CN103073514A - Rupestonic acid heterocyclic amide derivative, and preparation method and application of derivative - Google Patents

Rupestonic acid heterocyclic amide derivative, and preparation method and application of derivative Download PDF

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CN103073514A
CN103073514A CN2013100394066A CN201310039406A CN103073514A CN 103073514 A CN103073514 A CN 103073514A CN 2013100394066 A CN2013100394066 A CN 2013100394066A CN 201310039406 A CN201310039406 A CN 201310039406A CN 103073514 A CN103073514 A CN 103073514A
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methylene dichloride
rupestonic acid
rupestonic
derivative
eluent
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CN103073514B (en
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阿吉艾克拜尔·艾萨
贺耀武
董长治
赵江瑜
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Xinjiang Technical Institute of Physics and Chemistry of CAS
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Xinjiang Technical Institute of Physics and Chemistry of CAS
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Abstract

The invention relates to a rupestonic acid heterocyclic amide amide derivative, and a preparation method and an application of the derivative. The preparation method of a triazole heterocyclic derivative in the derivative comprises the steps that rupestonic acid and amino propyne react to form a rupestonic acid amide derivative containing terminal alkyne, and then catalysis of cupric sulfate and vitamin C sodium is conducted. The method is mild in reaction condition, and simple and direct in experimental step. The derivative has anti-influenza virus activity; partial compounds have anti-influenza A virus activity; most compounds have anti-influenza B virus activity; and the derivative can serve as an anti-influenza virus medicine for treating influenza.

Description

Rupestonic acid contains heterocyclic amide derivative and its production and use
Technical field
The present invention relates to separate in the Chinese medicine Herba Achilleae monomeric compound rupestonic acid that obtains and contain heterocyclic amide derivative as a series of new rupestonic acid that lead compound was synthesized, this analog derivative has the pharmaceutical use that anti-influenza A virus infects through active test section compound, and majority of compounds has the pharmaceutical use that anti-Influenza B virus infects.
Background technology
Rupestonic acid is isolated a kind of pockwood alkane type sesquiterpene compound from the Chinese medicine Artemisia rupestris L., studies show that rupestonic acid has certain inhibition activity to Influenza B virus.
Contain heterogeneous ring compound and have widely biological activity, be published in recently one piece of article on the International Pharmaceutical chemical periodical and just reported and contain the activity that 1,2,3-3-triazole compounds has resisiting influenza virus.And the synthetic method of heterocyclic derivative is a lot, can synthesize easily different heterogeneous ring compounds.Therefore design has been synthesized rupestonic acid and has been contained heterocyclic amide derivative, and has carried out preliminary anti-influenza virus activity screening.
The present invention is incorporated into heterocycle in the rupestonic acid molecule, has synthesized a series of rupestonic acids and has contained Hete rocyclic derivatives, and is synthetic simple fast.
Summary of the invention
The object of the invention is to, a kind of rupestonic acid Hete rocyclic derivatives and its production and use is provided, the synthetic of triazole Hete rocyclic derivatives is the rupestonic acid amide derivatives that is at first obtained containing end-group alkyne by rupestonic acid and aminopropan alkyne reaction in this analog derivative, then under the catalysis of copper sulfate and sodium ascorbate, obtain, the method reaction conditions is gentle, and experimental procedure is simple and direct.Part of compounds of the present invention has the pharmaceutical use that anti-influenza A virus infects, and majority of compounds has the pharmaceutical use that anti-Influenza B virus infects.
A kind of Herba Achilleae ketone of the present invention contains Hete rocyclic derivatives, its structure such as general formula (I)
Figure BDA00002804282200021
N is 0-10;
R is phenyl, substituted-phenyl, heterocyclic radical, substituted heterocyclic radical, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.
Described rupestonic acid contains the preparation method of heterocyclic amide derivative, it is characterized in that following these steps to carrying out:
A, rupestonic acid is dissolved in the methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride under the ice bath, 1-hydroxy benzo triazole and DMAP, drip amino propine, stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, residue is adopted the column chromatography gradient elution, and eluent is methylene dichloride and methyl alcohol, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides;
B, the N-propyl group-2-alkynes rupestonic acid acid amides that step a is obtained and organic azide are dissolved in the 10ml methylene dichloride, dropping contains the aqueous solution of copper sulfate, then drip the aqueous solution that contains sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, adopt the column chromatography eluent to separate thick product again, eluent is methylene dichloride and methyl alcohol, can obtain target product.
The volume ratio of eluent described in the step a is methylene dichloride: methyl alcohol=100:1-50:1.
The volume ratio of eluent described in the step b is methylene dichloride: methyl alcohol=50:1.
Described rupestonic acid contains the purposes of heterocyclic amide derivative in the medicine of preparation anti-influenza A virus.
Described rupestonic acid contains the purposes of heterocyclic amide derivative in the medicine of the anti-Influenza B virus of preparation.
Described rupestonic acid contains the purposes of heterocyclic amide derivative in the medicine of the anti-first type of preparation or Influenza B virus.
Rupestonic acid of the present invention contains heterocyclic amide derivative, is that the heterocycle that will replace is incorporated in the rupestonic acid molecule, and synthetic a series of rupestonic acids contain heterocyclic amide derivative, and the chemical equation that wherein contains the alpine yarrow herb ketoacid derivatives of triazole is:
R is benzyl, substituted benzyl, phenyl, substituted-phenyl, heterocyclic radical, substituted heterocyclic radical, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.
The present invention has carried out preliminary In Vitro Anti first type (H3N2, H1N1) and Influenza B virus active testing to the derivative that is synthesized, and experimental result shows that a lot of compounds have good inhibition activity to first type and Influenza B virus.The method reaction conditions is gentle, and experimental procedure is simple and direct.
Embodiment
Below by embodiment the present invention is described, these embodiment only are used for the purpose of illustration, do not consist of any restriction to the scope of the invention;
Reagent:
Rupestonic acid separates according to a conventional method, purity: 98%, HPLC detects, and remaining reagent is commercially available analytical pure;
Embodiment 1
N-((1-(2-methyl-benzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 1b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
1H?NMR(400MHz,CDCl 3)δ6.10(s,1H,N-H),5.55(s,1H,H-13a),5.37(s,1H,H-13b),4.11(dd,J=5.3,2.6Hz,2H,H-3’),3.21–3.14(m,1H,H-1),2.96-2.90(m,1H,H-7),2.89-2.83(m,1H,H-6α),2.58(ddd,J=18.8,6.6,1.2Hz,1H,H-2β),2.56(t,J=2.6Hz,H-1’),2.46(ddd,J=19.5,12.2,1.3Hz,1H,H-6β),2.18–2.06(m,1H,H-10),2.03(dt,J=18.8,1.4Hz,1H,H-2α),2.02–2.00(m,1H),1.84-1.74(m,3H,H-9,H-8a),1.66-1.55(m,4H,H-14,H-8b),0.64(d,J=7.1Hz,3H,H-15); 13C?NMR(101MHz,CDCl 3)δ208.14,174.18,168.55,151.21,137.81,115.55,79.32,71.84,45.85,41.38,38.65,38.12,36.56,35.33,31.26,29.47,12.08,7.99.IR(v/cm -1):3298,2958,2920,1734,1683,1659,1619,1519；
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 2-methyl-benzyl nitrine 0.25mol(36.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.38(s,1H,H-5’),7.32–7.13(m,4H,ary-H),6.67(br,1H,N-H),5.55(s,1H,H-13a),5.51(s,2H,H-7’),5.34(d,J=0.8Hz,1H,H-13b),4.54(s,2H,H-6’),3.19-3.13(m,1H,H-1),2.93-2.85(m,1H,H-7),2.82(d,J=19.6Hz,1H,H-6α),2.57(ddd,J=18.7,6.6,1.0Hz,1H,H-2β),2.43(dd,J=19.3,12.3Hz,1H,,H-6β),2.28(s,3H,OCH 3),2.15–2.07(m,1H,H-10),2.07–1.98(dt,J=18,1Hz,1H,H-2α),1.83–1.70(m,3H,H-9,H-8a),1.67–1.51(m,4H,H-14,H-8b),0.65(d,J=7.2Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.29,174.41,169.08,151.34,137.92,137.04,132.32,131.25,129.65,129.45,126.87,115.71,60.53,52.67,45.99,41.52,38.71,38.29,36.71,35.48,31.38,19.12,12.22,8.13.IR(v/cm -1):3330,2923,1687,1622。
Embodiment 2
N-((1-(3-methyl-benzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 2b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 3-methyl-benzyl nitrine 0.25mol(36.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.47(s,1H,H-5’),7.2(t,J=7.4Hz,1H,H-5”),7.16(d,J=7.6Hz,1H,H-6”),7.08-7.04(m,2H,H-2”,H-4”),6.72(t,J=4.8Hz,1H,N-H),5.55(s,1H,H-13a),5.45(s,2H,H-7’),5.33(d,1H,H-13b),4.53(d,J=5.6Hz,2H,H-6’),3.17–3.13(m,1H,H-1),2.94–2.86(m,1H,H-7),2.83(d,J=19.6Hz,1H,H-6α),2.56(ddd,J=18.7,6.6,0.9Hz,1H,H-2β),2.43(ddd,J=19.8,12.2,0.8Hz,1H,H-6β),2.33(s,3H,OCH 3),2.14-2.07(m,1H,H-10),2.02(d,J=19.0Hz,1H,H-2α),1.82–1.69(m,3H,H-9,H-8a),1.65-1.53(m,4H,H-14,H-8b),0.63(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.27,174.40,169.09,151.32,144.77,139.17,137.90,134.35,129.77,129.17,129.00,125.33,122.19,115.71,54.45,45.97,41.50,38.67,38.30,36.69,35.46,35.22,31.39,21.45,12.20,8.11.IR(v/cm -1):3330,3142,2956,2921,2873,1684,1658,1618。
Embodiment 3
N-((1-(4-methyl-benzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 3b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 4-methyl-benzyl nitrine 0.25mol(36.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.45(s,1H,H-5’),7.16(s,4H,ary-H),6.69(br,1H,N-H),5.55(s,1H,H-13a),5.45(s,2H,H-7’),5.33(d,J=0.6Hz,1H,H-13b),4.52(d,J=5.5Hz,2H,H-6’),3.18-3.13(m,1H,H-1),2.94-2.85(m,1H,H-7),2.82(d,J=19.9Hz,1H,H-6α),2.57(ddd,J=18.7,6.6,0.9Hz,1H,H-2β),2.42(ddd,J=19.5,11.7,0.8Hz,1H,H-6β),2.34(s,3H,OCH 3),2.16–2.07(m,1H,H-10),2.06–1.98(m,1H,H-2α),1.82-1.71(m,3H,H-9,H-8a),1.69–1.50(m,3H,H-14,H-8b),0.64(t,J=7.3Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.28,174.42,169.09,151.32,139.02,137.90,131.41,129.96,128.33,122.11,115.71,60.52,54.27,45.97,41.51,38.49,36.69,35.47,35.19,31.38,21.29,12.20,8.11.IR(v/cm -1):3331,2956,2923,2855,1683,1658,1617,1516。
Embodiment 4
The preparation of N-((1-benzyl-1H-1,2,3-triazole-4-yl) methyl)-rupestonic acid acid amides 4b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and benzyl azide 0.25mol(33.25mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use dried over mgso, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=100:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.49(s,1H,H-5’),7.36–7.23(m,5H,aryl-H),6.82(br,1H,N-H),5.56(s,1H,H-13a),5.48(s,2H,H-7’),5.33(s,1H,H-13b),4.52(d,J=4.9Hz,2H,H-6’),3.18–3.12(m,1H,H-1),2.93–2.76(m,2H,H-7,H-6α),2.56(dd,J=18.8,6.6Hz,1H,H-2β),2.42(dd,J=19.3,12.0Hz,1H,H-6β),2.17–2.05(1H,H-10),2.01(d,J=18.8Hz,1H,H-2α),1.82-1.71(m,3H,H-14,H-8a),1.65–1.47(m,4H,H-14,H-8b),0.62(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.34,174.53,169.11,151.24,137.87,134.47,129.28,129.00,128.95,128.38,128.33,128.24,122.31,115.75,54.41,45.97,41.49,38.63,38.29,36.67,35.44,35.17,31.36,12.19,8.10.IR(v/cm -1):3330,2957,2922,1683,1658,1621。
Embodiment 5
N-((1-(3-methoxy-benzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 5b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 3-methoxyl group nitrine 0.25mol(40.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation namely obtains target product;
1H?NMR(400MHz,CDCl 3)δ7.48(s,1H,H-5’),7.28(t,J=8.0Hz,1H,H-5”),6.89(ddd,J=8.3,2.5,0.7Hz,1H,H-6”),6.85(dd,J=7.5,0.6Hz,1H,H-4”),6.79(t,J=2.0Hz,1H,H-2”),6.63(t,J=4.3Hz,1H,N-H),5.55(s,1H,H-13a),5.47(s,2H,H-7’),5.34(d,J=0.9Hz,1H,H-13b),4.55(d,J=5.6Hz,2H,H-6’),3.78(s,3H,OCH 3),3.19–3.13(m,1H,H-1),2.94-2.87(m,1H,H-7),2.83(d,J=19.9Hz,1H,H-6α),2.57(ddd,J=18.7,6.6,1.1Hz,1H,H-2β),2.43(dd,J=19.0,12.8Hz,1H,H-6β),2.14-2.08(m,1H,H-10),2.07-1.99(m,1H,H-2α),1.82-1.72(m,3H,,H-9,H-8a),1.64–1.57(m,4H,H-14,H-8b),0.64(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.34,174.45,169.11,160.28,151.35,137.93,135.90,130.41,120.44,115.73,114.33,114.06,55.46,54.39,46.00,41.52,38.69,38.31,36.70,35.48,35.22,31.41,12.22,8.13.IR(v/cm -1):3331,2957,2922,2854,1683,1659,1614.Anal.Cal?cd.for?C 26H 32N 4O 2·0.17C 6H 12·0.9H 2O:C,67.73;H,7.54;N,11.70;Found:C,68.02;H,7.33;N,10.60.
Embodiment 6
N-((1-(4-methoxy-benzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 6b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 4-methoxyl group nitrine 0.25mol(40.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation namely obtains target product;
1H?NMR(400MHz,CDCl 3)δ7.44(s,1H,H-5’),7.21(dt,J=8.8,2.6Hz,2H,H-2”,H-6”),6.88(dt,J=8.8,2.6Hz,2H,H-3”,H-5”),6.76(t,J=5.2Hz,1H,N-H),5.55(s,1H,H-13a),5.42(s,2H,H-7’),5.32(d,J=0.8Hz,1H,H-13b),4.51(d,J=5.6Hz,2H,H-6’),3.79(s,3H,OCH 3),3.27–3.13(m,1H,H-1),2.93–2.86(m,1H,H-7),2.82(d,J=20.2Hz,1H,H-6α),2.56(ddd,J=18.8,6.6,1.2Hz,1H,H-2β),2.46(ddd,J=19.5,12.2,1.3Hz,1H,H-6β),2.14–2.06(m,1H,H-10),2.02(dt,J=18.8,1.4Hz,1H,H-2α),1.82–1.70(m,3H,H-9,H-8a),1.63-1.51(m,4H,H-14,H-8b),0.63(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.26,174.42,169.08,160.14,151.29,144.74,137.87,129.83,126.44,121.96,115.69,114.64,55.46,53.96,45.96,41.49,38.65,38.28,36.67,35.45,35.21,31.36,12.19,8.10.IR(v/cm -1):3323,3136,2956,2922,1683,1657,1613。
Embodiment 7
N-((1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 7b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 2-chlorobenzyl nitrine 0.25mol(41.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation namely obtains target product;
1H?NMR(400MHz,CDCl 3)δ7.87(s,1H,H-5’),7.44-7.20(m,4H,aryl-H),6.75(br,1H,N-H),5.66(s,2H,H-7’),5.56(s,1H,H-13a),5.34(s,1H,H-13b),4.62(br,2H,H-6’),3.19-3.13(m,1H,H-1),2.91(t,J=11.0Hz,1H,H-7),2.83(d,J=19.5Hz,1H,H-6α),2.57(dd,J=18.8,6.4Hz,1H,H-2β),2.43(dd,J=19.3,11.8Hz,1H,H-6β),2.15–2.07(m,1H,H-10),2.02(d,J=19.4Hz,1H,H-2α),1.82–1.71(m,3H,H-9,H-8a),1.65-1.53(m,4H,H-14,H-8b),0.63(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.26,174.38,169.07,151.34,137.93,133.85,132.22,130.69,130.60,130.13,127.72,115.87,53.53,52.36,46.03,41.51,38.75,38.30,36.74,35.47,31.38,12.22,8.13.IR(v/cm -1):3328,3142,2962,2921,2874,1682,1658,1619.Anal.Calcd.for?C 25H 29ClN 4O 2·0.23CHCl 3:C,63.07;H,6.13;N,11.66;Found:C,62.86;H,6.25;N,11.56。
Embodiment 8
N-((1-(3-chlorobenzyl)-1N-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 8b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 3-chlorobenzyl nitrine 0.25mol(41.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography eluent separates, and can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.53(s,1H,H-5’),7.36-7.12(m,4H,aryl-H),6.68(br,1H,N-H),5.56(s,1H,H-13a),5.47(s,2H,H-7’),5.34(s,1H,H-13b),4.56(d,J=5.2Hz,2H,H-6’),3.18-3.13(m,1H,H-1),2.96–2.77(m,2H,H-7,H-6α),2.57(ddd,J=18.7,6.6,1.0Hz,1H,H-2β),2.43(dd,J=18.7,12.1Hz,1H,H-6β),2.15-2.07(m,1H,H-10),2.02(d,J=19.2Hz,1H,,H-2α),1.82–1.71(m,3H,H-9,H-8a),1.64–1.52(m,4H,H-14,H-8b),0.63(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.26,174.34,169.15,151.30,137.93,136.40,135.24,130.60,129.27,128.29,126.28,115.80,53.76,45.98,41.51,38.69,38.30,36.70,35.47,35.19,31.41,12.21,8.13.IR(v/cm -1):3320,3137,3054,2957,2922,1683,1657,1619。
Embodiment 9
N-((1-(4-chlorobenzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 9b
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 4-chlorobenzyl nitrine 0.25mol(41.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.49(s,1H,H-5’),7.37–7.32(m,2H,H-2”,H-6”),7.23–7.18(m,2H,H-3”,H-5”,6.63(br,1H,N-H),5.55(s,1H,H-13a),5.47(s,2H,H-7),5.34(d,J=0.9Hz,1H,H-13b),4.54(d,J=5.6Hz,2H,H-6’),3.19–3.13(m,1H,H-1),2.94-2.86(m,1H,H-7),2.83(d,J=19.6Hz,1H,H-6α),2.57(ddd,J=18.8,6.6,1.1Hz,1H,H-2β),2.43(ddd,J=18.5,12.3,0.8Hz,1H,H-6β),2.16-2.09(m,1H,H-10),2.05(dt,J=18.8,2.4Hz,1H,H-2α),1.82–1.70(m,3H,H-9,H-8a),1.66–1.55(m,4H,H-14,H-8b),0.64(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.28,174.33,169.15,151.32,137.94,135.17,132.97,129.59,129.55,122.24,115.76,53.71,45.99,41.52,38.70,38.29,36.71,35.48,35.19,31.41,12.22,8.14.IR(v/cm -1):3330,2961,2922,1682,1657,1618。
Embodiment 10
N-((1-(2-luorobenzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 10b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 2-luorobenzyl nitrine 0.25mol(37.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.56(s,1H,H-5’),7.41–7.08(m,4H,aryl-H),6.65(br,1H,N-H),5.56(s,2H,H-7’),5.55(s,H,H-13a),5.34(d,J=0.9Hz,1H,H-13b),4.53(d,J=5.6Hz,2H,H-6’),3.19–3.13(m,1H,H-1),2.94-2.87(m,1H,H-7),2.83(d,J=19.6Hz,1H,H-6α),2.57(ddd,J=18.7,6.6,1.1Hz,1H,H-2β),2.43(dd,J=19.0,11.8Hz,1H,H-6β),2.15–2.07(m,1H,H-10),2.03(dt,J=19.2,1.2Hz,1H,H-2α),1.83-1.72(m,3H,H-9,H-8a),1.67–1.53(m,4H,H-14,H-8b),0.64(t,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.31,174.40,169.11,161.98,151.37,137.94,131.26,130.83,125.02,116.19,115.98,115.71,48.02,45.99,41.53,38.72,38.30,36.71,35.49,35.18,31.39,12.22,8.13.IR(v/cm -1):3315,2921,1682,1618。
Embodiment 11
N-((1-(3-luorobenzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 11b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 3-luorobenzyl nitrine 0.25mol(37.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography eluent separates, and namely obtains target product;
1H?NMR(400MHz,CDCl 3)δ7.52(s,1H,H-5’),7.34(m,1H,H-5”),7.09–6.87(m,3H,H-2”,H-4”,H-6”),6.70(br,1H,N-H),5.55(s,1H,H-13a),5.49(s,2H,H-7’),5.34(d,J=0.9Hz,1H,H-13b),4.55(d,J=5.5Hz,2H,H-6’),3.18-3.13(m,1H,,H-1),2.94–2.78(m,2H,H-7,H-6α),2.58(ddd,J=18.8,6.6,1.2Hz,1H,H-2β),2.46(ddd,J=19.5,12.2,1.3Hz,1H,H-6β),2.15-2.07(m,1H,H-10),2.02(dt,J=19.2,1.4Hz,1H,H-2α),1.82-1.71(m,3H,H-9,H-8a),1.64–1.50(m,4H,H-14,H-8b),0.63(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.27,174.23,166.75,164.40,161.93,145.92,143.50,137.98,136.86,131.98,124.26,123.71,116.08,115.17,58.06,53.71,45.99,41.48,38.37,38.09,36.68,35.44,31.79,12.23,8.12.IR(v/cm -1):3315,3138,3056,2958,2922,1683,1658,1618。
Embodiment 12
N-((1-(4-luorobenzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 12b
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 4-luorobenzyl nitrine 0.25mol(37.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.50(s,1H,H-5’),7.26–7.20(m,2H,H-2”,H-6”),7.03(m,2H,H-3”,H-5”),6.89(br,1H,N-H),5.55(s,1H,H-13a),5.45(s,2H,H-7’),5.32(s,1H,H-13b),4.51(d,J=5.5Hz,2H,H-6’),3.19–3.08(m,1H,H-1),2.92–2.85(m,1H,H-7),2.81(d,J=19.6Hz,1H,H-6α),2.54(ddd,J=18.7,6.6,1.0Hz,1H,H-2β),2.41(ddd,J=19.6,12.2,0.6Hz,1H,H-6β),2.16-2.04(m,1H,H-10),2.00(dt,J=19.2,1.2Hz,1H,H-2α),1.79–1.70(m,3H,H-9,H-8a),1.64–1.47(m,4H,H-14,H-8b),0.62(t,J=7.3Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.28,174.34,169.14,164.31,161.84,151.35,137.94,130.21,130.13,116.45,116.23,115.73,53.71,46.00,41.51,38.71,38.29,36.71,35.47,35.22,31.40,12.21,8.13.IR(v/cm -1):3321,2957,2922,1683,1657,1618。
Embodiment 13
N-((1-(3,4-dichloro benzyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 13b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and 3,4-dichloro benzyl nitrine 0.25mol(50mg) is dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml merges organic phase, washes 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, thicker product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation can obtain target product;
1H?NMR(400MHz,CDCl 3)δ7.55(s,1H,H-5’),7.43(d,J=8.2Hz,1H,H-5”),7.34(d,J=2.1Hz,1H,H-2”),7.10(dd,J=8.3,2.1Hz,1H,H-6”),6.82(t,J=5.3Hz,1H,N-H),5.56(s,1H,H-13a),5.44(s,2H,H-7),5.34(d,J=0.8Hz,1H,H-13b),4.54(d,J=5.7Hz,2H,H-6’),3.17-3.12(m,1H,H-1),2.93–2.86(m,1H,H-7),2.82(d,J=19.6Hz,1H,H-6α),2.55(ddd,J=18.7,6.6,1.0Hz,1H,H-2β),2.42(ddd,J=19.8,12.5,0.8Hz,1H,H-6β),2.14–2.06(m,1H,H-10),2.01(dt,J=18.8,1.2Hz,1H,H-2α),1.84–1.67(m,3H,H-9,H-8a),1.64–1.51(m,4H,H-14,H-8b),0.62(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.25,174.37,169.16,151.20,145.34,137.88,134.65,133.49,133.40,131.25,130.07,127.36,122.46,115.82,60.50,53.05,45.96,41.48,38.63,38.27,36.66,35.43,35.17,31.39,12.18,8.10.IR(v/cm -1):3317,2957,2922,1683,1658,1618。
Embodiment 14
N-((1-(hexamethylene-2-thiazolinyl)-1H-1,2,3-triazole-4-yl) methyl)-preparation of rupestonic acid acid amides 14b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and hexamethylene-2-thiazolinyl nitrine 0.25mol(30.75mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation namely obtains target product;
1H?NMR(400MHz,CDCl 3)δ7.57(s,1H,H-5’),6.72(brs,1H,N-H),6.14(m,1H,H-3’’),5.76(m,1H,,H-2’’),5.56(s,1H,,H-13a),5.34(s,1H,,H-13b),5.23(m,1H,H-1”),4.56(d,J=5.6Hz,2H?H-6’),3.23–3.14(m,1H,H-1),2.92(t,J=11.7Hz,1H,H-7),2.84(d,J=19.0Hz,1H,H-6α),2.57(dd,J=19.2,6.0Hz,1H,H-2β),2.44(dd,J=19.6,12.2Hz,1H,H-6β),2.18-2.15(m,1H,H-10),2.06–1.89(m,1H,H-2α),1.86–1.53(m,13H,H-9,H-8,H-4”,H-5”,H-6”,H-14),0.64(d,J=7.1Hz,3H,H-15). 13C?NMR(101MHz,CDCl 3)δ208.36,174.52,169.11,151.37,137.91,134.20,123.96,120.97,115.65,56.21,46.00,41.52,38.72,38.30,36.71,35.48,35.26,31.40,30.69,24.70,19.18,12.22,8.13.IR(v/cm -1):3335,2924,2872,1683,1658,1620。
Embodiment 15
The preparation of N-((1-cyclohexyl-1H-1,2,3-triazole-4-yl) methyl)-rupestonic acid acid amides 15b:
Rupestonic acid 1.24g (5mmol) is dissolved in the 10ml methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride 6mmol under the ice bath, 1-hydroxy benzo triazole 6mmol and N, N-diisopropyl ethyl amine 6mmol, drip amino propine 0.41g (7.5mmol), stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, it is methylene dichloride: methyl alcohol=100:1-50:1 column chromatography gradient elution that residue is adopted eluent, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides (b);
With the N-propyl group that obtains-2-alkynes rupestonic acid acid amides 0.2mmol(57mg) and cyclohexyl nitrine 0.25mol(31.25mg) be dissolved in the 10ml methylene dichloride, dropping contains the 5ml aqueous solution of 0.1mmol (25mg) copper sulfate, then drip the 5ml aqueous solution that contains 0.5mmol (100mg) sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, again thick product being adopted eluent is methylene dichloride: methyl alcohol=50:1 column chromatography for separation namely obtains target product;
1H?NMR(400MHz,CDCl 3)δ7.55(s,1H,H-5’),6.75(brs,1H,N-H),5.57(s,1H,H-13a),5.34(s,1H,H-13b),4.56(d,J=5.6Hz,2H,H-6’),4.41(m,1H,H-1”),3.20–3.15(m,1H,H-1),2.92(t,J=11.7Hz,1H,H-7),2.88–2.78(m,1H,H-6α),2.57(ddd,J=18.7,6.6,1.1Hz,1H,H-2β),2.49–2.37(m,1H,H-6β),2.18-2.15(m,2H,H-2”a,H-6”a),2.14–2.09(m,1H,H-10),2.07–1.98(m,1H,,H-2α),1.96–1.88(m,2H,H-2”b,H-6”b),1.84–1.21(m,13H,H-8,H-9,H-3”,H-4”,H-5”,H-13),0.64(t,J=6.0Hz,3H,H-15). 13CNMR(101MHz,CDCl 3)δ208.26,174.43,169.11,151.36,137.89,115.68,60.45,53.55,45.99,41.51,38.69,38.31,36.71,35.48,35.27,33.65,31.39,25.27,25.22,12.20,8.12
IR(v/cm -1):3336,3137,2929,2858,1688,1659,1620。
Embodiment 16
The rupestonic acid that embodiment 1-15 is synthesized contains 1,2, and 3-triazole amide derivatives has carried out preliminary In Vitro Anti influenza virus active testing:
Test event: anti-influenza virus activity screening;
Test philosophy: take MDCK(dog kidney) cell is as virus host, and working sample suppresses virus and causes cytopathy degree (CPE);
Test material and method:
Virus strain:
Influenza A/FM/1/47 (H1N1), subculture in chick embryo allantoic cavity (20012.5), temperature-80 ℃ preservation;
Influenza A/ Tianjin Jin Nan/15/2009(H1N1) is the Tamiflu persister, subculture in chick embryo allantoic cavity (20012.5), temperature-80 ℃ preservation;
The influenza A/ Chinese is anti-/ 359/95(H3N2), and subculture in chick embryo allantoic cavity (20012.5), temperature-80 ℃ preservation;
Influenza B/ Ji prevents/13/97, subculture in chick embryo allantoic cavity (20012.5), temperature-80 ℃ preservation;
Sample preparation: sample is made into 20mg/ml (self-dissolving), does suitable dilution with nutrient solution before use, does 3 times of dilutions with nutrient solution again, each 8 extent of dilution;
Positive control drug: virazole (RBV), Xinxiang Pharmacy stock Co., Ltd (lot number 20080301), Tamiflu (institute of materia medica, Shanghai)
Testing method: mdck cell is inoculated 96 well culture plates, puts 5%CO 2, 37 ℃ of temperature were cultivated 24 hours, and mdck cell adds influenza virus, and 37 ℃ of absorption of temperature hypsokinesis in 2 hours venom of preventing or cure a disease adds respectively the maintenance medium of different extent of dilution medicines; Establish simultaneously the contrast of virus control and cell, 37 ℃ of temperature are cultivated and to be treated that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing (about 40 hours) when reaching 4+, calculate each sample resisiting influenza virus half-inhibition concentration (IC 50);
Carried out the toxotest of compound to cell in the time of the anti-influenza virus activity screening.Testing method is as follows:
Cell toxicity determination method: mdck cell is inoculated in 96 porocyte culture plates, every hole 2.5 ten thousand cells, 37 ℃ of temperature, 5%CO 2Cultivated 24 hours, 3 times of dilutions of medicine are added on the cell monolayer, continue to cultivate 48 hours, and observation of cell pathology record result presses Reed﹠amp; The Muench method is calculated medicine median toxic concentration (TC 50);
Wherein, rupestonic acid contains 1,2,3-triazole derivatives activity and cytotoxicity result as shown in Table 1 and Table 2:
Table 1: rupestonic acid contains the anti-Influenza B virus activity of 1,2,3-triazole derivatives and cytotoxicity result
Figure BDA00002804282200221
Figure BDA00002804282200231
C 50: half-inhibition concentration
TC 50: the medicine median toxic concentration
SI: selectivity index.SI=TC 50/IC 50。
Every group of parallel testing twice, the result is the mean value of twice test
Nd: expression does not have data
Table 2: rupestonic acid contains 1,2,3-triazole derivatives anti-influenza A virus (H1N1 virus strain, H3N2 virus strain and H1N1 Tamiflu persister) activity and cytotoxicity result
Figure BDA00002804282200232
IC 50: half-inhibition concentration;
TC 50: the medicine median toxic concentration;
SI: selectivity index, SI=TC 50/ IC 50
Every group of parallel testing twice, the result is the mean value of twice test;
Nd: expression does not have data.

Claims (6)

1. a rupestonic acid contains heterocyclic amide derivative, it is characterized in that structure such as the general formula (I) of this derivative
Figure FDA00002804282100011
N is 0-10;
R is phenyl, substituted-phenyl, heterocyclic radical, substituted heterocyclic radical, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl.
2. rupestonic acid according to claim 1 contains the preparation method of heterocyclic amide derivative, it is characterized in that following these steps to carrying out:
A, rupestonic acid is dissolved in the methylene dichloride, add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride under the ice bath, 1-hydroxy benzo triazole and DMAP, drip amino propine, stirred overnight at room temperature, add the 10ml methylene dichloride, wash respectively 3 times with saturated sodium bicarbonate solution and water, use anhydrous magnesium sulfate drying, concentrating under reduced pressure, residue is adopted the column chromatography gradient elution, and eluent is methylene dichloride and methyl alcohol, obtains intermediate N propyl group-2-alkynes rupestonic acid acid amides;
B, the N-propyl group-2-alkynes rupestonic acid acid amides that step a is obtained and organic azide are dissolved in the 10ml methylene dichloride, dropping contains the aqueous solution of copper sulfate, then drip the aqueous solution that contains sodium ascorbate, room temperature reaction 2 hours, separatory, water layer dichloromethane extraction 3 times, each 10ml, merge organic phase, wash 3 times, use anhydrous magnesium sulfate drying, concentrate and obtain thick product, adopt the column chromatography eluent to separate thick product again, eluent is methylene dichloride and methyl alcohol, can obtain target product.
3. method according to claim 2 is characterized in that eluent volume ratio described in the step a is methylene dichloride: methyl alcohol=100:1-50:1.
4. method according to claim 2 is characterized in that eluent volume ratio described in the step b is methylene dichloride: methyl alcohol=50:1.
5. rupestonic acid according to claim 1 contains the purposes of heterocyclic amide derivative in the medicine of preparation anti-influenza A virus.
6. rupestonic acid according to claim 1 contains the purposes of heterocyclic amide derivative in the medicine of the anti-Influenza B virus of preparation.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103275157A (en) * 2013-06-20 2013-09-04 中国科学院新疆理化技术研究所 Rupestonic acid amide derivative containing heterocyclic ring and sugar, preparation method and purposes thereof
CN105820147A (en) * 2016-04-29 2016-08-03 新疆维吾尔自治区药物研究所 Preparation method and application of active ingredients of artemisia rupestris
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CN112961114A (en) * 2021-02-20 2021-06-15 中国科学院新疆理化技术研究所 2-substituted rupestonic acid isoxazole amide derivative and preparation method and application thereof
CN112979470A (en) * 2021-02-20 2021-06-18 中国科学院新疆理化技术研究所 Methyl rupestonic acid derivative containing benzoyl and preparation method and application thereof
CN115160160A (en) * 2022-02-14 2022-10-11 厦门稀土材料研究所 Rupestonic acid ephedrine derivative and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101712631A (en) * 2008-10-08 2010-05-26 中国科学院新疆理化技术研究所 Derivates of rupestonic acid and uses thereof
CN102351811A (en) * 2011-07-28 2012-02-15 中国科学院新疆理化技术研究所 Ester derivative of rupestonic acid, and preparation method and purpose thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101712631A (en) * 2008-10-08 2010-05-26 中国科学院新疆理化技术研究所 Derivates of rupestonic acid and uses thereof
CN102351811A (en) * 2011-07-28 2012-02-15 中国科学院新疆理化技术研究所 Ester derivative of rupestonic acid, and preparation method and purpose thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JIANGYU ZHAO等: "Synthesis and anti-influenza activity of aminoalkyl rupestonates", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 22, 15 March 2012 (2012-03-15), pages 2321 - 2325 *
MORTEN MELDAL等: "Cu-Catalyzed Azide-Alkyne Cycloaddition", 《CHEM. REV.》, vol. 108, 13 August 2008 (2008-08-13), pages 2952 - 3015 *
姜凤超: "《药物设计学》", 31 January 2007, article "电子等排原理", pages: 137-148 *
赵江瑜 等: "新型一枝蒿酮酸异噁唑衍生物的合成及其抗A, B型流感病毒活性研究", 《有机化学》, vol. 32, 25 February 2012 (2012-02-25), pages 333 - 337 *

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CN103275157B (en) * 2013-06-20 2016-06-08 中国科学院新疆理化技术研究所 The rupestonic acid amide derivatives containing heterocycle and sugar and preparation method and purposes
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