluene-D-tartaric acid (D-DTTA), R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L -Glutamic acid, D-glutamic acid, L-aspartic acid, D-aspartic acid, etc., preferably L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, L -Aspartic acid, D-aspartic acid, more preferably D-DTTA.

The molar ratio of the resolving agent to the compound represented by Formula II may be 1: 1 to 4: 1.

The process of resolving the compound represented by Formula II by a resolving agent can be performed in a general solvent. Preferred solvents include water or hydrophilic organic solvents (such as C ₁ to C ₆ alcohols such as methanol and ethanol; ketones such as acetone). And methyl ethyl ketone; ethers, such as tetrahydrofuran and dioxane; acetonitrile; N, N-dimethylformamide; and N, N-dimethylmethane); or a mixed solvent thereof, more preferably methanol Or ethanol.

The process of analysing the salt of the free intermediate is general. A base can be used for the free. The base used for the free is preferably an aqueous solution of an alkali metal hydroxide, preferably an aqueous solution of sodium hydroxide; the solvent can be a common solvent, such as dichloride. Methane, tetrahydrofuran, chloroform, etc.

In order to improve the optical purity of the compound III obtained by the analysis, the intermediate analytical salt obtained by the analysis may be recrystallized. The process of resolving into salts in the present invention can generally be carried out at normal temperature, if necessary, under heating conditions, and the recrystallization step can generally be carried out under heating conditions, first heating to dissolve the resolved salts in the solvent , And then slowly complete the recrystallization process at room temperature.

This aspect also provides a method for preparing a compound represented by Formula I or a pharmaceutically acceptable salt thereof, comprising a step of preparing a compound represented by Formula III according to the method of the present invention.

Further, the method for preparing the compound represented by Formula I or a pharmaceutically acceptable salt thereof according to the present invention further includes a step of preparing a compound represented by Formula IV by using the compound represented by Formula III as a reactant.

Wherein X is a leaving group selected from -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, acetamyloxy or phosphate , -SR, -SO ₂ R, R is C ₁ ~ C ₆ alkyl; X is preferably -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyl Oxygen.

This method can be a one-step reaction (such as Buckwald coupling) or a multi-step reaction (such as first reacting with cyclohexanedione to form a piperidinylphenol intermediate and then synthesizing compound IV).

Further, the method further includes the step of preparing a compound represented by formula VI by subjecting a compound represented by formula IV to a compound represented by formula V to a coupling reaction in the presence of a catalyst.

Wherein, Y is selected _{-BF 3 K, -BR a R b} , -Sn (R c) m or -Zn-X '; R _a and R _{b are} independently selected from -OH, alkyl, alkoxy or optionally requires substituted C ₁ ~ C ₆ mono- and dihydric alcohols, or R _a and R _b, together form a ring, R _c is independently selected from C ₁ ~ C ₆ alkyl group, X 'is selected from -Cl, -Br, -I; m is an integer of 0, 1, 2, 3 or 4; R _{1 is} selected from hydrogen or a hydroxy protecting group.

In certain preferred embodiments, Y is selected from BF ₃ K and BR _a R _b , wherein R _a and R _b in BR _a R _b are independently selected from -OH, alkyl, alkoxy, or BR _a R _b is a pinacol borate, ie The catalyst may include PdL _p , PdCl ₂ L _p , Pd (OAc) ₂ L _p , Pd ₂ (dba) ₃ L _p , Pd (II) L _p , Pd (0), NiCl ₂ L _p , Ni (COD) ₂ L _p , NiCl ₂ (NEt ₃ ) ₂ or NiCl ₂ (bipy), where L is a phosphine-containing ligand or an N-heterocyclic carbene ligand, and the phosphine-containing ligand may be PPh ₃ , dppf, PCy ₃ , tBu ₃ P, P (OMe) ₃ , dppe or dppb, p is an integer independently selected from 0, 1, 2, 3 or 4.

For example, the catalyst may be Pd (PPh ₃ ) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dppf) Cl ₂ , palladium carbon, Pd (OAc) ₂ , PCy ₃ / Pd ₂ (dba) ₃ , NiCl ₂ (dppf), NiCl ₂ (PPh ₃ ) ₂ , Ni {P (OMe) ₃ } ₂ Cl ₂ , NiCl ₂ (PCy ₃ ) ₂ , NiCl ₂ (dppe), NiCl ₂ (dppb), NiCl ₂ (NEt ₃ ) ₂ , NiCl ₂ (bipy), NiCl ₂ . 6H ₂ O, NiCl ₂ , or Ni (COD) ₂ , preferably Pd (PPh ₃ ) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dppf) Cl ₂ , palladium carbon, Pd (OAc) ₂ , PCy ₃ / Pd ₂ (dba) ₃ , more preferably Pd (PPh ₃ ) ₂ Cl ₂ .

In some embodiments, the reaction is performed in the presence of a basic substance, wherein the basic substance is preferably Li ₂ CO ₃ , Na ₂ CO ₃ , Ba (OH) ₂ , K ₃ PO ₄ , Cs ₂ CO ₃ , One or more of K ₂ CO ₃ , TlOH, KF, CsF, Bu ₄ NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, where R is independently selected from C ₁ ~ C ₆ alkyl group. Wherein NaOR, KOR or TlOR may be NaOMe, NaOEt, KOtBu or TlOEt, for example. The alkaline substance is more preferably one or more of Na ₂ CO ₃ or K ₂ CO ₃ .

The solvent used in this reaction may be a general solvent, and may be, for example, dimethylformamide, 1-methyl-2-pyrrolidone, tetrahydrofuran, dioxane, toluene, dimethylmethylene, dimethyl ether, isopropyl alcohol, One or more of ethanol and water, preferably one or more of dimethylformamide, dimethyl ether, dioxane, and water. The reaction temperature may be 60 ° C to 150 ° C.

In some embodiments, R ₁ is a hydroxy protecting group, and the method further includes a step of deprotecting the compound represented by Formula VI to obtain a compound represented by Formula I.

In the present invention, compound III is obtained by analyzing compound II to obtain compound III with high optical purity and then reacted. The subsequent products obtained always maintain high optical purity. The product is not racemic in the subsequent coupling reaction, and the final product has high optical purity, which avoids Finally, the problem of chilled pipe string preparation is stable and easy to reproduce. In addition, the analysis at Compound II is low in cost, more economical, and more suitable for industrial production.

When analyzing compound II, both chromatographic and chemical analysis can effectively isolate compound III. When using a resolving agent for analysis, the reaction is fast, the post-treatment is simple, the by-products can be recycled and reused, and the obtained compound III has high optical purity, which is very suitable for industrial scale-up production.

Unless stated to the contrary, the terms used in the specification and the scope of the patent application have the following meanings.

"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 10 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, third butyl, or pentyl, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or third butyl, pentyl, heptyl Base etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkoxy, halogen, hydroxy, nitro, cyano, and cycloalkane Group, heterocyclyl, aryl, heteroaryl, carbonyl.

"Aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group, preferably a 6 to 10 membered aryl group, having a conjugated pi-electron system , More preferably phenyl and naphthyl, and most preferably phenyl. Aryl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Naphthene.

"Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms include oxygen, sulfur, and nitrogen. It is preferably 6 to 10 members. Heteroaryl is preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carbonyl, -carboxylic acid or carboxylic acid ester.

"Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that includes 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) n ( Where n is a heteroatom of the integer 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably includes 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably the cycloalkyl ring contains 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic cycloalkyls include spiro, fused and bridged heterocyclic groups.

"Alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carbonyl, carboxylic acid or carboxylic acid ester. "Hydroxy" refers to the -OH group.

"Hydroxy protecting group" is a suitable group for protecting hydroxy groups known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & PGMWuts). As an example, preferably, the hydroxyl protecting group may be (C _1-10 alkyl or aryl) ₃ silyl, for example: triethylsilyl, triisopropylsilyl, third butyldimethyl Silyl, tert-butyldiphenylsilyl, etc .; may be C _1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 alkoxy substituted C _1-6 alkyl or phenyl substituted with C _1-6 alkyl, most preferably C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, tert-butyl, Allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc .; may be (C _1-10 alkyl or aromatic) fluorenyl, For example: formamyl, ethylamyl, benzamyl and the like; it can be (C _1-6 alkyl or C _6-10 aryl) sulfonyl; it can also be (C _1-6 alkoxy or C _6-10 aryloxy) carbonyl.

"As needed" or "as needed" means that the event or environment described later may, but need not, occur, and the description includes the place where the event or environment occurs or does not occur. For example, "heterocyclic group substituted with an alkyl group as necessary" means that the alkyl group may but need not exist, and the description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .

The following will explain the present invention in detail in conjunction with specific examples, so that those skilled in the art can more fully understand that the specific examples of the present invention are only used to explain the technical solution of the present invention, and do not limit the present invention in any way.

    Example 1    

Compound a (177 g, 0.495 mol, prepared according to the method disclosed in WO2016169421) was dissolved in 1.5 L of dichloromethane, 300 mL of 1,4-dioxane was added, and concentrated hydrochloric acid (412 mL, 4.95 mol) was added dropwise under cooling in an ice-water bath. The temperature was raised to room temperature, and the reaction was stirred for 2 hours. After the reaction was completed, 600 mL of water was added to the reaction solution, and the aqueous phase was separated by extraction. Dissolve sodium hydroxide (215 g, 5.38 mol) in 215 mL of water, slowly drop into the above aqueous phase, adjust to pH 8-9, extract the aqueous phase with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and filtrate Concentrated under reduced pressure to obtain 144.8 g of compound II. The product was directly subjected to the next reaction without purification.

    Example 2    

Chiral preparation of 128.6 g of compound II (isolation conditions: chiral preparation column Superchiral S-AY (Chiralway), 2cm ID * 25cm Length, 5um; mobile phase: CO ₂ /EtOH/DEA=60/40/0.05 ( v / v / v), flow rate: 50g / min), collect the target components, no clogging occurred during the preparation of the column, and concentrated under reduced pressure to obtain 63.6g of compound III, optical purity: 99.4%, chemical purity: 99.2% .

    Example 3    

Dissolve Compound II (35.1g) in 600mL of ethanol at 25-30 ° C, add 600ml of 142g of D-DTTA in ethanol, and stir at 25-30 ° C for 16 hours. A large amount of light yellow solid appears. Filter and filter cake. Add 600 mL of ethanol, heat to reflux and lower the temperature to 25-30 ° C, filter, and dry the filter cake to obtain 51.5 g of a white solid. Add the solid to 750 mL of dichloromethane and 500 mL of water, and adjust the pH with 2N sodium hydroxide solution while stirring To 10-11. The layers were separated, and the aqueous layer was extracted with dichloromethane (400 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain 12.85 g of pale yellow solid compound III, optical purity: 99.2%, chemical purity: 99.5%, yield of 36.6%, and effective isomer yield of 73.2%. .

    Example 4    

    First step    

Compound III (75 g, 292 mmol) was dissolved in 2 L of ethanol, compound c (49.1 g, 438 mmol) and 10% Pd / C 7.5 g were sequentially added, the temperature was raised to 75 ° C., and the reaction was stirred for 28 hours with air. After the reaction, Pd / C was removed by filtration, the filter cake was rinsed with methanol, and the filtrate was concentrated under reduced pressure and dried under vacuum to obtain 54.1 g of compound d, yield: 53%.

    Second step    

Compound d (54.1 g, 0.155 mol) was dissolved in 700 mL of dichloromethane. The temperature was lowered to 0 ° C, pyridine (61.3 g, 0.775 mol) was added, and Tf ₂ O (56.8 g, 0.201 mol) was added dropwise. The temperature was raised to room temperature, and the reaction was stirred for 1 hour. After the reaction, 60 mL of water was added to the reaction solution, the pH was adjusted to 2 with 1 M hydrochloric acid, and the layers were allowed to stand. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was reduced. The solution was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (eluent: DCM: MeOH = 10: 1) to obtain 41 g of compound e in a yield of 55%.

    Example 5    

Compound e (41 g, 85 mmol) and compound f (40.5 g, 170 mmol, prepared according to the method disclosed in CN105189461A) were dissolved in 800 mL of a mixed solvent of 1,4-dioxane and water (V: V = 5: 1), Sodium carbonate (27 g, 255 mmol) and Pd (dppf) Cl ₂ (6.2 g, 8.5 mmol) were added in this order, the temperature was raised to reflux under argon protection, and the reaction was stirred for 3 hours. After the reaction, the reaction solution was cooled to room temperature, 200 mL of water was added, and the mixture was stirred at room temperature for 30 min, filtered, and the filter cake was rinsed with water. The filter cake was collected, dispersed with 750 mL of methanol, concentrated hydrochloric acid (22 mL) was added, and the mixture was stirred for 30 min. Add 1.2 L of water, stir for 30 min, filter, rinse the solid with water, combine the aqueous phases, back extract with ethyl acetate (400 mL x 2), collect the aqueous phase, adjust the pH to basic with saturated NaHCO ₃ solution, and precipitate a solid. A solid was obtained by filtration, washed with water, and dried under vacuum to obtain 23.9 g of Compound I with a yield of 63.5% and optical purity: 99.7%.

Since the invention has been described in terms of its specific embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the invention.

Claims (26)

A compound of formula III, A compound of formula IV, Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO ₂ R, R is C ₁ to C ₆ alkyl.     The compound represented by formula IV as described in item 2 of the scope of patent application, wherein the X is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy or benzenesulfonyloxy .     A compound of formula VII, Wherein, R _{2 is} selected from a hydroxy protecting group. A compound represented by formula d, A method for preparing a compound represented by formula III, comprising the steps of chiral analysis of a compound represented by formula II,     The preparation method according to item 6 of the scope of patent application, wherein the method of chiral analysis is selected from chemical analysis, membrane analysis, chromatographic analysis, capillary electrophoresis analysis, and biological analysis.         The preparation method according to item 7 of the scope of patent application, wherein the method of chiral analysis is selected from chemical analysis and chromatographic analysis.         The preparation method according to item 7 or 8 of the scope of the patent application, wherein the resolving agent used in the chemical analysis is selected from the group consisting of L-tartaric acid, D-tartaric acid, L-DBTA, D-DBTA, L-DTTA or D-DTTA , R-camphorsulfonic acid, S-camphorsulfonic acid, D-mandelic acid, L-mandelic acid, L-glutamine, D-glutamic acid, L-aspartic acid, D-aspartic acid.         The preparation method according to item 9 of the scope of patent application, wherein the resolving agent used in the chemical analysis is selected from the group consisting of L-DTTA, D-DTTA, L-glutamic acid, D-glutamic acid, and L-aspartamine Acid, D-aspartic acid.         The preparation method according to item 10 of the scope of patent application, wherein the resolving agent used in the chemical analysis is D-DTTA.         The preparation method according to item 7 or 8 of the scope of patent application, wherein the molar ratio of the resolving agent used in the chemical analysis to the compound represented by Formula II is 1: 1 to 4: 1.     The preparation method according to item 7 or 8 of the scope of patent application, wherein the chemically resolved reaction solvent is selected from the group consisting of water, C ₁ to C ₆ alcohols, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, and acetonitrile. Or N, N-dimethylformamide, N, N-dimethylformamide.     The preparation method according to item 13 of the patent application scope, wherein the chemically resolved reaction solvent is selected from methanol or ethanol.     A method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, comprising the steps of preparing a compound represented by formula III by a method according to any one of claims 6 to 14 of the scope of application for a patent. The preparation method according to item 15 of the scope of patent application, wherein the method further comprises the step of preparing a compound represented by formula IV by using the compound represented by formula III as a reactant, Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO ₂ R, R is C ₁ to C ₆ alkyl.     The preparation method according to item 16 of the application, wherein the X is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, or benzenesulfonyloxy.     The preparation method according to item 15 of the scope of patent application, wherein the method further comprises the step of preparing a compound represented by formula VI by performing a coupling reaction with a compound represented by formula IV and a compound represented by formula V in the presence of a catalyst, Wherein X is selected from the group consisting of -Cl, -Br, -I, -F, trifluoromethanesulfonyloxy, methanesulfonyloxy, benzenesulfonyloxy, ethoxyl or phosphate, -SR,- SO ₂ R, R is C ₁ ~ C ₆ alkyl group; the Y is selected from _{-BF 3 K, -BR a R b} , -Sn (R c) m or -Zn-X '; R _a and R _{b are} independently selected from From -OH, alkyl, alkoxy, or optionally substituted C ₁ to C ₆ mono- and diol, or R _a and R _b together to form a ring, R _{c is} independently selected from C ₁ -C ₆ alkane group, X 'is selected from -Cl, -Br, -I; m is an integer of 3 or 4; R ₁ is selected from hydrogen or a hydroxy protecting group.     The preparation method according to item 18 of the scope of patent application, wherein the X is selected from -Cl, -Br, -I, trifluoromethanesulfonyloxy, methanesulfonyloxy, or benzenesulfonyloxy.     The preparation method according to item 18 of the scope of application for a patent, wherein the Y is selected from BF ₃ K and BR _a R _b , wherein R _a and R _b in the BR _a R _b are independently selected from -OH, alkyl , Alkoxy, or BR _a R _b is a pinacol borate. The preparation method according to any one of claims 18 to 20, wherein the catalyst is selected from the group consisting of PdL _p , PdCl ₂ L _p , Pd (OAc) ₂ L _p , Pd ₂ (dba) ₃ L _p , Pd (II) L _p , Pd (0), NiCl ₂ L _p , Ni (COD) ₂ L _p , NiCl ₂ (NEt ₃ ) ₂ or NiCl ₂ (bipy), where L is a phosphine-containing ligand or N-hetero A cyclocarbene ligand, the phosphine-containing ligand is selected from the group consisting of PPh ₃ , dppf, PCy ₃ , tBu ₃ P, P (OMe) ₃ , dppe, or dppb, and p is independently selected from 0, 1, 2, 3, or 4 Integer. The preparation method according to item 21 of the scope of patent application, wherein the catalyst is selected from the group consisting of Pd (PPh ₃ ) ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , Pd (dppf) Cl ₂ , palladium carbon, and Pd (OAc) ₂ , PCy ₃ / Pd ₂ (dba) ₃ . The preparation method according to item 22 of the scope of patent application, wherein the catalyst is Pd (PPh ₃ ) ₂ Cl ₂ .     The preparation method according to item 18 of the scope of patent application, wherein the reaction is performed in the presence of a basic substance.     The preparation method according to item 24 of the scope of patent application, wherein the basic substance is selected from Li ₂ CO ₃ , Na ₂ CO ₃ , Ba (OH) ₂ , K ₃ PO ₄ , Cs ₂ CO ₃ , K ₂ CO ₃ , one or more of TlOH, KF, CsF, Bu ₄ NF, LiOH, NaOH, KOH, triethylamine, DIPEA, DABCO, NaOR, KOR, TlOR, wherein R is independently selected from C ₁ ~ C ₆ alkyl . The preparation method according to item 25 of the scope of patent application, wherein the basic substance is selected from one or more of Na ₂ CO ₃ or K ₂ CO ₃ .