CN104151379A - Preparation method and application of Kinsenoside and GoodyerosideA analogues - Google Patents
Preparation method and application of Kinsenoside and GoodyerosideA analogues Download PDFInfo
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Abstract
The invention discloses a preparation method and application of compounds as shown in formula I and II, and in particular relates to preparation of Kinsenoside or GoodyerosideA analogue and medical application of the Kinsenoside or GoodyerosideA analogue in the treatment of some diseases.
Description
Technical field
The present invention relates to preparation method and the purposes of a kind of compound and this compound.Involved in the present invention is the preparation of the analogue of Kinsenoside or Goodyeroside A exactly, and the purposes aspect some disease treatment medicine.
Background technology
Herba Anoectochili roxburghii, has another name called Shorthairy Antenoron, golden silkworm etc., is the traditional rare medicinal material of China, has the multiple efficacies such as clearing heat and cooling blood, expelling wind and removing dampness, cardiac stimulant, is among the peoplely used for treating the various diseases such as diabetes, bronchitis, ephritis.At present existing Herba Anoectochili roxburghii compound preparation listing is used.
Kinsenoside is that the orchid family (Orchidaceae) is opened lip epidendrum Herba Anoectochili roxburghii
anoectochilus roxburghii(Wall.) the high-content activeconstituents in Lindl. (J Nat Med, 2008,62,132), its structural formula is suc as formula shown in one; And Goodyeroside A, its structural formula, suc as formula shown in two, is the isomer of Kinsenoside, from three kinds of variegated leaf Cymbidiums (
goodyerar. Br.) large rattlesnake plantain (the G. of plant
schlechtendalianareichb. fil.), net arteries and veins rattlesnake plantain (G.
matsumuranaschlter.) and blood aspidistra (G.
discolorker-Gawl.) in, all separation obtains this compound monomer (Biol. Pharm. Bull., 2000,23,731).Some plants of variegated leaf Cymbidium from Ancient Times in China among the people just for fever, pain, snake sting, pulmonary disorder etc. (Formosan Sci., 1990,47).
Research shows that Kinsenoside and Goodyeroside A have obvious anti-diabetic, the medical active (Formosan Sci., 1990,47) such as protect the liver.In addition, Kinsenoside also has the blood vessel injury level that alleviates under hepatic fibrosis, high sugared condition, reduces the medical actives (Biosci. Biotechnol. Biochem., 2010,74,781) such as hyperlipidemia.It is highly important that the multiple medical active of Kinsenoside and the anti-oxidation stress ability of Kinsenoside mutually closely related (Fitoterapia 2013,86,163).The analysis of structure activity relationship shows, the glycosyl of Kinsenoside is one of important group of medical active, and the replacement of different glycosyls has good application prospect.
the formula same form two.
Summary of the invention
The invention provides the analogue of a kind of Kinsenoside or Goodyeroside A, expect that this compounds can be some disease of clinical treatment more medicine is provided, the present invention provides the preparation method of this compound simultaneously, and uses thereof.
Compound of the present invention shows suc as formula three, or shows suc as formula four,
Formula three formulas four
Compound shown in it be configured as 3-S or 3-R.
Synthetic route in the preparation of compound of the present invention is suc as formula five:
Formula five
That is:
(1) D-semi-lactosi or D-wood sugar be under the catalysis of pyridine, and diacetyl oxide at room temperature reacts 24 hours, obtains the D-pyranose 1 of ethanoyl protection;
(2) 1,2,3,4,6-, five-oxy-acetyl-D-semi-lactosi or 1,2,3,4-, tetra--oxy-acetyl-D-wood sugar, under the catalysis of boron trifluoride diethyl etherate, react with toluene-ω-thiol, obtains p-methylphenyl-oxy-acetyl-1-sulfo--D-pyranoside 2;
(3) p-methylphenyl-oxy-acetyl-1-sulfo--D-pyranoside is under the effect of sodium methylate, and deacetylate, obtains p-methylphenyl-1-sulfo--D-pyranoside 3;
(4) p-methylphenyl-1-sulfo--D-pyranoside, under the catalysis of receiving, reacts with cylite in hydrogenation, obtains p-methylphenyl-oxygen-benzyl-1-sulfo--D-pyranoside 4 of benzyl protection;
(5) p-methylphenyl-oxygen-benzyl-1-sulfo--D-pyranoside is at N-N-iodosuccinimide and H
2sO
4under the effect of-silica, slough 1 sulphur glycosides part, obtain oxygen-benzyl-D-pyranose 5;
(6) oxygen-benzyl-D-pyranose and (S)-beta-hydroxy-gamma-butyrolactone or (R)-beta-hydroxy-gamma-butyrolactone, under the catalysis of three silyl triflate,-10 ℃ of reactions obtain 4S/R-4-oxygen-(2 for 2 hours, 3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones 6;
(7) 4S/R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones obtain target compound 7 under 10%Pd-C catalytic hydrogenation.
reagent and reaction conditions used in above-mentioned building-up reactions are:(i) pyridine/Ac
2o, room temperature 24 h; (ii) toluene-ω-thiol/BF
3.Et
2o; (iii) NaOMe/MeOH; (iv) BnBr/NaH; (v) NIS/H
2sO
4-silica; (vi) 3-hydroxyl-gamma-butyrolactone/TMSOTf/ acetonitrile; (vii) Pd-C/H
2.
Compound of the present invention can be in preparing anti-oxidation stress interference medicament application, or the application in the medicine of preparation treatment diabetes, or the application in the hypertensive medicine of preparation treatment.
Oxidative stress (oxidative stress) is that body is while suffering destructive stimulus, serious unbalance between the generation of free radical and anti-oxidative defense in body or in cell, degree of oxidation exceeds after body self removing ability, reactive oxygen species (ROS) in vivo or in cell, accumulate and cause cytotoxicity, causes the process of tissue injury.In the recent period a large amount of research show oxidative stress and diabetes and complication thereof, atherosclerotic plaque formation, develop and break, the generation of the various diseases such as hypertension, develop relevant.Because oxidative stress disturbs, be the effective way of the treatment various diseases relevant with oxidative stress, from the natural antioxidants of low toxicity, find oxidative stress interference medicament and there is very important status.Can be referring to about these contents: " Oxidative Stress, Nitric Oxide, and Diabetes "
rev Diabet Stud2010; 7:15-25; " Effect of antioxidants on amelioration of high-risk factors inducing hypertensive disorders in pregnancy "
chin Med J 2010; 123 (18): 2548-2554; "non-invasive oxidative stress markers for liver fibrosis development in the evolution of toxic hepatitis. "
acta Physiol Hung2011; 98:195-204; " Pharmacology in Health Foods:Improvement of Vascular Endothelial Function by French Maritime Pine Bark Extract (Flavangenol) "
journal of Pharmacological Sciencesj Pharmacol Sci 115,461 – 465 (2011); " Plant polyphenols as dietary antioxidants in human health and disease " Oxidative Medicine and Cellular Longevity 2:5,270-278; November/December.
Experiment in vitro shows, 1A, 1B, 2A, 2B be the same with kinsenoside has a good antioxygenation, and this present invention has prospect in preparing anti-oxidation stress interference medicament and preparation and caused by oxidative stress the related drugs of illness.
Embodiment
(1) preparation of compound
Embodiment 1:1,2,3,4,6-, five-oxy-acetyl-D-pyranose (
1) preparation, the reaction that the semi-lactosi of take is prepared as raw material shows suc as formula six,
Formula six
The reaction formula that the wood sugar of take is prepared as raw material is suc as formula seven,
Formula seven
Its concrete preparation process is as follows: get D-pyranose (60 mmole) in reaction flask, add respectively 94 milliliters of pyridines, 47 ml acetic anhydride.At room temperature stirring reaction is 24 hours, and (developping agent is sherwood oil: ethyl acetate=3:1), react substantially complete to carry out TLC detection.With Rotary Evaporators, by reaction solution evaporate to dryness, obtain soup compound.In soup compound, add 150 milliliters of ethyl acetate to be dissolved, proceed in separating funnel, with 1 M hcl as extraction agent, twice of distilled water wash of organic phase.Organic phase is merged, add appropriate anhydrous sodium sulfate drying.The dry completely rear Rotary Evaporators evaporate to dryness, 20.992 grams of yellow soup compounies used
1a, or15.132 gram white dope
1b.
Embodiment 2: p-methylphenyl-oxy-acetyl-1-sulfo--D-pyranoside (
2) preparation
With the resulting compound 1a of embodiment 1 or 1b prepare p-methylphenyl-oxy-acetyl-1-sulfo--D-pyranoside (
2), referring to formula eight,
Formula eight
Its concrete preparation process is as follows: the compound of getting 25.6 mmoles
1ain reaction flask, argon shield, adds 110 milliliters of dry methylene dichloride to dissolve.Under condition of ice bath, add successively toluene-ω-thiol (4.77 grams, 38.4 mmoles), 9.5 milliliters of boron trifluoride diethyl etherate, reacted after 10 minutes, rose to gradually room temperature, react at ambient temperature 3 hours, (developping agent is sherwood oil: ethyl acetate=3:1), react completely in TLC detection.In reaction solution, add a certain amount of methylene dichloride, respectively with saturated sodium hydrogen carbonate solution, water and saturated aqueous common salt extraction.Merge organic phase, add appropriate anhydrous sodium sulfate drying.After dry, use Rotary Evaporators evaporate to dryness, carrying out column chromatography, to obtain 4.973 grams of white solid 2a(productive rates be 40.6%), 2.570 grams of white solid 2b(productive rates are 26.3%).
Embodiment 3: p-methylphenyl-1-sulfo--D-pyranoside (
3) preparation
The 2a obtaining with embodiment 2 or 2b prepare p-methylphenyl-1-sulfo--D-pyranoside (
3) referring to formula nine,
Formula nine
Its concrete preparation process is as follows: get compound
2(6 mmole), in reaction flask, argon shield, adds 42 milliliters of anhydrous methanols.Under condition of ice bath, add 56 milliliters of sodium methylate/anhydrous methanols (0.5M).Add recession deicing and bathe, react 1 hour under room temperature, (developping agent is methylene dichloride: methyl alcohol=20:1), after reacting completely, with 732 type storng-acid cation exchange resins, pH is adjusted to acidity in TLC detection.Filter, filtrate is used Rotary Evaporators evaporate to dryness, and 1.851 grams of white solid 3b(productive rates are 98.0%), 1.443 grams of white solid 3c(productive rates are 93.9%).
Embodiment 4
:p-methylphenyl-oxygen-benzyl-1-sulfo--D-pyranoside (
4) preparation
The compound 3a obtaining with embodiment 3 or 3b prepare p-methylphenyl-oxygen-benzyl-1-sulfo--D-pyranoside (
4) referring to formula ten,
Formula ten
Its concrete preparation process is as follows: get compound
3(5.2 mmole) is in reaction flask, add 30 milliliters of N, dinethylformamide, at room temperature add 60% sodium hydride (1.2 grams), stir after 30 minutes, under condition of ice bath, slowly drip 4.5 milliliters of cylites, after stirring at room 3 hours, repeat above operation, stirring at room is after 3 hours again, add 0.9 gram of sodium hydride, after stirring at room 30 minutes, under condition of ice bath, slowly drip 2.6 milliliters of cylites, stirring at room 24 hours, (developping agent is sherwood oil: ethyl acetate=12:1) in TLC detection, after reacting completely, add 5 ml methanol to react away excessive sodium hydride.In reaction system, add appropriate methylene dichloride, then with distilled water and saturated aqueous common salt, extract respectively.Merge organic phase, add appropriate anhydrous sodium sulfate drying.After dry, use Rotary Evaporators evaporate to dryness, carry out column chromatography
4a(productive rate is 69.1%), 1.851 grams of white solid 4b(productive rates are 67.6%).
Embodiment 5: oxygen-benzyl-D-pyranose (
5) preparation
The compound 4a obtaining with embodiment 4 or 4b prepare oxygen-benzyl-D-pyranose (
5) see formula 11.
Formula 11
Its concrete preparation process is as follows: get compound
4(3 mmole), in reaction flask, adds 50 milliliters of methylene dichloride, then adds 5 ml distilled waters.In condition of ice bath, once add N-N-iodosuccinimide (1.12 grams, 5 mmoles), H
2sO
4-silica(1.5 gram), under condition of ice bath, react 30 minutes, (developping agent is sherwood oil: ethyl acetate=3:1) in TLC detection, after reacting completely, in reaction system, add appropriate methylene dichloride, then with hypo solution, saturated sodium bicarbonate solution and saturated aqueous common salt, extract respectively.Merge organic phase, add appropriate anhydrous sodium sulfate drying.After dry, use Rotary Evaporators evaporate to dryness, carrying out column chromatography, to obtain 1.040 grams of white solid 5b(productive rates be 64.2%), 0.876 gram of white solid 5c(productive rate is 69.4%).
The preparation of embodiment 6:4S/R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones (6)
(1) preparation of 4S-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones (6S)
With the resulting compound 5a of embodiment 5 or 5b, prepare 4S-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones (6S) referring to formula 12 and formula 13,
Formula 12
Formula 13
Its concrete preparation process is as follows: get compound
5(0.83 mmole) is in reaction flask; add 4 dust molecular sieves; argon shield; add 10 milliliters of dry acetonitriles; by (82 milligrams of (S)-beta-hydroxy-gamma-butyrolactones; 0.8 mmole) be dissolved in a small amount of acetonitrile and add reaction system;-10 ℃ of reactions 20 minutes; by (222 milligrams of three silyl triflate; 1 mmole) slowly add in reaction system after being dissolved in a small amount of acetonitrile;-10 ℃ of reactions 2 hours, (developping agent was sherwood oil: ethyl acetate=3:1), add 3 milliliters of triethylamine cancellation reactions after reacting completely in TLC detection.Filter, filtrate is used Rotary Evaporators evaporate to dryness, carries out column chromatography and obtains 0.233 gram of white solid
6Sa-1(productive rate is 44.9%), 0.106 gram of white solid 6Sa-2(productive rate is 20.4%), 0.149 gram of white solid 6Sb-1(productive rate is 35.5%), 0.107 gram of white solid 6Sb-2(productive rate is 25.5%).
(2) preparation of 4R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones (6R)
The compound 5a obtaining with embodiment 5 or 5b prepare 4R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones (6R) referring to formula 14 and formula 15,
Formula 14
Formula 15
Its concrete preparation process is as follows: get compound
5(0.83 mmole) is in reaction flask; add 4 dust molecular sieves; argon shield; add 10 milliliters of dry acetonitriles; by (82 milligrams of (R)-beta-hydroxy-gamma-butyrolactones; 0.8 mmole) be dissolved in a small amount of acetonitrile and add reaction system;-10 ℃ of reactions 20 minutes; by (222 milligrams of three silyl triflate; 1 mmole) slowly add in reaction system after being dissolved in a small amount of acetonitrile;-10 ℃ of reactions 2 hours, (developping agent was sherwood oil: ethyl acetate=3:1), add 3 milliliters of triethylamine cancellation reactions after reacting completely in TLC detection.Filter, filtrate is used Rotary Evaporators evaporate to dryness, carries out column chromatography and obtains 0.240 gram of white solid
6Sa-1(productive rate is 46.3%), 0.161 gram of white solid
6Sa-2(productive rate is 31.0%), 0.225 gram of white solid
6Sb-1(productive rate is 53.7%), 0.097 gram of white solid 6Sb-2(productive rate is 23.1%).
(3) 4S-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha-D-galactopyranose)-2 (5H)-furanones (
6Sa-1) preparation
6Sa-1(productive rate 44.9%): [α]
d+ 60.952; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.41 ~ 7.27 (m, 20H, Ar-H), 4.96 (d, 1H, H-3, J=11.6 Hz), 4.86 (dd, 2H, PhCH
2-H, J=8.4,12.4 Hz), 4.77 (d, 1H, H-1 ', J=4 Hz), 4.74 (d, 1H, PhCH
2-H, J=11.6 Hz), 4.59 (dd, 2H, H-4a and H-4b, J=12,14 Hz), 4.49 ~ 4.39 (m, 4H, PhCH
2-H), 4.36 ~ 4.33 (m, 1H, PhCH
2-H), 4.05 (dd, 1H, H-3 ', J=3.6,10 Hz),, 3.94 ~ 3.88 (m, 3H, H-6 ' and H-5 '), 3.52 (dd, 1H, H-4 ', J=6.8,9.6 Hz), 3.44 (dd, 1H, H-2 ', J=6,9.6 Hz), 2.66 (dd, 1H, H-2a, J=6.4,18Hz), 2.55 (dd, 1H, H-2b, J=2.8,18 Hz).
13c-NMR (CDCl
3, 400 MHz): δ 175.1 (C4), 138.6 (C4), 138.5 (C4), 138.4 (C4), 137.8 (C4), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.2 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.6 (CH), 127.5 (CH), 127.4 (CH), 98.0 (CH), 78.6 (CH), 77.3 (CH), 75.0 (CH), 74.7 (CH
2), 73.8 (CH
2), 73.6 (CH), 73.4 (CH
2), 73.4 (CH
2), 73.2 (CH
2), 70.3 (CH), 69.2 (CH
2), 34.8 (CH
2). FAB-MS:
m/z642.4 [M+NH
4]
+.
(4) 4S-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-β-D-galactopyranose)-2 (5H)-furanones (
6Sa-2) preparation
6Sa-2(productive rate 20.4%): [α]
d– 5.278; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.34 ~ 7.29 (m, 20H, Ar-H), 4.95 (d, 1H, H-3, J=11.6 Hz), 4.79 ~ 4.74 (m, 4H, PhCH
2-H), 4.64 (d, 1H, H-1 ', J=11.6 Hz), 4.62 ~ 4.31 (m, 6H, PhCH
2-H and H-4a, H-4b), 3.89 (d, 1H, H-3 ', J=2.8 Hz), 3.83 (dd, 1H, H-5 ', J=8,10 Hz), 3.58 ~ 3.51 (m, 4H, H-6 ', H-4 ' and H-2 '), 2.82 (dd, 1H, H-2a, J=2,18Hz), 2.72 (dd, 1H, H-2b, J=6.4,18 Hz).
13c-NMR (CDCl
3, 400 MHz): δ 175.0 (C4), 138.3 (C4), 138.2 (C4), 138.1 (C4), 137.7 (C4), 128.4 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.5 (CH), 102.5 (CH), 82.2 (CH), 79.0 (CH), 75.5 (CH
2), 74.5 (CH
2), 73.8 (CH), 73.6 (CH
2), 73.2 (CH), 73.1 (CH
2), 72.9 (CH
2), 68.9 (CH
2), 35.9 (CH
2). FAB-MS:
m/z642.3 [M+NH
4]
+.
(5) 4S-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha-D-xylopyranose)-2 (5H)-furanones (
6Sb-1) preparation
6Sb-1(productive rate 35.5%): [α]
d+ 26.667; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.40 ~ 7.27 (m, 15H, Ar-H), 4.91 (d, 1H, H-1 ', J=4 Hz), 4.85 (d, 1H, H-3, J=12 Hz), 4.79 ~ 4.36 (m, 8H, PhCH
2-H and H-4a, H-4b), 3.88 (t, 1H, H-3 ', J=8.4 Hz), 3.67 ~ 3.45 (m, 4H, H-5 ', H-4 ' and H-2 '), 2.66 (dd, 1H, H-2a, J=6,18Hz), 2.57 (dd, 1H, H-2b, J=2.8,18 Hz).
13c-NMR (CDCl
3, 400 MHz): δ 175.1 (C4), 138.7 (C4), 138.4 (C4), 138.3 (C4), 128.5 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 128.0 (CH), 128.0 (CH), 128.0 (CH), 127.8 (CH), 97.0 (CH), 81.1 (CH), 79.7 (CH), 77.9 (CH), 75.7 (CH
2), 74.0 (CH
2), 73.7 (CH
2), 73.3 (CH
2), 72.8 (CH), 60.9 (CH
2), 34.8 (CH
2). FAB-MS:
m/z522.3 [M+NH
4]
+.
(6) 4S-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-β-D-xylopyranose)-2 (5H)-furanones (
6Sb-2) preparation
6Sb-2(productive rate 25.5%): [α]
d– 35.000; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.34 ~ 7.29 (m, 15H, Ar-H), 4.88 ~ 4.36 (m, 10H, H-1 ', H-3, H-4a, H-4b and PhCH
2-H), 3.90 (dd, 1H, H-3 ', J=4.8,11.6 Hz), 3.65 ~ 3.50 (m, 2H, H-5 '), 3.38 ~ 3.34 (m, 1H, H-4 '), 3.19 (dd, 1H, H-2 ', J=9.6,11.6 Hz), 2.75 ~ 2.74 (m, 2H, H-2a and H-2b).
13c-NMR (CDCl
3400 MHz): δ 175.2 (C4), 138.5 (C4), 138.0 (C4), 138.0 (C4), 128.5 (CH), 128.4 (CH), 128.4 (CH), 128.1 (CH), 127.9 (CH), 127.9 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 103.0 (CH), 83.7 (CH), 81.5 (CH), 77.7 (CH), 75.6 (CH
2), 75.4 (CH
2), 74.1 (CH), 73.4 (CH
2), 73.0 (CH
2), 64.0 (CH
2), 36.0 (CH
2). FAB-MS:
m/z522.3 [M+NH
4]
+.
(7) 4R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha-D-galactopyranose)-2 (5H)-furanones (
6Ra-1) preparation
6Ra-1(productive rate 46.3%): [α]
d+ 101.770; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.41 ~ 7.30 (m, 20H, Ar-H), 4.98 (d, 1H, H-3, J=11.6 Hz), 4.81 ~ 4.77 (m, 4H, PhCH
2-H), 4.74 ~ 4.61 (m, 2H, H-4a and H-4b), 4.53 (dd, 1H, H-1 ', J=2.4,10.4 Hz), 4.46 ~ 4.39 (m, 4H, PhCH
2-H), 3.91 (d, 1H, H-3 ', J=2.8 Hz), 3.86 (dd, 1H, H-5 ', J=8,10 Hz), 3.61 ~ 3.53 (m, 4H, H-6 ', H-4 ' and H-2 '), 2.70 (dd, 1H, H-2a, J=6.4,18Hz), 2.62 (dd, 1H, H-2b, J=2.8,18 Hz).
13c-NMR (CDCl
3400 MHz): δ 175.4 (C4), 138.6 (C4), 138.6 (C4), 138.5 (C4), 137.9 (C4), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 97.9 (CH), 78.7 (CH), 77.4 (CH), 76.8 (CH), 76.5 (CH
2), 75.0 (CH
2), 74.8 (CH
2), 73.9 (CH
2), 73.5 (CH), 73.2 (CH
2), 70.3 (CH), 69.1 (CH
2), 35.5 (CH
2). FAB-MS:
m/z642.4 [M+NH
4]
+.
(8) 4R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-β-D-galactopyranose)-2 (5H)-furanones (
6Ra-2) preparation
6Ra-2(productive rate 31.0%): [α]
d+ 43.600; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.37 ~ 7.28 (m, 20H, Ar-H), 4.95 (d, 1H, H-3, J=11.6 Hz), 4.79 ~ 4.72 (m, 4H, PhCH
2-H), 4.65 ~ 4.60 (m, 2H, H-4a and H-4b), 4.51 (dd, 1H, H-1 ', J=2,10.4 Hz), 4.43 ~ 4.36 (m, 4H, PhCH
2-H), 3.88 (d, 1H, H-3 ', J=2.8 Hz), 3.83 (dd, 1H, H-5 ', J=7.6,9.6 Hz), 3.58 ~ 3.49 (m, 4H, H-6 ', H-4 ' and H-2 '), 2.69 (dd, 1H, H-2a, J=6.4,18Hz), 2.61 (dd, 1H, H-2b, J=3.2,18 Hz).
13c-NMR (CDCl
3, 400 MHz): δ 175.0 (C4), 138.3 (C4), 138.2 (C4), 138.1 (C4), 137.7 (C4), 128.4 (CH), 128.4 (CH), 128.3 (CH), 128.2 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.5 (CH), 102.6 (CH), 82.1 (CH), 79.0 (CH), 75.6 (CH
2), 74.5 (CH
2), 74.1 (CH
2), 73.9 (CH), 73.7 (CH), 73.5 (CH
2), 73.1 (CH
2), 73.1 (CH), 68.9 (CH
2), 34.9 (CH
2). FAB-MS:
m/z642.4 [M+NH
4]
+.
(9) 4R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha-D-xylopyranose)-2 (5H)-furanones (
6Rb-1) preparation
6Rb-1(productive rate 53.7%): [α]
d+ 99.667; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.35 ~ 7.31 (m, 15H, Ar-H), 4.90 (d, 1H, H-1 ', J=2.4 Hz), 4.87 ~ 4.84 (m, 2H, PhCH
2-H), 4.76 (d, 1H, H-3, J=11.6 Hz), 4.65 ~ 4.42 (m, 4H, PhCH
2-H), 4.32 ~ 4.31 (m, 2H, H-4a and H-4b), 3.87 (t, 1H, H-3 ', J=9.2 Hz), 3.67 ~ 3.44 (m, 4H, H-5 ', H-4 ' and H-2 '), 2.72 ~ 2.71 (m, 2H, H-2a and H-2b).
13c-NMR (CDCl
3, 400 MHz): δ 175.0 (C4), 138.7 (C4), 138.3 (C4), 138.1 (C4), 128.5 (CH), 128.5 (CH), 128.4 (CH), 128.0 (CH), 128.0 (CH), 127.8 (CH), 127.8 (CH), 127.6 (CH), 96.9 (CH), 81.0 (CH), 79.6 (CH), 77.7 (CH), 75.7 (CH
2), 73.9 (CH
2), 73.6 (CH
2), 72.7 (CH
2), 72.6 (CH), 60.7 (CH
2), 35.3 (CH
2). FAB-MS:
m/z522.3 [M+NH
4]
+
(10) 4R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-β-D-xylopyranose)-2 (5H)-furanones (
6Rb-2) preparation
6Rb-2(productive rate 23.1%): [α]
d+ 42.250; White solid,
1h-NMR (CDCl
3, 400 MHz): δ 7.35 ~ 7.11 (m, 15H, Ar-H), 4.95 (d, 1H, H-1 ', J=10.8 Hz), 4.81 (dd, 3H, PhCH
2-H, J=2.8,10.8Hz), 4.71 (d, 1H, H-3, J=3.6 Hz), 4.56 (dd, 2H, H-4a and H-4b, J=5.2,12 Hz), 4.47 ~ 4.26 (m, 3H, PhCH
2-H), 3.92 (t, 1H, H-3 ', J=9.2 Hz), 3.72 ~ 3.53 (m, 4H, H-5 ', H-4 ' and H-2 '), 2.72 ~ 2.61 (m, 2H, H-2a and H-2b).
13c-NMR (CDCl
3400 MHz): δ 174.8 (C4), 138.5 (C4), 138.0 (C4), 138.0 (C4), 128.5 (CH), 128.5 (CH), 128.4 (CH), 128.1 (CH), 127.9 (CH), 127.9 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH), 103.3 (CH), 83.7 (CH), 81.6 (CH), 77.7 (CH), 75.6 (CH
2), 75.4 (CH
2), 74.3 (CH), 74.2 (CH
2), 73.4 (CH
2), 64.0 (CH
2), 35.0 (CH
2). FAB-MS:
m/z522.3 [M+NH
4]
+.
The preparation of embodiment 7:4S/R-4-oxygen-(β-D-pyranose)-2 (5H)-furanones (7)
(1) preparation of 4S-4-oxygen-(β-D-pyranose)-2 (5H)-furanones (7S)
6Sa or 6Sb with embodiment 6 preparations prepare 4S-4-oxygen-(β-D-pyranose)-2 (5H)-furanones (7S) referring to formula 16,
Formula 16
Its concrete preparation process is as follows: get compound
6(0.16 mmole), in autoclave, first adds 0.5 milliliter of ethyl acetate by compound
6after dissolving, then add 4.5 milliliters of ethanol, in reaction solution, drop into 0.15 gram of 10%Pd-C.Then in autoclave, pass into hydrogen, under 5atm, react 24h, react complete and fall Pd-C with diatomite filtration, filtrate is used Rotary Evaporators evaporate to dryness, through going out chromatography, obtains target compound.
(2) preparation of 4R-4-oxygen-(β-D-pyranose)-2 (5H)-furanones (7R)
The compound 6Ra obtaining with embodiment 6 or 6Rb prepare that 4R-4-oxygen-(β-D-pyranose)-2 (5H)-furanones (7R) are referring to formula 17, and its concrete preparation method is the same.
Formula 17
(3) 4S-4-oxygen-(β-D-galactopyranose)-2 (5H)-furanones (
1A) preparation
1H-NMR (D
2O, 400 MHz) δ 5.10 (d, 1H, H-1’,
J = 3.2 Hz), 4.63 (d, 2H, H-4a and H-4b,
J = 2.8 Hz), 4.01 (br s, 2H, H-6’a and H-6’b), 3.86 (t, 2H, H-3’and H-5’,
J = 2.4Hz), 3.78 (d, 2H, H4’and H2’,
J = 6.8Hz), 3.01 (dd, 1H, H-2a,
J = 6.4, 18.4Hz), 2.77 (dd, 1H, H-2b,
J = 0.8, 18 Hz).
13C-NMR (D
2O, 400 MHz) δ 182.5 (C4), 100.2 (CH), 77.6 (CH
2), 76.1 (CH), 74.1 (CH), 71.8 (CH), 70.5 (CH), 63.8 (CH
2), 37.4 (CH). FAB-HRMS
m/z 287.0740 (calcd for C
10H
16NaO
8, 287.0737 ). IR(KBr) ν
max: 3400 (OH), 2928 (CH), 1770 (γ-lactone) 。
(4) 4S-4-oxygen-(β-D-xylopyranose)-2 (5H)-furanones (
2A) preparation
1H-NMR (D
2O, 400 MHz) δ 4.60 (m, 1H, H-1’), 4.48 (d, 2H, H-4a and H-4b,
J = 4 Hz), 3.60 (d, 1H, H-5’b,
J = 4.8 Hz), 3.55~3.47 (m, 3H, H-2’, H3’and H4’), 3.38 (dd, 1H, H-5a’,
J = 3.6, 9.2Hz), 2.84 (dd, 1H, H-2a,
J = 6, 18Hz), 2.65 (d, 1H, H-2b,
J = 17.2 Hz).
13C-NMR (D
2O, 400 MHz) δ 178.4(C4), 100.1 (CH), 75.4 (CH
2), 75.2 (CH), 74.9 (CH), 73.2 (CH), 71.4 (CH), 63.6 (CH
2), 35.8 (CH
2). FAB-HRMS
m/z 257.0634 (calcd for C
9H
14NaO
7, 257.0632 ). IR(KBr) ν
max: 3416 (OH), 2950 (CH), 1773 (γ-lactone)。
(5) 4R-4-oxygen-(β-D-galactopyranose)-2 (5H)-furanones (
1B) preparation
1H-NMR (D
2O, 400 MHz) δ 5.11 (d, 1H, H-1’,
J = 2.4 Hz), 4.57 (d, 2H, H-4a and H-4b,
J = 2.8 Hz), 3.99 ~ 3.95 (m, 2H, H-6’a and H-6’b), 3.84 (d, 2H, H-3’and H-5’,
J = 2.4 Hz), 3.75 (d, 2H, H4’and H2’,
J = 6.4 Hz), 3.04 (dd, 1H, H-2a,
J = 6.4, 18.4Hz), 2.79 (dd, 1H, H-2b,
J = 0.8, 18.4 Hz).
13C-NMR (D
2O, 400 MHz) δ 182.6 (C4), 100.1 (CH), 77.0 (CH
2), 75.7 (CH), 74.0 (CH), 71.7 (CH), 70.5 (CH), 63.7 (CH
2), 38.0 (CH). FAB-HRMS
m/z 287.0738 (calcd for C
10H
16NaO
8, 287.0737 ). IR(KBr) ν
max: 3397 (OH), 2929 (CH), 1770 (γ-lactone) 。
(6) 4R-4-oxygen-(β-D-xylopyranose)-2 (5H)-furanones (
2B) preparation
1H-NMR (D
2O, 400 MHz) δ 4.54~4.51 (m, 1H, H-1’), 4.42~4.34 (m, 2H, H-4a and H-4b), 3.52 (dd, 1H, H-5’b,
J = 1.2, 5.2 Hz), 3.49~3.439 (m, 3H, H-2’, H3’and H4’), 3.33~3.29 (m, 1H, H-5a’), 2.83 (dd, 1H, H-2a,
J = 6, 17.6 Hz), 2.56 (d, 1H, H-2b,
J = 18 Hz).
13C-NMR (D
2O, 400 MHz) δ 178.5(C4), 100.0 (CH), 75.0 (CH
2), 74.9 (CH), 73.2 (CH), 71.4 (CH), 63.6 (CH), 63.6 (CH
2), 35.8 (CH
2). FAB-HRMS
m/z 257.0634 (calcd for C
9H
14NaO
7, 257.0632 ). IR(KBr) ν
max: 3397 (OH), 2930 (CH), 1771 (γ-lactone) 。
(2) anti-oxidant experiment in vitro and result:
1. experimental technique:
1) remove the mensuration of OH effect
In 3mL reaction solution, contain 9.00 mmol/ L FeSO
4(1 mL), the medicine 1mL of 9.00 mmol/ L Whitfield's ointments (being dissolved in 50% ethanol 1 mL) and different concns, finally adds 8.8 mmol/ L H
2o
2(1 mL) reacts 0.5 h under the condition of 37 ℃, surveys the light absorption value at 510 nm places.Light absorption value is lower, removes OH effect better.
(A0 is contrast to clearance rate=[A0-(Ai-Ai0)]/A0 * 100 %, does not add the optical density of medicine; Optical density when Ai is the medicine of certain mass concentration, Ai0 is the drug absorption degree value during without Whitfield's ointment)
2) remove O
-
2
the mensuration of effect
0.05 mol/L Tirs-Hcl (pH 8.2), 4.6 ml, after 25 ℃ of 20 min of preheating, add the medicine 1ml of different concns, then add 10 mmol/L 0.4ml pyrogallols (with 10 mmol/L HCL preparations) and shake up rapidly.After 25 ℃ of accurate response 4 min, use immediately 8 mol/ L HCL 0.1ml termination reactions.325nm place surveys light absorption value.
Blank group: Tirs-Hcl (pH 8.2) 4.6 ml, distilled water 1ml, 10 mmol/ L 0.4 ml HCL
Control group: Tirs-Hcl (pH 8.2) 4.6 ml, distilled water 1ml, 10 mmol/ L 0.4ml pyrogallols
Administration group: Tirs-Hcl (pH 8.2) 4.6 ml, medicine 1ml, 10 mmol/ L 0.4 ml pyrogallols
With the zeroing of blank group, clearance rate=[A0-(Ai-Ai0)]/A0 * 100 %.
3) to generating MDA(lipid peroxidation) inhibiting mensuration
Get the tissue homogenate of 5% (w/ v).In the homogenate of 1.0ml, add the medicine that concentration is different, incubation 2h, then add 1.0ml Tricholroacetic Acid (TCA, 28 %, w/ v) and 1.5ml TBA (0. 67 %, w/ v), boiling water bath 15min, centrifugation, 721 type spectrophotometers for supernatant liquor (Shanghai analytical instrument factory product) are measured absorbance at 532nm.
Inhibiting rate=(A0-Ai)/A0 * 100 %
2. experimental result
Experimental result with
represent, between organizing
tcheck, with
p <0.05 for difference has significance,
p <0.01 has highly significant for difference.。
Compound 1A:
Table 1 compound 1A to the scavenging(action) of OH (
, n=6)
With control group comparison, *
p< 0.05, * *
p< 0.01
Table 2 compound 1A extract is to O
- 2clearance rate (
, n=6)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Table 3 compound 1A to the restraining effect of Mouse Kidney MDA (
, n=6)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Table 4 compound 1A to the restraining effect of Mouse Liver MDA (
, n=6)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Compound 1B:
Table 5 compound 1B to the scavenging(action) of OH (
, n=7)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Table 6 compound 1B is to O
- 2clearance rate (
, n=7)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Table 7 compound 1B to the restraining effect of Mouse Kidney MDA (
, n=6)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Table 8 compound 1B to the restraining effect of Mouse Liver MDA (
, n=6)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Compound 2A
Table 9 compound 2A is to the scavenging(action) of OH (X ± SD, n=4)
With control group comparison, *
p<0.05, * *
p<0.01.
Table 10 compound 2A is to O
- 2scavenging(action) (X ± SD, n=3)
With control group comparison, *
p<0.05, * *
p<0.01.
Table 11 compound 2A to the restraining effect of Mouse Kidney MDA (
, n=6)
With control group comparison, *
p<0.05, * *
p<0.01.
Table 12 compound 2A to the restraining effect of Mouse Liver MDA (
, n=7)
With control group comparison, *
p< 0.05, * *
p< 0.01.
Compound 2B:
Table 13 compound 2B is to the scavenging(action) of OH (x ± s, n=7)
* p<0.05,
* p<0.01 and control group ratio.
Table 14 compound 2B is to O
- 2scavenging(action) (x ± s, n=6)
* p<0.05,
* p<0.01 and control group ratio.
Table 15 compound 2B is to the restraining effect of Mouse Kidney MDA (x ± s, n=7)
* p<0.05,
* p<0.01 and control group ratio.
Table 16 compound 2B is to the restraining effect of Mouse Liver MDA (x ± s, n=7)
* p<0.05,
* p<0.01 and control group ratio.
Conclusion: compound 1A, 1B, 2A, 2B are to O
- 2generate the demonstration of determination experiment result with removing and the lipid peroxide (MDA) of OH, compound 1A, 1B, 2A, 2B all can significantly remove O
- 2and OH, and obviously reduce the generation of MDA.Prompting, compound 1A, 1B, 2A, 2B have good anti-oxidant activity.
Claims (6)
1. the compound showing suc as formula I,
It is configured as 3-S or 3-R.
2. the compound showing suc as formula II,
It is configured as 3-S or 3-R.
3. the preparation method of the compound described in claim 1 or 2, is characterized in that synthetic route shows suc as formula III,
That is:
(1) D-semi-lactosi or D-wood sugar, under the catalysis of pyridine, and diacetyl oxide at room temperature reacts the D-pyranose 1 that obtains ethanoyl protection,
(2) 1,2,3,4,6-, five-oxy-acetyl-D-semi-lactosi or 1,2,3,4-, tetra--oxy-acetyl-D-wood sugar, under the catalysis of boron trifluoride diethyl etherate, react with toluene-ω-thiol, obtains p-methylphenyl-oxy-acetyl-1-sulfo--D-pyranoside 2.
(3) p-methylphenyl-oxy-acetyl-1-sulfo--D-pyranoside 2 is under the effect of sodium methylate, and deacetylate, obtains p-methylphenyl-1-sulfo--D-pyranoside 3.
(4) under the catalysis that p-methylphenyl-1-sulfo--D-pyranoside 3 is received in hydrogenation, react with cylite, obtain p-methylphenyl-oxygen-benzyl-1-sulfo--D-pyranoside 4 of benzyl protection.
(5) p-methylphenyl-oxygen-benzyl-1-sulfo--D-pyranoside 4 is at N-N-iodosuccinimide and H
2sO
4under the effect of-silica, slough 1 sulphur glycosides part, obtain oxygen-benzyl-D-pyranose 5.
(6) oxygen-benzyl-D-pyranose and (S)-beta-hydroxy-gamma-butyrolactone or (R)-beta-hydroxy-gamma-butyrolactone, under the catalysis of three silyl triflate,-10 ℃ of reactions obtain 4S/R-4-oxygen-(2 for 2 hours, 3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones 6.
(7) 4S/R-4-oxygen-(2,3,4,6-, tetra--oxygen-benzyl-alpha/β-D-pyranose)-2 (5H)-furanones obtain target compound 7 under 10%Pd-C catalytic hydrogenation.
4. the application of the arbitrary compound described in claim 1 or 2 in preparing anti-oxidation stress interference medicament.
5. the application of the arbitrary compound described in claim 1 or 2 in the medicine of preparation treatment diabetes.
6. the application of the arbitrary compound described in claim 1 or 2 in the hypertensive medicine of preparation treatment.
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| CN108159067A (en) * | 2018-03-20 | 2018-06-15 | 深圳大学 | Application of the anoectochilus roxburghii glycosides in the drug for preparing treatment insulin resistance |
| WO2021121362A1 (en) * | 2019-12-20 | 2021-06-24 | 复旦大学 | Furaneol glycoside compound, pharmaceutical composition thereof, preparation method therefor, and application thereof |
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