CN105315248A - Tetrahydropyranol series chiral compound, synthesis method therefor and use of tetrahydropyranol series chiral compound - Google Patents

Tetrahydropyranol series chiral compound, synthesis method therefor and use of tetrahydropyranol series chiral compound Download PDF

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CN105315248A
CN105315248A CN201410415790.XA CN201410415790A CN105315248A CN 105315248 A CN105315248 A CN 105315248A CN 201410415790 A CN201410415790 A CN 201410415790A CN 105315248 A CN105315248 A CN 105315248A
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compound
hydrate
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alkyl
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CN105315248B (en
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彭成
韩波
谢欣
黄维
李想
杨磊
冷海军
王彪
赵倩
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Sichuan Zhongke Kim Ji Medical Technology Co ltd
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Chengdu University of Traditional Chinese Medicine
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Abstract

The invention provides a compound represented by a formula 5 shown in the description or pharmaceutically acceptable salts, hydrates or crystal forms thereof, wherein R1 is selected from a benzene ring, a substituted benzene ring or a five-membered or six-membered heterocyclic ring, R2 is selected from C1-C4 alkyl, and R3 is selected from H or C1-C4 alkyl. The invention also provides a synthesis method for a tetrahydropyranol series chiral compound. According to the method, the tetrahydropyranol series chiral compound is synthesized by employing MBH reaction, the control on continuous four chiral centers is realized through a micromolecular chiral catalyst, the operation is simple and convenient, the purity of the obtained chiral compound is high, and a novel choice is provided for the chiral synthesis of related compounds.

Description

A kind of tetrahydropyrans alcohol Series of Chiral compound and preparation method and use thereof
Technical field
The present invention relates to a kind of tetrahydropyrans alcohol Series of Chiral compound and preparation method and use thereof.
Background technology
Chirality tetrahydropyrans alcohol structure is the core skeleton of a lot of medicine.Chirality factor biology, chemistry and other multi-field in all there is extremely important influence power.Along with organic chemistry and biochemical development, the Chiral properties of compound has started to be subject to increasing attention.Numerous research shows, different optical isomers may have distinct physiologically active, transporting mechanism, metabolic rate and toxicity, is also not quite similar in absorption, distribution and excretion.
Summary of the invention
The object of the present invention is to provide a kind of tetrahydropyrans alcohol Series of Chiral compound and one-tenth method and purposes.
Particularly, the invention provides compound as shown in Equation 5 or its pharmacy acceptable salt, hydrate or crystal formation,
R1 is selected from phenyl ring, substituted benzene ring or five yuan or hexa-member heterocycle, and R2 is selected from C1-C4 alkyl, and R3 is selected from H or C1-C4 alkyl.
Further, described structural formula of compound is as follows:
Wherein, substituent R 4 quantity is 1 ~ 3, is independently selected from halogen or nitro.
Further, described halogen is selected from F, Cl or Br.
Further, substituent R 4 quantity is 1 or 2.
Further, described C1-C4 alkyl is selected from methyl or ethyl, is preferably ethyl.
Preferably, described structural formula of compound is one of following:
Present invention also offers the synthetic method of compound 5, reaction path is as follows:
Rac-3 is racemic modification;
R1 is selected from phenyl ring, substituted benzene ring or five yuan or hexa-member heterocycle, and R2 is selected from C1-C4 alkyl, and R3 is selected from H or C1-C4 alkyl.
(S)-3 is an optical isomer in Rac-3.
Further, the substituting group of described substituted-phenyl is selected from halogen or nitro, and substituting group quantity is 1 ~ 3.
Further, described halogen is selected from F, Cl or Br.
Further, substituting group quantity is 1 or 2.
Further, described C1-C4 alkyl is selected from methyl or ethyl.
Further, concrete operation step is as follows:
Nitroolefin 1 and carbonyl compound 2 are under DMAP exists, and make solvent with MeCN, stirring at room temperature obtains MBH adduct rac-3; Then one kettle way adds aldehyde 4, catalyzer and Glacial acetic acid; Reaction is at room temperature carried out, and with TLC monitoring to reacting end, concentrated and silica gel column chromatography (PE/EA=10:1) is successively separated and obtains MBH product (S)-3 and chirality tetrahydropyrans alcohol product 5; Described catalyzer is selected from N, N-diphenylprolinol silicon ether, L-dried meat ammonia alcohol or L-PROLINE.
MBH and Belize-Harry Hillman reaction.
Further, nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: Glacial acetic acid=0.5-1.0mmol:1.0mmol:0.05-0.2mmol:1.0-2.0mmol:0.1-0.3mmol: 0.1-0.2mmol.
Preferably, nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: Glacial acetic acid=0.5mmol:1.0mmol:0.05mmol:1.0mmol:0.1mmol:0.1mmol.
Present invention also offers above-claimed cpd or its pharmacy acceptable salt, hydrate or the crystal formation purposes in preparation antibacterium or anti-tumor drug.
Further, described bacterium is intestinal bacteria, Acinetobacter lwoffii, Pseudomonas Maltophilia, moraxelle catarrhalis, streptococcus aureus or staphylococcus epidermidis.
Further, described tumour is lung cancer, prostate cancer, adenocarcinoma of lung or leukemia.
In the present invention, described pharmacy acceptable salt can be selected from the hydrochloride of described compound, hydrobromate, hydrofluoride, vitriol, nitrate, phosphoric acid salt, formate, acetate, propionic salt, oxalate, malonate, succinate, fumarate, maleate, lactic acid salt, malate, tartrate, Citrate trianion, picrate, mesylate, esilate, benzene sulfonate, aspartate or glutaminate.
In one embodiment of the present invention, further comprises isotope-labeled above-claimed cpd or its pharmacy acceptable salt, described compound isotopically labelled refers to listed Compound Phase is same herein, but one or more atom is replaced by another atom, the atomic mass of this atom or total mass number are different from the common atomic mass of occurring in nature or total mass number.The isotropic substance can introduced in compound comprises hydrogen, carbon, nitrogen, oxygen, sulphur, i.e. 2H, 3H, 13C, 14C, 15N, 17O, 18O, 35S.Compound containing above-mentioned isotropic substance and/or other atom isotope and steric isomer thereof, and this compound, steric isomer pharmaceutically useful salt all should be included within the scope of the invention.
Medicine of the present invention can also comprise pharmaceutically acceptable auxiliary material or complementary composition.
Pharmaceutically acceptable auxiliary material of the present invention, refer to the material be included in addition to the active ingredient (s in formulation, include but are not limited to weighting agent (thinner), lubricant (glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, disintegrating agent etc.Tackiness agent comprises syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, cellulose and its derivates (as Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose or HPMC etc.), gelatine size, syrup, starch slurry or polyvinylpyrrolidone etc.; Weighting agent comprises lactose, Icing Sugar, dextrin, starch and derivative thereof, cellulose and its derivates, inorganic calcium salt (as calcium sulfate, calcium phosphate, secondary calcium phosphate, precipitated calcium carbonate etc.), sorbyl alcohol or glycine etc.; Lubricant comprises micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyoxyethylene glycol etc.; Disintegrating agent comprises starch and derivative (as sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch, W-Gum etc.), polyvinylpyrrolidone or Microcrystalline Cellulose etc.; Wetting agent comprises sodium lauryl sulphate, water or alcohol etc.; Antioxidant packages is containing S-WAT, sodium bisulfite, Sodium Pyrosulfite, dibutyl benzoic acid etc.; Fungistat comprises 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol etc.; Conditioning agent comprises hydrochloric acid, Citric Acid, potassium hydroxide (sodium), Sodium Citrate and buffer reagent (comprising phosphoric acid dioxy sodium and Sodium phosphate dibasic) etc.; Emulsifier package containing Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, fabaceous lecithin etc.; Solubilizing agent comprises tween-80, bile, glycerine etc.
Described pharmaceutically acceptable complementary composition, it has certain physiologically active, but adding of this composition can not change above-claimed cpd or the dominant position of derivative in treatment of diseases, and only play auxiliary effect, these auxiliary effects are only the utilizations to this composition known activity, are the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary composition and the compounds of this invention with the use of, still should belong to the scope of protection of the invention.
Tetrahydropyrans alcohol Series of Chiral compound provided by the invention, has good antibacterial and anti-tumor activity, for clinical application provides new selection.The present invention adopts MBH Reactive Synthesis tetrahydropyrans alcohol Series of Chiral compound, and the control of continuous four chiral centres is achieved by small molecules chiral catalyst, it is easy and simple to handle, and gained chipal compounds purity is high, and the chiral synthesize for related compound provides new selection.
Embodiment
Embodiment Chiral Synthesis of the present invention
Nitroolefin 1 (0.5mmol) and the activated carbonyl compound 2 (1.0mmol) of tool are under the existence of DMAP (6.1mg, 0.05mmol), and make solvent with MeCN, stirring at room temperature 30min obtains MBH adduct rac-3.Then one kettle way adds aldehyde 4 (1.0mmol), N, N-diphenylprolinol silicon ether (32.5mg, 0.1mmol) and Glacial acetic acid (6.0mg, 0.1mmol).Reaction is at room temperature carried out, and monitors reaction process with TLC.Concentrated and silica gel column chromatography (PE/EA=10:1) is successively separated and obtains MBH product (S)-3 and chirality tetrahydropyrans alcohol product 5.
The group of R1 ~ R3 described in reaction formula, all selects according to 5a ~ 5j compound structure, and gained compound is as follows:
-98.4 (c=0.10inCH 2cl 2); Hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.38-7.29 (m, 3H), 7.19 (d, J=7.6Hz, 2H), 5.35 (d, J=4.8Hz, 1H), 5.18 (dd, J=9.6Hz, J=6.0Hz, 1H), 5.07 (d, J=5.6Hz, 1H), 4.26-4.20 (m, 2H), 4.03 (brs, 1H), 3.16 (t, J=11.6Hz, 1H), 1.97-1.94 (m, 1H), (1.24 t, J=7.2Hz, 3H), 0.86 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.95,137.63,129.11,128.07,128.00,98.15,89.72,69.35,62.29,48.19,39.32,15.50,13.85ppm; ESIHRMS: calculated value C 15h 19nO 6+ Na332.1110, measured value 332.1112.
mL/min), UV254nm, t minor=13.97min, t major=17.28min. optically-active: [α] d 20+ 108.4 (c=0.21inCH 2cl 2).
hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.41 (d, J=7.6Hz, 1H), 7.31-7.19 (m, 3H), 5.30 (brs, 2H), 5.10 (d, J=4.8Hz, 1H), 4.34 (brs, 1H), 4.30-4.23 (m, 2H), 2.12-2.05 (m, 1H), (1.25 t, J=6.8Hz, 3H), 0.88 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.89,130.43,130.26,129.13,128.32,127.67,127.40,98.39,95.33,83.64,69.98,68.89,62.38,15.08,13.88ppm; ESIHRMS:calcd.ForC 15h 18clNO 6+ Na366.0720, measured value 366.0716.
2-propanol/n-hexane, 1mL/min), UV220nm, t minor=13.24min, t major=14.23min. optically-active: [α] d 20+ 86.2 (c=0.11inCH 2cl 2).
hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.31-7.29 (m, 2H), 7.20 (s, 1H), 7.10-7.08 (m, 1H), 5.34 (dd, J=7.6Hz, J=4.4Hz, 1H), 5.13 (dd, J=10.4Hz, J=6.0Hz, 1H), 5.04 (d, J=5.6Hz, 1H), 4.28-4.21 (m, 2H), 3.46 (d, J=4.0Hz, 1H), 3.21-3.15 (m, 1H), 1.95-1.85 (m, 1H), (1.26 t, J=7.2Hz, 3H), 0.87 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.64,139.71,135.02,130.40,128.41,128.09,126.32,97.82,88.98,69.60,62.34,47.65,39.49,15.36,13.87ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18clNO 6+ Na366.0720, measured value 366.0723.
2-propanol/n-hexane, 1mL/min), UV220nm, t minor=10.13min, t major=19.33min. optically-active: [α] d 20+ 97.6 (c=0.15inCH 2cl 2).
-86.2 (c=0.15inCH 2cl 2); Hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.35 (d, J=8.0Hz, 2H), 7.14 (d, J=7.6Hz, 2H), 5.33 (d, J=6.8Hz, 1H), 5.13 (dd, J=10.0Hz, J=6.0Hz, 1H), 5.06 (d, J=5.6Hz, 1H), 4.26-4.20 (m, 2H), 4.06 (brs, 1H), 3.15 (t, J=11.2Hz, 1H), 1.95-1.89 (m, 1H), (1.24 t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=166.80,135.12,132.96,128.34,128.31,96.94,88.37,68.25,61.35,46.58,38.26,14.41,12.82ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18clNO 6+ Na366.0720, measured value 366.0723.
2-propanol/n-hexane, 1mL/min), UV220nm, t minor=16.01min, t major=30.78min. optically-active: [α] d 20+ 82.4 (c=0.12inCH 2cl 2).
-65.4 (c=0.08inCH 2cl 2); Hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.44 (s, 1H), 7.31-7.21 (m, 2H), 5.28 (brs, 2H), 5.07 (d, J=4.4Hz, 1H), 4.32-4.23 (m, 2H), 4.09 (brs, 1H), 3.92-3.80 (m, 1H), 2.05 (brs, 1H), 1.25 (t, J=7.2Hz, 3H), 0.87 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.68,134.37,130.25,130.08,128.07,127.74,127.67,98.19,95.18,83.25,69.86,69.01,62.44,14.99,13.88ppm; High resolution mass spectrum ESIHRMS:calcd.ForC 15h 17cl 2nO 6+ Na400.0331, measured value 400.0328.
optically-active: [α] d 20+ 76.9 (c=0.21inCH 2cl 2).
-107.4 (c=0.10inCH 2cl 2); Hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.45 (d, J=8.4Hz, 1H), 7.37 (s, 1H), 7.24-7.23 (m, 1H), 7.14 (d, J=7.6Hz, 1H), 5.32 (d, J=7.2Hz, 1H), 5.15 (dd, J=9.6Hz, J=5.6Hz, 1H), 5.07 (d, J=5.6Hz, 1H), 4.44 (brs, 1H), 4.25-4.20 (m, 2H), 3.14 (t, J=11.2Hz, 1H), 1.97-1.89 (m, 1H), 1.24 (t, J=7.2Hz, 3H), 0.87 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=166.91,139.13,130.29,129.95,129.64,125.83,122.14,96.99,88.27,68.11,61.41,46.89,38.22,14.52,12.82ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18brNO 6+ Na410.0215, measured value 410.0211.
t major=18.88min. optically-active: [α] d 20+ 65.8 (c=0.16inCH 2cl 2).
-82.4 (c=0.20inCH 2cl 2); Hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.50 (d, J=7.6Hz, 2H), 7.08 (d, J=7.6Hz, 2H), 5.33 (d, J=4.0Hz, 1H), 5.12 (dd, J=9.6Hz, J=6.0Hz, 1H), 5.05 (d, J=5.2Hz, 1H), 4.25-4.21 (m, 2H), 4.08 (brs, 1H), 3.14 (t, J=11.2Hz, 1H), 1.95-1.88 (m, 1H), (1.24 t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=166.80,135.66,131.29,128.65,121.05,96.91,88.26,68.27,61.36,46.65,38.23,14.40,12.82ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18brNO 6+ Na410.0215, measured value 410.0217.
min, t major=32.45min. optically-active: [α] d 20+ 87.2 (c=0.16inCH 2cl 2).
-93.2 (c=0.19inCH 2cl 2); Hydrogen is composed 1hNMR (400MHz, CDCl 3): δ=7.19-7.16 (m, 2H), 7.08-7.04 (m, 2H), 5.35-5.33 (m, 1H), 5.13 (dd, J=9.6Hz, J=6.0Hz, 1H), 5.06 (d, J=5.6Hz, 1H), 4.29-4.17 (m, 3H), 3.15 (t, J=11.2Hz, 1H), 1.96-1.90 (m, 1H), 1.24 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.93,162.36 (d, J cF=246Hz), 133.38 (d, J cF=3Hz), 129.59 (d, J cF=8Hz), 116.14 (d, J cF=21Hz), 98.08,89.76,69.19,62.38,47.57,39.35,15.49,13.84ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18fNO 6+ Na350.1016, measured value 350.1011.
2-propanol/n-hexane, 1mL/min), UV220nm, t minor=12.73min, t major=24.56min. optically-active: [α] d 20+ 75.4 (c=0.20inCH 2cl 2).
7.67 (t, J=7.6Hz, 1H), 7.51-7.47 (m, 2H), 5.35-5.21 (m, 2H), 5.12 (d, J=5.2Hz, 1H), 4.32-4.18 (m, 3H), 4.03 (brs, 1H), 2.08 (brs, 1H), 1.25 (t, J=7.2Hz, 3H), 0.85 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.62,133.51,133.05,128.91,128.08,125.19,124.96,97.91,95.17,88.35,83.98,69.70,62.52,13.85,13.43ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18n 2o 8+ H355.1141, measured value 355.1145.
t major=34.45min. optically-active: [α] d 20+ 91.6 (c=0.16inCH 2cl 2).
cDCl 3): δ=8.25 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 5.35 (dd, J=6.8Hz, J=4.4Hz, 1H), 5.18 (dd, J=10.0Hz, J=6.0Hz, 1H), 5.10 (d, J=5.6Hz, 1H), 4.31-4.19 (m, 2H), 3.80 (d, J=3.6Hz, 1H), 3.34 (t, J=11.2Hz, 1H), 2.01-1.95 (m, 1H), 1.26 (t, J=7.2Hz, 3H), 0.86 (d, J=6.4Hz, 3H) ppm; Carbon is composed 13cNMR (100MHz, CDCl 3): δ=167.58,147.73,145.19,129.08,124.39,97.64,88.44,69.45,62.51,47.80,39.45,15.31,13.86ppm; High resolution mass spectrum ESIHRMS: calculated value C 15h 18n 2o 8+ Na377.0961, measured value 377.0958.
min, t major=24.45min. optically-active: [α] d 20+ 65.8 (c=0.22inCH 2cl 2).
Beneficial effect of the present invention is illustrated below by way of test example.
Test example 1 anti-microbial activity detects
Adopt mtt assay, measure the anti-microbial activity of the compounds of this invention, the results are shown in Table 1.
From table 1, compound provided by the invention has certain anti-microbial activity.
Test example 2 anti-tumor activity detects
Adopt mtt assay, measure the antitumour activity of the compounds of this invention, the results are shown in Table 2.
As shown in Table 2, compound provided by the invention has certain anti-tumor activity, particularly has good inhibit activities to cancer cells such as DU145, H1975, LANCAP, MV4-11, THP-1.

Claims (11)

1. compound as shown in Equation 5 or its pharmacy acceptable salt, hydrate or crystal formation,
R1 is selected from phenyl ring, substituted benzene ring or five yuan or hexa-member heterocycle, and R2 is selected from C1-C4 alkyl, and R3 is selected from H or C1-C4 alkyl.
2. compound according to claim 1 or its pharmacy acceptable salt, hydrate or crystal formation, is characterized in that: described structural formula of compound is as follows:
Wherein, substituent R 4 quantity is 1 ~ 3, is independently selected from halogen or nitro.
3. according to claim 2 or its pharmacy acceptable salt, hydrate or crystal formation, is characterized in that: described halogen is selected from F, Cl or Br.
4. according to Claims 2 or 3 or its pharmacy acceptable salt, hydrate or crystal formation, is characterized in that: substituent R 4 quantity is 1 or 2.
5. according to claim 1 or its pharmacy acceptable salt, hydrate or crystal formation, is characterized in that: described C1-C4 alkyl is selected from methyl or ethyl.
6. according to claim 1 or its pharmacy acceptable salt, hydrate or crystal formation, is characterized in that: one of described structural formula of compound is following:
7. the synthetic method of compound 5, is characterized in that: reaction path is as follows:
Rac-3 is racemic modification;
R1 is selected from phenyl ring, substituted benzene ring or five yuan or hexa-member heterocycle, and R2 is selected from C1-C4 alkyl, and R3 is selected from H or C1-C4 alkyl;
Carbonyl compound shown in nitroolefin and formula 2 shown in formula 1 is under DMAP exists, and make solvent with MeCN, stirring at room temperature obtains MBH adduct rac-3; Then one kettle way adds aldehyde, catalyzer and Glacial acetic acid shown in formula 4, react under room temperature, with TLC monitoring to reacting end, concentrated and through silica gel column chromatography, PE/EA=10:1 wash-out is separated and obtains the product of chirality tetrahydropyrans alcohol shown in MBH product (S)-3 and formula 5; Described catalyzer is selected from N, N-diphenylprolinol silicon ether, L-dried meat ammonia alcohol or L-PROLINE.
8. synthetic method according to claim 7, is characterized in that: nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: Glacial acetic acid=0.5-1.0mmol:1.0mmol:0.05-0.2mmol:1.0-2.0mmol:0.1-0.3mmol: 0.1-0.2mmol.
9. synthetic method according to claim 8, is characterized in that: nitroolefin shown in formula 1: carbonyl compound shown in formula 2: DMAP: aldehyde shown in formula 4: catalyzer: Glacial acetic acid=0.5mmol:1.0mmol:0.05mmol:1.0mmol:0.1mmol:0.1mmol.
10. the compound described in claim 1 ~ 6 any one or its pharmacy acceptable salt, hydrate or the crystal formation purposes in preparation antibacterium or anti-tumor drug.
11. purposes according to claim 10, is characterized in that: described bacterium is intestinal bacteria, Acinetobacter lwoffii, Pseudomonas Maltophilia, moraxelle catarrhalis, streptococcus aureus or staphylococcus epidermidis; Described tumour is lung cancer, prostate cancer, adenocarcinoma of lung or leukemia.
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HAYATO ISHIKAWA 等: "Asymmetric One-Pot Four-Component Coupling Reaction: Synthesis of Substituted Tetrahydropyrans Catalyzed by Diphenylprolinol Silyl Ether", 《ANGEW. CHEM.》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315159A (en) * 2014-06-26 2016-02-10 成都中医药大学 Resolution method for compounds
CN105315159B (en) * 2014-06-26 2017-12-15 成都中医药大学 A kind of method for splitting of compound
TWI599354B (en) * 2016-08-10 2017-09-21 國立臺灣師範大學 Use of tetrahydropyranol derivatives for manufacturing pharmaceutical composition of tau-associated diseases
CN107793389A (en) * 2016-09-05 2018-03-13 中国科学院上海药物研究所 Chiral tetrahydropyran derivatives and its preparation and purposes
CN107793389B (en) * 2016-09-05 2021-06-29 中国科学院上海药物研究所 Chiral tetrahydropyran derivative and preparation and application thereof

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