CN104672104A - Derivative of natural product spermatinamine and preparation method and application of derivative - Google Patents

Derivative of natural product spermatinamine and preparation method and application of derivative Download PDF

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CN104672104A
CN104672104A CN201510007102.0A CN201510007102A CN104672104A CN 104672104 A CN104672104 A CN 104672104A CN 201510007102 A CN201510007102 A CN 201510007102A CN 104672104 A CN104672104 A CN 104672104A
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CN104672104B (en
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尹胜
刘信
张革
郭艳琼
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Sun Yat Sen University
National Sun Yat Sen University
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Abstract

The invention belongs to the technical field of medicines and chemical engineering, and discloses design of an alkaloids derivative of a natural product spermatinamine and a synthesis method of the derivative, and an application of the derivative in antisepsis. A structure of the derivative of the natural product spermatinamine provided by the invention is shown in a formula (I). The invention discloses design of the derivative of the natural product and a synthesis method of the derivative, and an application of the derivative in antisepsis. The derivative of the natural product has a significant inhibiting effect on a plurality of strains, and has a wide application space in preparation of antibacterial medicines.

Description

The derivative of a kind of natural product spermatinamine and preparation and application thereof
Technical field
The present invention relates to medicine and chemical field, more specifically, relate to derivative and the preparation and application thereof of a kind of natural product spermatinamine.
Background technology
Infected by microbes is the major disease of serious threat human health, and current anti-infection drug is one of classification largest in China's bulk drug, and the market scale of China's classes of anti-infective medicinal chemicals in 2007 has reached 60,000,000,000 yuans.Have Document system, in sample hospital, anti-infectives is bought the amount of money and is ranked first place in hospital administration share.But the research and development speed of new antibiotic medicine eases up, and existing antibiotic abuse, caused the appearance of a series of problem, particularly superbacteria, the development that new antibiotic is accelerated in prompting is extremely urgent.There is obvious defect in most of microbiotic of current Clinical practice: 1) based on sterilization or antibacterial, and this can damage natural probiotic bacterium usually, causes human body bacterium colony unbalance and cause other problem; 2) long-term Clinical practice has created many Resistant strain, brings detrimentally affect to treatment.
Natural product is the important sources of newtype drug or drug leads structure, particularly anti-infectives.In 1981-2006 230 anti-infectives, about 70% source natural product or relevant with natural product.Therefore, from natural product, find that novel antibacterial medicine or drug leads structure are approach feasible fast in new drug development.From a kind of sponge (Pseudoceratinasp.), be separated the alkaloid spermatinamine obtained there is the rare bromine atoms of Lu Sheng resource and oxyammonia structure.By bioactivity screening, find that it has obvious anti-microbial activity, particularly to bacterial type III excretory system, there is significant inhibit activities.
Alkaloid is that a class exists in vivo, and great majority, containing nitrogen-atoms heterocycle structure, have the general designation of the compound of certain alkalescence, opticity and physiologically active.Alkaloid mainly has antitumor, antibacterial, anti-malarial isoreactivity at physiologically active.
Summary of the invention
The object of the invention is to provide a kind of alkaloid spermatinamine derivative with anti-microbial activity newly.
The invention provides a kind of derivative of natural product spermatinamine and the synthetic method of spermatinamine, its structural formula is such as formula shown in (I):
In formula (I), R 1for alkoxyphenyl radical, halogeno-benzene or naphthalene, R 2for hydrogen or benzyl, R 3for
Wherein said R 1be preferably methoxyphenyl, chlorophenyl, 2,4-bis-bromo-3-methoxyphenyl or naphthyls.
Alkaloid spermatinamine derivative preferred compound is more specifically:
SP-1: wherein R 1be the bromo-3-methoxyphenyl of 2,4-bis-, R 2for hydrogen, R 3for
SP-2: wherein R 1be the bromo-3-methoxyphenyl of 2,4-bis-, R 2for hydrogen, R 3for
SP-3: wherein R 1be the bromo-3-methoxyphenyl of 2,4-bis-, R 2for hydrogen, R 3for
Or
SP-4: wherein R 1for 1-naphthyl, R 2for hydrogen, R 3for
SP-5: wherein R 1for 1-naphthyl, R 2for hydrogen, R 3for
SP-6: wherein R 1for 1-naphthyl, R 2for hydrogen, R 3for
SP-7: wherein R 1for guaiacyl, R 2for hydrogen, R 3for
Or
SP-8: wherein R 1for guaiacyl, R 2for hydrogen, R 3for
SP-9: wherein R 1for guaiacyl, R 2for hydrogen, R 3for
SP-10: wherein R 1for Chloro-O-Phenyl, R 2for hydrogen, R 3for
Or
SP-11: wherein R 1for Chloro-O-Phenyl, R 2for hydrogen, R 3for
SP-12: wherein R 1for rubigan, R 2for hydrogen, R 3for
SP-13: wherein R 1for a chloro-phenyl-, R 2for hydrogen, R 3for
Or
SP-14: wherein R 1for a chloro-phenyl-, R 2for hydrogen, R 3for
SP-15: wherein R 1for rubigan, R 2for benzyl, R 3for
Or
SP-17: wherein R 1for rubigan, R 2for hydrogen, R 3for
SP-18: wherein R 1be the bromo-3-methoxyphenyl of 2,4-bis-, R 2for benzyl, R 3for
SP-19: wherein R 1for 1-naphthyl, R 2for benzyl, R 3for
Or
SP-20: wherein R 1for guaiacyl, R 2for benzyl, R 3for
SP-21: wherein R 1for Chloro-O-Phenyl, R 2for benzyl, R 3for
Or
SP-22: wherein R 1for a chloro-phenyl-, R 2for benzyl, R 3for
Or
SP-23: wherein R 1for rubigan, R 2for benzyl, R 3for
A kind of preparation method of spermatinamine derivative is further provided, comprises the following steps:
S1. phenyl aldehyde group (II) and acetyl glycine, diacetyl oxide, acetic acid sodium reaction, obtain structural formula such as formula the compound shown in (III);
R 1-CHO (II)
S2. the compound of step S1 gained as shown in structural formula (III) and 5%-20% aqueous hydrochloric acid are reacted, the compound obtained is obtained by reacting structural formula further such as formula the compound shown in (IV) with benzyl hydroxylamine hydrochloride;
S3. the structural formula obtained by step S2 reacts such as formula the compound shown in (IV) and N-hydroxy-succinamide, obtains the compound of structural formula as shown in formula V;
S4. with spermine or spermidine for raw material, carry out being obtained by reacting structural formula such as formula the compound shown in (VI) with 2-(uncle-butoxy carboxamide)-2-benzyl cyanide;
S5., after the compound of the structural formula obtained by step S4 as shown in (VI) and formaldehyde, glacial acetic acid, sodium cyanoborohydride or sodium borohydride react, structural formula is obtained such as formula the compound shown in (VII) or (VIII);
S6. structural formula step S4 obtained such as formula the compound shown in (VI) and formaldehyde, glacial acetic acid, react after, obtain structural formula such as formula the compound shown in (IX);
S7. the structural formula obtained by step S5 or S6 obtains structural formula such as formula the compound shown in (X), (XI) or (XII) such as formula the compound shown in (VII), (VIII) or (IX) and hydrochloric acid reaction;
S8. step S7 is obtained structural formula to obtain after the compound of structural formula as shown in formula V react, obtaining structural formula such as formula the compound shown in (XIII) such as formula the compound shown in (X), (XI) or (XII) and step S3;
S9., after the structural formula obtained by step S8 reacts with hydrogen under the catalysis of palladium such as formula the compound shown in (XIII), structural formula is obtained such as formula the compound shown in (XIV);
R in structural formula (II) ~ (XIV) 1, R 2, R 3be the arbitrary described R of claim 1,2 respectively 1, R 2, R 3substituting group.
A kind of application of spermatinamine derivative is provided more specifically, it is characterized in that, described spermatinamine derivative is applied in preparation antibacterials.
In order to understand the present invention better, do further explaination to the present invention program's association reaction formula below, listed reaction formula is only theory deduction gained, and it can not as the restriction of scope.Synthesize example with SP-1, concrete building-up process of the present invention, is illustrated in fig. 1 shown below:
Concrete steps are as follows:
2,4-bis-bromo-3-Methoxy-benzaldehyde (compound 1) is dissolved in dry DMF, adds excessive methyl iodide and salt of wormwood, stirred overnight at room temperature under nitrogen protection, and extraction obtains compound 2.The acetyl glycine of compound 2 and equivalent, sodium acetate are dissolved in acetic anhydride, and 120 DEG C of degree reflux 4h, are cooled to 0 DEG C of crystallize out, obtain compound 3.Compound 3 refluxes 6h in 4M hydrochloric acid, and extraction obtains enol intermediate.This intermediate and 1.5 equivalent benzyl hydroxylamine hydrochlorides and 2.5 eq. ethanol sodium are dissolved in dehydrated alcohol, stir 4h at 70 DEG C, cross column purification and obtain compound 4.Compound 4 and 1.2 equivalent N-hydroxy-succinamide is dissolved in anhydrous tetrahydro furan, and add 2 equivalent dicyclohexylcarbodiimide (DCC), stirred at ambient temperature 2h, obtains compound 5.
Spermine (compound 6) is dissolved in tetrahydrofuran (THF), and dropwise add 2-(uncle-butoxy carboxamide)-2-benzyl cyanide under ice bath, stirring at room temperature 3h, saturated sodium carbonate cancellation, extraction, obtain compound 7.Compound 7 is dissolved in ethanol, adds 3 equivalent of formaldehyde, 1 equivalent acetic acid, 4 equivalent sodium cyanoborohydrides.React 5h under room temperature, obtain compound 8.Compound 8 is dissolved in Isosorbide-5-Nitrae-dioxane, adds excessive 4M hydrochloric acid, room temperature for overnight, obtains compound 9.
Compound 5 and compound 9 are dissolved in DMF, add 3 eq of triethylamine, room temperature for overnight, obtain compound 10, cross column purification.Compound 10 is dissolved in Isosorbide-5-Nitrae-dioxane/acetic acid (1:1) solution, adds palladium powder, reacts and spend the night under 1MPa hydrogen.Cross column purification and obtain compound 11.
Compare with technology with existing remodeling method, the present invention has following beneficial effect:
(1) experiment shows, the compound synthesized by the present invention has significant restraining effect to various bacteria strain, has a good application prospect in the antibacterials that preparation is novel.
(2) experiment proves, during the derivative of novel spermatinamine disclosed in this invention is tested in vitro, our compound activity is better than natural product spermatinamine, therefore has significant creativeness.
Accompanying drawing explanation
Fig. 1 is Compound SP-1 synthetic route chart.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but embodiments of the present invention is not limited in any way.
Embodiment one: the logical method synthesis of the compound shown in structural formula (III)
Compound 1mol shown in structural formula (II), acetyl glycine 1mol, sodium acetate 1mol, in 100ml round-bottomed flask, add 20ml acetic anhydride, 120 DEG C of back flow reaction 4h.Be cooled to 0 DEG C after reacting completely, have yellow solid to separate out, filter, the pentane with cold: ether (1:1) washing leaching cake three times, dry cake, obtains the compound shown in formula (III).
Embodiment two: the logical method synthesis of the compound shown in structural formula (IV)
By the compound 0.9mol shown in the formula (III) that obtains in case study on implementation one in 50ml round-bottomed flask, add 30ml 10% aqueous hydrochloric acid, 100-120 DEG C of backflow 6h, extraction into ethyl acetate three times, merges organic layer and obtains white enol intermediate.Enol intermediate, 1.35mol benzyl hydroxylamine hydrochloride and 2.25mol sodium ethylate, in 50ml round-bottomed flask, add 20ml dehydrated alcohol, 70 DEG C of backflow 4h.Regulate pH to be 4 with dilute hydrochloric acid, extraction into ethyl acetate three times, merge organic layer, concentrating under reduced pressure, purification on normal-phase silica gel column purification, obtains white powder, is the compound shown in structural formula (IV).
Compound 4, productive rate 75.64%
1HNMR(400MHz,CDCl 3):δ(ppm)7.40(s,2H),7.38-7.33(m,5H),5.32(s, 2H),3.85(s,3H),3.82(s,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)163.6,153.2,149.1,135.6,133.8,133.5,128.93,128.90,128.7,118.1,78.8,60.7,29.3.
Compound 4a, productive rate 73%
1HNMR(400MHz,CDCl 3):δ(ppm)8.02(d,J＝9.1Hz,1H),7.76(d,J＝7.6Hz,1H),7.66(d,J＝7.9Hz,1H),7.42-7.34(m,3H),7.28-7.24(m,4H),7.21-7.17(m,2H),5.23(s,2H),4.31(s,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)164.4,150.3,135.9,133.9,132.0,131.0,128.8,128.7,128.7,128.6,127.8,126.8,126.3,125.8,125.5,123.8,78.5,29.8.
Compound 4b, productive rate 79.5%
1HNMR(400MHz,CDCl 3):δ(ppm)7.31(d,J＝4.4Hz,1H),7.27(dt,J＝6.3Hz,2.4Hz,2H),7.20-7.10(m,3H),7.04-6.99(m,1H),6.81(dt,J＝8.5Hz,2.4Hz,1H),6.77(d,J＝8.5Hz,1H),5.20(s,2H),3.89(s,2H),3.68(s,3H).
13CNMR(100MHz,CDCl 3):δ(ppm)165.0,157.2,150.9,136.4,130.0,128.5,128.3,128.1,127.9,124.1,120.5,110.5,78.0,55.3,26.3.
Compound 4c, productive rate 79%
1HNMR(400MHz,CDCl 3):δ(ppm)7.35(dd,J＝5.8Hz,1.7Hz,2H),7.33(d,J＝2.8Hz,2H),7.23(dd,J＝6.6Hz,3.0Hz,1H),7.18(dd,J＝7.4Hz,1.9Hz,1H),7.14(t,J＝1.9Hz,1H),7.11(dd,J＝7.3Hz,1.5Hz,1H),7.06(dd,J＝7.5Hz,1.8Hz,1H),5.30(s,2H),4.07(s,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)165.2,149.4,136.0,134.0,133.3,129.9,129.6,128.6,128.5,128.3,128.1,126.9,78.4,28.9.
Compound 4d, productive rate 77.3%
1HNMR(400MHz,CDCl 3):δ(ppm)7.40-7.36(m,3H),7.33(dd,J＝7.4Hz,2.0Hz,2H),7.19(t,J＝2.1Hz,1H),7.17(s,1H),7.16-7.12(m,2H),5.34(s,2H),3.91(s,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)162.5,149.6,137.2,135.8,134.4,129.9,129.4,128.8,128.8,128.6,127.5,127.1,78.6,30.4.
Compound 4e, productive rate 78%
1HNMR(400MHz,CDCl 3):δ(ppm)7.32-7.29(m,2H),7.38(d,J＝1.8Hz,2H),7.22(m,1H),7.21-7.19(m,2H),7.19-7.17(m,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)164.0,149.8,135.8,133.7,132.8,130.7,128.8(overlap),128.5,78.6.
Embodiment three: the logical method synthesis of the compound shown in structure formula V
By the compound 0.6mol shown in the structural formula (IV) that obtains in embodiment two and N-hydroxy-succinamide 0.75mol in 50ml round-bottomed flask, add 20ml dry tetrahydrofuran to dissolve, add dicyclohexylcarbodiimide (DCC) 1.2mol in batches, stirred at ambient temperature 2h, filter, with ice tetrahydrofuran (THF) washing leaching cake.Merging filtrate, concentrating under reduced pressure, obtains the compound shown in structure formula V.
Embodiment four: the logical method synthesis of the compound shown in structural formula (VI)
Spermine or spermidine 1mol, in 25ml round-bottomed flask, add 5ml tetrahydrofuran (THF) and dissolve.2-(uncle-butoxy carboxamide)-2-benzyl cyanide 2mol is dissolved in 10ml tetrahydrofuran (THF), and be dropwise added drop-wise in round-bottomed flask under ice bath, 1h dropwises.Stirred at ambient temperature 4h, TLC detection substrate is dissolved in cancellation with saturated sodium carbonate, dichloromethane extraction three times after disappearing, and merges concentrated organic phase.Purification on normal-phase silica gel column purification, obtains the compound shown in structural formula (VI).
Compound 7, productive rate 83%
1HNMR(400MHz,CDCl 3):δ(ppm)5.30(brs,1H),3.08(dd,J＝11.8,5.8Hz,2H),2.55(t,J＝6.7Hz,2H),2.50(t,J＝6.4Hz,2H),1.96(brs,1H),1.55(p,J＝6.4Hz,2H),1.46–1.39(m,2H),1.34(s,9H)
13CNMR(100MHz,CDCl 3):δ(ppm)156.2,78.9,49.4,47.2,38.8,29.7,28.4,27.5.
Compound 7a, productive rate 86.1%
1H NMR(400MHz,CDCl 3):δ(ppm)5.16(s,1H),4.84(s,1H),3.19(dd,J＝12.0,6.2Hz,2H),3.11(dd,J＝12.0,6.2Hz,2H),2.65(t,J＝6.6Hz,2H),2.60(t,J＝6.5Hz,2H),1.74(brs,1H),1.65(dt,J＝13.1,6.5Hz,2H),1.53–1.49(m,4H),1.43(s,18H).
13C NMR(100MHz,CDCl 3)：δ(ppm)156.2,79.0,49.3,47.5,40.4,39.1,29.7,28.4,27.8,27.1.
Embodiment five: the logical method synthesis of the compound shown in structural formula (IX)
By the compound 7 (0.3mol) that obtains in embodiment four in 100ml round-bottomed flask, add 20ml dissolve with ethanol, add 2.0mol formaldehyde successively, 35ml acetic acid, stirred at ambient temperature 40min.Reaction terminates rear sodium hydroxide solution and regulates pH to 7, extraction into ethyl acetate three times, and merge organic phase, concentrating under reduced pressure obtains the compound shown in structural formula (IX), productive rate 100%.
1H NMR(400MHz,CDCl 3):δ(ppm)4.08(brs,2H),3.44(brs,2H),2.71(brs,2H),2.41(brs,2H),1.64–1.56(m,2H),1.52(m,2H),1.44(s,9H).
13C NMR(100MHz,CDCl 3):δ(ppm)154.5,79.8,65.3,52.41,52.39,43.2,29.8,28.5,25.4.
Embodiment six: the logical method synthesis of structural formula (VII) or the compound shown in (VIII)
By the compound 0.3mol that obtains in embodiment four in 100ml round-bottomed flask, add 30ml dissolve with ethanol, add 0.9mol formaldehyde successively, 17ml acetic acid (0.3mol), 1.2mol sodium cyanoborohydride, room temperature for overnight.Reaction terminates rear adjustment pH to neutral, and extraction into ethyl acetate three times, merge organic phase, concentrating under reduced pressure, normal phase column purifying obtains formula (VII) or the compound shown in (VIII).
Compound 8, productive rate 78.3%.
1H NMR(400MHz,CDCl 3):δ(ppm)5.31(s,1H),3.17(dd,J＝12.0,6.4Hz,2H),2.70(s,2H),2.49(m,4H),2.29(s,3H),1.75–1.61(m,2H),1.56(m,2H),1.42(s,9H).
Compound 8a, productive rate 75%.
1H NMR(400MHz,CDCl 3):δ(ppm)5.16(s,1H),4.85(s,1H),3.19(dd,J＝12.0,6.2Hz,2H),3.10(dd,J＝12.0,6.2Hz,2H),2.65(t,J＝6.6Hz,2H),2.60(t,J＝6.5Hz,2H),2.27(s,3H)1.65(dt,J＝13.1,6.5Hz,2H),1.53–1.49(m,4H),1.43(s,18H).
Embodiment seven: the logical method synthesis of structural formula (X), (XI) or the compound shown in (XII)
The formula (VII) obtained by embodiment five, six, (VIII) or (IX) 0.15mol are in 150ml round-bottomed flask, add 4M methanol hydrochloride solution 80ml, stirred at ambient temperature 4h, vacuum rotary steam removing methanol hydrochloride solution, obtaining white solid, is the compound shown in formula (X), (XI) or (XII).
Compound 9, productive rate 95%.
1H NMR(400MHz,D 2O):δ(ppm)3.50–3.37(m,2H),3.33(m,2H),3.21(t,J＝7.6Hz,2H),3.00(s,3H),2.25(m,2H),1.93(brs,2H).
Compound 9a, productive rate 96.3%.
1H NMR(400MHz,D 2O):δ(ppm)3.48(m,2H),3.27(m,2H),3.15(t,J＝6.6Hz,2H),3.10(t,J＝6.5Hz,2H),2.98(s,3H),2.45(m,2H),1.92–1.88(m,4H).
Compound 9b, productive rate 95.8%.
1H NMR(400MHz,D 2O):δ(ppm)3.56(brs,2H),2.79(brs,2H),2.55(brs,2H),2.36(brs,2H),2.03(m,2H),1.89(m,2H).
Embodiment eight: the logical method synthesis of the compound shown in structural formula (I)
The compound 0.01mol shown in structure formula V obtained by embodiment three, in 25ml round-bottomed flask, adds 10ml DMF and dissolves; The structural formula (X) obtained by embodiment seven, (XI) or the compound 0.005mol shown in (XII) and 1.5ml triethylamine are dissolved in 5ml DMF, slowly join in the compound solution shown in structure formula V.Room temperature for overnight, extract three times after reacting completely, organic phase concentrating under reduced pressure, normal phase column purifying, obtains white powder.
Above-mentioned white solid is dissolved in Isosorbide-5-Nitrae-dioxane/acetic acid (1:1) solution, adds 10% palladium powder, as in autoclave, fills hydrogen, and adjustment pressure is 1MPa.Reaction 15-20h, normal phase column purifying obtains white powder.
SP-1, productive rate 50.6%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.47(s,2H),3.78(s,2H),3.76(s,3H),3.21(t,J＝6.1Hz,2H),2.95(m,2H),2.73(m,2H),2.25(s,3H),1.83(m,2H),1.62(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)163.2,153.7,151.6,135.1,133.6,117.8,60.7,54.6,53.0,40.1,36.9,27.9,24.1,20.6.
SP-2, productive rate 47.1%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.47(s,2H),4.08(brs,2H),3.78(s,2H),3.76(s,3H),3.44(brs,2H),2.71(brs,2H),2.41(brs,2H),1.64–1.56(m,2H),1.52(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)163.3,153.7,151.7,135.2,133.6,117.8,65.5,60.7,52.41,52.40,43.2,29.7,28.5,25.4.
SP-3, productive rate 47.1%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.47(s,2H),3.24(dd,J＝12.2Hz,6.0Hz,4H),2.36(brs,4H),2.07(s,3H),1.66(m,4H),1.33(brs,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)163.3,153.7,151.7,135.2,133.6,117.8,60.7,56.7,55.3,41.0,38.8,38.2,29.8,27.6,27.2,25.5.
SP-4, productive rate 43%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)8.11(m,2H),7.74(m,2H),7.63(m,3H),3.81(s,2H),3.20(t,J＝6.1Hz,2H),2.91(m,2H),2.75(m,2H),2.25(s,3H),1.84(m,2H),1.72(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.2,151.6,133.8,132.2,132.1,128.6,127.2,127.0,126.0,123.6,125.5,124.2,57.6,56.0,41.7,38.9,28.9,26.1,24.6.
SP-6, productive rate 51.3%.
1H NMR(400MHz,CDCl 3):δ(ppm)8.11(m,2H),7.74(m,2H),7.63(m,2H),7.38(m,6H),7.26(m,8H),7.19(m,4H),5.15(s,4H),4.35(s,4H),3.24(dd,J＝12.2Hz,6.0Hz,4H),2.36(brs,4H),2.07(s,3H),1.66(m,4H),1.33(brs,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)163.0,152.9,136.9,133.8,132.2,132.1,128.6,128.5,128.3,128.2,127.2,127.0,126.0,125.6,125.5,124.2,77.4,56.7,55.3,41.0,38.8,38.2,29.8,27.6,27.2,25.5.
SP-7, productive rate 45%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.15(d,J＝6.8Hz,1H),7.04-6.99(m,1H),6.81-6.77(m,2H),5.30(s,2H),3.90(s,2H),3.70(s,3H),3.21(t,J＝6.2Hz,2H),2.96(m,2H),2.73(m,2H),2.25(s,3H),1.84(m,2H),1.62(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)163.0,157.1,151.9,129.3,127.5,124.6,120.4,110.4,57.6,56.0,55.6,41.7,38.9,28.9,26.4,24.6.
SP-8, productive rate 47%.
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.18(d,J＝6.8Hz,1H),7.04-6.99(m,1H),6.81-6.77(m,2H),5.30(s,2H),4.10(brs,2H),3.90(s,2H),3.70(s,3H),3.44(brs,2H),2.71(brs,2H),2.41(brs,2H),1.64–1.56(m,2H),1.52(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.2,157.2,151.6,129.4,127.5,124.6,120.4,110.4,75.8,55.1,54.0,43.3,28.9,26.8,25.7.
SP-9, productive rate 39.6%.
1HNMR(400MHz,CDCl 3):δ(ppm)7.27-7.22(m,6H),7.18-7.15(m,4H),7.12(d,J＝7.7Hz,2H),6.94(t,J＝7.29Hz,2H),6.82-6.76(m,4H),5.15(s,4H),3.90(s,4H),3.70(s,6H),3.34-3.27(m,4H),2.87-2.80(m,4H),2.46(s,3H),1.73(brs,4H),1.55(brs,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)163.5,157.2,152.8,137.0,129.3,128.4,128.0,127.8,127.5,124.6,120.4,110.4,77.3,55.6,55.4,54.0,39.6,37.8,36.6,29.7,27.0,24.9,24.5.
SP-10, productive rate 41.1%
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.23(dd,J＝6.6Hz,3.0Hz,1H),7.18-7.17(m,2H),7.06(dd,J＝7.5Hz,1.8Hz,1H),4.07(s,2H),3.20(t,J＝6.3Hz,2H),2.98(m,2H),2.75(m,2H),2.27(s,3H),1.83(m,2H),1.62(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.2,151.6,134.3,134.0,130.0,129.5,127.8,126.8,57.6,56.0,41.7,38.9,28.9,26.1,24.6.
SP-12, productive rate 48%
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.42(d,J＝8.8Hz,4H),7.37(d,J＝8.8Hz,4H),3.96(s,4H),3.46(m,2H),3.36(m,2H),2.78(brs,3H),2.50(brs,2H),2.01(brs,2H),1.75(brs,2H),1.63(brs,2H),1.33(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.2,151.6,134.8,132.3,130.8,128.7,56.3,53.6,38.5,37.1,34.1,29.8,28.9,25.7,25.1.
SP-13, productive rate 46.2%
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.40(d,J＝2.0Hz,1H),7.31-7.29(m,2H),7.13(dd,J＝8.5Hz,1.6Hz,1H),3.94(s,2H),3.36(dd,J＝12.4Hz,6.2Hz,2H),2.74(t,J＝6.9Hz,2H),2.39(brs,2H),2.22(s,3H),1.73(m,2H),1.49(brs,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.2,151.6,136.8,134.1,129.7,129.5,127.8,126.7,57.6,56.0,41.7,38.9,28.9,26.1,24.6.
SP-14, productive rate 40.9%
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.40(d,J＝2.0Hz,1H),7.31-7.29(m,2H),7.13(dd,J＝8.5Hz,1.6Hz,1H),4.08(brs,2H),3.93(s,2H),3.44(brs,2H),2.71(brs,2H),2.41(brs,2H),1.64–1.56(m,2H),1.52(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.0,151.6,136.8,134.3,129.7,129.5,127.8,126.8,75.8,55.1,54.0,43.3,28.9,26.8,25.7.
SP-15, productive rate 59.5%
1H NMR(400MHz,CDCl 3):δ(ppm)7.43-7.37(m,12H),7.29(m,6H),5.29(s,4H),3.96(s,4H),3.46(m,2H),3.36(m,2H),2.78(brs,3H),2.50(brs,2H),2.01(brs,2H),1.75(brs,2H),1.63(brs,2H),1.33(m,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)162.8,152.0,136.7,134.8,132.3,130.9,128.7,128.6,128.4,128.2,77.5,56.3,53.6,38.5,37.1,34.1,29.8,27.1,25.7,25.1.
SP-16, productive rate 42%
1H NMR(400MHz,DMSO-d 6):δ(ppm)7.42(d,J＝8.8Hz,2H),7.37(d,J＝8.8Hz,2H),3.96(s,2H),3.23(t,J＝6.1Hz,2H),2.95(m,2H),2.73(m,2H),2.25(s,3H),1.83(m,2H),1.62(m,2H).
13C NMR(100MHz,DMSO-d 6):δ(ppm)162.2,151.6,134.8,132.3,130.8,128.7,57.6,56.0,41.7,38.9,28.9,26.3,25.1.
SP-18, productive rate 60%
1HNMR(400MHz,CDCl 3):δ(ppm)7.37(s,1H),7.23(m,1H),7.29(m,1H),7.22(m,1H),5.14(s,2H),3.77(s,overlap,5H),3.30(q,2H),2.40(t,2H),2.30(t,2H),2.15(s,3H),1.65(t,2H),1.41(m,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)162.2,152.7,151.6,135.1,133.6,128.8,128.4,128.2,117.8,77.6,60.7,57.6,56.0,41.7,38.9,28.9,26.1,24.6.
SP-19, productive rate 58.3%
1HNMR(400MHz,CDCl 3):δ(ppm)8.12(m,1H),7.75(m,1H),7.64(m,1H),7.51(brs,1H),7.33(m,2H),7.27-7.24(m,4H),7.16(m,2H),5.13(s,2H),4.35(s,2H),3.26(dd,J＝12.2Hz,6.0Hz,4H),2.31(t,J＝6.6Hz,2H),2.22(brs,2H),2.06(s,3H),1.64-1.55(m,2H),1.36(d,J＝12.2Hz,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)162.9,153.1,137.0,133.9,132.3,131.0,128.6,128.5,128.2,128.1,127.2,127.0,126.0,125.6,125.5,124.2,77.3,57.5,55.8,41.6,38.7,27.6,26.0,19.3.
SP-20, productive rate 61.3%
1HNMR(400MHz,CDCl 3):δ(ppm)7.49(brs,1H),7.27-7.25(m,2H),7.16-7.13(m,3H),7.00(d,J＝7.1Hz,1H),6.80(d,J＝7.6Hz,1H),6.79(d,J＝8.2Hz,1H),5.13(s,2H),3.94(s,2H),3.71(s,3H),3.35(dd,J＝12.4Hz,6.3Hz,2H),2.43(t,J＝6.6Hz,2H),2.34(brs,2H),2.18(s,3H),1.70(m,2H),1.46(brs,2H).
13CNMR(100MHz,CDCl 3):δ(ppm)163.1,157.3,153.5,137.3,129.5,128.4,127.9,127.7,127.5,125.0,120.4,110.4,76.9,57.5,55.8,55.4,41.6,38.6,26.2,25.0,25.0
SP-21, productive rate 60.9%
1H NMR(400MHz,CDCl 3):δ(ppm)7.31(dd,J＝6.9Hz,1.9Hz,2H),7.23(d,J＝2.8Hz,2H),7.18(dd,J＝6.6Hz,3.0Hz,1H),7.13(dd,J＝7.3Hz,2.0Hz,1H),7.10(t,J＝3.2Hz,1H),7.08(dd,J＝7.2Hz,1.7Hz,1H),7.04(dd,J＝6.8Hz,2.4Hz,1H),5.17(s,2H),4.04(s,2H),3.36(dd,J＝12.5Hz,6.3Hz,2H),2.58(t,J＝ 6.8Hz,2H),2.52(brs,2H),2.32(s,3H),1.81(m,2H),1.58(brs,2H).
13C NMR(100MHz,CDCl 3):δ(ppm)162.9,151.9,136.9,134.3,134.0,130.0,129.5,128.5,128.2,128.0,127.8,126.8,77.3,56.7,55.1,41.1,38.0,29.8,28.3,25.7.
SP-22, productive rate 67%
1H NMR(400MHz,CDCl 3):δ(ppm)7.37-7.31(m,3H),7.28-7.26(m,3H),7.17-7.13(m,3H),5.20(s,2H),3.91(s,2H),3.36(dd,J＝12.4Hz,6.2Hz,2H),2.74(t,J＝6.9Hz,2H),2.39(brs,2H),2.22(s,3H),1.73(m,2H),1.49(brs,2H).
13C NMR(100MHz,CDCl 3):δ(ppm)162.5,152.0,138.4,136.8,134.1,129.7,129.5,128.7,128.3,128.1,127.8,126.7,77.4,57.4,55.8,41.5,38.6,29.8,25.9,24.3.
SP-23, productive rate 65.4%
1H NMR(400MHz,CDCl 3):δ(ppm)7.46-7.35(m,9H),5.31(s,2H),3.96(s,2H),3.47(dd,J＝12.7Hz,6.4Hz,2H),2.89(m,4H),2.63(s,3H),2.13-1.98(m,2H),1.90(brs,2H).
13C NMR(100MHz,CDCl 3):δ(ppm)163.1,151.8,136.7,134.8,132.3,130.8,128.7,128.6,128.4,128.3,77.6,55.9,54.5,40.4,37.1,29.5,25.0,22.3.
Embodiment nine: spermatinamine derivative bacteriostatic activity
Anti-microbial activity testing method REFERENCE TO RELATED people can deliver document: Steroids, 2013,78 volumes, the page number: 1353 – 1358.
The anti-microbial activity test data of the compounds of this invention is as table 1.
Table 1. Compound SP-1 ~ SP-23 anti-microbial activity (20hours)
Structure activity relationship is discussed:
1, the number of N and activity are proportionate, and the more activity of number of N are stronger.Spermine fragment containing four N is stronger more than 4 times than the compound activity of the spermidine fragment containing three N.
2, its anti-microbial activity of species influence of amine, secondary amine activity is obviously better than tertiary amine.After N in spermine fragment becomes six-ring, activity reduces greatly.
3, electronegativity size and activity are proportionate, and electronegativity is larger, and activity is stronger.Chlorine-containing compound, bromine-containing compound, oxygenatedchemicals electronegativity reduce successively, and activity weakens successively.
4, introducing benzyl makes compound activity improve 1 times.
5, on phenyl ring, substituent position does not almost affect activity.

Claims (4)

1. a derivative of natural product spermatinamine, is characterized in that, its structural formula is such as formula shown in (I):
In formula (I), R 1for alkoxyphenyl radical, halogeno-benzene or naphthalene, R 2for hydrogen or benzyl,
R 3for or
2. the derivative of natural product spermatinamine according to claim 1, is characterized in that, described R 1for methoxyphenyl, chlorophenyl, 2,4-bis-bromo-3-methoxyphenyl or naphthyls.
3., according to a preparation method for the arbitrary described spermatinamine derivative of claim 1,2, it is characterized in that, comprise the following steps:
S1. phenyl aldehyde group (II) and acetyl glycine, diacetyl oxide, acetic acid sodium reaction, obtain structural formula such as formula the compound shown in (III);
R 1CHO(II)
S2. the compound of step S1 gained as shown in structural formula (III) and 5%-20% aqueous hydrochloric acid are reacted, the compound obtained is obtained by reacting structural formula further such as formula the compound shown in (IV) with benzyl hydroxylamine hydrochloride;
S3. the structural formula obtained by step S2 reacts such as formula the compound shown in (IV) and N-hydroxy-succinamide, obtains the compound of structural formula as shown in formula V;
S4. with spermine or spermidine for raw material, carry out being obtained by reacting structural formula such as formula the compound shown in (VI) with 2-(uncle-butoxy carboxamide)-2-benzyl cyanide;
S5., after the structural formula obtained by step S4 reacts such as formula the compound shown in (VI) and formaldehyde, glacial acetic acid, sodium cyanoborohydride or sodium borohydride, structural formula is obtained such as formula the compound shown in (VII) or (VIII);
S6. structural formula step S4 obtained such as formula the compound shown in (VI) and formaldehyde, glacial acetic acid, react after, obtain structural formula such as formula the compound shown in (IX);
S7. the structural formula obtained by step S5 or S6 obtains structural formula such as formula the compound shown in (X), (XI) or (XII) such as formula the compound shown in (VII), (VIII) or (IX) and hydrochloric acid reaction;
S8. step S7 is obtained structural formula to obtain after the compound of structural formula as shown in formula V react, obtaining structural formula such as formula the compound shown in (XIII) such as formula the compound shown in (X), (XI) or (XII) and step S3;
S9., after the structural formula obtained by step S8 reacts with hydrogen under the catalysis of palladium such as formula the compound shown in (XIII), structural formula is obtained such as formula the compound shown in (XIV);
R in structural formula (II) ~ (XIV) 1, R 2, R 3be the arbitrary described R of claim 1,2 respectively 1, R 2, R 3substituting group.
4., according to an application for the arbitrary described spermatinamine derivative of claim 1,2, it is characterized in that, described spermatinamine derivative is applied in preparation antibacterials.
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