CN103435622B - A kind of spiro indole diketopiperazine Alkaloid and synthetic method thereof and application - Google Patents

A kind of spiro indole diketopiperazine Alkaloid and synthetic method thereof and application Download PDF

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CN103435622B
CN103435622B CN201310330063.9A CN201310330063A CN103435622B CN 103435622 B CN103435622 B CN 103435622B CN 201310330063 A CN201310330063 A CN 201310330063A CN 103435622 B CN103435622 B CN 103435622B
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马养民
吴昊
任德成
张金
李延超
张弘弛
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Shaanxi University of Science and Technology
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Abstract

A kind of spiro indole diketopiperazine Alkaloid and synthetic method thereof and application; react close enantiomorph hydrochloride with L-Trp methyl ester hydrochloride and alkanoic through Pictet-Spengler; the inductor induced asymmetric transformation transformed through crystallization induced asymmetric after this obtains single anomeric product; single anomeric product is after Schotten-Baumann reaction forms amido linkage; reset through NBS and obtain spirane structure, spirane structure is sloughed protecting group and is closed ring and obtains spiro indole diketopiperazine Alkaloid under base catalysis.The method has that cost is low, route is easy, high yield, easily process, the advantages such as end product is consistent with natural product configuration; The spiro indole diketopiperazine Alkaloid that the present invention obtains can also be applied in the preparation of antibacterials.

Description

A kind of spiro indole diketopiperazine Alkaloid and synthetic method thereof and application
Technical field
The present invention relates to the complete synthesis field of natural alkaloid, be specifically related to a kind of spiro indole diketopiperazine Alkaloid and synthetic method thereof and application.
Background technology
Spiro indole diketopiperazine Alkaloid, as a kind of indole alkaloid of special construction, is distributed widely in occurring in nature, especially exists with the form of secondary fungus metabolite.Research finds, mouse mastopathy cell (tsFT210) can suppress in the G2/M phase by this Alkaloid, and confirms that it has cytotoxic activity to clones such as human chronic's myelocytic leukemia (K562) cell and mankind's promyelocytic leukemia (HL-60) cells.Separately report that some these compounds also have AntiHIV1 RT activity, antibacterial, insect trembles isoreactivity.Based on above feature, in recent years, a lot of report has been had around its study on the synthesis.At present, free radical addition Cheng Huan, metal complexes is mainly adopted to participate in [5+2] cycloaddition, 1 about such alkaloidal synthesis, the methods such as 3-dipole-diople interaction, though these methods successfully construct spirane structure and the connection to indoles and diketopiperazine unit, most method has the defects such as cost is high, reaction scheme is complicated, yield is on the low side, aftertreatment is loaded down with trivial details.In addition, the target product steric configuration that certain methods synthesizes and natural product different, and demonstrate different biological activitys, this makes the chiral synthesize based on native configurations become more crucial.
Summary of the invention
The object of the present invention is to provide a kind of spiro indole diketopiperazine Alkaloid and synthetic method thereof and application, the method is with low cost, reaction yield is high, be convenient to aftertreatment, its steric configuration of spiro indole diketopiperazine Alkaloid obtained is consistent with natural product, and obtained spiro indole diketopiperazine Alkaloid can be applied in antibacterials.
In order to achieve the above object, the alkaloidal general structure of spiro indole diketopiperazines of the present invention is as described below:
wherein, R is short-chain alkyl.
Described R is the straight chained alkyl of C2 ~ C4.
The alkaloidal synthetic method of a kind of spiro indole diketopiperazines, comprises the following steps:
1) back flow reaction in Virahol by L-Trp methyl ester hydrochloride and short-chain fat aldehyde, boil off Virahol and unnecessary short-chain fat aldehyde after having refluxed, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride; Wherein, the L-Trp methyl ester hydrochloride added and the mol ratio of alkanoic are (1:1) ~ (1:1.2), monitor reaction carry out in reflux course with TLC, until TLC detects that L-Trp methyl ester hydrochloride raw material point terminates reaction when disappearing;
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms; Then reflux in inductor mixing enantiomorph hydrochloride transformed at crystallization induced asymmetric, monitor reaction with TLC in reflux course and carry out, until TLC detects that on silica-gel plate, surplus next raw material point terminates to react; After backflow, cooling makes solid separate out, and by the solid suction filtration of precipitation out, obtains filter cake, and the inductor drip washing post-drying that filter cake crystallization induced asymmetric transforms must have 1-alkyl-1,2,3, the 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride of single configuration;
3) by the 1-alkyl-1 of single configuration, 2,3,4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, methylene dichloride and saturated aqueous sodium carbonate is mixed to form two-phase system, then in two-phase system, under agitation drip the dichloromethane solution of N-(9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine, dropwise rear stirring at room temperature 1h, stratification again, separatory, retain organic phase, aqueous phase methylene dichloride extracts repeatedly, the organic phase that the organic phase that merging retains and repeatedly aqueous phase extracted obtain, by evaporate to dryness after the organic phase drying after merging, obtain solid B; Wherein, the 1-alkyl-1 added, 2,3,1-alkyl-1 in the dichloromethane solution of 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, the mol ratio of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine in the dichloromethane solution of 2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester hydrochloride and N-(9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine is (1:1) ~ (1:1.2);
4) being dissolved in by solid B by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds reaction system that glacial acetic acid makes to obtain in acid; Reaction system is cooled to 0 ° of C, then under 0 ° of C, drip the mixing solutions of bromo-succinimide, stir under 0 ° of C after dropwising, then rise to room temperature continuation reaction 40min, then add the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then repeatedly uses dichloromethane extraction, merge the organic phase extracting and obtain, the dry also evaporate to dryness of organic phase after merging is obtained solid C; Be dissolved in methylene dichloride by solid C, then add morpholine, evaporate to dryness stir 40min under 20 ° of C ~ 40 ° C after, the solid D obtained, through purifying, obtains spiro indole diketopiperazine Alkaloid; Wherein, the mixing solutions of the bromo-succinimide dripped is that to be dissolved in by bromo-succinimide by volume ratio be obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF); In the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is (1.5 ~ 2): 1.
In described step 1), alkanoic is propionic aldehyde, butyraldehyde, valeraldehyde or isovaleric aldehyde.
Described step 1) and step 2) in the developping agent of TLC be the ethyl acetate of 10:1 and methanol mixed by volume ratio.
The 1-alkyl-1 of single configuration in described step 3), 2,3, the method that 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, methylene dichloride and saturated aqueous sodium carbonate is mixed to form two-phase system is: first by the 1-alkyl-1 of single configuration, 2,3,4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride salt is in methylene dichloride, and then add saturated aqueous sodium carbonate formation two-phase system wherein, and every 30mL methylene dichloride dissolves the 1-alkyl-1 of the single configuration of 2.5mmol, 2,3,4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride; The saturated aqueous sodium carbonate added is identical with the methylene chloride volume of 1-alkyl-1,2,3, the 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride for dissolving single configuration.
In described step 4), the volume of glacial acetic acid is 10:25 with the volume ratio for the tetrahydrofuran (THF) in the mixed solvent of dissolved solids B, after the pH value of the reaction solution that described step 4) has obtained after having regulated cancellation, first remove the tetrahydrofuran (THF) in reaction solution, then extract.
The morpholine added in described step 4) is 1:10 with the volume ratio for the methylene dichloride of dissolved solids C.
In described step 4), solid D adopts silica gel column chromatography gradient elution and recrystallizing methanol to carry out purifying successively, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, and the volume ratio of the mixed solvent PetroChina Company Limited. ether of sherwood oil and ethyl acetate and ethyl acetate is (1:0) ~ (0:1), spiro indole diketopiperazine Alkaloid obtains in the cut flowed out from silicagel column when the volume ratio of sherwood oil and ethyl acetate is 2:1.
The application of a kind of spiro indole diketopiperazine Alkaloid in preparation antibacterials.
Further, described antibacterials are the medicine of anti-gram-bacteria or the medicine of anti-plant pathogenic fungi.
Further, in described step 1), every 50mL Virahol dissolves the alkanoic of 10mmol, and reflux time is 4h.
Further, described step 2) reflux time is 18 ~ 22h.
Further, in described step 3), the dichloromethane solution of N-(9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine is formulated according to the methylene dichloride of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine of every 10mL methylene dichloride dissolving 3mmol;
Further, the organic phase after merging in step 3) and step 4) adopts anhydrous MgSO 4dry.
Further, the solid B of every milliliter of mixed solvent dissolving 0.05mmol in described step 4); Bromo-succinimide solution is the bromo-succinimide dissolving 5mmol according to the mixed solvent of every 10mL.
Compared with prior art, beneficial effect of the present invention is:
The present invention is mixing enantiomorph hydrochloride after the inductor process that crystallization induced asymmetric transforms (CIAT), the 1-alkyl-1 of the single configuration obtained, 2, 3, 4-tetrahydrochysene-β-hydrochloride is directly dissolved in methylene dichloride without desalination acidifying by click porphyrin-3-carboxylate methyl ester hydrochloride, then add saturated aqueous sodium carbonate and form two-phase system, the dichloromethane solution stirring of N-(9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine is added again to two-phase system, in whipping process, the 1-alkyl-1 of single configuration, 2, 3, 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride carries out desalination acidifying and Xiao Dun-Bao Man (Schotten-Baumann) reaction simultaneously, effectively can save reaction substrate like this, be conducive to improving reaction yield.In this step 3), for the formation of the saturated sodium carbonate solution of two-phase system on the one hand for sloughing the HCl molecule in intermediate, on the other hand for being absorbed in the HCl that in Schotten-Baumann reaction, condensation produces, so both significantly can reduce Na 2cO 3consumption, improve its utilization ratio, make again the treating processes of reaction become more convenient.
The present invention is before the spirocyclization carrying out step 4), and in 1-alkyl-1,2,3,4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, the protection of 2-NH takes direct acid amides to protect, and namely forms amido linkage by Schotten-Baumann reaction.This operation has been abandoned previously to be needed to introduce the protection of Boc-protecting group and the tedious steps of final deprotection, provides cost savings, simplifies synthesis step, improve yield simultaneously.
In addition, by structural characterization analysis, the spiro indole diketopiperazine Alkaloid that the present invention obtains finds that its steric configuration is consistent with natural product.
Accompanying drawing explanation
Fig. 1 is reaction scheme figure of the present invention, and wherein, R is ethyl, propyl group, normal-butyl or 2-methyl-propyl.
Embodiment
See Fig. 1, the present invention with L-Trp methyl ester hydrochloride 1 for raw material, to be obtained by reacting through Pickett-Shi Penggele (Pictet-Spengler) with alkanoic aldehyde and to mix enantiomorph hydrochloride, i.e. 1-alkyl-1, 2, 3, the 1-chirality mixture (mix-2-HCl) of the hydrochloride of 4-tetrahydrochysene-β-click porphyrin-3-carboxylicesters, after this in toluene-Nitromethane 99Min. mixed solvent, there is crystallization induced asymmetric transform the 1-alkyl-1 that (CIAT) obtains single configuration, 2, 3, 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride (cis-2-HCl), after cis-2-HCl forms amido linkage by Xiao Dun-Bao Man (Schotten-Baumann) reaction, its product is reset through NBS and is obtained solid C, i.e. spirane structure compound, spirane structure compound is sloughed protecting group and is closed ring and obtains final product target compound 3 under base catalysis, i.e. spiro indole diketopiperazine Alkaloid.The method has that cost is low, route is easy, high yield, easily process, the advantages such as end product is consistent with natural product configuration.The structure of intermediate cis-2-HCl and target compound 3 is determined through means such as fusing point test, NMR, ultimate analyses, and passes through 1h- 1hNOESY determines its configuration.
Embodiment 1:
1) agitator is being housed, constant pressure funnel, 50mL Virahol is added in the 100mL there-necked flask of condensation reflux unit, then in there-necked flask, under agitation add the propionic aldehyde of 12mmol, after being uniformly mixed, add the L-Trp methyl ester hydrochloride of 10mmol, reheat to reflux state and react, monitor reaction with TLC in back flow reaction process to carry out, reaction 4h, now TLC detects that L-Trp methyl ester hydrochloride raw material point disappears and generates two new product points, terminate reaction, pressure reducing and steaming Virahol and unnecessary propionic aldehyde, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride (the suitable back mixing compound of mix-2a-HCl), wherein, the developping agent of TLC is the ethyl acetate of 10:1 and methanol mixed by volume ratio,
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms, then the inductor that the mixing dried product of enantiomorph hydrochloride and 50mL crystallization induced asymmetric transform is rejoined in the there-necked flask of 100mL, heating reflux reaction, monitor reaction with TLC in back flow reaction process to carry out, reaction 20h, now TLC detects surplus next raw material point on silica-gel plate, terminate reaction, being cooled to room temperature makes a large amount of solid precipitation separate out, by the solid decompress filter of precipitation out, the inductor drip washing post-drying that the filter cake crystallization induced asymmetric obtained transforms, obtain white flaky solid (1S, 3S)-1-ethyl-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole-3-carboxylic acid methyl ester's hydrochloride (cis-2a-HCl), yield 87.82%, fusing point: 146 ° of C ~ 149 ° C.Wherein, the developping agent of TLC is the ethyl acetate of 10:1 and methanol mixed by volume ratio; The present embodiment (1S, 3S)-1-ethyl-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester hydrochloride (cis-2a-HCl) warp 1hNMR, 13cNMR, 1h- 1hNOESY and elemental analysis are determined:
1HNMR(400MHz,DMSO-d 6)δ:11.33(s,1H,indole-NH),10.21(brs,1H,NH 2 +Cl),9.87(brs,1H,NH 2 +Cl),7.50(d,J=7.1Hz,1H,Ar-H),7.39(d,J=7.4Hz,1H,Ar-H),7.13(t,J=7.2Hz,1H,Ar-H),7.05(t,J=6.9Hz,1H,Ar-H),4.68(d,J=7.2Hz,1H,4-Hα),4.56(t,J=5.2Hz,1H,1-H),3.87(s,3H,COOC H 3 ),3.28(dd,J=15.2,4.9Hz,1H,3-H),3.16-3.01(m,1H,4-Hβ),2.38-2.32(m,1H,1'-H),2.09-2.05(m,1H,1'-H),1.10(t,J=7.3Hz,3H,2'-H).
13CNMR(101MHz,DMSO-d 6)δ:169.53,136.96,130.27,126.02,122.36,119.62,118.55,111.94,105.28,55.44,55.31,53.54,46.85,24.31,10.04.
1H- 1HNOESYdata:1-H(3-H,4-Hα),3-H(1-H,4-Hα),4-Hα(4-Hβ,1-H,3-H),4-Hβ(4-Hα,3-H).
Ultimate analysis: C 15h 19n 2o 2cl, observed value, C61.11, H6.47, N9.47; Calculated value, C61.12, H6.50, N9.50%.
3) in the 100mL there-necked flask that agitator and constant pressure funnel are housed, add 30mL methylene dichloride, the cis-2a-HCl then adding 2.5mmol makes cis-2a-HCl dissolve completely, then adds the saturated Na of 30mL 2cO 3aqueous solution forms two-phase system; Then continue the two-phase system be slowly added drop-wise to by the dichloromethane solution of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine (Fmoc-L-prolyl chlorine) being placed in constant pressure funnel under stirring in there-necked flask, drip speed control and drip built in 1s/; Dropwise rear stirring at room temperature 1h to make to react completely, separatory, retain organic phase, aqueous phase methylene dichloride extracts 3 times repeatedly, the organic phase that the organic phase that merging retains and repeatedly aqueous phase extracted obtain, organic phase anhydrous magnesium sulfate carries out drying, and then evaporated under reduced pressure solvent obtains solid B; Wherein, be added drop-wise to the Fmoc-L-prolyl chlorine containing 3mmol in the dichloromethane solution of the Fmoc-L-prolyl chlorine in two-phase system, and the dichloromethane solution of Fmoc-L-prolyl chlorine is dissolved in 10mL methylene dichloride by the Fmoc-L-prolyl chlorine of 3mmol to make;
4) 2.5mmol solid B being dissolved in 50mL by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds the glacial acetic acid of 10mL, obtains reaction system; Mixing solutions dropper ice bath being cooled to the bromo-succinimide of 0 ° of C dropwise joins ice bath and is cooled in the reaction system of 0 ° of C, dropwise rear continuation to make to mix at ice bath stirring 5min, then remove ice bath and rise to room temperature and continue reaction 40min, then add the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then after boiling off the lower tetrahydrofuran (THF) of boiling point under the water-bath decompression of 56 ° of C, remaining solution with dichloromethane is extracted three times, merge the organic phase of extraction and carry out drying with anhydrous magnesium sulfate, then evaporated under reduced pressure solvent, obtains solid C; Solid C is dissolved in 50mL methylene dichloride, add 5mL morpholine as catalyzer, under 30 ° of C, after stirring reaction 1h, underpressure distillation removes desolventizing, the solid D obtained, through silica gel column chromatography gradient elution and recrystallizing methanol, obtains spiro indole diketopiperazine Alkaloid (cis-3a); Wherein, in the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is 2:1, the mixing solutions of bromo-succinimide is that bromo-succinimide is dissolved in by volume ratio is obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), and every 10mL mixed solvent dissolves the bromo-succinimide of 5mmol; Eluent is the positive gradient mixture of sherwood oil and ethyl acetate, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, according to sherwood oil: ethyl acetate volume ratio is 1:0,10:1,5:1,2:1,1:1,0:1, carries out wash-out successively, and spiro indole diketopiperazine Alkaloid is from V sherwood oil: V ethyl acetateobtain in the cut flowed out from silicagel column during=2:1.
The alkaloidal structural formula of the present embodiment spiro indole diketopiperazines is:
Chemical name is: (2S, 3S, 5aS, 10aS)-3-ethyl-5a, 6,7,8-tetrahydrochysene-1H-spiral shell [two pyrrolo-es [1,2-a:1', 2'-d] pyrazine-2,3'-indoline]-2', 5,10 (3H, 10aH)-triketone (cis-3a) white needles, yield 57.44%, fusing point: 133 ° of C ~ 134 ° C.
1HNMR(400MHz,DMSO-d 6)δ:10.59(s,1H,indole-NH),7.36(d,J=7.08Hz,1H,4'-H),7.26(t,J=7.62Hz,1H,5'-H),6.99(t,J=7.48Hz,1H,6'-H),6.87(d,J=7.64Hz,1H,7'-H),4.81(t,J=8.34Hz,1H,10a-H),4.40(t,J=7.86,1H,5a-H),3.78(dd,J=8.56,3.08Hz,1H,3-H),2.51(m,3H,1-Hβ,8-H),2.26(dd,J=13.16,7.48Hz,1-Hα),2.23-2.16(m,2H,3a-H),2.05-1.95(m,1H,3a-H),1.95-1.92(m,3H,6-H,7-H),1.80-1.63(m,1H,7-H),0.44(t,J=7.32Hz,3H,3b-H).
13CNMR(101MHz,DMSO-d 6)δ:180.75,168.34,166.54,142.64,129.18,127.81,125.78,122.10,110.10,63.66,60.99,58.45,54.95(spiro-C),45.02,34.13,27.90,23.70,23.65,11.21.
1H- 1HNOESYdata:1-Hα(1-Hβ),1-Hα(1-H a,10a-H,3-H),10a-H(1-Hβ,3-H),3-H(1-Hβ,10a-H),3a-H(4'-H),4'-H(3a-H).
Ultimate analysis, C 19h 21n 3o 3, observed value, C67.25, H6.25, N12.37; Calculated value, C67.24, H6.24, N12.38%.
Embodiment 2:
1) agitator is being housed, constant pressure funnel, about 50mL Virahol is added in the 100mL there-necked flask of condensation reflux unit, then in there-necked flask, under agitation add the butyraldehyde-n of 12mmol, after being uniformly mixed, add the L-Trp methyl ester hydrochloride of 10mmol, reheat to reflux state and react, monitor reaction with TLC in back flow reaction process to carry out, reaction 4h, now TLC detects that L-Trp methyl ester hydrochloride raw material point disappears and generates two new product points, terminate reaction, pressure reducing and steaming Virahol and unnecessary butyraldehyde-n, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, right drying, obtain mixing enantiomorph hydrochloride (the suitable back mixing compound of mix-2b-HCl).
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms, then the inductor that the mixing dried product of enantiomorph hydrochloride and 50mL crystallization induced asymmetric transform is rejoined in the there-necked flask of 100mL, heating reflux reaction, monitor reaction with TLC in back flow reaction process to carry out, reaction 20h, now TLC detects surplus next raw material point on silica-gel plate, terminate reaction, being cooled to room temperature makes a large amount of solid precipitation separate out, by the solid decompress filter of precipitation out, the inductor drip washing post-drying that the filter cake crystallization induced asymmetric obtained transforms, obtain white flaky solid (1S, 3S)-1-propyl group-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole-3-carboxylic acid methyl ester's hydrochloride (cis-2b-HCl), yield 84.41%, fusing point: 155 ° of C ~ 156 ° C.The present embodiment (1S, 3S)-1-propyl group-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester hydrochloride (cis-2b-HCl) warp 1hNMR, 13cNMR, 1h- 1hNOESY and elemental analysis are determined:
1HNMR(400MHz,DMSO-d 6)δ:11.36(s,1H,indole-NH),10.28(brs,1H,NH 2 +Cl),9.94(brs,1H,NH 2 +Cl),7.49(d,J=7.8Hz,1H,Ar-H),7.39(d,J=8.0Hz,1H,Ar-H),7.13(t,J=7.5Hz,1H,Ar-H),7.03(t,J=7.4Hz,1H,Ar-H),4.72(d,J=7.2Hz,1H,4-Hα),4.52(t,J=5.2Hz,1H,1-H),3.86(s,3H,COOC H 3 ),3.28(dd,J=15.6,4.7Hz,1H,3-H),3.14-3.02(m,1H,4-Hβ),2.31-2.22(m,1H,1'-H),2.05-2.01(m,1H,1'-H),1.69-1.45(m,2H,2'-H),1.00(t,J=7.3Hz,3H,3'-H).
13CNMR(101MHz,DMSO-d 6)δ:169.50,136.94,130.50,126.02,122.29,119.62,118.50,111.94,105.09,55.42,53.84,53.48,33.37,22.74,18.46,14.32.
1H- 1HNOESYdata:1-H(3-H,4-Hα),3-H(1-H,4-Hα),4-Hα(4-Hβ,1-H,3-H),4-Hβ(4-Hα,3-H).
Ultimate analysis, C 16h 21n 2o 2cl, observed value, C62.21, H6.87, N9.08; Calculated value, C62.23, H6.85, N9.07%.
3) in the 100mL there-necked flask that agitator and constant pressure funnel are housed, add 30mL methylene dichloride, the cis-2b-HCl then adding 2.5mmol makes cis-2b-HCl dissolve completely, then adds the saturated Na of 30mL 2cO 3aqueous solution forms two-phase system; Then continue the two-phase system be slowly added drop-wise to by the dichloromethane solution of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine (Fmoc-L-prolyl chlorine) being placed in constant pressure funnel under stirring in there-necked flask, drip speed control and drip built in 1s/; Dropwise rear stirring at room temperature 1h to make to react completely, separatory, retain organic phase, aqueous phase methylene dichloride extracts 3 times repeatedly, the organic phase that the organic phase that merging retains and repeatedly aqueous phase extracted obtain, organic phase anhydrous magnesium sulfate carries out drying, and then evaporated under reduced pressure solvent obtains solid B; Wherein, be added drop-wise to the Fmoc-L-prolyl chlorine containing 3mmol in the dichloromethane solution of the Fmoc-L-prolyl chlorine in two-phase system, and the dichloromethane solution of Fmoc-L-prolyl chlorine is dissolved in 10mL methylene dichloride by the Fmoc-L-prolyl chlorine of 3mmol to make;
4) 2.5mmol solid B being dissolved in 50mL by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds 10mL glacial acetic acid, obtains reaction system; Mixing solutions dropper ice bath being cooled to the bromo-succinimide of 0 ° of C dropwise joins ice bath and is cooled in the reaction system of 0 ° of C, dropwise rear continuation to make to mix at ice bath stirring 5min, then remove ice bath and rise to room temperature and continue reaction 40min, then add the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then after boiling off the lower tetrahydrofuran (THF) of boiling point under the water-bath decompression of 56 ° of C, remaining solution with dichloromethane is extracted three times, merge the organic phase of extraction and carry out drying with anhydrous magnesium sulfate, then evaporated under reduced pressure solvent, obtains solid C; Solid C is dissolved in 50mL methylene dichloride, add 5mL morpholine as catalyzer, under 20 ° of C, after stirring reaction 1h, underpressure distillation removes desolventizing, the solid D obtained, through silica gel column chromatography gradient elution and recrystallizing methanol, obtains spiro indole diketopiperazine Alkaloid (cis-3b); Wherein, in the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is 2:1, the mixing solutions of bromo-succinimide is that bromo-succinimide is dissolved in by volume ratio is obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), and every 10mL mixed solvent dissolves the bromo-succinimide of 5mmol; Eluent is the positive gradient mixture of sherwood oil and ethyl acetate, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, according to sherwood oil: ethyl acetate volume ratio is 1:0,10:1,5:1,2:1,1:1,0:1, carries out wash-out successively, and spiro indole diketopiperazine Alkaloid is from V sherwood oil: V ethyl acetateobtain in the cut flowed out from silicagel column during=2:1.
The alkaloidal structural formula of the present embodiment spiro indole diketopiperazines is:
Chemical name is: (2S, 3S, 5aS, 10aS)-3-propyl group-5a, 6,7,8-tetrahydrochysene-1H-spiral shell [two pyrrolo-es [1,2-a:1', 2'-d] pyrazine-2,3'-indoline]-2', 5,10 (3H, 10aH)-triketone (cis-3b) white needles, yield 51.08%, fusing point: 144 ° of C ~ 145 ° C.
1HNMR(400MHz,DMSO-d 6)δ:11.75(s,1H,indole-NH),7.76(d,J=8.2Hz,1H),7.47(d,J=8.3Hz,1H),7.31(t,J=7.6Hz,1H),7.09(t,J=7.3Hz,1H),4.41-4.35(m,1H),4.15(t,J=7.6Hz,1H),3.66(dd,J=14.1,4.9Hz,1H),3.61-3.53(m,1H),3.30(dd,J=14.2,7.8Hz,1H),3.02(td,J=7.1,2.9Hz,1H),2.10-2.02(m,1H),1.79-1.73(m,1H),1.68(dd,J=14.7,7.4Hz,1H),0.97(t,J=7.4Hz,1H).
13CNMR(101MHz,DMSO-d 6)δ:195.61,170.00,166.10,136.75,133.03,125.95,120.38,117.84,113.05,58.88,57.70(spiro-C),56.39,45.29,42.14,27.89,25.46,24.43,22.74,17.54,14.15.
1H- 1HNOESYdata:1-Hα(1-Hβ),1-Hα(1-H a,10a-H,3-H),10a-H(1-Hβ,3-H),3-H(1-Hβ,10a-H),3a-H(4'-H),4'-H(3a-H).
Ultimate analysis, C 20h 23n 3o 3, observed value, C67.95, H6.55, N11.92; Calculated value, C67.97, H6.56, N11.89%.
Embodiment 3:
1) agitator is being housed, constant pressure funnel, 50mL Virahol is added in the 100mL there-necked flask of condensation reflux unit, then under agitation in there-necked flask, 12mmol valeraldehyde is added, after being uniformly mixed, add the L-Trp methyl ester hydrochloride of 10mmol, reheat to reflux state and react, monitor reaction with TLC in back flow reaction process to carry out, reaction 4h, now TLC detects that L-Trp methyl ester hydrochloride raw material point disappears and generates two new product points, terminate reaction, pressure reducing and steaming Virahol and unnecessary valeraldehyde, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride (the suitable back mixing compound of mix-2c-HCl), wherein, the developping agent of TLC is the ethyl acetate of 10:1 and methanol mixed by volume ratio,
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms, then the inductor that the mixing dried product of enantiomorph hydrochloride and 50mL crystallization induced asymmetric transform is rejoined in 100mL there-necked flask, heating reflux reaction, monitor reaction with TLC in back flow reaction process to carry out, reaction 20h, now TLC detects surplus next raw material point on silica-gel plate, terminate reaction, being cooled to room temperature makes a large amount of solid precipitation separate out, by the solid decompress filter of precipitation out, the inductor drip washing post-drying that the filter cake crystallization induced asymmetric obtained transforms, obtain white flaky solid (1S, 3S)-1-butyl-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole-3-carboxylic acid methyl ester's hydrochloride (cis-2c-HCl), yield 87.44%, fusing point: 161 ° of C ~ 163 ° C.The present embodiment (1S, 3S)-1-butyl-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester hydrochloride (cis-2c-HCl) warp 1hNMR, 13cNMR, 1h- 1hNOESY and elemental analysis are determined:
1HNMR(400MHz,DMSO-d 6)δ:11.38(s,1H,indole-NH),10.29(brs,1H,NH 2 +Cl),9.94(brs,1H,NH 2 +Cl),7.49(d,J=7.8Hz,1H,Ar-H),7.39(d,J=8.1Hz,1H,Ar-H),7.13(t,J=7.5Hz,1H,Ar-H),7.03(t,J=7.3Hz,1H,Ar-H),4.71(t,J=4.3Hz,1H,1-H),4.52(d,J=7.2Hz,1H,4-Hα),3.86(s,3H,COOC H 3 ),3.28(dd,J=15.6,4.5Hz,1H,3-H),3.13-3.03(m,1H,4-Hβ),2.33-2.28(m,1H,1'-H),2.20-1.94(m,1H,1'-H),1.67-1.30(m,4H,2'-H,3'-H),0.95(t,J=7.2Hz,3H,4'-H).
13CNMR(101MHz,DMSO-d 6)δ:169.51,136.94,130.51,126.02,122.29,119.60,118.50,111.95,105.08,55.43,54.04,53.47,30.99,27.05,22.73,22.57,14.27.
1H- 1HNOESYdata:1-H(3-H,4-Hα),3-H(1-H,4-Hα),4-Hα(4-Hβ,1-H,3-H),4-Hβ(4-Hα,3-H).
Ultimate analysis, C 17h 23n 2o 2cl, observed value, C63.23, H7.17, N8.69; Calculated value, C63.25, H7.18, N8.68%.
3) in the 100mL there-necked flask that agitator and constant pressure funnel are housed, add 30mL methylene dichloride, the cis-2c-HCl then adding 2.5mmol makes cis-2c-HCl dissolve completely, then adds the saturated Na of 30mL 2cO 3aqueous solution forms two-phase system; Then continue the two-phase system be slowly added drop-wise to by the dichloromethane solution of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine (Fmoc-L-prolyl chlorine) being placed in constant pressure funnel under stirring in there-necked flask, drip speed control and drip built in 1s/; Dropwise rear stirring at room temperature 1h to make to react completely, separatory, retain organic phase, aqueous phase methylene dichloride extracts 3 times repeatedly, the organic phase that the organic phase that merging retains and repeatedly aqueous phase extracted obtain, organic phase anhydrous magnesium sulfate carries out drying, and then evaporated under reduced pressure solvent obtains solid B; Wherein, be added drop-wise to the Fmoc-L-prolyl chlorine containing 3mmol in the dichloromethane solution of the Fmoc-L-prolyl chlorine in two-phase system, and the dichloromethane solution of Fmoc-L-prolyl chlorine is dissolved in 10mL methylene dichloride by the Fmoc-L-prolyl chlorine of 3mmol to make;
4) 2.5mmol solid being dissolved in 50mL by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds 10mL glacial acetic acid, obtains reaction system; Mixing solutions dropper ice bath being cooled to the bromo-succinimide of 0 ° of C dropwise joins ice bath and is cooled in the reaction system of 0 ° of C, dropwise rear continuation to make to mix at ice bath stirring 5min, then remove ice bath and rise to after room temperature continues reaction 40min, then adding the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then after boiling off the lower tetrahydrofuran (THF) of boiling point under 56 ° of C water-bath decompressions, remaining solution with dichloromethane is extracted three times, merge the organic phase of extraction and carry out drying with anhydrous magnesium sulfate, then evaporated under reduced pressure solvent, obtains solid C; Solid C is dissolved in 50mL methylene dichloride, add 5mL morpholine as catalyzer, under 40 ° of C, after stirring reaction 1h, underpressure distillation is except desolventizing, and the solid D obtained, through silica gel column chromatography and recrystallizing methanol, obtains spiro indole diketopiperazine Alkaloid (cis-3c); Wherein, in the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is 2:1, the mixing solutions of bromo-succinimide is that bromo-succinimide is dissolved in by volume ratio is obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), and every 10mL mixed solvent dissolves the bromo-succinimide of 5mmol; Eluent is the positive gradient mixture of sherwood oil and ethyl acetate, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, according to sherwood oil: ethyl acetate volume ratio is 1:0,10:1,5:1,2:1,1:1,0:1, carries out wash-out successively, and spiro indole diketopiperazine Alkaloid is from V sherwood oil: V ethyl acetateobtain in the cut flowed out from silicagel column during=2:1.
The alkaloidal structural formula of the present embodiment spiro indole diketopiperazines is:
Chemical name is: (2S, 3S, 5aS, 10aS)-3-butyl-5a, 6,7,8-tetrahydrochysene-1H-spiral shell [two pyrrolo-es [1,2-a:1', 2'-d] pyrazine-2,3'-indoline]-2', 5,10 (3H, 10aH)-triketone (cis-3c) white needles, yield 49.25%, fusing point: 157 ° of C ~ 159 ° C.
1HNMR(400MHz,DMSO-d 6)δ:11.74(s,1H,indole-NH),7.76(d,J=8.2Hz,1H),7.47(d,J=8.3Hz,1H),7.31(t,J=7.6Hz,1H),7.09(t,J=7.5Hz,1H),4.37(d,J=6.0Hz,1H),4.15(t,J=7.6Hz,1H),3.66(dd,J=14.1,4.8Hz,1H),3.43-3.27(m,4H),3.09-3.00(m,2H),2.09-2.02(m,1H),1.79-1.70(m,3H),1.70-1.58(m,2H),1.38(dq,J=14.5,7.3Hz,2H),0.93(t,J=7.3Hz,3H).
13CNMR(101MHz,DMSO-d 6)δ:195.69,169.99,166.10,133.03,127.74,125.95,120.38,117.84,113.04,58.88,56.40(spiro-C),45.29,41.11,27.89,26.14,25.50,25.47,25.46,22.74,22.29,14.37.
1H- 1HNOESYdata:1-Hα(1-Hβ),1-Hα(1-H a,10a-H,3-H),10a-H(1-Hβ,3-H),3-H(1-Hβ,10a-H),3a-H(4'-H),4'-H(3a-H).
Ultimate analysis, C 21h 25n 3o 3, observed value, C68.65, H6.85, N11.42; Calculated value, C68.64, H6.86, N11.44%.
Embodiment 4:
1) agitator is being housed, constant pressure funnel, 50mL Virahol is added in the 100mL there-necked flask of condensation reflux unit, then in there-necked flask, under agitation add the isovaleric aldehyde of 12mmol, after being uniformly mixed, add the L-Trp methyl ester hydrochloride of 10mmol, reheat to reflux state and react, monitor reaction with TLC in back flow reaction process to carry out, reaction 4h, now TLC detects that L-Trp methyl ester hydrochloride raw material point disappears and generates two new product points, terminate reaction, pressure reducing and steaming Virahol and unnecessary isovaleric aldehyde, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride (the suitable back mixing compound of mix-2d-HCl), wherein, the developping agent of TLC is the ethyl acetate of 10:1 and methanol mixed by volume ratio,
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms, then the inductor that the mixing dried product of enantiomorph hydrochloride and 50mL crystallization induced asymmetric transform is rejoined in the there-necked flask of 100mL, heating reflux reaction, monitor reaction with TLC in back flow reaction process to carry out, reaction 20h, now TLC detects surplus next raw material point on silica-gel plate, terminate reaction, being cooled to room temperature makes a large amount of solid precipitation separate out, by the solid decompress filter of precipitation out, the inductor drip washing post-drying that the filter cake crystallization induced asymmetric obtained transforms, obtain white flaky solid (1S, 3S)-1-(2-methyl-propyl)-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole-3-carboxylic acid methyl ester's hydrochloride (cis-2d-HCl), yield 84.20%, fusing point: 153 ° of C ~ 154 ° C.The present embodiment (1S, 3S)-1-(2-methyl-propyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole-3-carboxylic acid methyl ester hydrochloride (cis-2d-HCl) warp 1hNMR, 13cNMR, 1h- 1hNOESY and elemental analysis are determined:
1HNMR(400MHz,DMSO-d 6)δ:11.27(s,1H,indole-NH),10.20(brs,1H,NH 2 +Cl),9.96(brs,1H,NH 2 +Cl),7.48(d,J=7.8Hz,1H,Ar-H),7.38(d,J=8.0Hz,1H,Ar-H),7.13(t,J=7.7Hz,1H,Ar-H),7.03(t,J=7.3Hz,1H,Ar-H),4.78(t,J=4.3Hz,1H,1-H),4.53(t,J=8.4Hz,1H,4-Hα),3.86(s,3H,-COOC H 3 ),3.30(dd,J=16.0,4.7Hz,1H,3-H),3.03(ddd,J=14.4,11.9,1.64Hz,1H,4-Hβ),2.11-2.00(m,2H,1'-H),1.98-1.89(m,1H,2'-H),1.06(d,J=5.2Hz,3H,3'-H),1.00(d,J=5.3Hz,3H,3'-H).
13CNMR(101MHz,DMSO-d 6)δ:169.75,136.90,130.73,126.02,122.40,119.70,118.54,111.99,104.94,55.39,53.53,52.00,40.72,40.19,23.94,22.97,21.99.
1H- 1HNOESYdata:1-H(3-H,4-Hα),3-H(1-H,4-Hα),4-Hα(4-Hβ,1-H,3-H),4-Hβ(4-Hα,3-H).
Ultimate analysis, C 17h 23n 2o 2cl, observed value, C63.24, H7.16, N8.70; Calculated value, C63.25, H7.18, N8.68%.
3) in the 100mL there-necked flask that agitator and constant pressure funnel are housed, add 30mL methylene dichloride, the cis-2d-HCl then adding 2.5mmol makes cis-2d-HCl dissolve completely, adds the saturated Na of 30mL 2cO 3aqueous solution forms two-phase system; Then continue the two-phase system be slowly added drop-wise to by the dichloromethane solution of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine (Fmoc-L-prolyl chlorine) being placed in constant pressure funnel under stirring in there-necked flask, drip speed control and drip built in 1s/; Dropwise rear stirring at room temperature 1h to make to react completely, separatory, retain organic phase, aqueous phase methylene dichloride extracts 3 times repeatedly, the organic phase that the organic phase retained and repeatedly aqueous phase extracted obtain, organic phase anhydrous magnesium sulfate carries out drying, and then evaporated under reduced pressure solvent obtains solid B; Wherein, be added drop-wise to the Fmoc-L-prolyl chlorine containing 3mmol in the dichloromethane solution of the Fmoc-L-prolyl chlorine in two-phase system, and the dichloromethane solution of Fmoc-L-prolyl chlorine is dissolved in 10mL methylene dichloride by the Fmoc-L-prolyl chlorine of 3mmol to make;
4) 2.5mmol solid B being dissolved in again 50mL by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds 10mL glacial acetic acid, obtains reaction system; Mixing solutions dropper ice bath being cooled to the bromo-succinimide of 0 ° of C dropwise joins ice bath and is cooled in the reaction system of 0 ° of C, dropwise rear continuation to make to mix at ice bath stirring 5min, then remove ice bath and rise to room temperature and continue reaction 40min, then add the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then after boiling off the lower tetrahydrofuran (THF) of boiling point under the water-bath decompression of 56 ° of C, remaining solution with dichloromethane is extracted three times, merge the organic phase of extraction and carry out drying with anhydrous magnesium sulfate, then evaporated under reduced pressure solvent, obtains solid C; Solid C is dissolved in 50mL methylene dichloride, add 5mL morpholine as catalyzer, under 25 ° of C, after stirring reaction 1h, underpressure distillation is except desolventizing, and the solid D obtained, through silica gel column chromatography and recrystallizing methanol, obtains spiro indole diketopiperazine Alkaloid (cis-3d); Wherein, in the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is 2:1, the mixing solutions of bromo-succinimide is that bromo-succinimide is dissolved in by volume ratio is obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), and every 10mL mixed solvent dissolves the bromo-succinimide of 5mmol; Eluent is the positive gradient mixture of sherwood oil and ethyl acetate, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, according to sherwood oil: ethyl acetate volume ratio is 1:0,10:1,5:1,2:1,1:1,0:1, carries out wash-out successively, and spiro indole diketopiperazine Alkaloid is from V sherwood oil: V ethyl acetateobtain in the cut flowed out from silicagel column during=2:1.
The alkaloidal structural formula of the present embodiment spiro indole diketopiperazines is:
Chemical name is: (2S, 3S, 5aS, 10aS)-3-(2-methyl-propyl)-5a, 6,7,8-tetrahydrochysene-1H-spiral shell [two pyrrolo-es [1,2-a:1', 2'-d] pyrazine-2,3'-indoline]-2', 5,10 (3H, 10aH)-triketone (cis-3d) white needles, yield 47.21%, fusing point: 150 ° of C ~ 151 ° C.
1HNMR(400MHz,DMSO-d 6)δ:11.14(s,1H,indole-NH),7.57(d,J=7.7Hz,1H),7.37(d,J=8.0Hz,1H),7.10-7.08(m,1H),7.04-6.99(m,1H),5.36(dd,J=8.8,4.3Hz,1H),4.30-4.23(m,2H),3.51-3.27(m,4H),2.89(dd,J=15.6,11.9Hz,1H),1.94-1.83(m,3H),1.61-1.54(m,1H),1.50-1.40(m,2H),0.98(d,J=6.2Hz,3H),0.75(d,J=6.3Hz,3H).
13CNMR(101MHz,DMSO-d 6)δ:182.39,169.57,166.14,135.54,126.33,121.31,119.27,118.31,111.86,58.96,56.48(spiro-C),50.21,46.61,45.29,28.34,24.71,24.14,22.40,21.47.
1H- 1HNOESYdata:1-Hα(1-Hβ),1-Hα(1-Hβ,10a-H,3-H),10a-H(1-Hβ,3-H),3-H(1-Hβ,10a-H),3a-H(4'-H),4'-H(3a-H).
Ultimate analysis, C 21h 25n 3o 3, observed value, C68.63, H6.88, N11.45; Calculated value, C68.64, H6.86, N11.44%.
Embodiment 5:
1) agitator is being housed, constant pressure funnel, 50mL Virahol is added in the 100mL there-necked flask of condensation reflux unit, then in there-necked flask, under agitation add the isovaleric aldehyde of 10mmol, after being uniformly mixed, add the L-Trp methyl ester hydrochloride of 10mmol, reheat to reflux state and react, monitor reaction with TLC in back flow reaction process to carry out, reaction 4h, now TLC detects that L-Trp methyl ester hydrochloride raw material point disappears and generates two new product points, terminate reaction, pressure reducing and steaming Virahol and unnecessary isovaleric aldehyde, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride (the suitable back mixing compound of mix-2d-HCl), wherein, the developping agent of TLC is the ethyl acetate of 10:1 and methanol mixed by volume ratio,
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms, then the inductor that the mixing dried product of enantiomorph hydrochloride and 50mL crystallization induced asymmetric transform is rejoined in the there-necked flask of 100mL, heating reflux reaction, monitor reaction with TLC in back flow reaction process to carry out, reaction 22h, now TLC detects surplus next raw material point on silica-gel plate, terminate reaction, being cooled to room temperature makes a large amount of solid precipitation separate out, by the solid decompress filter of precipitation out, the inductor drip washing post-drying that the filter cake crystallization induced asymmetric obtained transforms, obtain white flaky solid (1S, 3S)-1-(2-methyl-propyl)-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole-3-carboxylic acid methyl ester's hydrochloride (cis-2d-HCl), yield 84.20%, fusing point: 153 ° of C ~ 154 ° C.
3) in the 100mL there-necked flask that agitator and constant pressure funnel are housed, add 30mL methylene dichloride, the cis-2d-HCl then adding 2.5mmol makes cis-2d-HCl dissolve completely, adds the saturated Na of 30mL 2cO 3aqueous solution forms two-phase system; Then continue the two-phase system be slowly added drop-wise to by the dichloromethane solution of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine (Fmoc-L-prolyl chlorine) being placed in constant pressure funnel under stirring in there-necked flask, drip speed control and drip built in 1s/; Dropwise rear stirring at room temperature 1h to make to react completely, separatory, retain organic phase, aqueous phase methylene dichloride extracts 3 times repeatedly, the organic phase that the organic phase retained and repeatedly aqueous phase extracted obtain, organic phase anhydrous magnesium sulfate carries out drying, and then evaporated under reduced pressure solvent obtains solid B; Wherein, be added drop-wise to the Fmoc-L-prolyl chlorine containing 2.5mmol in the dichloromethane solution of the Fmoc-L-prolyl chlorine in two-phase system, and the dichloromethane solution of Fmoc-L-prolyl chlorine is dissolved in 10mL methylene dichloride by the Fmoc-L-prolyl chlorine of 2.5mmol to make;
4) 2.5mmol solid B being dissolved in again 50mL by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds 10mL glacial acetic acid, obtains reaction system; Mixing solutions dropper ice bath being cooled to the bromo-succinimide of 0 ° of C dropwise joins ice bath and is cooled in the reaction system of 0 ° of C, dropwise rear continuation to make to mix at ice bath stirring 5min, then remove ice bath and rise to room temperature and continue reaction 40min, then add the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then after boiling off the lower tetrahydrofuran (THF) of boiling point under the water-bath decompression of 56 ° of C, remaining solution with dichloromethane is extracted three times, merge the organic phase of extraction and carry out drying with anhydrous magnesium sulfate, then evaporated under reduced pressure solvent, obtains solid C; Solid C is dissolved in 50mL methylene dichloride, add 5mL morpholine as catalyzer, under 25 ° of C, after stirring reaction 1h, underpressure distillation is except desolventizing, and the solid D obtained, through silica gel column chromatography and recrystallizing methanol, obtains spiro indole diketopiperazine Alkaloid (cis-3d); Wherein, in the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is: 1.5:1, the mixing solutions of bromo-succinimide is that bromo-succinimide is dissolved in by volume ratio is obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), and every 10mL mixed solvent dissolves the bromo-succinimide of 5mmol; Eluent is the positive gradient mixture of sherwood oil and ethyl acetate, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, according to sherwood oil: ethyl acetate volume ratio is 1:0,10:1,5:1,2:1,1:1,0:1, carries out wash-out successively, and spiro indole diketopiperazine Alkaloid is from V sherwood oil: V ethyl acetateobtain in the cut flowed out from silicagel column during=2:1.
Embodiment 6:
1) agitator is being housed, constant pressure funnel, 50mL Virahol is added in the 100mL there-necked flask of condensation reflux unit, then under agitation in there-necked flask, 11mmol valeraldehyde is added, after being uniformly mixed, add the L-Trp methyl ester hydrochloride of 10mmol, reheat to reflux state and react, monitor reaction with TLC in back flow reaction process to carry out, reaction 4h, now TLC detects that L-Trp methyl ester hydrochloride raw material point disappears and generates two new product points, terminate reaction, pressure reducing and steaming Virahol and unnecessary valeraldehyde, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride (the suitable back mixing compound of mix-2c-HCl), wherein, the developping agent of TLC is the ethyl acetate of 10:1 and methanol mixed by volume ratio,
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms, then the inductor that the mixing dried product of enantiomorph hydrochloride and 50mL crystallization induced asymmetric transform is rejoined in 100mL there-necked flask, heating reflux reaction, monitor reaction with TLC in back flow reaction process to carry out, reaction 18h, now TLC detects surplus next raw material point on silica-gel plate, terminate reaction, being cooled to room temperature makes a large amount of solid precipitation separate out, by the solid decompress filter of precipitation out, the inductor drip washing post-drying that the filter cake crystallization induced asymmetric obtained transforms, obtain white flaky solid (1S, 3S)-1-butyl-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] indole-3-carboxylic acid methyl ester's hydrochloride,
3) in the 100mL there-necked flask that agitator and constant pressure funnel are housed, add 30mL methylene dichloride, the cis-2c-HCl then adding 2.5mmol makes cis-2c-HCl dissolve completely, then adds the saturated Na of 30mL 2cO 3aqueous solution forms two-phase system; Then continue the two-phase system be slowly added drop-wise to by the dichloromethane solution of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine (Fmoc-L-prolyl chlorine) being placed in constant pressure funnel under stirring in there-necked flask, drip speed control and drip built in 1s/; Dropwise rear stirring at room temperature 1h to make to react completely, separatory, retain organic phase, aqueous phase methylene dichloride extracts 3 times repeatedly, the organic phase that the organic phase that merging retains and repeatedly aqueous phase extracted obtain, organic phase anhydrous magnesium sulfate carries out drying, and then evaporated under reduced pressure solvent obtains solid B; Wherein, be added drop-wise to the Fmoc-L-prolyl chlorine containing 2.75mmol in the dichloromethane solution of the Fmoc-L-prolyl chlorine in two-phase system, and the dichloromethane solution of Fmoc-L-prolyl chlorine is dissolved in 10mL methylene dichloride by the Fmoc-L-prolyl chlorine of 2.75mmol to make;
4) 2.5mmol solid being dissolved in 50mL by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds 10mL glacial acetic acid, obtains reaction system; Mixing solutions dropper ice bath being cooled to the bromo-succinimide of 0 ° of C dropwise joins ice bath and is cooled in the reaction system of 0 ° of C, dropwise rear continuation to make to mix at ice bath stirring 5min, then remove ice bath and rise to after room temperature continues reaction 40min, then adding the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then after boiling off the lower tetrahydrofuran (THF) of boiling point under 56 ° of C water-bath decompressions, remaining solution with dichloromethane is extracted three times, merge the organic phase of extraction and carry out drying with anhydrous magnesium sulfate, then evaporated under reduced pressure solvent, obtains solid C; Solid C is dissolved in 50mL methylene dichloride, add 5mL morpholine as catalyzer, under 40 ° of C, after stirring reaction 1h, underpressure distillation is except desolventizing, and the solid D obtained, through silica gel column chromatography and recrystallizing methanol, obtains spiro indole diketopiperazine Alkaloid (cis-3c); Wherein, in the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is 1.8:1, the mixing solutions of bromo-succinimide is that bromo-succinimide is dissolved in by volume ratio is obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), and every 10mL mixed solvent dissolves the bromo-succinimide of 5mmol; Eluent is the positive gradient mixture of sherwood oil and ethyl acetate, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, according to sherwood oil: ethyl acetate volume ratio is 1:0,10:1,5:1,2:1,1:1,0:1, carries out wash-out successively, and spiro indole diketopiperazine Alkaloid is from V sherwood oil: V ethyl acetateobtain in the cut flowed out from silicagel column during=2:1.
Bacteriostatic activity test is carried out to four kinds of spiro indole diketopiperazine Alkaloids that the present invention obtains below.
1) test strain
Bacterium: intestinal bacteria (Escherichiacoli, EC, Gram-negative bacteria), Pseudomonas aeruginosa (Pseudomonasaeruginosa, PA, Gram-negative bacteria); Streptococcus aureus (Staphylococcusaureus, SA, gram-positive microorganism), subtilis (Bacillussubtilis, BS, gram-positive microorganism).
Plant pathogenic fungi: Peony Anthracnose (Colletotirchumgloeosporioides, CG), Valsa mali (Valsamali, VM), Alternaria brassicae (Alternariabrassicae, AB), tobacco brown spot pathogen (Alternariaalternata, AA).
2) substratum
Bacteria culture medium: NaCl5g, water 1000mL, extractum carnis 3.0g, peptone 10g, pH7.4 ~ 7.6,121 ° of C sterilizing 20min are for subsequent use.
Plant pathogenic fungi substratum: the potato 200g of peeling, is cut into small pieces, boils 30min, with eight layers of filtered through gauze removing potato ball, add glucose 20g, add distilled water to 1L, be dispensed in Erlenmeyer flask, 121 ° of C sterilizing 20min are for subsequent use.
3) preparation of substratum and bacteria suspension
The preparation method of substratum: adopt liquid nutrient medium equimultiple dilution method to carry out the alkaloidal anti-microbial activity test of spiro indole diketopiperazines.To learn from else's experience 96 orifice plates (12 row × 8 row) of ultraviolet sterilization, often arrange from left to right and be numbered respectively 1 ~ No. 10 (last 2 row are not numbered).With the first behavior example, accurately add with microsyringe the 100 μ g/mL spiro indole diketopiperazines alkaloid compound stostes that 0.2mL prepared in No. 1 hole, 0.1mL liquid nutrient medium is respectively added in No. 2 to No. 9 holes, then from No. 1 hole, 0.1mL to 2 hole is drawn, from No. 2 holes, 0.1mL to 3 hole is drawn again after mixing ... by that analogy, till being diluted to No. 9 holes, and from No. 9 holes, draw 0.1mL discard, No. 10 holes are not containing the blank control wells of compound, only add 0.2mL liquid nutrient medium.The compound concentration in No. 2 to No. 9 holes is made to be formulated as 50 μ g/mL, 25 μ g/mL, 12.5 μ g/mL, 6.25 μ g/mL, 3.13 μ g/mL, 1.56 μ g/mL, 0.78 μ g/mL, 0.39 μ g/mL successively.Often row culture plate can be used for a kind of compound to carry out testing the MIC of a strain bacterium.
The preparation of bacteria suspension: the bacteria suspension concentration of test bacterium is made into 106CFU/mL with counting method of blood cell.Positive control benzylpenicillin sodium (penicillinsodium, gram-positive microorganism (G +) positive control), Vetstrep (streptomycinsulfate, Gram-negative bacteria (G -) positive control), KETOKONAZOL (ketoconazole, the positive control of fungi).
3) mensuration of spiro indole diketopiperazine Alkaloid minimal inhibitory concentration (MIC)
By above-mentioned 96 orifice plates preparing substratum through ultraviolet sterilization and after drying, the various bacteria suspension for examination bacterium of accurate measuring 0.1mL adds often in row 1 ~ No. 10 hole respectively, build with special lid after sample mix is even, be placed in constant incubator to cultivate, bacterium cultivates 24h under 37 ° of C conditions, and fungi cultivates 48h under 28 ° of C conditions.The growing state of test bacterium can be found out roughly by visual inspection: if liquid-transparent clarification in culture hole, represent that test bacteria growing is suppressed, if liquid is that muddy shape or bottom have precipitation to occur in culture hole, the not suppressed growth of test bacterium is described.
Table 1 spiro indole diketopiperazine Alkaloid is to the minimum inhibition concentration result of bacterium
As can be seen from the table, the alkaloidal bacteriostatic activity of spiro indole diketopiperazines is better, wherein a lot of active in penicillin or Vetstrep, and generally must show and be better than Gram-negative bacteria active to gram-positive bacteria activity.
Table 2 spiro indole diketopiperazine Alkaloid is to the minimum inhibition concentration result of fungi
As can be seen from the table, spiro indole diketopiperazine Alkaloid is to the inhibit activities of fungi close to KETOKONAZOL, and this may be relevant with fungal cell wall composition and metabolic pathway.

Claims (7)

1. the alkaloidal synthetic method of spiro indole diketopiperazines, is characterized in that, comprise the following steps:
1) back flow reaction in Virahol by L-Trp methyl ester hydrochloride and short-chain fat aldehyde, boil off Virahol and unnecessary short-chain fat aldehyde after having refluxed, obtain solid A, solid A through toluene drip washing to remove the impurity of solubility, then dry, obtain mixing enantiomorph hydrochloride; Wherein, the L-Trp methyl ester hydrochloride added and the mol ratio of short-chain fat aldehyde are (1:1) ~ (1:1.2), monitor reaction with TLC in reflux course to carry out, until TLC detects the product point that L-Trp methyl ester hydrochloride raw material point disappearance generation two is new; Wherein, short-chain fat aldehyde is propionic aldehyde, butyraldehyde or valeraldehyde;
2) according to the volume ratio of 1:1, Nitromethane 99Min. is mixed with toluene, obtain the inductor that crystallization induced asymmetric transforms; Then reflux in inductor mixing enantiomorph hydrochloride transformed at crystallization induced asymmetric, monitor reaction with TLC in reflux course and carry out, until TLC detects that on silica-gel plate, surplus next raw material point terminates to react; After backflow, cooling makes solid separate out, and by the solid suction filtration of precipitation out, obtains filter cake, and the inductor drip washing post-drying that filter cake crystallization induced asymmetric transforms must have 1-alkyl-1,2,3, the 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride of single configuration; Wherein, the alkyl in 1-alkyl-1,2,3, the 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride of single configuration is the straight chained alkyl of C2 ~ C4;
3) by the 1-alkyl-1 of single configuration, 2,3,4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, methylene dichloride and saturated aqueous sodium carbonate is mixed to form two-phase system, then in two-phase system, under agitation drip the dichloromethane solution of N-(9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine, dropwise rear stirring at room temperature 1h, stratification again, separatory, retain organic phase, aqueous phase methylene dichloride extracts repeatedly, the organic phase that the organic phase that merging retains and repeatedly aqueous phase extracted obtain, by evaporate to dryness after the organic phase drying after merging, obtain solid B; Wherein, the 1-alkyl-1 added, 2,3,1-alkyl-1 in the dichloromethane solution of 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, the mol ratio of N-(the 9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine in the dichloromethane solution of 2,3,4-tetrahydro-beta-carboline-3-carboxylate methyl ester hydrochloride and N-(9-fluorenylmethyloxycarbonyl)-L-prolyl chlorine is (1:1) ~ (1:1.2);
4) being dissolved in by solid B by volume ratio is in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF), then adds reaction system that glacial acetic acid makes to obtain in acid; Reaction system is cooled to 0 DEG C, then at 0 DEG C, drip the mixing solutions of bromo-succinimide, stir at 0 DEG C after dropwising, then rise to room temperature continuation reaction 40min, then add the solid water-free Na being enough to destroy unreacted bromo-succinimide 2sO 3react with cancellation, the pH value of the reaction solution obtained after cancellation is adjusted to 6 ~ 7, then repeatedly uses dichloromethane extraction, merge the organic phase extracting and obtain, the dry also evaporate to dryness of organic phase after merging is obtained solid C; Be dissolved in methylene dichloride by solid C, then add morpholine, evaporate to dryness stir 40min at 20 DEG C ~ 40 DEG C after, the solid D obtained, through purifying, obtains spiro indole diketopiperazine Alkaloid; Wherein, the mixing solutions of the bromo-succinimide dripped is that to be dissolved in by bromo-succinimide by volume ratio be obtain in the mixed solvent that mixes of the water of 1:1 and tetrahydrofuran (THF); In the mixing solutions of the bromo-succinimide dripped, the mol ratio of bromo-succinimide and solid B is (1.5 ~ 2): 1; The alkaloidal structure of spiro indole diketopiperazines obtained is as follows:
wherein, R is the straight chained alkyl of C2 ~ C4.
2. the alkaloidal synthetic method of spiro indole diketopiperazines according to claim 1, is characterized in that: described step 1) and step 2) in the developping agent of TLC be the ethyl acetate of 10:1 and methanol mixed by volume ratio.
3. the alkaloidal synthetic method of spiro indole diketopiperazines according to claim 1, it is characterized in that, described step 3) in the 1-alkyl-1 of single configuration, 2, 3, 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, the method that methylene dichloride and saturated aqueous sodium carbonate are mixed to form two-phase system is: first by the 1-alkyl-1 of single configuration, 2, 3, 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride salt is in methylene dichloride, and then add saturated aqueous sodium carbonate formation two-phase system wherein, and every 30mL methylene dichloride dissolves the 1-alkyl-1 of the single configuration of 2.5mmol, 2, 3, 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride, the saturated aqueous sodium carbonate added is identical with the methylene chloride volume of 1-alkyl-1,2,3, the 4-tetrahydrochysene-β-click porphyrin-3-carboxylate methyl ester hydrochloride for dissolving single configuration.
4. the alkaloidal synthetic method of spiro indole diketopiperazines according to claim 1, it is characterized in that: described step 4) in glacial acetic acid volume be 10:25 for the volume ratio of the tetrahydrofuran (THF) in the mixed solvent of dissolved solids B, described step 4) after the pH value of reaction solution that obtained after having regulated cancellation, first remove the tetrahydrofuran (THF) in reaction solution, then extract.
5. the alkaloidal synthetic method of spiro indole diketopiperazines according to claim 1, is characterized in that: described step 4) in the morpholine that adds be 1:10 with the volume ratio for the methylene dichloride of dissolved solids C.
6. the alkaloidal synthetic method of spiro indole diketopiperazines according to claim 1 or 5, it is characterized in that: described step 4) in solid D adopt silica gel column chromatography gradient elution and recrystallizing methanol to carry out purifying successively, the method of silica gel column chromatography gradient elution is: with the mixed solvent of sherwood oil and ethyl acetate for eluent carries out positive gradient elution, and the volume ratio of the mixed solvent PetroChina Company Limited. ether of sherwood oil and ethyl acetate and ethyl acetate is (1:0) ~ (0:1), spiro indole diketopiperazine Alkaloid obtains in the cut flowed out from silicagel column when the volume ratio of sherwood oil and ethyl acetate is 2:1.
7. the application of spiro indole diketopiperazine Alkaloid as claimed in claim 1 in preparation antibacterials.
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