A method for preparing elastostat intermediate and its derivatives

Abstract

The present invention provides a method for preparing an elastostrat intermediate and its derivatives, and relates to the field of organic chemical synthesis, specifically, to the field of asymmetric catalytic hydrogenation of organic compounds. The method for preparing an elastostrat intermediate and its derivatives is as follows: Compound 1 and compound SM1 are coupled by palladium catalysis to obtain compound 2; Compound 2 is subjected to asymmetric hydrogenation reduction of the carbonyl group to obtain compound 3; and compound 3 is hydrogenated to obtain compound 4. The preparation method of the present invention is simple, shortens the preparation steps, and is conducive to scale-up production; at the same time, the present invention shortens the reaction route, reduces the price of starting materials, and saves costs.

Description

Technical Field

[0001] The invention provides a method for preparing an elastostratum intermediate and a derivative thereof, and relates to the field of organic chemical synthesis, in particular to the field of asymmetric catalytic hydrogenation of organic compounds. Background Art

[0002] Elastrogen is a small molecule anti-breast cancer drug developed by Menarini of Italy and Radius Health of the United States. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on January 27, 2023, under the trade name Orserdu. This is also the first non-steroidal oral selective estrogen receptor degrader approved by the FDA. Compound 4 is an important intermediate of Elastrogen:

[0003] PCT international application WO2020167855A1 discloses the following preparation method:

[0004]

[0005] The above route uses 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-5-methoxyacetanilide as starting materials and undergoes four-step reactions to obtain intermediate A6. A6 also needs to be chirally resolved to obtain the desired R-configuration compound A7 (i.e., compound 4 of the present invention). Regardless of whether it is a chiral resolution reagent or supercritical fluid chromatography (SFC) resolution, the waste of another S configuration cannot be avoided. Moreover, this resolution process requires a large amount of reagents, time and money costs, which is not conducive to industrial production.

[0006] The starting material A1, CAS: 722536-73-4, 4500 / 1KG, is relatively expensive and needs to be synthesized through three steps:

[0007]

[0008] Chinese patent CN117362142A discloses a method for preparing a compound of formula II-1-2 (i.e., compound 4 of the present invention) by asymmetric hydrogenation reduction of a compound of formula I-1-2 in a solvent in the presence of a catalyst formed by a ligand, an iridium salt, and an inorganic salt under a hydrogen atmosphere:

[0009]

[0010] In order to prepare the elastomeric intermediate compound A7, the route disclosed in WO2020167855A1 was optimized by combining the method disclosed in CN117362142A. However, it is still unavoidable to first use compound A1 as the starting material to synthesize the compound shown in formula I-1-2 through multiple steps of reaction. However, compound A1 is relatively expensive, and the overall cost is still relatively high and the economy is low. Summary of the invention

[0011] The present invention aims at solving the problems in the prior art and provides a method for preparing an elastomeric intermediate and a derivative thereof. The preparation method has a simple route, low raw material cost and high yield.

[0012] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0013] A method for preparing an elastomeric intermediate and its derivatives comprises the following steps:

[0014] S1, coupling compound 1 with compound SM1 by palladium catalysis to obtain compound 2;

[0015] S2, reducing the carbonyl group of compound 2 by asymmetric hydrogenation to obtain compound 3;

[0016] S3. Hydrogenate compound 3 to obtain compound 4.

[0017] Further, the compound 1 is

[0018] Further, the compound SM1 is

[0019] Further, the compound 2 is

[0020] Further, the compound 3 is

[0021] Further, the compound 4 is

[0022] The R 1 The group is a hydroxyl protecting group; the X group is a halogen; the R 2 and R 3 The groups are each independently selected from H, alkyl, acyl-containing groups, wherein the alkyl is optionally substituted with one or more halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, phenyl and acyl-containing substituents; the R 4 The group is an alkoxy group.

[0023] Furthermore, the palladium-catalyzed coupling is the reaction of compound 1 with compound SM1 in the presence of a palladium catalyst, a ligand and a base to generate compound 2.

[0024] Furthermore, the palladium catalyst is tris(dibenzylideneacetone)dipalladium.

[0025] Furthermore, the ligand is: tri-tert-butylphosphine tetrafluoroborate.

[0026] Furthermore, the alkali is sodium hydroxide.

[0027] Furthermore, the molar ratio of compound 1, compound SM1, palladium catalyst, ligand and base is: 30-35:35-45:1-1.5:4-8:90-110.

[0028] Furthermore, the palladium-catalyzed coupling is carried out at a temperature of 90-110° C. and for a time of 1.5-3 h.

[0029] Furthermore, the solvents for the palladium-catalyzed coupling are 1,4-dioxane and water.

[0030] Furthermore, the volume ratio of 1,4-dioxane to water is 3-4:1.

[0031] Furthermore, the asymmetric hydrogenation reduction of carbonyl groups is any one of asymmetric transfer hydrogenation, CBS asymmetric reduction of carbonyl groups, biocatalysis and asymmetric transition metal hydrogenation.

[0032] Furthermore, the asymmetric transfer hydrogenation method is to generate compound 3 from compound 2 under the action of a hydrogen source and a ligand.

[0033] Furthermore, the hydrogen source is formic acid and triethylamine.

[0034] Furthermore, the volume ratio of formic acid to triethylamine is: 4-6:1-2.

[0035] Furthermore, the ligand is (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride.

[0036] Furthermore, the solvent of the asymmetric transfer hydrogenation method is toluene.

[0037] Furthermore, the reaction temperature of the asymmetric transfer hydrogenation method is 45-65°C.

[0038] Furthermore, the molar ratio of the compound 2 to the ligand is 8-10:1-2.

[0039] Furthermore, the CBS asymmetric carbonyl reduction method is to generate compound 3 from compound 2 in the presence of a catalyst and a reducing agent.

[0040] Furthermore, the catalyst is S-CBS.

[0041] Furthermore, the reducing agent is borane dimethyl sulfide.

[0042] Furthermore, the reaction temperature of the CBS asymmetric carbonyl reduction method is -55°C to -65°C.

[0043] Furthermore, the molar ratio of the compound 2, the catalyst, and the reducing agent is 0.8-1.2:0.08-0.12:1.5-2.5.

[0044] Furthermore, the biocatalytic method is that compound 2 produces compound 3 under the action of enzyme.

[0045] Furthermore, the enzyme is a reduced coenzyme and a ketoreductase.

[0046] Furthermore, the reduced coenzyme is any one of reduced coenzyme I and reduced coenzyme II.

[0047] Furthermore, the enzyme-catalyzed reaction temperature is 20-30°C, and the reaction time is 20-26h.

[0048] Furthermore, the asymmetric transition metal hydrogenation of compound 2 produces compound 3 under the catalysis of a ligand and a rhodium salt.

[0049] Furthermore, the ligand is Any of .

[0050] Furthermore, the rhodium salt is any one of 1,5-cyclooctadiene rhodium chloride dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate and bis(1,5-cyclooctadiene) iridium tetrafluoroborate.

[0051] Furthermore, the hydrogenation in step S3 is as follows: compound 3, an acid and a catalyst are reacted under a hydrogen atmosphere to generate compound 4.

[0052] Furthermore, the catalyst is a palladium-based catalyst.

[0053] Furthermore, the acid is at least one of trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid, acetic acid or hydrochloric acid.

[0054] Furthermore, the molar ratio of the compound 3, the acid and the catalyst is: 1-1.2: 1: 0.005-0.008.

[0055] Preferably, the R 1 The group is one of p-methoxybenzyl, tert-butyl, triphenylmethyl, trimethylsilyl, tert-butyldimethylsilyl, benzyl and tert-butyldiphenylsilyl.

[0056] Preferably, the X group is one of bromine, chlorine and OTf.

[0057] Preferably, the R 2 The group is one of tert-butyloxycarbonyl, acetyl, ethyl and H.

[0058] Preferably, the R 3 The group is one of tert-butyloxycarbonyl, acetyl, ethyl and H.

[0059] Preferably, the R 4 The group is OCH3.

[0060] More preferably, the R 1 The group is benzyl.

[0061] Further preferably, the X group is bromine.

[0062] More preferably, the R 2 The group is tert-butyloxycarbonyl, R 3 The group is H, or R 3 The group is tert-butyloxycarbonyl, R 2 The group is H.

[0063] Definition and Description

[0064] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without a special definition, but should be understood according to the ordinary meaning.

[0065] In the present invention, "substituted by..." means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical feasibility; if substituted, any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable; when the listed substituent does not specify which atom it is connected to the substituted group through, such substituent may be bonded through any atom thereof, as long as the valence state of the specific atom is normal and the substituted compound is stable.

[0066] As used herein, "halogen" by itself or as part of another substituent refers to a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.

[0067] In the present invention, "alkyl" is used to represent any stable straight chain, branched chain, monocyclic, polycyclic saturated hydrocarbon group, which may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine), and may be chain (such as propyl) or cyclic (such as cyclopropyl). Examples of alkyl include methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), cyclopropyl, etc.

[0068] In the present invention, "acyl-containing group" refers to a compound containing an acyl functional group, wherein the acyl group is a functional group in an organic compound formed by combining a carbonyl group of a carboxylic acid with a hydrocarbon group. Specifically, the structure of the acyl group is -COR.

[0069] In the present invention, "alkoxy" means an alkyl group connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention.

[0070] In the present invention, "cycloalkyl" means an alicyclic hydrocarbon group, wherein the carbon atoms form a ring structure, and the ring may be a single ring or a polycyclic ring. Common examples include cyclopropyl (containing 3 carbon atoms), cyclobutyl (containing 4 carbon atoms) and cyclopentyl (containing 5 carbon atoms).

[0071] In the present invention, "room temperature" refers to ambient temperature, which is from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 20°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 25°C to 30°C; in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0072] The beneficial effects of the present invention are:

[0073] (1) The present invention simplifies the route and shortens the preparation steps. The key intermediate compound 4 can be efficiently obtained in only three steps without the need for splitting. The preparation method is simple and efficient, which is conducive to large-scale production.

[0074] (2) The present invention reduces the price of starting materials from 1KG / 4500 yuan to 1KG / 2500 yuan by optimizing the preparation route, while improving the product yield and increasing the profit. DETAILED DESCRIPTION

[0075] The present invention will be further described in detail below in conjunction with preferred embodiments, but those skilled in the art will appreciate that these are only for the purpose of explaining preferred embodiments and therefore should not be regarded as limiting the scope of the present invention.

[0076] Unless otherwise specified, the raw materials of the present invention are all commercially available reagents.

[0077] 1. Examples and Comparative Examples

[0078] Example 1

[0079] The synthetic route is as follows:

[0080]

[0081] Step 1: Synthesis of tert-butyl (2-(6-(benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate

[0082]

[0083] Under N2 atmosphere, tris(dibenzylideneacetone)dipalladium (456 mg, 1.5 mol%), tri-tert-butylphosphine tetrafluoroborate (578 mg, 6 mol%) and sodium hydroxide (3.98 g, 99.6 mmol, 3.0 eq.) were added to a 25 mL vial equipped with a magnetic stirrer. Then, 6-benzyloxy-3,4-dihydro-2H-naphthalen-1-one (8.37 g, 33.2 mmol, 1.0 eq.) and N-BOC-2-bromo-5-methoxyaniline (12.0 mg, 39.8 mmol, 1.2 eq.) were added, and 1,4-dioxane (60 mL) and water (15 mL) were added respectively. The mixture was stirred at 100° C. (oil bath) for 2 hours. LCMS detected that the raw material was completely converted. The reaction was cooled to room temperature, extracted with EtOAc, washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc=10 / 1) to obtain tert-butyl (2-(6-(benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate (9.7 g, yield=62%, purity=96%).

[0084] 1 H NMR (400MHz, DMSO-d6) δ8.46 (s, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.51-7.45 (m, 2H), 7 .42(t,J=7.3Hz,2H),7.39-7.32(m,1H),7.07-6.93(m,4H),6.69(dd,J=8.6,2.7H z,1H),5.22(s,2H),4.03(dd,J=12.0,4.6Hz,1H),3.73(s,3H),3.09(ddd,J=16.2 ,11.3,4.6Hz,1H),2.96(dt,J=16.8,4.1Hz,1H),2.36-2.13(m,2H),1.44(s,9H).

[0085] Step 2: Synthesis of tert-butyl (2-((1R,2S)-6-(benzyloxy)-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate

[0086]

[0087] Under N2 atmosphere, to a 25 mL vial equipped with a magnetic stirrer was added tert-butyl (2-(6-(benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate (8.5 g, 18 mmol, 1.0 eq.), (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine(p-isopropylbenzene)ruthenium chloride (1.14 g, 1.8 mmol, 0.1 eq. CAS: 192139-90-5) and 50 ml of toluene, followed by formic acid / triethylamine (100 mL, 5:2). The reaction solution was stirred at 50° C. (oil bath) for 48 hours. LCMS detected that the raw material was completely converted. The reaction was cooled to room temperature, washed with saturated ammonium chloride aqueous solution, extracted with EtOAc, and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EtOAc=5 / 1) to obtain the target product (7.7 g, yield=90%, ee=97.5%, purity=96%).

[0088] 1 H NMR (400MHz, CDCl3) δ7.47-7.29(m,6H),7.24(s,1H),7.16(d,J=8.6Hz,1H),6.99( s,1H),6.87(dd,J=8.4,2.6Hz,1H),6.81(d,J=2.6Hz,1H),6.69(dd,J=8.6,2.7Hz,1 H),5.08(s,2H),4.73(s,1H),3.82(s,3H),3.12-2.96(m,2H),2.89(ddd,J=17.1,1 2.0,5.6Hz,1H),2.53(qd,J=12.5,5.4Hz,1H),1.82(d,J=13.4Hz,1H),1.49(s,9H).

[0089] Step 3: Synthesis of (R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0090]

[0091] To a hydrogenation tube equipped with a stirrer, tert-butyl (2-((1R, 2S)-6-(benzyloxy)-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate (6.0 g, 12.6 mmol), Pd / C (600 mg, 10% mmol) and methanol (20 mL) were added, and then trifluoromethanesulfonic acid (1.9 g, 12.6 mmol, 1.0 eq.) was added. The hydrogenation tube was then placed in an autoclave, and hydrogen was charged to 30 bar. After three replacements, the reaction solution was stirred at room temperature for 12 hours. LCMS detected that the raw material was completely converted. The crude product was evaporated under reduced pressure and purified by silica gel column chromatography to obtain a white solid (3.0 g, yield = 90%, purity = 98%).

[0092] 1 H NMR (400MHz, DMSO-d6) δ9.00(s,1H),6.92(d,J=8.5Hz,1H),6.86(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,2H),6.28(d,J=2.6Hz,1H),6.18(dd,J=8 .4,2.6Hz,1H),5.34(s,2H),3.65(s,3H),2.95-2.67(m,4H),2.56(dd,J=15.8,11.3Hz,1H),1.94-1.82(m,1H),1.72(qd,J=11.8,5.3Hz,1H).

[0093] Example 2

[0094] The difference from Example 1 is that step 2 is different, and the synthesis method of step 2' is:

[0095]

[0096] After N2 protection, S-CBS (27.7 mg, 0.1 mmol, 0.1 eq.) and borane dimethyl sulfide (1.0 mL, 2.0 mmol, 2.0 eq, 2.0 mol / L) were added to a dry three-necked flask. After stirring at room temperature for 15 min, DCM (2 mL) was added, the temperature was lowered to -20 °C, and a mixture of tert-butyl (2-(6-(benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate (473 mg, 1.0 mmol, 1.0 eq.) and DCM (5 mL) was added dropwise. The temperature was controlled at -60±5 °C. After the addition was completed, the mixture was kept warm for 1.5 hours. Methanol was added dropwise to quench the mixture, and the mixture was concentrated to dryness to obtain a yellow oil. The crude product was purified by column chromatography to obtain the target product as a white solid (451 mg, yield = 95%, dr = 77:23, 70% ee, purity = 95%).

[0097] Example 3

[0098] The difference from Example 1 is that step 2 is different, and the synthesis method of step 2 is:

[0099]

[0100] In a 25 ml round-bottom flask, weigh tert-butyl (2-(6-(benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate (47.3 mg, 0.1 mmol, 1.0 eq.), reduced coenzyme I (NADH), glucose (50 mg), ketoreductase (CES K-1) (5 mg), phosphate buffer (pH 7.0, 5 mL), control the reaction temperature at 20-30 ° C and stir (500 rpm) for 24 hours. The mixture was extracted with ethyl acetate and centrifuged three times, the organic phases were combined and dried over anhydrous sodium sulfate, and the organic phase was evaporated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EtOAc=5 / 1) to obtain the target product (40.4 mg, yield=85%, dr=90:10, ee=85%, purity=95%)

[0101] Example 4

[0102] The difference from Example 1 is that step 2 is different, and the synthesis method of step 2 is:

[0103]

[0104] Weigh the ligand (any one of L1-L5) (2% mol), (1,5-cyclooctadiene)ene)chlororhodium (I) dimer (1% mol), and place them in a 50 ml round-bottom flask. Then add 10 ml of degassed ethanol (bubbling nitrogen with a long needle for 5 minutes). Stir at room temperature for 10 minutes and then add the hydrogenation substrate (tert-butyl 2-(6-(benzyloxy)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)carbamate (473 mg, 1.0 mmol, 1.0 eq.), sodium tert-butoxide (106 mg, 1.1 mmol, 1.1 eq.). After stirring evenly, place the round-bottom flask in a hydrogenation reactor. After replacing the gas in the reactor with hydrogen three times, add hydrogen pressure to 5 MPa. After the reaction was stirred at room temperature for 48 hours, hydrogen was slowly released, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE / EtOAc=5 / 1) to obtain the target product.

[0105] Ligands L1-L5 and their purity, ee and yield are shown in Table 1.

[0106] Table 1

[0107]

[0108] Comparative Example 1

[0109] The difference from Example 4 is that the types of ligands are different. Ligands L6-L7 and their purity, ee and yield are shown in Table 2.

[0110] Table 2

[0111]

[0112] In Examples 1-4 of the present invention, the ee value of step 2 reaches more than 85%, and there is no need to perform separation, which can simplify the process and save costs; meanwhile, the yield of step 2 is greater than 85%, and the purity is greater than 94%.

[0113] In Comparative Example 1, the type of ligand was changed, and its ee values ​​were 23% and 50%, which required separation, complicated preparation steps and increased costs; its purity was 77% and 81%, and the yield was 16% and 22%.

[0114] Compared with Example 4, the purity, yield and ee value of Comparative Example 1 are all reduced.

[0115] The preparation method of the present invention can reduce costs, improve yield and purity, and at the same time does not need to be split, thereby achieving the technical effects of saving costs, improving profits and simplifying processes, which is conducive to further scale-up production.

[0116] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings 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 claims attached to this application.

Claims

1. A method for preparing an elastomeric intermediate and its derivatives, characterized in that: The steps include: S1, coupling compound 1 with compound SM1 by palladium catalysis to obtain compound 2; S2, reducing the carbonyl group of compound 2 by asymmetric hydrogenation to obtain compound 3; S3, hydrogenating compound 3 to obtain compound 4; The compound 1 is The compound SM1 is The compound 2 is The compound 3 is The compound 4 is The R 1 The group is a hydroxyl protecting group; The X group is a halogen; The R 2 and R 3 The groups are each independently selected from H, alkyl, acyl-containing groups, the alkyl being optionally substituted with one or more halogen, nitro, cyano, amino, alkyl, alkoxy, cycloalkyl, phenyl, and acyl-containing substituents; The R 4 The group is an alkoxy group.

2. The preparation method according to claim 1, characterized in that: The palladium-catalyzed coupling is that compound 1 and compound SM1 generate compound 2 under the action of palladium catalyst, ligand and base; and / or The palladium catalyst is tris(dibenzylideneacetone)dipalladium; and / or The ligand is: tri-tert-butylphosphine tetrafluoroborate; and / or The alkali is: sodium hydroxide; and / or The molar ratio of compound 1, compound SM1, palladium catalyst, ligand and base is: 30-35:35-45:1-1.5:4-8:90-110; and / or The palladium catalyzed coupling is carried out at a temperature of 90-110° C. and for a time of 1.5-3 h.

3. The preparation method according to claim 1, characterized in that: The asymmetric hydrogenation reduction of carbonyl groups is any one of asymmetric transfer hydrogenation, CBS asymmetric carbonyl reduction, biocatalysis and asymmetric transition metal hydrogenation.

4. The preparation method according to claim 3, characterized in that: The asymmetric transfer hydrogenation method is to generate compound 3 from compound 2 under the action of a hydrogen source and a ligand; and / or The hydrogen source is formic acid and triethylamine; and / or The volume ratio of formic acid to triethylamine is: 4-6:1-2; and / or The ligand is (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride; and / or The reaction temperature of the asymmetric transfer hydrogenation method is 45-65°C; and / or The molar ratio of the compound 2 to the ligand is 8-10:1-2.

5. The preparation method according to claim 3, characterized in that: The CBS asymmetric carbonyl reduction method is to generate compound 3 from compound 2 under the action of a catalyst and a reducing agent; and / or The catalyst is S-CBS; and / or The reducing agent is borane dimethyl sulfide; and / or The reaction temperature of the CBS asymmetric carbonyl reduction method is -55°C to -65°C; and / or The molar ratio of the compound 2, the catalyst and the reducing agent is 0.8-1.2:0.08-0.12:1.5-2.

5.

6. The preparation method according to claim 3, characterized in that: The biocatalytic method is that compound 2 generates compound 3 under the action of enzyme; and / or The enzyme is a reduced coenzyme and a ketoreductase; and / or The reduced coenzyme is any one of reduced coenzyme I and reduced coenzyme II; and / or The enzyme-catalyzed reaction temperature is 20-30° C., and the reaction time is 20-26 h.

7. The preparation method according to claim 3, characterized in that: The asymmetric transition metal hydrogenation is carried out to produce compound 3 under the action of a ligand and a rhodium salt to form compound 2; and / or The ligand is Any of; and / or The rhodium salt is any one of 1,5-cyclooctadiene rhodium chloride dimer, bis(1,5-cyclooctadiene) rhodium tetrafluoroborate and bis(1,5-cyclooctadiene) iridium tetrafluoroborate.

8. The preparation method according to claim 1, characterized in that: The hydrogenation in step S3 is: compound 3, acid and catalyst are reacted under hydrogen atmosphere to generate compound 4; and / or The catalyst is a palladium-based catalyst; and / or The acid is at least one of trifluoromethanesulfonic acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid, acetic acid or hydrochloric acid; and / or The molar ratio of the compound 3, the acid and the catalyst is: 1-1.2: 1: 0.005-0.

008.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The R 1 The group is one of p-methoxybenzyl, tert-butyl, triphenylmethyl, trimethylsilyl, tert-butyldimethylsilyl, benzyl and tert-butyldiphenylsilyl; and / or The X group is one of bromine, chlorine and OTf; The R 2 The group is one of tert-butyloxycarbonyl, acetyl, ethyl and H; The R 3 The group is one of tert-butyloxycarbonyl, acetyl, ethyl and H; The R 4 The group is OCH3.

10. The preparation method according to claim 9, characterized in that: The R 1 The group is benzyl; The X group is bromine; The R 2 The group is tert-butyloxycarbonyl, R 3 The group is H, or R 3 The group is tert-butyloxycarbonyl, R 2 The group is H.

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