CN101333207A - Preparation method of 1,2-ketal protecting group-1,2,4-butanetriol - Google Patents
Preparation method of 1,2-ketal protecting group-1,2,4-butanetriol Download PDFInfo
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- CN101333207A CN101333207A CNA2007100426752A CN200710042675A CN101333207A CN 101333207 A CN101333207 A CN 101333207A CN A2007100426752 A CNA2007100426752 A CN A2007100426752A CN 200710042675 A CN200710042675 A CN 200710042675A CN 101333207 A CN101333207 A CN 101333207A
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- ketal
- ketal protected
- kbh
- lewis acid
- nabh
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Substances OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 title claims description 13
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002841 Lewis acid Substances 0.000 claims abstract description 11
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims 10
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 abstract description 6
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 239000012279 sodium borohydride Substances 0.000 abstract description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-M 4-hydroxybutyrate Chemical compound OCCCC([O-])=O SJZRECIVHVDYJC-UHFFFAOYSA-M 0.000 abstract 2
- 229960000281 trometamol Drugs 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000010992 reflux Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- ULYONBAOIMCNEH-HNNXBMFYSA-N (3s)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1h-indol-2-one Chemical compound COC1=CC=C(Cl)C=C1[C@@]1(F)C2=CC=C(C(F)(F)F)C=C2NC1=O ULYONBAOIMCNEH-HNNXBMFYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229910010082 LiAlH Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 2
- 229930190515 Madumycin Natural products 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YSEKNCXYRGKTBJ-UHFFFAOYSA-N dimethyl 2-hydroxybutanedioate Chemical compound COC(=O)CC(O)C(=O)OC YSEKNCXYRGKTBJ-UHFFFAOYSA-N 0.000 description 2
- UXWOXTQWVMFRSE-SXTNSRNPSA-N griseoviridin Chemical compound C([C@H](OC1=O)C)\C=C(C(NC/C=C\C=C/[C@@H](O)C[C@@H](O)C2)=O)/SC[C@H]1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-SXTNSRNPSA-N 0.000 description 2
- 108010033580 griseoviridin Proteins 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Classifications
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- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域 technical field
本发明涉及药物合成中间体1，2-缩酮保护基-1，2，4-丁三醇的制备方法。The invention relates to a preparation method of a drug synthesis intermediate 1,2-ketal protecting group-1,2,4-butanetriol.
背景技术 Background technique
1，2-缩酮保护基-1，2，4-丁三醇(I)是许多天然产物全合成中的重要合成子，比如抗菌素灰绿链霉素和马杜霉素(Griseoviridin and Madumycin；J.Org.Chem.，1986，51(26)：5111-5123)、大环内酯类抗肿瘤药海绵素(Spongistatin；Org.Lett.，2003，5(25)：4819-4822)等，文献报道其合成方法按原料划分主要有如下两种：The 1,2-ketal protecting group-1,2,4-butanetriol (I) is an important synthon in the total synthesis of many natural products, such as the antibiotics Griseoviridin and Madumycin (Griseoviridin and Madumycin; J.Org.Chem., 1986, 51(26):5111-5123), macrolide antineoplastic drug spongistatin (Spongistatin; Org.Lett., 2003, 5(25):4819-4822), etc., According to literature reports, its synthetic method mainly contains the following two types according to the raw materials:
一种是以苹果酸为原料经硼烷-二甲硫醚络合物直接还原[TetrahedronLett.，1982，23(47)：4883-4886；J.Org.Chem.，1983，48：4427-4430；Can.J.Chem.1984，62(11)：2146-2147；J.Org.Chem.，1984，49：2834-2837]或由三氟化硼-乙醚与NaBH4预反应制备乙硼烷进行还原[Heterocycles，1986，24(5)：1331-1346]制成1，2，4-丁三醇或以苹果酸二甲酯为原料经LiAlH4[Tetrahedron，1992，48(30)：6325-6334]或LiCl/NaBH4[WO98/08793(1998)]还原制得1，2，4-丁三醇，然后再选择性保护1，2位羟基制得1，2-缩酮产物I。这一选择性保护过程不可避免地产生2，4-缩酮异构体III，且此异构体理化性质与产物非常相近无法通过常规手段直接将其分离除去，只能将羟基衍生化成酯后经过重结晶或柱层析除去2，4-缩酮异构体，再水解制得1，2-缩酮产物纯品I，操作步骤繁琐，缺乏大规模制备应用前景。One is direct reduction of borane-dimethyl sulfide complex [Tetrahedron Lett., 1982, 23 (47): 4883-4886 with malic acid as raw material; J.Org.Chem., 1983, 48: 4427-4430 ; Can.J.Chem.1984,62 (11): 2146-2147; J.Org.Chem., 1984,49:2834-2837] or by boron trifluoride-ether and NaBH pre-reaction diborane Carry out reduction [Heterocycles, 1986,24(5):1331-1346] to make 1,2,4-butanetriol or use dimethyl malate as raw material through LiAlH 4 [Tetrahedron, 1992,48(30):6325 -6334] or LiCl/NaBH 4 [WO98/08793(1998)] reduction to obtain 1,2,4-butanetriol, and then selectively protect the 1,2-position hydroxyl to obtain 1,2-ketal product I. This selective protection process inevitably produces 2,4-ketal isomer III, and the physical and chemical properties of this isomer are very similar to the product and cannot be directly separated and removed by conventional means. The 2,4-ketal isomers are removed by recrystallization or column chromatography, and the pure 1,2-ketal product I is obtained by hydrolysis. The operation steps are cumbersome, and there is no prospect of large-scale preparation.
另一种是以3，4-缩酮保护基-3，4-二羟基丁酸酯(II)为原料[Synthesis，1988：226-228(R1＝R2＝R3＝Me)；J.Org.Chem.，2005，70(12)：4762-4773(R1＝R2＝Me，R3＝Et)；Chem.& Pharm.Bull.，2005，53(2)：207-213(R1＝R2＝Et，R3＝Me)]在四氢呋喃中用LiAlH4将其分子内酯基还原为醇制得1，2-缩酮产物I。相对于第一种合成方法，此法优点在于避免了2，4-缩酮异构体III的产生，但缺点在于采用昂贵的LiAlH4作为还原剂，只能用于实验室小规模制备。The other is based on 3,4-ketal protecting group-3,4-dihydroxybutyrate (II) [Synthesis, 1988: 226-228 (R 1 =R 2 =R 3 =Me); J .Org.Chem., 2005, 70(12): 4762-4773 (R 1 =R 2 =Me, R 3 =Et); Chem. & Pharm.Bull., 2005, 53(2): 207-213 ( R 1 ＝R 2 ＝Et, R 3 ＝Me)] in tetrahydrofuran with LiAlH 4 to reduce its intramolecular ester group to alcohol to obtain 1,2-ketal product I. Compared with the first synthesis method, this method has the advantage of avoiding the production of 2,4-ketal isomer III, but the disadvantage is that it uses expensive LiAlH 4 as a reducing agent, which can only be used for small-scale preparation in the laboratory.
另有专利[WO00/55155(2000)]报道用相对于原料3，4-缩酮保护基-3，4-二羟基丁酸酯(II)的6倍摩尔量的NaBH4于甲醇中还原制得I，此法中还原剂利用率太低，势必造成成本增加、可操作性差，不适于规模化生产。Another patent [WO00/55155 (2000)] reports with respect to raw material 3,4-ketal protecting group-3,4-dihydroxybutyrate (II) 6 times the molar amount of NaBH in methanol Reduction preparation Obtain 1, the reducing agent utilization rate is too low in this method, will certainly cause cost increase, operability is poor, is not suitable for large-scale production.
发明内容 Contents of the invention
本发明需要解决的技术问题是公开一种1，2-缩酮保护基-1，2，4-丁三醇的制备方法，以克服上述现有技术存在的缺陷，提供更有利于规模化生产的合成方法。The technical problem to be solved in the present invention is to disclose a preparation method of 1,2-ketal protecting group-1,2,4-butanetriol, so as to overcome the above-mentioned defects in the prior art and provide a method that is more conducive to large-scale production synthetic method.
本发明的思路是通过下述技术方案来实现的。The idea of the present invention is realized through the following technical solutions.
本发明以3，4-缩酮保护基-3，4-二羟基丁酸酯(II)为原料，在Lewis酸存在下用NaBH4或KBH4进行还原而制得1，2-缩酮保护基-1，2，4-丁三醇(I)。In the present invention, 3,4-ketal protecting group-3,4-dihydroxybutyrate (II) is used as raw material, and NaBH 4 or KBH 4 is used for reduction in the presence of Lewis acid to obtain 1,2-ketal protecting -1,2,4-butanetriol (I).
其中：R1、R2相同或不同，为C1～C6烷基；R3为C1～C6烷基。优选R1＝R2＝Me、Et或-(CH2)5-。Wherein: R 1 and R 2 are the same or different, and are C 1 -C 6 alkyl; R 3 is C 1 -C 6 alkyl. Preferably R 1 =R 2 =Me, Et or -(CH 2 ) 5 -.
其中的Lewis酸包括氯化镁或氯化锂。Among the Lewis acids are magnesium chloride or lithium chloride.
其中的I为(S)-1，2-缩酮保护基-1，2，4-丁三醇或(R)-1，2-缩酮保护基-1，2，4-丁三醇。Wherein I is (S)-1,2-ketal protecting group-1,2,4-butanetriol or (R)-1,2-ketal protecting group-1,2,4-butanetriol.
其中，3，4-缩酮保护基-3，4-二羟基丁酸酯(II)与NaBH4或KBH4的投料摩尔比为1∶0.5～1.5，优选为1∶0.8～1.2；3，4-缩酮保护基-3，4-二羟基丁酸酯(II)与Lewis酸的投料摩尔比为1∶0.5～1.5，优选为1∶0.8～1.2。Wherein, the molar ratio of 3,4-ketal protecting group-3,4-dihydroxybutyrate (II) to NaBH4 or KBH4 is 1:0.5～1.5, preferably 1:0.8～1.2; 3, The molar ratio of 4-ketal protecting group-3,4-dihydroxybutyrate (II) to Lewis acid is 1:0.5-1.5, preferably 1:0.8-1.2.
本发明是在有机溶剂中进行的，适合本发明的有机溶剂选自四氢呋喃、2-甲基四氢呋喃、乙醚、叔丁基甲醚、异丙醚、1，4-二氧六环、二甘醇二甲醚、二甲亚砜、甲苯或上述溶剂的混合物，优选四氢呋喃或其与甲苯的混合溶剂。The present invention is carried out in an organic solvent, and the organic solvent suitable for the present invention is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ether, tert-butyl methyl ether, isopropyl ether, 1,4-dioxane, diglyme Ether, dimethyl sulfoxide, toluene or a mixture of the above solvents, preferably tetrahydrofuran or its mixed solvent with toluene.
适合本发明中的反应温度为25℃～120℃，优选为66℃～100℃，合适的反应时间为2至4小时。The suitable reaction temperature in the present invention is 25°C to 120°C, preferably 66°C to 100°C, and the suitable reaction time is 2 to 4 hours.
在本发明中，溴化镁、溴化锂、碘化锂等Lewis酸也可以使用，但价格不菲，因此优选相对较便宜的氯化锂、氯化镁。Lewis酸可与NaBH4或KBH4形成还原能力较强的复合硼氢化物，从而大大减少了还原剂的用量，只需一倍摩尔量左右的NaBH4或KBH4就可在四氢呋喃等非质子性溶剂中将II还原为I；而专利[WO00/55155(2000)]报道以质子性溶剂甲醇为溶剂用NaBH4还原II为I，使得NaBH4的利用率非常低，以致需要用6倍摩尔量的NaBH4才能反应完全。因此Lewis酸的加入大大减少了还原剂的使用从而使得成本降低。In the present invention, Lewis acids such as magnesium bromide, lithium bromide, and lithium iodide can also be used, but they are expensive, so relatively cheap lithium chloride and magnesium chloride are preferred. Lewis acid can form complex borohydride with NaBH 4 or KBH 4 with strong reducing ability, thus greatly reducing the amount of reducing agent. Only about one times the molar amount of NaBH 4 or KBH 4 can be used in aprotic properties such as tetrahydrofuran. II is reduced to I in the solvent; and the patent [WO00/55155 (2000)] reports that the protic solvent methanol is a solvent with NaBH Reduction of II to I makes the utilization rate of NaBH very low, so that 6 times the molar amount needs to be used NaBH 4 can react completely. Therefore, the addition of Lewis acid greatly reduces the use of reducing agent and thus reduces the cost.
综上所述，与现有技术相比，本发明所用还原剂经济实用、利用率高、安全可靠，适于规模化生产。In summary, compared with the prior art, the reducing agent used in the present invention is economical and practical, has a high utilization rate, is safe and reliable, and is suitable for large-scale production.
具体实施方式 Detailed ways
下面结合实施例对本发明作进一步阐述，但这些实施例不对本发明构成任何限制。The present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention.
实施例1Example 1
在装有电磁搅拌、温度计及回流冷凝管的250ml三颈瓶中依次加入100ml四氢呋喃、3.27g KBH4、5.46g氯化镁、氮气保护下油浴加热回流2小时后滴加入10.0g II，约2分钟滴完，继续回流40分钟后换冰水浴冷至内温5～10℃，小心加入15ml甲醇淬灭反应，过滤反应液，用40ml四氢呋喃与甲醇的混合溶液(10∶1)洗涤滤饼，滤液浓缩至干后加入200ml甲醇溶解所得残余物并再次浓缩至干，用200ml乙酸乙酯溶解所得残余物，经饱和食盐水洗涤、无水MgSO4干燥，减压蒸除溶剂得到7.58g无色透明油状产物(S)-I[R1＝R2＝Me；GC：97.8％；bp：75-76℃/2mmHg；1H-NMR(CDCl3，400MHZ)：1.35(3H，s)，1.42(3H，s)，1.82(2H，m)，2.39(1H，s)，3.58(1H，dd)，3.78(2H，t)，4.08(1H，dd)，4.25(1H，m)；m/z：[m+Na]+169]。Add 100ml tetrahydrofuran, 3.27g KBH 4 , 5.46g magnesium chloride successively into a 250ml three-necked flask equipped with electromagnetic stirring, a thermometer and a reflux condenser, heat and reflux in an oil bath under nitrogen protection for 2 hours, then add 10.0g II dropwise for about 2 minutes After dripping, continue to reflux for 40 minutes, change the ice-water bath to cool to an internal temperature of 5-10°C, carefully add 15ml of methanol to quench the reaction, filter the reaction solution, wash the filter cake with a mixed solution of 40ml of tetrahydrofuran and methanol (10:1), and the filtrate After concentrating to dryness, add 200ml of methanol to dissolve the resulting residue and again concentrate to dryness, dissolve the resulting residue with 200ml of ethyl acetate, wash with saturated brine, dry over anhydrous MgSO4 , evaporate the solvent under reduced pressure to obtain 7.58g colorless and transparent Oily product (S)-I[R 1 =R 2 =Me; GC: 97.8%; bp: 75-76°C/2mmHg; 1 H-NMR (CDCl 3 , 400MH Z ): 1.35 (3H, s), 1.42 (3H,s), 1.82(2H,m), 2.39(1H,s), 3.58(1H,dd), 3.78(2H,t), 4.08(1H,dd), 4.25(1H,m); m/ z: [m+Na] +169 ].
实施例2Example 2
在装有电磁搅拌、温度计及回流冷凝管的250ml三颈瓶中依次加入80ml四氢呋喃、2.61g KBH4、4.37g氯化镁、氮气保护下油浴加热回流2小时后滴加入10.0g(R)-II(R1＝R2＝Me，R3＝Et)，约2分钟滴完，继续回流2小时后换冰水浴冷至内温5～10℃，小心加入10ml甲醇淬灭反应。过滤反应液，用60ml四氢呋喃与甲醇的混合溶液(10∶1)分次洗涤滤饼，滤液浓缩至干后加入50ml甲醇溶解所得残余物并再次浓缩至干，用200ml乙酸乙酯溶解所得残余物，经饱和食盐水洗涤、无水MgSO4干燥，减压蒸除溶剂得到7.31g无色透明油状产物(S)-I(R1＝R2＝Me)。Add 80ml THF, 2.61g KBH 4 , 4.37g Magnesium Chloride successively into a 250ml three-neck flask equipped with electromagnetic stirring, thermometer and reflux condenser, heat and reflux in an oil bath under nitrogen protection for 2 hours, then add 10.0g (R)-II dropwise (R 1 ＝R 2 ＝Me, R 3 ＝Et), drop it in about 2 minutes, continue to reflux for 2 hours, then change to an ice-water bath to cool to an internal temperature of 5-10°C, and carefully add 10ml of methanol to quench the reaction. Filter the reaction solution, wash the filter cake with a mixed solution of 60ml tetrahydrofuran and methanol (10:1), and concentrate the filtrate to dryness, then add 50ml methanol to dissolve the residue and concentrate again to dryness, and dissolve the residue with 200ml ethyl acetate , washed with saturated brine, dried over anhydrous MgSO 4 , and the solvent was evaporated under reduced pressure to obtain 7.31 g of a colorless and transparent oily product (S)-I (R 1 =R 2 =Me).
实施例3Example 3
在装有电磁搅拌、温度计及回流冷凝管的500ml四颈瓶中依次加入150ml四氢呋喃、5.88g KBH4、4.40g氯化锂、15.0g(S)-II(R1＝R2＝R3＝Me)，氮气保护下油浴加热回流3小时后换冰水浴冷至内温5～10℃，小心加入50ml饱和食盐水淬灭反应，用3×200ml乙酸乙酯萃取，有机层合并后经无水MgSO4干燥，减压蒸除溶剂得到11.33g无色透明油状产物(S)-I(R1＝R2＝Me)。Add 150ml tetrahydrofuran, 5.88g KBH 4 , 4.40g lithium chloride, 15.0g (S)-II (R 1 =R 2 =R 3 = Me), heated to reflux in an oil bath under the protection of nitrogen for 3 hours, then changed to an ice-water bath and cooled to an internal temperature of 5-10°C, carefully added 50ml of saturated saline to quench the reaction, extracted with 3×200ml of ethyl acetate, and the organic layers were combined and washed through dry After drying with water MgSO 4 , the solvent was distilled off under reduced pressure to obtain 11.33 g of a colorless and transparent oily product (S)-I (R 1 =R 2 =Me).
实施例4Example 4
在装有电磁搅拌、温度计及回流冷凝管的150ml三颈瓶中依次加入60ml四氢呋喃、1.81g KBH4、2.52g氯化镁、氮气保护下油浴加热回流2小时后滴加入5.0g(R)-II(R1＝R2＝Me，R3＝Et)，约2分钟滴完，继续回流60分钟后换冰水浴冷至内温5～10℃，小心加入10ml甲醇淬灭反应，过滤反应液，用40ml四氢呋喃与甲醇的混合溶液(10∶1)分次洗涤滤饼，滤液浓缩至干后加入30ml甲醇溶解所得残余物并再次浓缩至干，用100ml乙酸乙酯溶解所得残余物，经饱和食盐水洗涤、无水MgSO4干燥，减压蒸除溶剂得到3.65g无色透明油状产物(R)-I[R1＝R2＝Me；GC：97.1％；1H-NMR(CDCl3，400MHZ)：1.36(3H，s)，1.43(3H，s)，1.83(2H，m)，2.40(1H，s)，3.59(1H，dd)，3.78(2H，t)，4.09(1H，dd)，4.25(1H，m)]。Add 60ml tetrahydrofuran, 1.81g KBH 4 , 2.52g magnesium chloride in sequence to a 150ml three-necked flask equipped with electromagnetic stirring, a thermometer and a reflux condenser, heat and reflux in an oil bath under nitrogen protection for 2 hours, then add 5.0g (R)-II dropwise (R 1 ＝R 2 ＝Me, R 3 ＝Et), after about 2 minutes, continue to reflux for 60 minutes, then change to an ice-water bath to cool to an internal temperature of 5-10°C, carefully add 10ml of methanol to quench the reaction, filter the reaction solution, Wash the filter cake with a mixed solution of 40ml tetrahydrofuran and methanol (10:1), concentrate the filtrate to dryness, add 30ml methanol to dissolve the residue and concentrate to dryness again, dissolve the residue with 100ml ethyl acetate, wash with saturated salt Washed with water, dried over anhydrous MgSO 4 , evaporated the solvent under reduced pressure to obtain 3.65 g of colorless and transparent oily product (R)-I[R 1 =R 2 =Me; GC: 97.1%; 1 H-NMR (CDCl 3 , 400MH Z ): 1.36(3H,s), 1.43(3H,s), 1.83(2H,m), 2.40(1H,s), 3.59(1H,dd), 3.78(2H,t), 4.09(1H,dd ), 4.25(1H, m)].
实施例5Example 5
在装有机械搅拌、温度计及回流冷凝管的1L四颈瓶中依次加入500ml四氢呋喃、14.07g KBH4、23.51g氯化镁，氮气保护下油浴加热回流2小时后滴加入50.0g(S)-II(R1＝R2＝Et，R3＝Me)，约5分钟滴完，继续回流60分钟后换冰水浴冷至内温5～10℃，小心加入30ml甲醇淬灭反应，过滤反应液，用200ml四氢呋喃与甲醇的混合溶液(10∶1)分次洗涤滤饼，滤液浓缩至干后加入200ml甲醇溶解所得残余物并再次浓缩至干，用600ml乙酸乙酯溶解所得残余物，经饱和食盐水洗涤、无水MgSO4干燥，减压蒸除溶剂得到39.62g无色透明油状产物(S)-I[R1＝R2＝Et；GC：96.2％；bp：90-91℃/2mmHg；1H-NMR(CDCl3，400MHZ)：0.86(6H，m)，1.60(4H，m)，1.78(2H，m)，2.39(1H，s)，3.50(1H，dd)，3.74(2H，t)，4.06(1H，dd)，4.20(1H，m)]。Add 500ml tetrahydrofuran, 14.07g KBH 4 , and 23.51g magnesium chloride successively into a 1L four-necked flask equipped with mechanical stirring, a thermometer and a reflux condenser, heat and reflux in an oil bath under nitrogen protection for 2 hours, then add 50.0g (S)-II dropwise (R 1 ＝R 2 ＝Et, R 3 ＝Me), drop it in about 5 minutes, continue to reflux for 60 minutes, then change to an ice-water bath to cool to an internal temperature of 5-10°C, carefully add 30ml of methanol to quench the reaction, filter the reaction solution, Wash the filter cake with a mixed solution of 200ml tetrahydrofuran and methanol (10:1), concentrate the filtrate to dryness, add 200ml methanol to dissolve the residue and concentrate again to dryness, dissolve the residue with 600ml ethyl acetate, wash with saturated salt Washed with water, dried over anhydrous MgSO 4 , evaporated the solvent under reduced pressure to obtain 39.62g colorless and transparent oily product (S)-I [R 1 =R 2 =Et; GC: 96.2%; bp: 90-91°C/2mmHg; 1 H-NMR (CDCl 3 , 400MH Z ): 0.86 (6H, m), 1.60 (4H, m), 1.78 (2H, m), 2.39 (1H, s), 3.50 (1H, dd), 3.74 (2H , t), 4.06 (1H, dd), 4.20 (1H, m)].
实施例6Example 6
在装有电磁搅拌、温度计及回流冷凝管的500ml四颈瓶中依次加入150ml四氢呋喃、7.35g KBH4、5.50g氯化锂、15.0g(S)-II(R1＝R2＝R3＝Me)，氮气保护下油浴加热回流0.5小时后加入100ml干燥甲苯继续回流2h，换冰水浴冷至内温5～10℃，小心加入50ml饱和食盐水淬灭反应，用3×200ml乙酸乙酯萃取，有机层合并后经无水MgSO4干燥，减压蒸除溶剂后经减压蒸馏得到7.68g无色透明油状产物(S)-I(R1＝R2＝Me)。Add 150ml tetrahydrofuran, 7.35g KBH 4 , 5.50g lithium chloride, 15.0g (S)-II (R 1 =R 2 =R 3 = Me), heated to reflux in an oil bath under the protection of nitrogen for 0.5 hours, then added 100ml of dry toluene and continued to reflux for 2h, changed to an ice-water bath to cool to an internal temperature of 5-10°C, carefully added 50ml of saturated saline to quench the reaction, and used 3×200ml of ethyl acetate After extraction, the organic layers were combined and dried over anhydrous MgSO 4 . After the solvent was evaporated under reduced pressure, 7.68 g of a colorless and transparent oily product (S)-I (R 1 =R 2 =Me) was obtained by distillation under reduced pressure.
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