CN116693424A - Preparation method of Sha Kuba curved intermediate - Google Patents
Preparation method of Sha Kuba curved intermediate Download PDFInfo
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- CN116693424A CN116693424A CN202310592064.4A CN202310592064A CN116693424A CN 116693424 A CN116693424 A CN 116693424A CN 202310592064 A CN202310592064 A CN 202310592064A CN 116693424 A CN116693424 A CN 116693424A
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- compound
- trimethylsilyl
- amide
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 206010019280 Heart failures Diseases 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 230000000171 quenching effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 4
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 4
- 229960004699 valsartan Drugs 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000002792 enkephalinase inhibitor Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229940100321 entresto Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 description 1
- 229960003953 sacubitril Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, in particular to the technical field of organic drug synthesis, and more particularly relates to a preparation method of a Sha Kuba yeast intermediate. The invention surprisingly discovers that the target compound I is prepared by the condensation reaction of the compound II and the compound III or the compound IV respectively, the reaction condition is mild, the safety is high, the preparation process is simple, more importantly, the yield and the purity of the target compound are high, the utilization rate of raw materials can be greatly improved, the synthesis cost is reduced, and the method is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of organic synthesis, in particular to the technical field of organic drug synthesis, and more particularly relates to a preparation method of a Sha Kuba yeast intermediate.
Background
Heart failure has become a global public health problem seriously jeopardizing human health, and is the final stage of occurrence and development of cardiovascular diseases, the morbidity, the readmission rate and the mortality of the cardiovascular diseases are continuously increased year by year, so that further development of more effective novel medicines for treating heart failure is urgent, and the market of Sha Kuba qu/valsartan with dual action mechanisms of an angiotensin receptor-enkephalinase inhibitor brings new reforms for treatment of heart failure patients.
Sha Kuba Qu/valsartan (Entresto) is a dual-effect angiotensin receptor-enkephalinase inhibitor developed by North Corp and is clinically useful in the treatment of hypertension and heart failure. The medicine consists of Sha Kuba yeast acting on enkephalinase and valsartan acting on renin-angiotensin-aldosterone system, can effectively improve heart failure symptoms, reduce blood pressure and positively improve kidney functions, and is an ideal heart failure treatment medicine.
Since the valsartan synthesis process is relatively mature, the research focus of those skilled in the art is on the synthesis optimization of the Sha Kuba starter.
Sha Kuba yeast (Sacubitril), having the chemical name 4- (((2S, 4R) -1- ([ 1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopropan-2-yl) amino) -4-oxobutanoic acid, has the structure:
compound I is an important intermediate for preparing Sha Kuba yeast medicaments,
in the original patent US5217996, a preparation method of Sha Kuba starter is disclosed, and the synthetic route is as follows:
in the synthetic route, the compound I is prepared by reacting a compound II with a phosphorus ylide reagent, wherein the structure of the phosphorus ylide reagent is shown as a formula a,
this approach is currently commonly employed in the art to prepare compound I by the classical Wittig reaction. However, the yield of the compound I in the method is only 78%, and the lower reaction yield not only causes the waste of chiral alcohol raw materials, but also makes the cost of the industrial synthesis of Sha Kuba yeast high.
Therefore, developing a preparation method of the sabobactrum intermediate (compound I) with high yield and low synthesis cost, which is more suitable for industrial production, becomes a hot spot problem for the study of the technicians in the field.
Disclosure of Invention
The invention aims to provide a novel preparation method of a Sha Kuba yeast intermediate (compound I), which can improve the product yield and reduce the synthesis cost, thereby reducing the industrial synthesis cost of Sha Kuba yeast.
In order to solve the technical problems, the invention discloses a preparation method of a sabatier intermediate, which comprises the following steps: in the presence of strong alkali and solvent, carrying out condensation reaction on the compound II and the compound M to obtain a compound I, wherein the specific synthetic route is as follows:
the compound M is
Preferably, the molar ratio of compound II to compound M is 1:1 to 1.5.
Preferably, the base is one of sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, butyllithium, sodium hydride, or potassium hydride.
Preferably, the molar ratio of compound II to strong base is 1:1 to 1.5.
Preferably, the solvent is one or more of tetrahydrofuran, dimethoxyethane, toluene, methylene chloride or dimethylformamide.
Preferably, when compound M isWhen the reaction temperature is preferably-90 to-20 ℃; preferably, when compound M is +.>In the case of the reaction, the reaction temperature is preferably-80 to 0 ℃.
The invention surprisingly discovers that the target compound I is prepared by the condensation reaction of the compound II and the compound III or the compound IV respectively, the reaction condition is mild, the safety is high, the preparation process is simple, more importantly, the yield and the purity of the target compound are high, the utilization rate of raw materials can be greatly improved, the synthesis cost is reduced, and the method is suitable for industrial large-scale production.
Detailed Description
For a better understanding of the present invention, we will further describe the present invention with reference to specific examples.
Unless otherwise specified, the reagents used in the examples of the present invention are all commercially available products.
Example 1
To the reaction vessel were added compound III (27.8 g,92 mmol) and 250ml of tetrahydrofuran, the solution was stirred and purged, the mixture was cooled to-75℃under nitrogen protection, a solution of sodium bis (trimethylsilyl) amide (16.2 g,88 mmol) in tetrahydrofuran (30 ml) was slowly added dropwise thereto, and the reaction was stirred at-75 ℃. To the mixture was added dropwise a solution of compound II (25.4 g,78 mmol) in tetrahydrofuran (50 ml), -the reaction was continued with stirring at 75 ℃. After the reaction, the temperature is raised to room temperature, 100ml of saturated ammonium chloride solution is added for quenching the reaction, after the quenching, the materials are distilled under reduced pressure, evaporated to dryness, 200ml of toluene is added for dissolution, water washing and concentration are carried out, 200ml of methanol is used for crystallization, and the compound I is obtained, the yield is 94.5%, and the purity is 99.3%.
Example 2
To the reaction vessel were added compound III (23.6 g,78 mmol) and 250ml toluene, the solution was stirred and purged, the mixture was cooled to-90℃under nitrogen protection, a toluene solution (30 ml) of butyllithium (7.49 g,117 mmol) was slowly added dropwise thereto, and the reaction was stirred at-90 ℃. To the mixture was added dropwise a toluene solution (50 ml) of compound II (25.4 g,78 mmol), -the reaction was continued with stirring at 90 ℃. After the reaction, the temperature is raised to room temperature, 100ml of saturated ammonium chloride solution is added for quenching the reaction, after the quenching, the materials are distilled under reduced pressure, evaporated to dryness, 200ml of toluene is added for dissolution, water washing and concentration are carried out, 200ml of methanol is used for crystallization, and the compound I is obtained, the yield is 90.2%, and the purity is 99.1%.
Example 3
To the reaction vessel were added compound III (35.3 g,117 mmol) and 250ml of dimethoxyethane, the solution was stirred and purged, nitrogen was substituted 3 times, the mixture was cooled to-20℃under nitrogen protection, and a solution of sodium hydride (1.9 g,78 mmol) in dimethoxyethane (30 ml) was slowly dropped to react under stirring at-20 ℃. To the mixture was added dropwise a solution of compound II (25.4 g,78 mmol) in dimethoxyethane (50 ml), -the reaction was continued with stirring at 20 ℃. After the reaction, the temperature is raised to room temperature, 100ml of saturated ammonium chloride solution is added for quenching the reaction, after the quenching, the materials are distilled under reduced pressure, evaporated to dryness, 200ml of toluene is added for dissolution, water washing and concentration are carried out, 200ml of methanol is used for crystallization, and the compound I is obtained, the yield is 87.1%, and the purity is 98.7%.
Example 4
Sodium hydride (1.3 g,55 mmol) and 100ml tetrahydrofuran were added to the reaction vessel under nitrogen atmosphere and dissolved with stirring. Compound IV (14.3 g,60 mmol) was then added and stirred at-78deg.C for 0.5h. Compound II (15 g,46 mmol) was dissolved in 50ml of tetrahydrofuran, and then added dropwise to the reaction mixture, followed by stirring at-78 ℃. After the completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography gave compound I in 93.6% yield, 99.2% purity.
Example 5
Butyl lithium (3 g,46 mmol) and 100ml dimethoxyethane were added to the reaction vessel under nitrogen and dissolved with stirring. Compound IV (16.4 g,69 mmol) was then added and stirred at-40℃for 0.5h. Compound II (15 g,46 mmol) was dissolved in 50ml of dimethoxyethane and then added dropwise to the reaction mixture, followed by stirring at-40 ℃. After the completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography gave compound I in 89.4% yield and 98.8% purity.
Example 6
Potassium bis (trimethylsilyl) amide (13.7 g,69 mmol) and 100ml toluene were added to the reaction vessel under nitrogen atmosphere and dissolved with stirring. Compound IV (11 g,46 mmol) was then added and stirred at 0deg.C for 0.5h. Compound II (15 g,46 mmol) was dissolved in 50ml of toluene, and then added dropwise to the reaction solution, followed by stirring at 0 ℃. After the completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography gave compound I in 87.5% yield and 99.1% purity.
What has been described above is a specific embodiment of the present invention. It should be noted that modifications and adaptations to the invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be within the scope of the present invention.
Claims (10)
1. The preparation method of the sabatier starter intermediate is characterized by comprising the following steps of: in the presence of strong alkali, carrying out condensation reaction on the compound II and the compound III to obtain a compound I, wherein the specific synthetic route is as follows:
。
2. the process for preparing a Sha Kuba curved intermediate according to claim 1, wherein the molar ratio of compound II to compound III is 1:1 to 1.5; the molar ratio of the compound II to the alkali is 1:1 to 1.5.
3. The method for preparing a Sha Kuba yeast intermediate according to claim 1, wherein the base is one of sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, butyllithium, sodium hydride or potassium hydride.
4. The method of claim 1, wherein the solvent is one or more of tetrahydrofuran, dimethoxyethane, toluene, methylene chloride, and dimethylformamide.
5. The process for preparing a Sha Kuba yeast intermediate according to claim 1, wherein the reaction temperature is from-90 ℃ to-20 ℃.
6. The preparation method of the sabatier starter intermediate is characterized by comprising the following steps of: in the presence of strong alkali, carrying out condensation reaction on the compound II and the compound IV to obtain a compound I, wherein the specific synthetic route is as follows:
。
7. the method for preparing Sha Kuba yeast intermediate according to claim 6, wherein the molar ratio of compound II to compound IV is 1:1 to 1.5; the molar ratio of the compound II to the alkali is 1:1 to 1.5.
8. The method for preparing Sha Kuba curve intermediate according to claim 6, wherein the base is one of sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, butyllithium, sodium hydride, or potassium hydride.
9. The method of claim 6, wherein the solvent is one or more of tetrahydrofuran, dimethoxyethane, toluene, methylene chloride, and dimethylformamide.
10. The process for preparing a Sha Kuba yeast intermediate according to claim 6, wherein the reaction temperature is from-80 to 0 ℃.
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