CN105601630A - Synthesizing method for 6-oxo-13H-substitued benzo [b] quinoline [3,4-f][1,4] diazepine compound - Google Patents
Synthesizing method for 6-oxo-13H-substitued benzo [b] quinoline [3,4-f][1,4] diazepine compound Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a synthesizing method for a 6-oxo-13H-substituted benzo [b] quinoline [3,4-f][1,4] diazepine compound. Substituted-4-hydroxyl-1,2-quinoline 2-ketone is converted into substituted-4-chloro-1,2-dihydro-2-oxoquinline-3-formaldehyde which acts with DMF and phosphoryl chloride by the utilization of Vilsmeier reaction conditions to complete the reaction; substituted-4-chloro-1,2-dihydro-2-oxoquinline-3-formaldehyde and substituted diphenylamine are subjected to a ring closing reaction to obtain 6-oxo-13H-substituted benzo [b] quinoline [3,4-f][1,4] diazepine. The number of synthesizing reaction steps in the synthesizing method is small, operation is easy, and the product is easy to separate, purify, high in yield and small in economic and environmental pollution in the process.
Description
Technical field
The present invention relates to material and synthesize and the synthetic field of medicine, be specifically related to a kind of 6-oxo-13H-and replace benzo [b] benzeneAnd the synthetic method of pyridine [3,4-f] [Isosorbide-5-Nitrae] Diazepines.
Background technology
6-oxo-13H-replaces benzo [b] chromene [3,4-f] [Isosorbide-5-Nitrae] Diazepines and alkylation thereofProduct, has a wide range of applications as drug candidate. The synthetic method of such analog has been reported, and is that replace-4-is chloro-1,2-dihydro-2-oxo-pyrans-3-formaldehyde reacts preparation (AndreaSabati é, DanielV é gh, Andr é with substituted diphenylamineLoupy,andFloch；Synthesisofaromaticandheteroaromaticannelated[1,4]diazepines,ARKIVOC2001(vi)122-128)：
But chloro-1 with replace-4-, 2-dihydro-2-oxoquinoline-3-formaldehyde reacts synthetic 6-oxygen with substituted diphenylamineGeneration-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] Diazepines and alkylate thereof, there are no literary compositionOffer report. We wish the synthetic biologically active that obtains this compounds and study them.
Summary of the invention
The object of this invention is to provide a kind of 6-oxo-13H-and replace benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] phenodiazineAssorted tall and erect compounds and synthetic method thereof, this synthetic method synthetic reaction step is few, simple to operate, product is easy to separating-purifying,Productive rate is high, process economy and environmental pollution little.
The present invention is achieved by the following technical programs:
A kind of 6-oxo-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] Diazepines, its structureFormula is as follows:
Wherein: R1Be selected from the one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group; R2Be selected from alkaneOne in base, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group.
A kind of 6-oxo-13H-replaces the synthetic of benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] DiazepinesMethod, is made up of following steps:
Wherein: R1Be selected from alkyl, aryl, substituted aryl, halogen, trifluoromethyl, amino, substituted-amino, alkoxyl, carboxylicOne in base, ester group or acyl group; R2Be selected from one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl groupKind; R3Be selected from the one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group; X is halogen or sulphonic acid ester.
Inventor replaces the synthetic method of benzo [b] chromene [3,4-f] [Isosorbide-5-Nitrae] diazepine to 6-oxo-13H-Carry out Study of synthesis method, in practical study process, find, replacement-4-is chloro-1 in preparation, 2-dihydro-2-oxoquinoline-3-firstThe raw material that aldehyde needs is 4-oxyquinoline-2 (1H)-one, and replacements-4-is chloro-1 in preparation, 2-dihydro-2-oxo-pyrans-3-formaldehyde needThe raw material of wanting is 4-hydroxyl-2H-2-chromone difference. The two close of 4-oxyquinoline-2 (1H)-one and 4-hydroxyl-2H-2-chromoneOne-tenth method is completely different, and preparation replacements-4-is chloro-1 thus, 2-dihydro-2-oxoquinoline-3-formaldehyde and to prepare replacement-4-chloro-1,2-dihydro-2-oxo-pyrans-3-formaldehyde method difference. Bibliography report method is prepared 4-oxyquinoline-2 (1H)-oneAfter, then it is chloro-1 to prepare replacement-4-, 2-dihydro-2-oxoquinoline-3-formaldehyde. And then and substituted diphenylamine suitable anti-Answer under condition, prepare 6-oxo-13H-and replace benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] Diazepines. BySolubility in this compounds is poor, and for solving its solubility, inventor has studied the alkylation of this compounds, andSucceed.
In the present invention, utilize Vilsmeier reaction, replacement-4-hydroxyl-1,2-EEDQ-2-ketone be converted into replacement-4-is chloro-1,2-dihydro-2-oxoquinoline-3-formaldehyde, and this chloro aldehyde reacts synthetic 6-oxo-13H-and replaces with substituted diphenylamineBenzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine, the latter carries out alkylation again and obtains end product.
Preferably, replacement-4-is chloro-1 in step (2), the rubbing of 2-dihydro-2-oxoquinoline-3-formaldehyde and substituted diphenylamineYou are than being 1:5～5:1.
Preferably, in step (2), solvent is selected from the one in DMF, DMSO or DMA.
Preferably, in step (2), reaction temperature is 50-140 DEG C.
Preferably, described in step (3) 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketoneWith the mol ratio of alkyl halide be 1:5～5:1.
Preferably, described in step (3), solvent is DMF or DMA.
Preferably, described in step (3), alkali is selected from NaH, NaNH2、KNH2Or one in lithium salts.
Further, described lithium salts is selected from the one in butyl lithium, phenyl lithium or diisobutyl amido lithium.
Preferably, in step (3), reaction temperature is 50-140 DEG C.
The invention has the beneficial effects as follows: the present invention is replacement-4-hydroxyl-1, and 2-EEDQ 2-ketone is converted into replacement-4-Chloro-1,2-dihydro-2-oxoquinoline-3-formaldehyde, utilizes Vilsmeier reaction condition, with DMF and POCl3 effect can be completeBecome this reaction; Replacement-4-is chloro-1,2-dihydro-2-oxoquinoline-3-formaldehyde and substituted diphenylamine ring closure reaction obtain 6-oxo-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine; This synthetic method synthetic reaction step is few, operation letterSingle, product is easy to that separating-purifying, productive rate are high, process economy and environmental pollution little.
Detailed description of the invention
Below to further illustrate of the present invention, instead of limitation of the present invention.
Except special instruction, the equipment that the present invention uses and reagent are the conventional commercial product of the art.
A kind of 6-oxo-13H-replaces the synthetic of benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] DiazepinesMethod, is made up of following steps:
Wherein: R1Be selected from alkyl, aryl, substituted aryl, halogen, trifluoromethyl, amino, substituted-amino, alkoxyl, carboxylicOne in base, ester group or acyl group; R2Be selected from one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl groupKind; R3Be selected from the one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group; X is halogen or sulphonic acid ester.
Embodiment 1
5,13-diamyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone (compound 1)
(1) 4-chloro-2-oxo-1,2-EEDQ-3-formaldehyde synthetic:
By 4-hydroxyl-1 of 0.01 mole, the DMF (DMF) of 2-EEDQ 2-ketone and 20 milliliters is mixedClose, ice bath is cooled to 0-5 DEG C, drips the POCl3 of 0.03 mole (4.56 grams) under stirring in 30 minutes. In 0-5 DEG C of stirringReact 2 hours, rise to stirring at room temperature 2 hours, be warming up to 60 DEG C and stir 2 hours. TLC follows the tracks of reaction. After reaction finishes, reaction is mixedCompound is poured into water, and leaves standstill, precipitates. Filter, dry after, obtain 4-chloro-2-oxo-1 with ethyl alcohol recrystallization, 2-EEDQ-3-formaldehyde.
Synthesizing of (2) 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone:
Get 4-chloro-2-oxo-1,5 mMs, 2-EEDQ-3-formaldehyde, is dissolved in 20 milliliters of DMF, adds and replaces two5 mMs of aniline add thermal agitation 3 hours at 100 DEG C. TLC follows the tracks of reaction. After reaction finishes, reactant mixture is poured into water,Leave standstill, precipitate. Filter, dry after, obtain 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-with ethyl alcohol recrystallizationC] 2.30 grams of quinoline-6-ketone, productive rate 88%. ESI-MS (m/z): 262.1[M+H]+。
Synthesizing of (3) 5,13-diamyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone:
Get 50 milliliters of dry DMFs (DMF), 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene[6,5-c] quinoline-6-ketone 2.61 grams of (10.0 mMs), 1.32 grams of sodium hydrides (NaH, 40%) (22.0 mMs), room temperature is stirredMix reaction after 10 minutes, then drip 3.32 grams of 1-bromo pentane silanes (22.0 mMs). Continue stirring at room temperature 2-4h, TLC follows the tracks of reaction.After reaction finishes, mixture is poured in 100 grams of frozen water, with 10 milliliters of dichloromethane extraction organic layers 3 times. Combining extraction liquid,With anhydrous sodium sulfate drying, to remove after carrene, column chromatography for separation, purifies and obtains 2.99 grams of target products (compound 1), producesRate 75%.
1HNMR(300MHz,CDCl3)δ:0.95-1.01(m,6H),1.39-1.57(m,8H),1.79-1.90(m,4H)3.31(q,J＝6Hz,2H),4.03(t,J＝6Hz,2H),6.16(s,1H),6.72(d,J＝6Hz,1H),6.78(d,J＝3Hz,1H),6.91(dd,J1＝9Hz,J2＝3Hz,1H),7.09(d,J＝6Hz,1H),7.36(t,J＝9Hz,1H),8.44(d,J＝9Hz,1H),8.90(s,1H)。ESI-MS(m/z):402.2[M+H]+。
Embodiment 2
Identical with embodiment 1, difference is:
In step (2), substituted diphenylamine is 10 mMs, obtains 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene2.33 grams of [6,5-c] quinoline-6-ketone, productive rate 89%. ESI-MS (m/z): 262.1[M+H]+。
Embodiment 3
Identical with embodiment 1, difference is:
In step (2), substituted diphenylamine is 25 mMs, obtains 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene2.35 grams of [6,5-c] quinoline-6-ketone, productive rate 90%. ESI-MS (m/z): 262.1[M+H]+。
Embodiment 4
Identical with embodiment 1, difference is:
Substituted diphenylamine is 1 mM in step (2), obtain 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] 0.48 gram of quinoline-6-ketone, productive rate 18%. ESI-MS (m/z): 262.1[M+H]+。
More known with embodiment 2, embodiment 3 and embodiment 4 by embodiment 1, although the amount of substituted diphenylamine increases,Be that reactant molar ratio changes, but product yield is not significantly increased, from economic benefit, selects embodiment 1 to beGood.
Embodiment 5
Identical with embodiment 1, difference is:
Get 4-chloro-2-oxo-1,5 mMs, 2-EEDQ-3-formaldehyde, is dissolved in 25 milliliters of DMAsIn, add 5 mMs of substituted diphenylamines, at 90 DEG C, add thermal agitation 4.5 hours. TLC follows the tracks of reaction. After reaction finishes, reactionMixture is poured into water, and leaves standstill, precipitates. Filter, dry after, obtain 5,13-dihydro-6H-benzo [2,3] with ethyl alcohol recrystallization2.23 grams of [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone, productive rate 85%. ESI-MS (m/z): 262.1[M+H]+。
Embodiment 6
Identical with embodiment 1, difference is:
Get 4-chloro-2-oxo-1,5 mMs, 2-EEDQ-3-formaldehyde, is dissolved in 25 milliliters of DMSO, adds replacement5 mMs of diphenylamines add thermal agitation 2.5 hours at 110 DEG C. TLC follows the tracks of reaction. After reaction finishes, reactant mixture is poured intoIn water, leave standstill, precipitate. Filter, dry after, obtain 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene with ethyl alcohol recrystallization2.19 grams of [6,5-c] quinoline-6-ketone, productive rate 84%. ESI-MS (m/z): 262.1[M+H]+。
Relatively can find out the yield of anti-solvent-applied to product by embodiment 1 and embodiment 5 and embodiment 6Impact is little. When reaction temperature is lower, can improve product yield by extending the reaction time, therefore reaction temperature is to yieldAffect also not too obvious. Comprehensive Correlation finds, embodiment 1 product yield is higher, selects embodiment 1 for well.
Embodiment 7
Identical with embodiment 1, difference is:
The amount of 1-bromo pentane silane is 1.66 grams (11.0 mMs). Obtain 1.61 grams of target products (compound 1), productive rate40％。ESI-MS(m/z):402.2[M+H]+。
Embodiment 8
Identical with embodiment 1, difference is:
The amount of 1-bromo pentane silane is 2.41 grams (16.0 mMs). Obtain 2.67 grams of target products (compound 1), productive rate67％。ESI-MS(m/z):402.2[M+H]+。
Embodiment 9
Identical with embodiment 1, difference is:
The amount of 1-bromo pentane silane is 7.55 grams (50.0 mMs). Obtain 3.05 grams of target products (compound 1), productive rate76％。ESI-MS(m/z):402.2[M+H]+。
Relatively can find out embodiment 9 product yield comparisons by embodiment 1 and embodiment 7, embodiment 8 and embodiment 9Height, but consider from economic benefit, selects embodiment 1 condition for well.
Embodiment 10
Synthetic (compound 2) of 5,13-dihexyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone
According to embodiment 1 method of operating, (22.0 millis rub to replace 3.32 grams with 3.63 grams of (22.0 mMs) 6-bromohexanesYou) 1-bromo pentane silane, obtain 4.30 grams of target products (compound 2), productive rate 70%.1HNMR(300MHz,CDCl3)δ:0.95-1.00(m,6H),1.42-1.52(m,12H),1.79-1.88(m,4H),3.33(q,J＝6Hz,2H),4.04(t,J＝6Hz,2H),6.20(s,1H),6.74(d,J＝6Hz,1H),6.80(s,1H),6.95(d,J＝9Hz,1H),7.12(d,J＝6Hz,1H),7.38(t,J＝9Hz,1H),8.48(d,J＝9Hz,1H),8.94(s,1H)。ESI-MS(m/z):430.3[M+H]+。
Embodiment 11
2-is chloro-5,13-diisobutyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone (compound 3)
(1) 4,6-, bis-chloro-2-oxo-1,2-EEDQ-3-formaldehyde synthetic:
With synthetic 4-chloro-2-oxo-1 in embodiment 1, the method for 2-EEDQ-3-formaldehyde is synthetic, and to obtain 4,6-bis-chloro-2-oxo-1,2-EEDQ-3-formaldehyde.
(2) 2-is chloro-5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone synthetic:
Get 5 mMs of 4-chloro-2-oxo-1,2-EEDQ-3-formaldehyde and 5 mMs of adjacent aniline diamines are dissolved in 20 millisRise in DMSO, at 100 DEG C, add thermal agitation 3 hours. The synthetic 2-that obtains is chloro-5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azepineTall and erect [6,5-c] quinoline-6-ketone (compound 2) 2.31 grams, productive rate 78%. ESI-MS (m/z): 296.0[M+H]+。
(3) 2-is chloro-5,13-diisobutyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone synthetic:
Get 50 milliliters of dry DMFs (DMF), 2-chloro-5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] nitrogenAssorted tall and erect [6,5-c] quinoline-6-ketone 2.96 grams of (10.0 mMs), 1.32 grams of sodium hydrides (NaH, 40%) (22.0 mMs), chamberTemperature stirring reaction after 10 minutes, then drip 3.01 grams of 2-methyl isophthalic acid-N-Propyl Bromides (22.0 mMs). Continue stirring at room temperature 2-4 littleTime, TLC follows the tracks of reaction. After reaction finishes, mixture is poured in 100 grams of frozen water, with 10 milliliters of dichloromethane extraction organic layers 3Inferior. Combining extraction liquid, with anhydrous sodium sulfate drying, removes after carrene, and column chromatography for separation is purified and obtained target product (changeCompound 3) 5.29 grams, productive rate 71%.
1HNMR(300MHz,CDCl3)δ:1.06(d,J＝6Hz,6H),1.45-1.56(m,8H),1.13(dd,dd,J1＝6Hz,J2＝3Hz,6H),2.15-2.31(m,2H),3.26(d,J＝6Hz,2H),4.29(d,J＝6Hz,2H),6.52(s,1H),6.76(d,J＝9Hz,1H),6.79(d,J＝9Hz,1H),7.23(s,1H),7.29(s,1H),7.33(d,J＝9Hz,1H),7.42-7.54(m,2H),8.92(d,J＝3Hz,1H),9.19(s,1H)。ESI-MS(m/z):408.2[M+H]+。
Embodiment 12
Identical with embodiment 11, difference is:
Get 5 mMs of 4-chloro-2-oxo-1,2-EEDQ-3-formaldehyde and 5 mMs of adjacent aniline diamines are dissolved in 25 millisRise in DMF, at 110 DEG C, add thermal agitation 2.5 hours. The synthetic 2-that obtains is chloro-5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azepineTall and erect [6,5-c] quinoline-6-ketone (compound 2) 2.40 grams, productive rate 81%. ESI-MS (m/z): 296.0[M+H]+。
Embodiment 13
Identical with embodiment 11, difference is:
Get 5 mMs of 4-chloro-2-oxo-1,2-EEDQ-3-formaldehyde and 5 mMs of adjacent aniline diamines are dissolved in 25 millisRise in DMA, at 90 DEG C, add thermal agitation 4.5 hours. The synthetic 2-that obtains is chloro-5,13-dihydro-6H-benzo2.37 grams of [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone (compound 2), productive rate 80%. ESI-MS (m/z): 296.0[M+H]+。
Can draw by embodiment 11, embodiment 12 and embodiment 13, embodiment 12 reaction conditions are better. According to enforcementAlkylation reaction condition in example 1 is optimized situation, has carried out the optimization of reactant molecule mol ratio, finds this alkylated reaction barPart is better, therefore alkylated reaction is selected this condition.
Embodiment 14
2-is chloro-5,13-diamyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone (compound 4)
According to embodiment 11 methods of operating, (22.0 millis rub to replace 3.01 grams with 3.32 grams of (22.0 mMs) 1-bromo pentane silanesYou) 2-methyl isophthalic acid-N-Propyl Bromide obtains 6.34 grams of target products (compound 4), productive rate 77%.1HNMR(300MHz,CDCl3)δ:0.87-1.03(m,6H),1.45-1.56(m,8H),1.76-1.93(m,4H),3.39(t,J＝6Hz,2H),4.32(t,J＝6Hz,2H),6.37(s,1H),6.76(d,J＝6Hz,1H),7.23(d,J＝9Hz,1H),7.29(s,1H),7.44(t,J＝9Hz,1H),7.50(dd,J1＝9Hz,J2＝3Hz,1H),8.88(d,J＝3Hz,1H),9.13(s,1H)。ESI-MS(m/z):436.2[M+H]+。
Embodiment 15
2-is chloro-5,13-dihexyl-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] quinoline-6-ketone (compound 5)
According to embodiment 11 methods of operating, (22.0 millis rub to replace 3.01 grams with 3.63 grams of (22.0 mMs) hexyl bromide 1 bromohexanesYou) 2-methyl isophthalic acid-N-Propyl Bromide obtains 7.34 grams of target products (compound 5), productive rate 74%.
1HNMR(300MHz,CDCl3)δ:0.85-0.98(m,6H),1.38-1.53(m,12H),1.79-1.89(m,4H),3.35(t,J＝6Hz,2H),4.30(t,J＝6Hz,2H),6.31(s,1H),6.73(d,J＝6Hz,1H),7.18-7.23(m,3H),7.39-7.49(m,2H),7.44(t,J＝9Hz,1H),8.83(d,J＝3Hz,1H),9.10(s,1H)。ESI-MS(m/z):464.2[M+H]+。
Above-listed detailed description is for the illustrating of possible embodiments of the present invention, and this embodiment is not in order to limit thisBright the scope of the claims, the equivalence that all the present invention of disengaging do is implemented or is changed, and all should be contained in the scope of patent protection of this caseIn.
Claims (10)
1. 6-oxo-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] Diazepines, and its feature existsIn, its structural formula is as follows:
Wherein: R2Be selected from the one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group; R3Be selected from alkyl, virtueOne in base, substituted aryl, alkoxyl, carboxyl, ester group or acyl group.
2. the synthetic side of 6-oxo-13H-replacement benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] DiazepinesMethod, is characterized in that, is made up of following steps:
(1)
(2)
(3)
Wherein: R1Be selected from alkyl, aryl, substituted aryl, halogen, trifluoromethyl, amino, substituted-amino, alkoxyl, carboxyl, ester groupOr one in acyl group; R2Be selected from the one in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group; R3Be selected fromOne in alkyl, aryl, substituted aryl, alkoxyl, carboxyl, ester group or acyl group; X is halogen or sulphonic acid ester.
3. 6-oxo according to claim 2-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine classThe synthetic method of compound, is characterized in that, replacements-4-is chloro-1 in step (2), 2-dihydro-2-oxoquinoline-3-formaldehyde and gettingBe 1:5～5:1 for the mol ratio of diphenylamines.
4. 6-oxo according to claim 2-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine classThe synthetic method of compound, is characterized in that, in step (2), solvent is selected from one in DMF, DMSO or DMAKind.
5. 6-oxo according to claim 2-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine classThe synthetic method of compound, is characterized in that, in step (2), reaction temperature is 50-140 DEG C.
6. 6-oxo according to claim 2-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine classThe synthetic method of compound, is characterized in that, described in step (3) 5,13-dihydro-6H-benzo [2,3] [Isosorbide-5-Nitrae] azatropylidene [6,5-c] mol ratio of quinoline-6-ketone and alkyl halide is 1:5～5:1.
7. 6-oxo according to claim 6-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine classThe synthetic method of compound, is characterized in that, described in step (3), solvent is DMF or N, N-dimethyl secondAcid amides.
8. replace benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diaza according to the 6-oxo described in claim 2 or 6-13H-The synthetic method of tall and erect compounds, is characterized in that, described in step (3), alkali is selected from NaH, NaNH2、KNH2Or one in lithium saltsKind.
9. 6-oxo according to claim 8-13H-replaces benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diazepine classThe synthetic method of compound, is characterized in that, described lithium salts is selected from one in butyl lithium, phenyl lithium or diisobutyl amido lithiumKind.
10. replace benzo [b] benzo pyridine [3,4-f] [Isosorbide-5-Nitrae] diaza according to the 6-oxo described in claim 2 or 6-13H-The synthetic method of tall and erect compounds, is characterized in that, in step (3), reaction temperature is 50-140 DEG C.
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| CN107216337A (en) * | 2017-05-24 | 2017-09-29 | 广东省测试分析研究所（中国广州分析测试中心） | A kind of synthetic method of ketone compounds of 3,4 dihydropyran [3,2 c] chromene 5 and its application |
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| CN107216337A (en) * | 2017-05-24 | 2017-09-29 | 广东省测试分析研究所（中国广州分析测试中心） | A kind of synthetic method of ketone compounds of 3,4 dihydropyran [3,2 c] chromene 5 and its application |
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