TW201028374A - Method of preparing ezetimibe and intermediates used therein - Google Patents

Abstract

Disclosed is a method for preparing ezetimibe which is effective for preventing or treating arteriosclerosis, and novel intermediates used therein. In accordance with the method which does not use expensive reagents, unwanted diastereoisomers can be easily removed by a step-by-step crystallization procedure, and the ezetimibe of formula 1 can be prepared in a high yield without the use of a hydrogenation procedure under a high pressure.

Description

201028374 VI. Description of invention:

C FIELD OF THE INVENTION Field of the Invention The present invention relates to a process for the preparation of an improved ezetimibe and novel intermediates thereof. C previous 3 invention background

Ezetimibe, a derivative of azetidinone of formula 1, has been used as a drug for the prevention and treatment of arteriosclerosis, which is effective for reducing the absorption of cholesterol in the small intestine and inhibiting it with statins. Cholesterol synthesis in the liver:

A variety of methods for the preparation of ezetimibe have been disclosed, as disclosed in U.S. Patent No. 5,721, pp, U.S. Patent No. 5,856,473, U.S. Patent No. 6,207,822, WO 2007072088, and WO 2007120824. U.S. Patent Reissue No. 37,721 discloses a process for the preparation of ezetimibe using the method as shown in Reaction Scheme 1. However, this method has the disadvantage that the synthesis of the compound of the formula F is obtained by the synthesis reaction of the carbonyl chloride of the formula E with the fluorinated phenylmagnesium bromide, the yield is relatively low, and it needs to be purified by column chromatography to obtain the formula F. The compound, and requires high pressure hydrogenation reaction 3 201028374 to remove the benzyl protecting group on the compound of formula G. Reaction process 1

Wherein Me is a methyl group, Ph is a phenyl group, and Bn is a benzyl group. U.S. Patent No. 5,856,473 discloses a method of preparing ezetimibe, which involves the steps shown in Reaction Scheme 2. However, this method has the disadvantage that the reaction for preparing the compound of the formula I is carried out at -78 ° C and requires a high pressure hydrogenation reaction to remove the benzyl protecting group on the compound of the formula J, and column chromatography is used to obtain the formula J. An amorphous compound. 201028374 Reaction Process 2

Wherein Bn is a benzyl group.

WO 2007072088 and WO 2007120824 disclose a process for the preparation of ezetimibe, comprising the step of introducing a ketal protecting group onto a formula K-ketone, as shown in Reaction Scheme 3. However, the problem with this method is that it is not easy to remove the protecting group, and an expensive metal catalyst is required to carry out the asymmetric reduction reaction of the compound of the formula Q to obtain the compound of the formula R. 5 201028374 Reaction Process 3

Wherein each of X and Y is independently hydrogen or an optionally substituted alkyl group, η is 0 to 3, Ph is a phenyl group, and Prot is a hydroxy protecting group. U.S. Patent No. 6,207,822 discloses a process for the preparation of ezetimibe comprising the following steps: a compound of formula U is subjected to a non-progressive reduction of 201028374, and is oxazaborolidine in (R)-methyl CBS0 oxazaborolidine. In the presence of a compound of formula V; while protecting the compound of formula V from the imine compound, followed by a Manichi synthesis reaction to a compound of formula W; and the compound of formula W with tetrabutylammonium fluoride/N,0-double ( Trimethylnonane) acetaminophen is reacted to prepare a β-indoleamine compound of formula X, as shown in Reaction Scheme 4. However, the problem with this method is that in the above Manichi coupling reaction, 1 to 2% of the compound of the formula W is converted back to the compound of the formula v, since the acid used therein counteracts the reaction.

Reaction flow <4

Wherein t-Bu is a third butyl group, Ph is a phenyl group, and TMS is trimethyl stellite 7 201028374. Therefore, the present invention is directed to the development of a novel ezetimibe preparation method which is exempt from the above. Problems associated with traditional methods.

BRIEF SUMMARY OF THE INVENTION Accordingly, it is a primary object of the present invention to provide an improved process for the preparation of ezetimibe and intermediates thereof. According to one aspect of the present invention, a preparation of ezetimibe is provided.

The compound of the formula 2 is placed in a surface reaction with the imine of the formula 6, in the presence of Lewis acid and a base to prepare a compound of the formula 3; the compound of the formula 3 is introduced into the cyclization reaction, and the test is carried out. In the presence of the compound of formula 4; the compound of formula 4 is subjected to an asymmetric reduction reaction, in the presence of a borane compound and a chiral catalyst, to prepare a compound of formula 5;

Removal of the hydroxy protecting group on the compound of formula 5, in the presence of a base:

8 201028374

among them

Ph is a phenyl group, TMS is a trimethyldecyl group, and Piv is a trimethylethenyl group. According to another aspect of the present invention, there is provided a compound of formula 2 as an intermediate product which can be used to prepare Ezetimibe of formula 1:

F

(2) 9 201028374 where Ph and TMS have the same definition as described above. According to another aspect of the present invention, a compound of formula 3 is provided as an intermediate product which can be used to prepare ezetimibe of formula 1:

(3)

Wherein Ph, TMS and Piv have the definitions as described above. According to another aspect of the present invention, a compound of formula 4 is provided as an intermediate product which can be used to prepare ezetimibe of formula 1:

Wherein Piv has the definition as defined above.

According to another aspect of the present invention, a compound of formula 5 is provided as an intermediate product which can be used to prepare ezetimibe of formula 1:

Wherein Piv has the definition as defined above. According to another aspect of the present invention, a compound of formula 6 is provided as an intermediate product which can be used to prepare ezetimibe of formula 1: 10 201028374

Wherein Piv has the definition as defined above. C 实方武] Detailed description of the preferred embodiment

The preparation method of the present invention is characterized in that the compound of the formula 2 and the compound of the formula 6 are cyclized to obtain a compound of the formula *, and the compound of the formula * is obtained by asymmetric reduction of the compound of the formula * The intermediate product of ezetimibe of formula 1 is then used, after which the compound of formula 2 is obtained by reacting a compound of formula 7 with cyanotrimethylnonane in the presence of a hydrogen catalyst. In the embodiment, the ezetimibe of the formula 1 of the present invention can be prepared from the compound of the formula 8, using the method as in Reaction Scheme 5, but not limited to 201028374.

Wherein Ph, TMS and Piv have the definitions as described above. Step i In this step, a ketone compound of the formula 7 which is an intermediate product of the present invention is used, and a chelating reaction is carried out by a chiral acid of the formula 8 and a chiral auxiliary of the formula 9

preparation. The chiral auxiliary of formula 9 is used in an amount ranging from 0.9 to 1.1 mole equivalents based on the carboxylic acid of formula 8. Preferably, the coupling reaction is carried out in a solvent comprising N,N'-dicyclohexylcarbenium imine and 4-dimethylaminopyridine. In this case, the N,N'-dicyclohexylcarbenium imide is used in an amount ranging from 0.8 to 1.1 mole equivalents, based on the carboxylic acid of the formula 8 and the use of 4-didecylamino" The amount ranges from 0.05 to 0.5 molar equivalents, preferably 0.1 mole equivalents, based on the carboxylic acid of formula 8. Examples of solvents include, but are not limited to, dichloromethane, gas imitation, and mixtures thereof. 12 201028374 Step ii The ketal compound of formula 2 'a novel intermediate for the preparation of ezetimibe by reacting a ketone compound of formula 7 with a gas-based trimethyl oxime The catalyst is obtained in the presence of a catalyst. The cyanidation = methyl geranium is used in an amount ranging from 1 to 3 mole equivalents, preferably from 13 to 1.7 moles, based on the ketone compound of the formula 7. Examples of the halogen catalyst include bromine, iodine, etc., preferably iodine. The dentate catalyzing agent is used in an amount ranging from 0. to 0.1 mole equivalent, based on the ketone compound of the formula 7. Preferably, the reaction is carried out at a temperature of from -10 to 25 °C. Examples of solvents used in this step include, but are not limited to, methylene chloride, gas, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Step iii In this step, a compound of the formula 3 is prepared by reacting a compound of the formula 2 obtained in the step (u) with an imine compound of the formula 6 having a protected hydroxyl group in the presence of a Lewis acid and a base. The amount of the compound of the formula 6 used in this step is preferably from 丨 to 3 mol equivalents to 1.2 mol equivalents, based on the ketal compound of the formula 2. Examples of Lewis acid include, but are not limited to, titanium tetraoxide, tributyl sulfonate, and mixtures thereof, and the amount of Lewis acid used in this step is 丨 to 3 molar equivalents, preferably 1.5 molar equivalents, based on the formula 2 compound. Examples include, but are not limited to, amines; amines having a C(penta) group, such as 13 201028374 diethylamine, diisopropylethylamine, and tributylamine; pyridine; aminopyridinium, having Cl.6 The amine group of the alkyl group is more than a bite, such as n to bite and 4 to dimethylamino group, and the mixture thereof is used in this step in an amount ranging from 1 to 3 mole equivalents, preferably丨3 to 丨7 molar equivalents based on the ketal compound of formula 2. Preferably, the reaction is at a temperature of -75. (3 to 25. (:: proceeding below, preferably -45 to 30 C. Examples of solvents used in this step include, but are not limited to, monochloromethane, gas, toluene, tetrahydrofuran, ethyl acetate, And a mixture thereof ❹ Step iv In this step, the β-indoleamine cyclic compound of the formula 4 is prepared by subjecting the compound of the formula 3 obtained in the step to a cyclization reaction in the presence of a base. Not limited to, n-butyl lithium, t_T oxy aluminum, lithium hexamethyldioxane amide, and mixtures thereof, and the amount used in this step ranges from 1 to 3 mole equivalents, based on the compound of formula 3 Preferably, the reaction is carried out at a temperature of -2 Torr. (: to 2 51, preferably -5. (: to 5.): Examples of solvents used in the next step include, but are not limited to, 'dichloromethane , gas imitation, tetrahydrofuran, and mixtures thereof. Step v In this step, the compound of formula 5 is subjected to an asymmetric reduction reaction of the indoleamine ring compound obtained in step iv, in the presence of a borane compound and a chiral catalyst. Used as a "chiral catalyst", which is also referred to as Symmetrical catalyst, 14 201028374 refers to a material that allows the conversion of an achiral compound to an optically active chiral compound by asymmetric reduction of the carbonyl group on the achiral compound. Examples of catalysts include, but are not limited to, (R)-methyl-CBS oxazolidine borane, (R)-propyl-CBS oxazolidine borane, (R)-butyl-CBS oxazolidine borane, (R) - 〇-tolyl-CBS oxazolidine borane, and mixtures thereof. The amount of chiral catalyst used in this step ranges from 0.05 to 0.3 mole equivalents, preferably from 0.09 to 0.11 mole equivalents, of the compound of formula For reference, examples of borane compounds include, but are not limited to, borane-dimethyl sulfide, borane-tetrahydrofuran, catechol boron choline, and mixtures thereof. The amount of borane used in this step The range is from 1 to 3 mole equivalents, preferably from 1.3 to 1.7 mole equivalents, based on the compound of formula 4. Preferably, the reaction is carried out at a temperature of from -30 ° C to 0 ° C. Examples of solvents include, but are not limited to, dichloromethane, gas, tetrahydrofuran, diethyl ether, toluene And a mixture thereof, preferably tetrahydrofur. Shouting vi In this step, the compound of formula 1 is prepared by removing the base protecting group on the compound of formula 5 obtained in step v, in the presence of the test. Examples of bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetrabutylammonium fluoride, tetrabutylcyclohexane, tetrabutylammonium bromide, and mixtures thereof. The amount of base used is in the range of i to 4 mole equivalents, preferably from 1.5 to 2 moles, based on the compound of formula 5. Preferably, the reaction is carried out at a temperature of from -20 ° C to 0 ° C. 15 201028374 Examples of solvents used in this step include, but are not limited to, decyl alcohol, ethanol, propanol, isopropanol, butanol, acetonitrile, 1,4-dioxane, acetone, tetrahydrofuran, dichloro Methane, gas imitation and its mixture. Further, the hydroxy-protected imine compound of the formula 6 obtained in the step iii is prepared by the method shown in Reaction Scheme 6, but is not limited thereto: Reaction Scheme 6

Wherein Piv is a trimethylethenyl radical and TEA is a triethylamine. The novel compound of formula 6 is prepared by reacting 4-[(4-fluorophenylamine)-methyl]phenol (imine-A) with trimethylacetamidine in the presence of triethylamine.

The imine-A is prepared by the method disclosed in U.S. Patent No. 6,207,822. Preferably, the reaction is carried out in a solvent at a temperature of from 〇 ° C to 25 ° C. Examples of solvents include, but are not limited to, dioxane, chloroform, tetrahydrofuran, and mixtures thereof. The preparation method of the present invention does not require the use of expensive reagents, and can easily remove undesired diastereomers step by step in a crystallization process, and can produce a high yield of ezetimibe of formula 1 (Ezetimibe). ) without the need for a high pressure hydrogenation process. The following preparations and examples further illustrate the invention and are not intended to limit its scope. Example 1: Preparation of ezetimibe (1·1) to prepare 3-[5-(fluorophenyl)-1,5-dioxapentyl]_4(s)·pentyl-2-oxazole Alkanone (Formula 7) 200 g of 5-(4-fluorophenyl)-5-oxopentanoic acid of formula 8, 16 〇g of (s)-4 phenyl oxastatin-2-one of formula 9 and 11.6 g of 4-dimethylaminopyridine was dissolved in 600-methane-methane® to prepare a reaction mixture. Dissolve in 157 g of hydrazine, Ν'-dicyclohexylcarbenium imine solution in 2 Torr., and add to the reaction mixture and stir for 2 hours. After the reaction was completed, the resulting reaction mixture was filtered to remove by-products. The resulting liquid was washed successively with 1 t of 6 Ν HCl, 1 liter of water, and 1 ton of saturated sodium chloride, dried over anhydrous magnesium sulfate and filtered. The resulting residue was dissolved in heated 2 sterol and cooled to initiate crystallization. Add 2 £ of water and stir for 30 minutes. The resulting solid was removed by filtration to give 289 g (yield: 86%). !H NMR (300MHz, CDC13) : δ 7.92 (2Η, Μ), 7.35-7.13 ( (5Η, m), 7.04 (2H, m), 5.43 (1H, q), 4.75(1H, t), 4.22 ( 1H, q)» 3.05-2.93 (4H, m), 2.03 (2H, m) (1-2) Preparation of 2-(4-fluorophenyl)-6-oxo-6-(2-oxo-4 -Phenyloxazolidin-3-yl)-2-trimethyldecaneoxyhexanylacetonitrile (Formula 2) (100) of 100 g of 3-[5-(fluorophenyl)-1, 5-Dioxapentyl]-4(S)-phenyl-2-oxazolone, dissolved in 1 ton of di-methane and cooled to. After adding 3.55 g of 'breaking', 53 of cyanotrimethylnonane was added for 2 minutes. After 2 hours, the reaction mixture was washed twice with 50 quenched Na 2 s 2 〇 3 aqueous solution 17 201028374, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford 127.9 g (yield: 100%). !H NMR (300MHz, CDC13) : δ 7.35-7.14 (7Η, m), 6.94 (2H, t), 5.26 (2H, dd), 4.56 (1H, t), 4.15 (2H, dd), 2.83 (2H , t), 1.90-1.48 (4H, m), 0.02 (9H, s) (1-3) Preparation of 2,2-dimethyl-propionic acid 4_[(4-fluorophenylimino) fluorenyl] •Phenyl vinegar (Formula 6)

180 g of 4-[(4-fluorophenylimino)-indenyl]-phenol is obtained by reacting 4-hydroxybenzaldehyde with 4-aniline according to the method described in U.S. Patent No. 6,207,822. Dissolved in 1.26 C of di-methane and stirred to obtain a slurry. 354 Triethylamine and 113 Methylenetrimethylethane were added to the slurry and allowed to pass for 30 minutes. The resulting reaction mixture was combined with 630 m of water to separate an organic layer, which was then washed with 1 liter of water. The washed organic layer was dehydrated with anhydrous sulfuric acid and the solvent was removed under reduced pressure. The residue obtained was dissolved in 54 Torr (iv) of hexane and stirred for 1 hour to give a solid amount of _]H NMR (300 MHz, CDC13): δ 8.42 (ΐΗ

Filtration gave 233 g (yield: 93%). s), 7.91(2Η, d), 7.22-67.16 (4Η, m), 7.07 (2H, t), 1.38 (9H, S) (1-4) Preparation of 2,2-dimethylpropanol 4-[ 5-cyano (heart phenyl (4-fluorophenylamino)-2-(2-oxo-4-phenyl·rabbityl)-^ benzyloxypentyl]-pentyl ester ( Formula 3) 127.9 g of the compound of formula 2 from (1-2), and 1 〇 1 〇 8 g of the formula 6 imine compound from (13) are dissolved in 1.02 £ digas and cooled to - 4 (TC. Add 73.69 bis-diisopropylethylamine) and maintain for 1 Torr plus 18 201028374 into 0.31 £ titanium tetrachloride (1M in CH/l2 solution) for 3 minutes and mix for 30 minutes. After completion of the reaction, isopropanol/dichloromethane (256 ad / 128 111 g) was added to the resulting reaction mixture, which was maintained at -25 ° C or lower for a period of time, followed by heating to 0 ° C. The mixture was washed with 640 ml of cc water and 640 of saturated sodium chloride, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. 256 in ethyl acetate, then cooled to room temperature, causing solid precipitation. Add 768 Μ hexane to solid The mixture was stirred for 1 hour to give the title compound as a white solid (yield: 58%). 4 NMR (300 MHz, CDC13): δ 7.25-6.84 (13H, m), 6.66-6.62 (2H, m ), 6.27-6.25 (2H, m), 5.31 (1H, m), 4.84 (1H, d), 4.58 (1H, m), 4.39 (1H, m), 4.27 (1H, m), 4.10 (2H, Dd), 1.97-1.43 (4H, m), 1.28 (9H, m) 0.02 (9H, s) (1-S) Preparation of 2,2· dimethyl-propionic acid 4-{1·(4-fluorobenzene _3_[3_(4_Fluorophenyl)-3-oxopropyl]·4·oxoazetidin-2-yl}-pentyl ester (Formula 4) 15.9 hexamethyldioxane decylamine Lithium (1 Torr in toluene) is added to the solution by dissolving (1_4) the obtained 1 〇g of the compound of formula 3 in 5 annihilation of the second gas, and then cooling to 〇. Add 2 Torr to methanol and continue stirring for 15 minutes to obtain a reaction mixture. Add 5 〇 dichloromethane, 50 water, and 50 3N hydrogen acid to the reaction mixture, and stir to separate the aqueous layer. Extracted with dichloromethane at 5 Torr, the organic layer was separated. The organic layer was washed with 100 saturated sodium sulfate solution, water was removed with anhydrous sulfuric acid, and the solvent was removed under reduced pressure.5〇Additional gas and 〇92 Μdiethylamine are added to the residue. Add 〇.82 to the trimethyl b 19 201028374 Disorder and mix. The resulting reaction mixture was extracted with 50 mL of water and then 3N hydrogen acid, and the organic layer was separated. The organic layer was washed with sodium bicarbonate and 50 M saturated sodium sulfate in vacuo, and water was evaporated over anhydrous magnesium sulfate. The resulting residue was dissolved in 60 methanol. Add 20 Μ of water and mix for 1 hour to initiate solid precipitation. The solid was isolated by filtration afforded 5.2 g (yield: mp. 'H NMR (300MHz, CDC13) : δ 8.01-7.96 (2Η, m), 7.35-6.90 (10H, m), 4.75 (1H, s), 3.29-3.11 (3H, m), 2.42- 2.27 (2H, m), 1.34 (9H, s) _ (1.6) Preparation of 4-((2S,3R)_l-(4.fluorophenyl)-3-((S)_3-(4-fluorophenyl)-3- Benzyl)-4-oxoazetidin-2-yl)phenyl pivalate (Formula 5) 3〇 tetrahydrofuran is placed in the reactor and cooled to _25 . Hey. Add 2.89 of BMS (borane-didecyl sulfide complex) to 2 (R)-(+)-2-methyl-CBS-oxazolborane (1 M in toluene) and stir for 15 minutes. . The resulting reaction mixture was added to a solution of 10 g of the compound of the formula 4 obtained in (1-5) in 30 min of tetrahydrofuran, for 30 minutes, and mixed for 5 hours. After the reaction is complete, add 30% of 10% hydrogen peroxide and stir for 1 minute to stop the reaction. The resulting reaction mixture was extracted with 30 ethyl acetate and 3 EtOAc. The organic layer was washed successively with 2 hydrazine sulphuric acid and 20 m of saturated sodium sulphate, dried over anhydrous magnesium sulfate, and evaporated to remove solvent. The residue obtained was dissolved in 50 mM decyl alcohol, and 20 aqueous water was added, and the mixture was allowed to stand for 1 hour to initiate solid precipitation. The solid was isolated by filtration to give 8 82 g (yield: 88%). NMR (300MHz, CDC13): δ 7.33-6.82 (12H, m), 4.70 20 201028374 (1H, t), 4.61 (1H, d), 3.08 (1H, q), 2.19 (1H, s), 2.07-1.84 (4H, m), 1.30 (9H, m) (1-7) Preparation of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4- (4-Hydroxyphenyl)-azetidin-2-one (Formula 1) 10 g of the compound of formula 5 obtained in (1-6) is dissolved in 7〇Μ tetrahydrotetramine and cooled to -15 °C. The resulting reaction solution was added to a 30 (tetra) methanol solution containing 1.6 g of sodium hydroxide and stirred for 30 minutes. The resulting reaction mixture was extracted with 100 N of 1N hydrochloric acid and 50 ethyl acetate. The aqueous layer was extracted with 30 ethyl acetate and the organic layer was separated. The organic layer was washed three times with water, water was removed with anhydrous magnesium sulfate, and solvent was evaporated under reduced pressure. The resulting residue was dissolved in 50 mM decyl alcohol. Add 37.5 of water adjacent to the water and give it a solid to precipitate. The solid was isolated by filtration to give EtOAc (yield: 92%). ]H NMR (300MHz, DMSO-d6): 59.53 (1H, s), 7.46-7.〇9 (10H, m), 6.78 (2H, d), 5.29 (1H, d), 4.89 (1H, s) , 4.51 (iH d), 3.09 (1H, m), 1.88-1.73 (4H, m) (1-8) Purified 10 g of ezetimib in ezetimibe (1-7) Ezetimibe is dissolved in 6〇n^4〇°C acetonitrile and cooled to room temperature. Add 60 Die water and search for ^, to induce solid precipitation. The solid was isolated to give 9.0 g (yield: 90%). While the invention has been described in terms of the specific embodiments described above, it is understood that the subject matter of the invention may be practiced in the scope of the invention as described in the appended claims. 21 201028374 [Simple description of the diagram: j (none) [Description of main component symbols] (none)

twenty two

Claims (1)

201028374 VII. Patent application scope: 1. A method for preparing Ezetimibe according to Formula 1, comprising: formulating compound of formula 2 with formula 6 in the presence of Lewis acid and test The imine is subjected to a coupling reaction to prepare a compound of formula 3; in the presence of a base, a cyclization reaction of the compound of formula 3 is carried out to prepare a compound of formula 4; In the presence of a boron-fired compound and a chiral catalyst, an asymmetric reduction of the compound of formula 4 is carried out to prepare a compound of formula 5; and in the presence of a base, the hydroxy protecting group on the compound of formula 5 is removed: 23 201028374 Wherein Ph is phenyl, TMS is trimethyldecyl, and Piv is trimethylethenyl. 2. The method of claim 1, wherein the compound of formula 6 in step i is used in an amount ranging from 1 to 3 mole equivalents based on the compound of formula 2. 3. The method of claim 1, wherein the Lewis acid used in the step i is selected from the group consisting of titanium tetrahydride, dibutylboron triplate, and mixtures thereof. A group of constituents, which is used in an amount ranging from 1 to 3 mole equivalents, based on the compound of formula 2. 4. The method of claim 1, wherein the base used in the step i is selected from the group consisting of triethylamine, diisopropylethylamine, tributylamine, and 4-dimethylamino. A group consisting of pyridine, pyridine, N,N-dimethylaminopyridine, and a mixture thereof, and used in an amount ranging from 1 to 3 mole equivalents, based on the compound of formula 2. 5. The method of claim 1, wherein the test used in the step ii is selected from the group consisting of lithium hexamethyldifluoride, η-butyl, and lithium t-butoxide, and A mixture of mixtures thereof, and used in an amount ranging from 1 to 3 molar equivalents, based on the compound of formula 3. 6. The method of claim 1, wherein the chiral catalyst used in the step iii is selected from the group consisting of (R)-methyl-CBS oxazaborolidine, (R)-propyl- CBS^D is a group consisting of (R)-butyl-CBS oxazolidine borane, (R)-o-indoleyl-CBS oxazolidine borane, and mixtures thereof, and its use range is 0.05 to 0.3 molar equivalents based on the compound of formula 4. 7. The method of claim 1, wherein the amount of the borane compound used in the step iii ranges from 1 to 3 mole equivalents, based on the compound of the formula 4. 8. The method of claim 1, wherein the test used in step iv is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, tetrabutylammonium fluoride, tetrabutylammonium chloride, A group consisting of tetrabutylammonium bromide, and mixtures thereof, and used in an amount ranging from 1 to 4 mole equivalents, based on the compound of formula 7. 9. The method of claim 1, wherein the compound of formula 2 is prepared by reacting a compound of formula 7 with trimethyl decane cyanide in the presence of a halogen catalyst: 25 201028374 F (7) wherein Ph is a phenyl group. 10. The method of claim 9, wherein the cyanuric cyanide is used in an amount ranging from 1 to 3 mole equivalents based on the compound of formula 7. 11. The method of claim 9, wherein the halogen catalyst is used in an amount ranging from 0.01 to 0.1 mole equivalents based on the compound of formula 7. 12. The method of claim 9, wherein the compound of formula 7 is a compound of formula 8 in the presence of hydrazine, Ν'-dicyclohexylcarbenium imine and 4-dimercaptoaminopyridine. 9 compound coupling reaction, and obtained: 〇〇 Ph,,, (9) wherein Ph is a phenyl group. 13. A compound of formula 2: Among them, Ph and TMS have the same meaning as those defined in item 1 of the patent application scope. 14. A compound of formula 3: 26 201028374 TMSO-k^. HC T I (3) where Ph, TMS and Piv have the same meaning as those defined in the first item of the patent application. 15. A compound of formula 4: Where Piv has the same meaning as defined in item 1 of the scope of application. 16. A compound of formula 5: Piv has the same meaning as defined in item 1 of the scope of patent application. 17. A compound of formula 6: Piv has the same definition as defined in item 1 of the scope of application. 27 201028374 201028374 IV. Designation of representative representatives: (1) The representative representative of the case is: ( ). (None) (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: