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 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.