CN111056918A - 一种(s)-1,2,4-丁三醇的制备方法 - Google Patents
一种(s)-1,2,4-丁三醇的制备方法 Download PDFInfo
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- ARXKVVRQIIOZGF-BYPYZUCNSA-N 2-deoxyerythritol Chemical compound OCC[C@H](O)CO ARXKVVRQIIOZGF-BYPYZUCNSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 16
- -1 magnesium halide Grignard reagent Chemical class 0.000 claims abstract description 25
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 15
- OQRYLHKBIBPOHV-SFHVURJKSA-N (2s)-1,4-bis(phenylmethoxy)butan-2-ol Chemical compound C([C@H](O)COCC=1C=CC=CC=1)COCC1=CC=CC=C1 OQRYLHKBIBPOHV-SFHVURJKSA-N 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- QNYBOILAKBSWFG-SNVBAGLBSA-N (2s)-2-(phenylmethoxymethyl)oxirane Chemical compound C([C@H]1OC1)OCC1=CC=CC=C1 QNYBOILAKBSWFG-SNVBAGLBSA-N 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000011777 magnesium Substances 0.000 abstract description 3
- 229910052749 magnesium Inorganic materials 0.000 abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
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- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FUDDLSHBRSNCBV-UHFFFAOYSA-N (+)-(R)-3-hydroxytetrahydrofuranone Natural products OC1COC(=O)C1 FUDDLSHBRSNCBV-UHFFFAOYSA-N 0.000 description 3
- FUDDLSHBRSNCBV-VKHMYHEASA-N (4s)-4-hydroxyoxolan-2-one Chemical compound O[C@@H]1COC(=O)C1 FUDDLSHBRSNCBV-VKHMYHEASA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N L-(-)-Malic acid Natural products OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 229940116298 l- malic acid Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 description 2
- NNDIXBJHNLFJJP-UHFFFAOYSA-N 20-Hydroxyeicosatetraenoic acid Chemical compound OCCCCCC=CCC=CCC=CCC=CCCCC(O)=O NNDIXBJHNLFJJP-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229960001830 amprenavir Drugs 0.000 description 2
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- QAWLNTIPTFOWKZ-UHFFFAOYSA-N bromomethoxymethylbenzene Chemical compound BrCOCC1=CC=CC=C1 QAWLNTIPTFOWKZ-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
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- 231100000086 high toxicity Toxicity 0.000 description 2
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- 239000011630 iodine Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 3,4-dihydroxybutyric acid Chemical compound OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229940122440 HIV protease inhibitor Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- 239000003529 anticholesteremic agent Substances 0.000 description 1
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- 238000009835 boiling Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
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- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N lithium oxide Chemical compound [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
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- 229930014626 natural product Natural products 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
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- 239000002341 toxic gas Substances 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/02—Magnesium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种(S)‑1,2,4‑丁三醇的制备方法,包括:将(S)‑苄氧甲基环氧乙烷与苄基卤甲醚的卤化镁格式试剂反应,得到(S)‑1,4‑二苄氧基‑2‑丁醇;然后在钯碳催化剂作用下,氢化脱去苄基保护基得到最终产品。本发明合成路线短、三废少,适合工业化生产。
Description
技术领域
本发明属于化合物合成领域,特别涉及一种(S)-1,2,4-丁三醇的制备方法。
背景技术
(S)-1,2,4-丁三醇是一种重要的医药中间体,其衍生物是许多天然产物合成中的重要手性合成砌块,如以(S)-1,2,4-丁三醇为原料关环合成(S)-3-羟基四氢呋喃等。
(S)-l,2,4-丁三醇作为关鍵中间体可以制备降胆固醇药物Movinolin[吉林农业大学学报,20,92-98(1998)]抗癌药物coapatin[生命的化学,14,32-34(1994)]治疗皮肤病药羟基二十碳四烯酸(12-HETE)[中华血液学杂志,15,145-146(1996):天津药学,12,29-30(2000)]。同时(S)-1,2,4-丁三醇经环合后生成的(S)-3-羟基四氢呋喃为艾滋病药物安普那韦(Agenerase;HIV蛋白酵抑制剂)的基本中间体[J.Am.Chem.Soc.,117,1181(1995);国际专利公开3094/05,639]。在制备这些手性化合物中,光学纯度是重要的因素。
目前制备(S)-1,2,4-丁三醇的常规方法主要有以下五种:
第一种是以L-苹果酸二酯为原料,以四氢铝锂(LiAlH)为还原剂进行还原反应制备(S)-l,2,4-丁三醇[J.Org.Chem,48,2767-2769(1983)]。该方法存在明显不足,即所用还原剂较为昂贵,无任何商业价值,只能用于实验室制备。
第二种是以硼烷-二甲硫醚为还原体系,直接还原苹果酸二酯制备(S)-l,2,4-丁三醇[Asymmetry,2,191-194(1991)],但硼烷-二甲硫体系需要特殊的设备和无水无氧操作环境,该法所用原料硼烷毒性大,二甲硫醚也是有毒气体,整个还原体系成本高,也难于工业生产,反应式如下:
第三种是以L-苹果酸二酯为原料,以硼氢化钠与无水氯化锂原位生成硼氢化锂(LiBH4)为还原剂进行还原反应制备(S)-l,2,4-丁三醇[USP5,808,107],该方法不足之处在于还原不完全。反应混合物中含有部分还原的副产物3,4-二羟基丁酸酯,难于分离。该方法所得产品为粗品,未给出(S)-l,2,4-丁三醇含量及光学纯度等任何物理测试数据,反应式如下:
第四种是以L-酒石酸为原始原料,经过环磷酸酯还原等四步反应,来制备(R)-l,2,4-丁三醇[有机化学,22,501—503(2002)].若改以D-酒石酸为原料,即可得(S)-l,2,4-丁三醇。但该法步骤较多,且操作繁琐,同样也还用到四氢铝锂(LiAlH4)等高昂的还原剂,因此难于工业化生产,反应式如下:
第五种是以(S)-3-羟基-γ-丁内酯为原料,用硼氢化钠作为还原剂,在醇类或醚类有机溶剂中直接还原,制得(S)-1,2,4-丁三醇(中国专利公开号:CN1066736A)。反应式如下:
因此,以L-苹果酸二酯为原料进行还原可采用不同的还原试剂,但由于四氢铝锂法价格昂贵,硼氢化钠直接还原酸类又相当困难,而且氧化锂法还原不完全,有部分还原的副产物,与产品难于分离,硼烷-二甲硫醚还原体系对反应设备则有特殊要求且毒性较大:D-酒石酸二酯法步骤冗长,也避不开使用四氢铝锂,成本较高,难于工业化生产。同时还原L-苹果酸二甲酯的过程中,会产生大量的硼酸钠盐或其他无机盐。这些盐包裹在粘稠的产物(S)-1,2,4-丁三醇中,使得蒸馏产品非常困难。由于产品沸点高150℃(0.04mm Hg),蒸馏过程容易夹带部分无机盐,造成产品质量不合格。工业化大批量生产极为困难。
用硼氢化钠还原(S)-3-羟基-γ-丁内酯制备(S)-1,2,4-丁三醇同样存在上述问题。并且原料(S)-3-羟基-γ-丁内酯为原料价格昂贵,不易得到。
发明内容
本发明所要解决的技术问题是提供一种(S)-1,2,4-丁三醇的制备方法,该方法合成路线短、三废少,适合工业化生产。
本发明提供了一种(S)-1,2,4-丁三醇的制备方法,包括:
(1)将(S)-苄氧甲基环氧乙烷溶于有机溶剂中,按摩尔比1:1-1:1.5(优选1:1.05-1:1.3)加入苄基卤甲醚卤化镁格式试剂,在-40--30℃下反应2~3h,得到(S)-1,4-二苄氧基-2-丁醇;
(2)(S)-1,4-二苄氧基-2-丁醇在钯碳催化剂作用下,氢化脱去苄基得到(S)-1,2,4-丁三醇。
所述步骤(1)中的有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚中的一种或几种。
所述步骤(1)中的苄基卤甲醚卤化镁格式试剂为苄基氯甲醚氯化镁格式试剂或苄基溴甲醚溴化镁格式试剂。
所述步骤(2)中的氢化反应条件为:以甲醇或乙醇为溶剂,采用10%的Pd/C,氢气压力为0.3-5MPa,优选1.0MPa-3.0MPa,反应温度为50-60℃,反应时间为20-24h。
本发明的反应方程式如下:
(1)
(2)
有益效果
(1)本发明合成反应温和,避免了现有技术反应危险性高、环保压力大的缺点;
(2)本发明工艺副反应少,合成收率高,产品质量好,便于纯化;
(3)本发明简单实用,原材料易得、价格低廉,适用于工业化批量生产。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(1)苄基氯甲醚氯化镁格式试剂的制备
配制苄基氯甲醚(195.8g,1.25mol)与四氢呋喃500mL的混合液,备用。
反应瓶中投入四氢呋喃300mL,氮气保护下依次加入镁条29.16g(1.2mol),一粒碘,滴加20mL上述配制好的苄基氯甲醚四氢呋喃溶液。缓慢加热至回流。当反应夜色变浅褪去,滴加剩余的苄基氯甲醚四氢呋喃溶液。滴毕,继续保温回流反应2小时。冷却至室温,得到的苄基氯甲醚氯化镁格式试剂,氮气保护备用。
(2)(S)-1,4-二苄氧基-2-丁醇的制备
将(S)-苄氧甲基环氧乙烷(164.2g,1mol)与无水四氢呋喃500mL搅拌混合,冷却至-40℃,滴加上述制备的苄基氯甲醚氯化镁格式试剂。反应放热。控制滴加速度使反应温度不高于-30℃。滴毕,保温反应2小时。关闭冷冻,自然升温至室温。然后滴加400克的饱和氯化铵水溶液。室温搅拌1小时,反应液用二氯甲烷萃取,每次用500mL,萃取3次。合并有机相,无水硫酸钠干燥,过滤,滤液浓缩除去溶剂,高真空蒸馏得到淡黄色液体206.36g(S)-1,4-二苄氧基-2-丁醇,纯度98.26%,收率72.13%。
(3)(S)-1,2,4-丁三醇的制备
在3000毫升的高压反应釜中,投入步骤(1)得到的(S)-1,4-二苄氧基-2-丁醇(143.2g,0.5mol),乙醇800mL搅拌混合,加入10%钯碳催化剂。密闭,通入氮气置换空气,然后通入氢气置换氮气。加热、加压至60℃,3.0MPa。保温、保压反应20小时。降温至室温,通入氮气置换氢气后。打开反应釜,反应液过滤除去催化剂。减压浓缩除去乙醇至干。高真空蒸馏产品,得无色油状物51.6克,纯度98.86%,收率97.35%。
1HNMR(400MHz,DO2):δ1.63(m,2H,CH2),3.30(m,1H,CH),3.53(m,2H,CH2),3.68(m,2H,CH2)。
实施例2
(1)苄基溴甲醚溴化镁格式试剂的制备
配制苄基溴甲醚(221.5g,1.1mol)与甲基叔丁基醚600mL的混合液,备用。
反应瓶中投入四氢呋喃300mL,氮气保护下依次加入镁条26.76g(1.1mol),一粒碘,滴加20mL上述配制好的苄基溴甲醚甲基叔丁基醚溶液。缓慢加热至回流。当反应夜色变浅褪去,滴加剩余的苄基溴甲醚与甲基叔丁基醚的混合溶液。滴毕,继续保温回流反应3小时。冷却至室温,得到的苄基溴甲醚溴化镁格式试剂,氮气保护备用。
(2)(S)-1,4-二苄氧基-2-丁醇的制备
将(S)-苄氧甲基环氧乙烷(164.2g,1mol)与甲基叔丁基醚600mL搅拌混合,冷却至-50℃,滴加上述制备的苄基溴甲醚溴化镁格式试剂。反应放热。控制滴加速度使反应温度不高于-40℃。滴毕,保温反应1.5小时。关闭冷冻,自然升温至室温。然后加600克的饱和氯化铵水溶液。室温搅拌1小时,静止分层,反应液用500mL甲基叔丁基醚萃取一次。合并有机相,无水硫酸钠干燥,过滤,滤液浓缩除去溶剂,高真空蒸馏得到淡黄色液体213.52g(S)-1,4-二苄氧基-2-丁醇,纯度98.32%,收率74.66%。
(3)(S)-1,2,4-丁三醇的制备
在3000毫升的高压反应釜中,投入步骤(1)得到的(S)-1,4-二苄氧基-2-丁醇(143.2g,0.5mol),乙醇800mL搅拌混合,加入10%钯碳催化剂。密闭,通入氮气置换空气,然后通入氢气置换氮气。加热、加压至60℃,2.50MPa。保温、保压反应30小时。降温至室温,通入氮气置换氢气后。打开反应釜,反应液过滤除去催化剂。减压浓缩除去乙醇至干。高真空蒸馏产品,得无色油状物52.1克,纯度98.86%,收率98.30%。
Claims (4)
1.一种(S)-1,2,4-丁三醇的制备方法,包括:
(1)将(S)-苄氧甲基环氧乙烷溶于有机溶剂中,按摩尔比1:1-1:1.5加入苄基卤甲醚卤化镁格式试剂,在-40--30℃下反应2~3h,得到(S)-1,4-二苄氧基-2-丁醇;
(2)(S)-1,4-二苄氧基-2-丁醇在钯碳催化剂作用下,氢化脱去苄基得到(S)-1,2,4-丁三醇。
2.根据权利要求1所述的制备方法,其特征在于:所述步骤(1)中的有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙醚、甲基叔丁基醚中的一种或几种。
3.根据权利要求1所述的制备方法,其特征在于:所述步骤(1)中的苄基卤甲醚卤化镁格式试剂为苄基氯甲醚氯化镁格式试剂或苄基溴甲醚溴化镁格式试剂。
4.根据权利要求1所述的制备方法,其特征在于:所述步骤(2)中的氢化反应条件为:以甲醇或乙醇为溶剂,采用10%的Pd/C,氢气压力为0.3-5MPa,反应温度为50-60℃,反应时间为20-24h。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6355848B1 (en) * | 1998-01-31 | 2002-03-12 | Bayer Aktiengesellschaft | Method for producing optically active alcohols |
US6620977B1 (en) * | 1998-01-30 | 2003-09-16 | Daiso Co., Ltd. | Process for producing butanetriol derivative |
WO2003106392A1 (ja) * | 2002-06-14 | 2003-12-24 | ダイソー株式会社 | 1,2,4−ブタントリオールの製造方法 |
KR20050064889A (ko) * | 2003-12-24 | 2005-06-29 | 에스케이 주식회사 | 1,2,4-부탄트리올의 연속 제조방법 |
CN1660736A (zh) * | 2004-12-30 | 2005-08-31 | 东南大学 | 光学纯(s)-1,2,4-丁三醇的制备方法 |
CN101817851A (zh) * | 2009-07-03 | 2010-09-01 | 南京理工大学 | 一种由糖酸内酯出发合成稀有己酮糖和庚酮糖的方法 |
CN102924540A (zh) * | 2012-10-22 | 2013-02-13 | 山东鲁抗舍里乐药业有限公司 | 一种2-脱氧-d-葡萄糖的制备方法 |
CN107955044A (zh) * | 2017-11-13 | 2018-04-24 | 天津现代职业技术学院 | 一种2-脱氧-d-葡萄糖的制备方法 |
CN109503523A (zh) * | 2018-12-28 | 2019-03-22 | 南京天越星生物技术有限公司 | 一种s-(+)-3-羟基四氢呋喃的化学合成方法 |
-
2019
- 2019-12-23 CN CN201911336921.4A patent/CN111056918B/zh active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620977B1 (en) * | 1998-01-30 | 2003-09-16 | Daiso Co., Ltd. | Process for producing butanetriol derivative |
US6355848B1 (en) * | 1998-01-31 | 2002-03-12 | Bayer Aktiengesellschaft | Method for producing optically active alcohols |
WO2003106392A1 (ja) * | 2002-06-14 | 2003-12-24 | ダイソー株式会社 | 1,2,4−ブタントリオールの製造方法 |
KR20050064889A (ko) * | 2003-12-24 | 2005-06-29 | 에스케이 주식회사 | 1,2,4-부탄트리올의 연속 제조방법 |
CN1660736A (zh) * | 2004-12-30 | 2005-08-31 | 东南大学 | 光学纯(s)-1,2,4-丁三醇的制备方法 |
CN101817851A (zh) * | 2009-07-03 | 2010-09-01 | 南京理工大学 | 一种由糖酸内酯出发合成稀有己酮糖和庚酮糖的方法 |
CN102924540A (zh) * | 2012-10-22 | 2013-02-13 | 山东鲁抗舍里乐药业有限公司 | 一种2-脱氧-d-葡萄糖的制备方法 |
CN107955044A (zh) * | 2017-11-13 | 2018-04-24 | 天津现代职业技术学院 | 一种2-脱氧-d-葡萄糖的制备方法 |
CN109503523A (zh) * | 2018-12-28 | 2019-03-22 | 南京天越星生物技术有限公司 | 一种s-(+)-3-羟基四氢呋喃的化学合成方法 |
Non-Patent Citations (8)
Title |
---|
BYUNGSOOK KIM等: "Concise Substrate-controlled Asymmmetric Total Synthesis of (+)-3-(Z)-Dihydrorhodophytin", 《HETEROCYCLES》 * |
HIROYA KAN-NO等: "Synthesis of a Dihydropyranonucleoside Using an Oxidative Glycosylation Reaction Mediated by Hypervalent Iodine", 《SYNTHESIS》 * |
JOHN MANN等: "Two synthetic routes to 2,,3,,-dideoxy-3,-C-(hydroxymethyl)-4,-thionucleosides", 《J.CHEM.SOC.PERKIN TRANS 1》 * |
K.C.NICOLAOU等: "Total Synthesis of Ionophore Antibiotic X-14547A", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
KRZYSZTOF JAROWICKI等: "Synthesis of the C16-C23 Effector Domain of FK-506 via Copper-Catalysed Metallate Rearrangement of an α-Alkoxyalkenylcuprate", 《SYNTHESIS》 * |
孙小玲等: "重要手性合成砌块R-丁三醇的合成及纯化", 《有机化学》 * |
杨萌等: "D-1,2,4-丁三醇的绿色合成", 《生命科学仪器》 * |
蔡征宇等: "(S)-3-羟基-γ-丁内酯一步法合成(S)-1,2,4-丁三醇的研究", 《合肥工业大学学报(自然科学版)》 * |
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