CN106608864B - Preparation method of sofosbuvir intermediate - Google Patents
Preparation method of sofosbuvir intermediate Download PDFInfo
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- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a preparation method of a sofosbuvir intermediate 6, which comprises the following steps: the compound 1 is obtained by nucleophilic fluorine substitution reaction in an aprotic solvent at a proper temperature; the reaction formula is as follows:
wherein, the fluorine substitution reagent selected for nucleophilic fluorine substitution reaction is selected from HF/Pyridine and Bu4NH2F3、Et3N.3HF、Me3N.2HF、SiF4And a nucleophilic reagent such as DAST, preferably HF/Pyridine. According to the novel preparation method of the sofosbuvir intermediate 6, the reaction conditions are optimized and selected, the product yield and purity are greatly improved compared with those reported in the existing documents, the reaction conditions are mild, the post-treatment is simple, the cost is reduced, the process is stable, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and particularly relates to a preparation process of a new-generation anti-hepatitis C drug sofosbuvir intermediate 6.
Background
Sofosbuvir (sofosbuvir) is the first oral anti-hepatitis c drug worldwide developed by gillidae science. Sofosbuvir acts on the nucleotide analogue NS5B polymerase site of viral RNA replication to terminate HCV replication, and is a novel HCV polymerase inhibitor. American FDA approved the market at 6.12.2013 under the trade name SovaldiTMIt is used clinically in treating HCV infection and HCV/HIV-1 co-infection. The drug was approved by the european medicines agency (EMEA) to be marketed in countries of the european union at 1/16 d 2014. Sofosbuvir has the molecular formula C22H29FN3O9P, CAS accession no: 1190307-88-0 has the following structural formula:
the sofosbuvir can safely and effectively treat hepatitis C of various types (HCV types 1, 2,3 and 4); clinical trials demonstrated that the overall sustained virological response rate (SVR) of this drug in combination with peginterferon and ribavirin was as high as 90% for type 1 and 4 hepatitis c; aiming at type 2 hepatitis C, the SVR of the medicine and ribavirin is 89-95 percent; for type 3 hepatitis C, the SVR of the drug in combination with ribavirin is 61% -63%.
The intermediate 6, the chemical name of which is (2R,3R) -2-methyl-3-hydroxy-2-fluoro-3- ((R) -2, 2-dimethyl-1, 3-dioxolane-4-yl) ethyl propionate, is an important intermediate for synthesizing sofosbuvir.
The intermediate 6 is prepared into sofosbuvir through the following route, wherein the 6 is hydrolyzed and lactonized in ethanol by hydrochloric acid to generate (2R) -3, 5-dihydroxy-2-deoxy-2-C-methyl-2-fluoro-D-ribono acid-gamma-lactone (11), and the 11 is protected by benzoyl chloride (BzCl) hydroxyl to obtain (2R) -3, 5-di-O-benzoyl-2-deoxy-2-C-methyl-2-fluoro-D-ribono acid-gamma-lactone (12). 12 Tri-tert-butoxyaluminum lithium hydride (Li (O-tBu)3AlH) to obtain (2R) -2-deoxy-2-C-methyl-2-fluoro-3, 5-di-O-benzoyl- α/β -D-ribofuranose (13)[3]13 reacts with acetic anhydride under the action of 4-Dimethylaminopyridine (DMAP) to generate (2R) -2-deoxy-2-C-methyl-2-fluoro-1-O-acetyl-3, 5-di-O-benzoyl- α/β -D-ribofuranose (14), and the 14 and N-benzoyl-O-trimethylsilyl cytosine (16) are subjected to nucleophilic substitution to generate (2R) -3',5' -O-N4-tribenzoyl-2 ' -deoxy-2 ' -fluoro-2 ' -C-methylcytidine (17). 17 by treatment with 70% acetic acid to give (2R) -3',5' -O-dibenzoyl-2 ' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (18), deprotection of 18 with methanolic ammonia to give (2' R) -2' -deoxy-2 ' -fluoro-2 ' -C-methyluridine (19), 19 and the compound N- [ (S) -2,3,4,5, 6-phenoxyphenoxyphosphoryl]Affinity substitution of isopropyl-L-alaninate (20) gives sofosbuvir. As shown in route one:
regarding the synthesis of the intermediate 6, the literature reports mainly relate to the following methods and processes:
1) the synthetic route provided by US 20080145901: forming carbanion by 2-ethyl fluoropropionate (compound 7) under the action of diisopropylamine and methyllithium, and adding the carbanion to aldehyde group of (R) - (+) -2, 2-dimethyl-1, 3-dioxolane-4-formaldehyde (compound 4) to obtain an intermediate 6; oily product is obtained by post-treatment, and the yield is 43.4 percent; see scheme two:
the method needs ultralow temperature of-75 ℃, has low yield and cannot be applied to industrial large-scale production.
2) CN102933570 synthetic route, (2S,3R) 2-methyl-2, 3-dihydroxy-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -propionic acid ethyl ester (8) in organic base and fluoride ion source (Et)4NF 3HF) with sulfonyl fluoride (SO)2F2) 6 is obtained after the reaction, and the comprehensive yield is 66%; see route three:
in the method, the used reagent amount is large, specifically, triethylamine is 6-7 equivalents of a compound 8, and a fluoride ion source (Et) is used4NF 3HF) was 2 equivalents, sulfonyl fluoride (SO)2F2) Is 8 equivalents; and the reagents are difficult to recover, thus increasing the reaction cost and being not favorable for industrial production.
The invention aims to overcome the defects in the prior art, break through the technical barrier and provide an improved preparation process of the intermediate 6, which has the advantages of mild reaction conditions, simple and convenient operation, cheap and easily obtained reagents, high yield and suitability for industrial production.
Disclosure of Invention
In one aspect, the invention provides a preparation method of sofosbuvir intermediate ethyl (2R,3R) -2-methyl-3-hydroxy-2-fluoro-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) propionate (referred to as intermediate or compound 6), comprising the steps of obtaining ethyl 2-methyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) -2-epoxypropionate (referred to as compound 1) by nucleophilic fluorine substitution reaction in an aprotic solvent at a proper temperature; the reaction formula is as follows:
the fluorine substitution reagent selected for nucleophilic fluorine substitution reaction is selected from HF/Pyridine and Bu4NH2F3、Et3N.3HF、Me3N.2HF、SiF4And DAST and the like.
In a preferred embodiment of the above method for producing sofosbuvir intermediate 6, the fluorine substitution reagent is preferably HF/Pyridine.
In a preferred embodiment of the preparation method of sofosbuvir intermediate 6, the amount of the fluorine substitution reagent is 1.1 to 5.0 equivalents, preferably 1.1 to 1.5 equivalents, of compound 1.
In a preferred embodiment of the preparation method of sofosbuvir intermediate 6, the aprotic solvent used in the reaction is selected from dichloromethane, trichloromethane, dichloroethane, benzene, toluene, ethylbenzene, xylene or chlorobenzene; preferably dichloromethane.
In a preferred embodiment of the preparation method of sofosbuvir intermediate 6, the reaction temperature is appropriately 0-70 ℃; preferably 15 to 35 ℃.
In another aspect, the invention also provides compound 1 and a process for its preparation.
As for compound 1, it can be prepared by the following two methods:
method (1): 2-methyl-3- ((R) -2, 2-dimethyl-1, 3-dioxolane-4-yl) -2-ethyl acrylate (or called as reaction substrate 3) and an epoxidation reagent are epoxidized in an aprotic solvent at a proper temperature to obtain a compound 1. The reaction formula is as follows;
in The reaction of The above method (1), The reaction substrate 3 can be prepared by The Journal of organic chemistry,2009,74(17):6819-6824.
In a preferred embodiment of the reaction of process (1) above, the epoxidizing agent is selected from peroxy acid agents such as: h2O2Peracetic acid, perbenzoic acid, m-chloroperoxybenzoic acid (mCPBA), and the like, with m-chloroperoxybenzoic acid (mCPBA) being preferred.
In a preferred embodiment of the reaction of the above process (1), the aprotic solvent used in the reaction is selected from the group consisting of dichloromethane, trichloromethane, dichloroethane, benzene, toluene, ethylbenzene, xylene and chlorobenzene; preferably dichloromethane.
In a preferred embodiment, the reaction of the method (1) is carried out at a suitable temperature of 10-90 ℃; preferably 35 to 45 ℃.
Method (2): compound 4 is reacted with ethyl 2-bromopropionate (5) in the presence of a base in an aprotic solvent at an appropriate temperature by Darzens to give 1, of the formula:
the reaction of the above process (2), the compound 4 and the compound 5 used were each obtained by purchase.
In a preferred embodiment of the reaction of the above process (2), the base is selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, sodium amide, preferably sodium ethoxide.
In a preferred embodiment of the reaction of the method (2), when the base is sodium ethoxide, the amount of sodium ethoxide is 1 to 5 equivalents, preferably 1.1 to 1.5 equivalents, of the compound 4.
In a preferred embodiment of the reaction of the above method (2), the molar ratio of the compound 4 to the compound 5 is 1:1 to 1:10, preferably 1:1 to 1.2.
In a preferred embodiment of the reaction of the above process (2), the aprotic solvent used in the reaction is selected from dichloromethane, chloroform, dichloroethane, benzene, toluene, ethylbenzene, xylene or chlorobenzene; preferably dichloromethane.
In a preferred embodiment, the reaction of the method (2) is carried out at a suitable temperature of-10 to 50 ℃; preferably 0 to 25 ℃.
In the above preparation method, the monitoring of the reaction process can be carried out according to the conventional methods and means in the art, such as thin layer chromatography TLC, column chromatography HPLC, GC and the like.
The invention has the advantages that: (1) the yield of the intermediate 6 prepared by the invention is higher than that of the preparation routes of the patents US20080145901 and CN102933570, and the operation is simple. (2) The preparation method of the intermediate 6 has mild conditions, saves energy sources compared with the low temperature of-75 ℃ in the patent US20080145901, and is more suitable for industrial production. (3) The reagent used in the invention is cheap and easy to obtain, and when the reagent is HF/Pyridine, the dosage of the HF/Pyridine is 1.1-1.5 equivalents of the substrate, compared with the patent CN102933570, the reagent dosage is saved, the green chemical atom economy is met, the cost is reduced, and the three-waste pollution is reduced.
In conclusion, the invention provides a new preparation method of the sofosbuvir intermediate 6, the reaction conditions are optimized and selected, the product yield and purity are greatly improved compared with those reported in the existing documents, the reaction conditions are mild, the post-treatment is simple, the cost is reduced, the process is stable, and the method is suitable for industrial production.
The invention is further illustrated by the following examples; it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the spirit of the invention, and these modifications and decorations should be regarded as being within the protection scope of the invention.
Detailed Description
The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The reagents and starting materials used in the present invention are commercially available or can be prepared according to known literature methods. Specifically, compounds 4,5 are commercial technical grade reagents and are used as received without treatment. Other reagents are purchased from Chinese medicines and are directly used without treatment.
Comparative example: the corresponding fluorinated hydroxy compound was obtained by ring-opening of an epoxypropane compound with HF, according to the Synthetic method described in references F.Ammadi, M.M.Chaaboundi, H.Amri & A.Baklouti, Synthesis of α -cyanoo- β -fluoro- α -hydroxyethers, Synthesis Communications,1993,23:17, 2389-2395. The yield of this comparative example was 61%.
Example 1 preparation of Compound 6
To a solution of 70% HF/Py (w/w%) (10ml) in dichloromethane (10ml) was added dropwise a solution of compound 1(2.30g, 10.0mmol) in dichloromethane (10ml) at room temperature, and the reaction was stirred for further 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), and the organic layer was washed with 5% sodium hydrogencarbonate solution (15ml), water (15ml) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure evaporation of the solvent, recrystallization with methyl tert-butyl ether-N-hexane system, obtained 2.26g of compound 6 as a white solid (yield 90.1%), purity 99.3% (gas phase system: Agilent 6890N).
Example 2 preparation of Compound 6
To a solution of 70% HF/Py (w/w%) (10ml) in dichloromethane (10ml) was added dropwise a solution of compound 1(2.30g, 10.0mmol) in dichloromethane (10ml) at 0 ℃ and the reaction was stirred for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), and the organic layer was washed with 5% sodium hydrogencarbonate solution (15ml), water (15ml) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure evaporation of the solvent, recrystallization with methyl tert-butyl ether-N-hexane system, to obtain 1.64g of compound 6 as a white solid (yield 65.4%), purity 99.3% (gas phase system: Agilent 6890N).
Example 3 preparation of Compound 6
To a solution of 70% HF/Py (w/w%) (10ml) in dichloromethane (10ml) was added dropwise a solution of compound 1(2.30g, 10.0mmol) in dichloromethane (10ml) at 15 ℃ and the reaction was stirred for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), and the organic layer was washed with 5% sodium hydrogencarbonate solution (15ml), water (15ml) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure evaporation of the solvent, recrystallization with methyl tert-butyl ether-N-hexane system, obtained 2.22g of Compound 6 as a white solid (yield 88.6%), purity 99.3% (gas phase system: Agilent 6890N).
Example 4 preparation of Compound 6
To a solution of 70% HF/Py (w/w%) (10ml) in dichloromethane (10ml) was added dropwise a solution of compound 1(2.30g, 10.0mmol) in dichloromethane (10ml) at 35 ℃ and the reaction was stirred for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), and the organic layer was washed with 5% sodium hydrogencarbonate solution (15ml), water (15ml) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure evaporation of the solvent, recrystallization with methyl tert-butyl ether-N-hexane system, obtained 2.14g of compound 6 as a white solid (yield 85.3%), purity 99.3% (gas phase system: Agilent 6890N).
Example 4 preparation of Compound 6
To a solution of 70% HF/Py (w/w%) (10ml) in dichloromethane (10ml) was added dropwise a solution of compound 1(2.30g, 10.0mmol) in dichloromethane (10ml) under reflux, and the reaction was stirred for additional 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), and the organic layer was washed with 5% sodium hydrogencarbonate solution (15ml), water (15ml) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure evaporation of the solvent, recrystallization with methyl tert-butyl ether-N-hexane system, to obtain 1.82g of compound 6 as a white solid (yield 72.5%), purity 99.3% (gas phase system: Agilent 6890N).
Example 5 preparation of Compound 6
To a solution of 70% HF/Py (w/w%) (10ml) in toluene (10ml) was added dropwise a solution of compound 1(2.30g, 10.0mmol) in toluene (10ml) at 70 ℃ and the reaction was stirred for 2 hours. The reaction solution was poured into cold water (50ml), extracted with dichloromethane (20ml), and the organic layer was washed with 5% sodium hydrogencarbonate solution (15ml), water (15ml) and dried over anhydrous sodium sulfate. Suction filtration, reduced pressure evaporation of the solvent, recrystallization with methyl tert-butyl ether-N-hexane system, to obtain 1.13g of compound 6 as a white solid (yield 45.2%), purity 99.3% (gas phase system: Agilent 6890N).
Example 6 preparation of Compound 1
Dissolving compound 3(1.07g, 5.0mmol) in dichloromethane (10ml), adding 75% m-chloroperoxybenzoic acid (mCPBA) (1.17g, 5.1mmol), heating at 45 deg.C under reflux for 24h, detecting the reaction completion in gas phase, washing the reaction solution with saturated sodium bisulfite (5ml), removing m-chlorobenzoic acid with 5% sodium bicarbonate solution, and drying the organic layer with anhydrous sodium sulfate. 1.0g of Compound 1 as a colorless oil of the solvent was distilled off under reduced pressure (yield 87.0%).
Compound 3 is prepared according to The literature Wang P, Chun B-K, Rachakonda S, et al, an Efficient and hydrolytic Synthesis of PSI-6130: A clinical efficacy inhibition of HCV NS5B Polymer [ J ]. The Journal of Organic Chemistry,2009,74(17): 6819-. The gas phase system was Agilent 6890N. Other reagents were purchased from the national pharmaceutical group and used without treatment.
Example 7 preparation of Compound 1
Compound 3(1.07g, 5.0mmol) was dissolved in dichloromethane (10ml), 75% m-chloroperoxybenzoic acid (mCPBA) (1.17g, 5.1mmol) was added and the reaction was carried out at 25 ℃ for 48 hours, the reaction was detected to be almost complete in the gas phase, the reaction solution was washed with saturated sodium hydrogen sulfite (5ml), m-chlorobenzoic acid was removed with 5% aqueous sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate. 0.75g of Compound 1 as a colorless oil of the solvent was distilled off under reduced pressure (yield 65.2%).
Example 8 preparation of Compound 1
Dissolving compound 3(1.07g, 5.0mmol) in toluene (10ml), adding 75% m-chloroperoxybenzoic acid (mCPBA) (1.17g, 5.1mmol), reacting at 90 deg.C for 24h, detecting the reaction completion in gas phase, washing the reaction solution with saturated sodium bisulfite (5ml), removing m-chlorobenzoic acid with 5% sodium bicarbonate aqueous solution, and drying the organic layer with anhydrous sodium sulfate. 0.39g of Compound 1 as a colorless oil of the solvent was distilled off under reduced pressure (yield: 34.2%).
Example 9: preparation of Compound 1
To dichloromethane (20ml) containing compound 4(1.30g, 10mmol) and compound 5(1.81g, 10mmol) was slowly added sodium ethoxide (0.81g, 12mmol) dropwise at-10 deg.C for 15min, the reaction was maintained at-10 deg.C for 6h, the reaction mixture was concentrated to dryness under reduced pressure, extracted with methyl t-butyl ether, and the ether solvent was distilled off under reduced pressure to give compound 1 (0.82 g, 35.6% yield) as a colorless oil.
Example 10: preparation of Compound 1
To dichloromethane (20ml) containing compound 4(1.30g, 10mmol) and compound 5(1.81g, 10mmol) dissolved therein was slowly added sodium ethoxide (0.81g, 12mmol) in dichloromethane (5ml) at 0 ℃ dropwise, after 15min, the reaction was maintained at 0 ℃ for 6h, the reaction mixture was concentrated to dryness under reduced pressure, extracted with methyl t-butyl ether, and the ether solvent was distilled off under reduced pressure to obtain 0.93g of compound 1 as a colorless oil (yield 40.5%).
Example 11: preparation of Compound 1
To dichloromethane (20ml) containing compound 4(1.30g, 10mmol) and compound 5(1.81g, 10mmol) dissolved therein was slowly added sodium ethoxide (0.81g, 12mmol) in dichloromethane (5ml) at 0 ℃ dropwise, after 15min, the reaction was maintained at 15 ℃ for 6h, the reaction mixture was concentrated to dryness under reduced pressure, extracted with methyl t-butyl ether, and the ether solvent was distilled off under reduced pressure to give compound 1, 1.26g of a colorless oil (yield 54.7%).
Example 12: preparation of Compound 1
A solution of sodium ethoxide (0.81g, 12mmol) in dichloromethane (5ml) was slowly added dropwise to dichloromethane (20ml) containing compound 4(1.30g, 10mmol) and compound 5(1.81g, 10mmol) at 0 deg.C, the mixture was refluxed at 45 deg.C for 6 hours after 15min, the reaction mixture was concentrated to dryness under reduced pressure, extracted with methyl t-butyl ether, and the ether solvent was distilled off under reduced pressure to obtain 0.70g of compound 1 as a colorless oil (yield 30.2%).
Claims (20)
1. The preparation method of the sofosbuvir intermediate 6 with low cost and greatly improved yield and purity comprises the following steps: the compound 1 is obtained by nucleophilic fluorine substitution reaction in an aprotic solvent at a proper temperature; the reaction formula is as follows:
wherein, the fluorine substitution reagent selected for the nucleophilic fluorine substitution reaction is HF/Pyridine, and the aprotic solvent used for the reaction is dichloromethane.
2. The method according to claim 1, wherein the fluorine-substituting reagent is used in an amount of 1.1 to 5.0 equivalents based on the compound 1.
3. The method according to claim 2, wherein the fluorine-substituting reagent is used in an amount of 1.1 to 1.5 equivalents based on the compound 1.
4. The method according to claim 1, wherein the reaction temperature is suitably 0 to 70 ℃.
5. The method according to claim 4, wherein the reaction temperature is 15 to 35 ℃.
6. Compound 1 in the preparation process as claimed in claim 1.
7. The process according to claim 1, wherein Compound 1 is prepared by: carrying out epoxidation on a reaction substrate 3 and an epoxidation reagent in an aprotic solvent at a proper temperature to obtain a compound 1, wherein the reaction formula is as follows;
characterized in that the epoxidizing agent is selected from H2O2Peracetic acid, perbenzoic acid, m-chloroperoxybenzoic acid (mCPBA).
8. The method of claim 7, wherein the epoxidizing agent is m-chloroperoxybenzoic acid (mCPBA).
9. The process according to claim 7, wherein the aprotic solvent used in the reaction is methylene chloride.
10. The process according to claim 7, wherein the reaction is carried out at a suitable temperature of 10 to 90 ℃.
11. The method according to claim 10, wherein the reaction is carried out at a suitable temperature of 35 to 45 ℃.
12. The process according to claim 1, wherein Compound 1 is prepared by: compound 4 is reacted with ethyl 2-bromopropionate 5 in the presence of a base in an aprotic solvent at an appropriate temperature by Darzens to give 1, of the formula:
characterized in that the base is selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide and sodium amide.
13. The process according to claim 12, wherein the base is sodium ethoxide.
14. The method according to claim 12, wherein the base is used in an amount of 1 to 5 equivalents based on the compound 4.
15. The method according to claim 14, wherein the base is used in an amount of 1.1 to 1.5 equivalents based on the compound 4.
16. The method according to claim 12, wherein the molar ratio of compound 4 to compound 5 is 1:1 to 1: 10.
17. The method according to claim 16, wherein the molar ratio of compound 4 to compound 5 is 1:1 to 1.2.
18. The process according to claim 12, wherein the aprotic solvent used in the reaction is methylene chloride.
19. The method according to claim 12, wherein the reaction is carried out at a temperature of from-10 to 50 ℃.
20. The method according to claim 19, wherein the reaction is carried out at a suitable temperature of 0 to 25 ℃.
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| CN102933570A (en) * | 2010-06-03 | 2013-02-13 | 中央硝子株式会社 | Method for producing (2r)-2-fluoro-2-c-methyl-d-ribono-y-lactone precursor |
| CN103508918A (en) * | 2012-06-18 | 2014-01-15 | 上海医药工业研究院 | Cyclobutyl-containing alpha-hydroxy-beta-amino ester compound and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102933570A (en) * | 2010-06-03 | 2013-02-13 | 中央硝子株式会社 | Method for producing (2r)-2-fluoro-2-c-methyl-d-ribono-y-lactone precursor |
| CN103508918A (en) * | 2012-06-18 | 2014-01-15 | 上海医药工业研究院 | Cyclobutyl-containing alpha-hydroxy-beta-amino ester compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| Stereo- and Regiocontrolled Synthesis of Fluorohydrins from Optically Active Epoxides;Junko Umezama，等;《Tetrahedron:Assymmetry》;19931231;第4卷(第9期);2053-2060 * |
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