CN102212030A - Substituted tetrahydrocarbazole antifungal compounds and preparation method thereof - Google Patents

Substituted tetrahydrocarbazole antifungal compounds and preparation method thereof Download PDF

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CN102212030A
CN102212030A CN2011100945854A CN201110094585A CN102212030A CN 102212030 A CN102212030 A CN 102212030A CN 2011100945854 A CN2011100945854 A CN 2011100945854A CN 201110094585 A CN201110094585 A CN 201110094585A CN 102212030 A CN102212030 A CN 102212030A
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benzyl
methyl
hydrogen
carbazole
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CN102212030B (en
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盛春泉
张万年
王文雅
张永强
王胜正
董国强
祝令建
程鹏飞
缪震元
姚建忠
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Second Military Medical University SMMU
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Abstract

The invention discloses substituted tetrahydrocarbazole compounds and a preparation method thereof. The compounds have a general structural formula shown in the specification, wherein R1 represents various substituents on aromatic rings and can be selected from low alkyl and -CH2-X-Y, (1) X represents O or NH, and (2) Y is H, low alkyl, fatty cycloalkyl, substituted phenyl, substituted benzyl, heterocyclic ring substituent, pyridine-3-methyl and benzoyl; R2 represents H or hydroxyl; and R3 represents cyclohexyl, pyridine-3-methyl and various substituted phenyl groups and substituted benzyl groups. The substituents in the substituted phenyl groups and substituted benzyl groups are positioned at ortho-positions, meta-positions and para- positions, and can be mono-substituted or multi-substituted. The antifungal compounds with a novel structure, disclosed by the invention, provide a new way for the intensive study and development of novel antifungal drugs.

Description

Substituted-tetrahydro carbazoles antifungal compound and preparation method thereof
Technical field
The present invention relates to medical technical field, is a kind of novel substituted-tetrahydro carbazoles antifungal compound---and N-[3-(6-replaces-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] aminated compounds and its esters and preparation method.
Background technology
In recent years, factors such as the abuse of antibiotic, tumor chemoradiotherapy and organ transplantation cause immunosuppression, the AIDS patient increases rapidly in addition, read bacterium, aspergillus fumigatus, Pneumocystis carinii and cryptococcus neoformans deep infection in vain and rise significantly, deep fungal infection has now become major disease main causes of death such as acquired immune deficiency syndrome (AIDS) and tumour.Yet the ideal antifungal drug extremely lacks clinically.The polyene antibiotics (for example amphotericin B) that acts on fungal cell's membrane lipid is first-selected curative, but toxic side effect is big, and clinical application is seriously limited.The azole drug (for example fluconazole, itraconazole and voriconazole) that acts on lanosterol 14 α-demethylase (CYP51) is to use maximum a kind of antifungal drugs at present, but such medicine is because the restraining effect of pair cell cytochrome p 450 enzyme system, can cause tangible drug-drug interactions, and invalid to Resistant strain.There is problem such as cost an arm and a leg, bioavailability is lower again in the lipopeptid class medicine (for example Caspofungin and Mi Kafen are clean) that acts on fungal cell wall β-1,3 glucan synthase.Therefore, except the structure and preparation of optimizing the existing medicine of improvement, seek the important directions that tool brand new type and brand-new mechanism of action lead compound have become antifungal drug research.N-mnyristoyl based transferase (NMT) is a newfound in recent years antifungal drug effect target enzyme, and fungi NMT inhibitor has the Fungicidally active of wide spectrum, is expected to develop into the novel anti fungi-medicine with brand-new mechanism of action.N-[3-(6-replaces-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] aminated compounds is the inhibitor of NMT, has not yet to see the report of the synthetic and anti-mycotic activity of this compounds.
Summary of the invention
The invention provides a kind of novel substituted-tetrahydro carbazoles antifungal compound, comprise N-[3-(6-replaces-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] aminated compounds.
The general structure of The compounds of this invention is as follows:
Figure BDA0000055496920000021
Wherein: R 1Group is represented the various substituting groups on the aromatic ring, can for low alkyl group ,-CH 2-X-Y,
(1) low alkyl group is selected from methyl, ethyl, propyl group, sec.-propyl;
(2) X represents O or NH;
(3) Y is hydrogen, low alkyl group, cycloaliphatic ring alkyl, substituted-phenyl, substituted benzyl, heterocyclic substituent, pyridine-3-methyl and benzoyl:
A. low alkyl group nail base, ethyl, propyl group;
B. cycloaliphatic ring alkyl, finger ring hexyl, piperidines-1-base, piperidin-4-yl, N-methyl piperidine-4-base, piperidin-4-one--1-base, morpholine-1-base;
C. the various substituting group positions in substituted-phenyl and the substituted benzyl can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to: hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, nitro, cyano group, trifluoromethyl or halogen.Wherein, halogen is selected from F, Cl, Br, I or 2,4-difluoro;
D. heterocyclic substituent is selected from pyridine-2-base, pyridin-3-yl, 5-picoline-2-base or thiazol-2-yl;
R 2Group is represented hydrogen or hydroxyl;
R 3Group is represented cyclohexyl, pyridine-3-methyl, various substituted-phenyl and substituted benzyl.Various substituting group positions in substituted-phenyl and the substituted benzyl can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to: hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, nitro, cyano group, trifluoromethyl or halogen.Wherein, halogen is selected from F, Cl, Br, I or 2,4-dichloro;
Through the test anti-mycotic efficiency preferably compound be R 1, R 2And R 3The combination of group is respectively following compound:
(1) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is a cyclohexyl;
(2) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is a phenyl;
(3) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is a benzyl;
(4) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is pyridine-3-methyl;
(5) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a cyclohexyl;
(6) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a phenyl;
(7) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(8) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is pyridine-3-methyl;
(9) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 4-luorobenzyl;
(10) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 3-luorobenzyl;
(11) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 2-luorobenzyl;
(12) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a 4-benzyl chloride base;
(13) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a 2-benzyl chloride base;
(14) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a 3-benzyl chloride base;
(15) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 4-methyl-benzyl;
(16) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 4-methoxy-benzyl;
(17) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is 2, the 4-dichloro benzyl;
(18) R 1Group is-CH 2-X-Y, X group are oxygen, and Y group is a hydrogen, R 2Group is a hydrogen, R 3Group is a benzyl;
(19) R 1Group is-CH 2-X-Y, X group are oxygen, and Y group is a benzoyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(20) R 1Group is-CH 2-X-Y, X group are oxygen, and Y group is the 4-nitrophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(21) R 1Group is-CH 2-X-Y, X group are NH, and Y group is a phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(22) R 1Group is-CH 2-X-Y, X group are NH, and Y group is the 4-bromophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(23) R 1Group is-CH 2-X-Y, X group are NH, and Y group is the 4-aminomethyl phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(24) R 1Group is The X group is an oxygen, and Y group is an ethyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(25) R 1Group is
Figure BDA0000055496920000042
The X group is an oxygen, and Y group is a phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(26) R 1Group is
Figure BDA0000055496920000043
The X group is an oxygen, and Y group is the 4-fluorophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(27) R 1Group is
Figure BDA0000055496920000044
The X group is an oxygen, and Y group is the 4-aminomethyl phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(28) R 1Group is
Figure BDA0000055496920000045
The X group is an oxygen, and Y group is a piperidin-4-yl, R 2Group is a hydrogen, R 3Group is a benzyl;
(29) R 1Group is
Figure BDA0000055496920000046
The X group is an oxygen, and Y group is N-methyl piperidine-4-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(30) R 1Group is
Figure BDA0000055496920000051
The X group is NH, and Y group is a phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(31) R 1Group is
Figure BDA0000055496920000052
The X group is NH, and Y group is the 4-fluorophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(32) R 1Group is
Figure BDA0000055496920000053
The X group is NH, and Y group is the 4-aminomethyl phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(33) R 1Group is
Figure BDA0000055496920000054
The X group is NH, and Y group is the 4-bromophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(34) R 1Group is
Figure BDA0000055496920000055
The X group is NH, and Y group is the 4-ethoxyl phenenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(35) R 1Group is
Figure BDA0000055496920000056
The X group is NH, and Y group is the 2,4 difluorobenzene base, R 2Group is a hydrogen, R 3Group is a benzyl;
(36) R 1Group is
Figure BDA0000055496920000057
The X group is NH, and Y group is a benzyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(37) R 1Group is
Figure BDA0000055496920000058
The X group is NH, and Y group is pyridine-3-methyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(38) R 1Group is
Figure BDA0000055496920000059
The X group is NH, and Y group is a cyclohexyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(39) R 1Group is
Figure BDA00000554969200000510
The X group is NH, and Y group is piperidin-4-one--1-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(40) R 1Group is The X group is NH, and Y group is piperidines-1-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(41) R 1Group is
Figure BDA00000554969200000512
The X group is NH, and Y group is morpholine-1-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(42) R 1Group is
Figure BDA0000055496920000061
Y group is pyridine-2-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(43) R 1Group is Y group is a pyridin-3-yl, R 2Group is a hydrogen, R 3Group is a benzyl;
(44) R 1Group is Y group is 5-picoline-2-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(45) R 1Group is Y group is a thiazol-2-yl, R 2Group is a hydrogen, R 3Group is a benzyl;
The building-up reactions flow process of The compounds of this invention is as follows:
Figure BDA0000055496920000065
Figure BDA0000055496920000071
Concrete steps are:
(1) prepares alpha-brominated pimelinketone (II)
Pimelinketone (I) is in anhydrous diethyl ether, and through ammonium acetate catalysis, with the N-bromo-succinimide, at room temperature stirring reaction 0.5h generates alpha-brominated pimelinketone (II);
(2) preparation 6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (III)
Under the nitrogen protection condition, alpha-brominated pimelinketone (II) and para-totuidine reflux in ethylene glycol ethyl ether, reaction 12h generates 6-methyl isophthalic acid H-2, and 3,4,9-tetrahydro carbazole (III);
(3) preparation 6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4,9-tetrahydro carbazole (IV)
6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (III) is an alkali with KOH in DMSO, with epoxy chloropropane room temperature reaction 2h, generates 6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4,9-tetrahydro carbazole (IV);
(4) preparation target compound 1-substituted-amino-3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl)-2-propyl alcohol (V)
6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4,9-tetrahydro carbazole (IV) respectively with various amine back flow reaction 4h in ethanol, generate 1-substituted-amino-3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl)-2-propyl alcohol (V);
(5) preparation 9-(3-bromopropyl)-6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (VI)
6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (III) is an alkali with KOH in DMSO, with 1,3-dibromopropane room temperature reaction 3h generates 9-(3-bromopropyl)-6-methyl isophthalic acid H-2, and 3,4,9-tetrahydro carbazole (VI);
(6) preparation target compound N-[3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] replace amine (VII)
9-(3-bromopropyl)-6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (VI) is an alkali with the Anhydrous potassium carbonate in DMF, reacts 4 hours at 80 ℃ with various amine respectively, generation N-[3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] replacement amine (VII);
(7) preparation 2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (VIII)
Under the nitrogen protection condition, alpha-brominated pimelinketone (II) and parathesin reflux in ethylene glycol ethyl ether, reaction 12h generates 2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (VIII);
(8) preparation 9-(3-bromopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (IX)
2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (VIII) is an alkali with KOH in DMSO, and with 1,3-dibromopropane room temperature reaction 3h generates 9-(3-bromopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (IX);
(9) preparation target compound 9-[3-(benzamido group) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X)
9-(3-bromopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (IX) they are alkali with the Anhydrous potassium carbonate in DMF, react 4 hours at 80 ℃ with benzylamine, generate 9-[3-(benzamido group) propyl group]-2,3,4, and 9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X);
(10) preparation target compound 9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI)
Lithium Aluminium Hydride is suspended in the tetrahydrofuran (THF), under the ice bath, add 9-[3-(benzamido group) propyl group]-2,3,4, the tetrahydrofuran solution of 9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X), back room temperature reaction 1h, hydro-reduction generates 9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI);
(11) preparation target compound N-benzyl-3-[6-(4-nitrophenol oxygen base) methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl]-1-propylamine (XII)
At N 2Under the protective condition, 9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI) and 4-nitrophenols and tributylphosphine (TBuP) are in tetrahydrofuran (THF), under the ice bath, the tetrahydrofuran solution that adds azo two formyls, two piperidines (ADDP), back room temperature reaction 24h generates N-benzyl-3-[6-(4-nitrophenol oxygen base) methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl]-1-propylamine (XII);
(12) preparation benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII)
9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI) under the ice bath, is an alkali with the triethylamine in methylene dichloride, add tert-Butyl dicarbonate, back room temperature reaction 2h, and the generation benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII);
(13) preparation 9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl] and-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XIV)
Benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII) is in methylene dichloride, with the triethylamine is alkali, with Benzoyl chloride room temperature reaction 12h, generate 9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XIV);
(14) preparation target compound { 9-[3-(benzyl amino) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XV)
9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XIV) is in the ethyl acetate solution of hydrogenchloride, and room temperature reaction 2h removes the Boc protecting group, generate 9-[3-(benzyl amino) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XV);
(15) preparation benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XVI)
Benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII) is in methylene dichloride, with pyridinium chlorochromate (PCC) room temperature reaction 2h, the generation benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XVI);
(16) preparation target compound N-{[9-(3-benzyl aminopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-yl] methyl } substituted aniline (XVII)
At N 2Under the protective condition; various substituted anilines and glacial acetic acid add the methanol solution of benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XVI) in methyl alcohol; add sodium cyanoborohydride again, stirring at room reaction 12h.At last, in the ethyl acetate solution of hydrogenchloride, room temperature reaction 2h removes the Boc protecting group with this product that reacts generation, generates N-{[9-(3-benzyl aminopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-yl] methyl } substituted aniline (XVII);
(17) preparation 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII)
9-[3-(benzamido group) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X) under the ice bath, is an alkali with the triethylamine in methylene dichloride, add tert-Butyl dicarbonate, back room temperature reaction 2h generates 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII) (18) preparation 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX)
9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII) is at THF: MeOH: H 2In O (4: 2: the 1) solution, react 24h in 50 ℃ with lithium hydroxide, hydrolysis generates 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX);
(19) preparation target compound 9-[3-(benzamido group) propyl group]-2,3,4, the 9-1H-tetrahydro carbazole-6-carboxylicesters (or acid amides) is (XX)
9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX) respectively with phenol, alcohol or amine in methylene dichloride, use the EDC/DMAP catalyzing and condensing, room temperature reaction 12h.At last, in the ethyl acetate solution of hydrogenchloride, room temperature reaction 2h removes the Boc protecting group with this product that reacts generation, generates 9-[3-(benzamido group) propyl group]-2,3,4, the 9-1H-tetrahydro carbazole-6-carboxylicesters (or acid amides) is (XX);
(20) preparation benzyl { 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] propyl group } t-butyl carbamate (XXI)
9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX) and morpholine are in methylene dichloride, use the EDC/DMAP catalyzing and condensing, room temperature reaction 12h, the generation benzyl 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] and propyl group } t-butyl carbamate (XXI);
(21) preparation benzyl [3-(6-oxo methyl heterocycle-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII)
At N 2Under the protective condition, Tetramethyl Ethylene Diamine (TMEDA) exists down, benzyl { 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] propyl group } t-butyl carbamate (XXI) and bromo heterocycle and n-Butyl Lithium react 1h at-78 ℃ in tetrahydrofuran (THF), the generation benzyl [3-(6-oxo methyl heterocycle-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII);
(22) preparation target compound { 9-[3-(benzamido group) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl } (heterocycle) ketone (XXIII)
Benzyl [3-(6-oxo methyl heterocycle-3; 4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII) is in the ethyl acetate solution of hydrogenchloride; room temperature reaction 2h; remove the Boc protecting group; generate 9-[3-(benzamido group) propyl group]-2; 3,4,9-1H-tetrahydro carbazole-6-yl } (heterocycle) ketone (XXIII).
The present invention synthetic part preferred compound chemical structure and 1The H-NMR data see Table 1.
The chemical structure of table 1 part preferred compound and 1The H-NMR data
Figure BDA0000055496920000121
Figure BDA0000055496920000122
Figure BDA0000055496920000131
Figure BDA0000055496920000141
Figure BDA0000055496920000151
Figure BDA0000055496920000161
Figure BDA0000055496920000171
Figure BDA0000055496920000181
Compound of the present invention is the anti-mycotic activity compound of a class brand new type, has certain anti-mycotic activity, has opened up new approach for furtheing investigate and develop new texture type antifungal drug, can be used for preparing the medicine for the treatment of anti-fungal infection.
Embodiment:
Embodiment 1: the preparation of alpha-brominated pimelinketone (II)
Get NBS (19.46g, 0.11mol, 1.1equiv) and pimelinketone (9.81g, 0.10mol 1.0equiv) place the 500ml three-necked bottle.To wherein adding anhydrous diethyl ether 100mL, add again ammonium acetate (0.77g, 0.01mol, 0.1equiv), stirring reaction 0.5h under the room temperature.After reaction finishes, filtering insolubles, filtrate washing (25mL * 3), anhydrous Na 2SO 4Drying is filtered, concentrate, resistates through purification by silica gel column chromatography (developping agent: hexane: EtOAc=40: 1, v/v), obtain faint yellow oily thing 13.68g, yield 77.7%. 1H-NMR(500MHz，CDCl 3)：4.43～4.46(m，1H)，2.96～2.99(m，1H)，2.30～2.36(m，2H)，2.23～2.25(m，1H)，2.01～2.04(m，2H)，1.74～1.83(m，2H).
Embodiment 2:6-methyl isophthalic acid H-2,3,4, the preparation of 9-tetrahydro carbazole (III)
Get para-totuidine (22.48g, 0.21mol 3.0equiv) are dissolved among the ethylene glycol ethyl ether 150mL, treat para-totuidine dissolving after, add Compound I I (12.32g, 0.07mol, 1.0equiv).Feed N 2Under the condition, reflux, stirring reaction 12h.After reaction finishes, solvent evaporated, resistates adds the 250mL ethyl acetate extraction, and filtering insolubles, filtrate water are washed (100mL * 3), and saturated nacl aqueous solution is washed (100mL * 3).Isolate organic layer, use anhydrous Na 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, resistates through purification by silica gel column chromatography (developping agent: hexane: EtOAc=40: 1, v/v), obtain white, needle-shaped crystals 6.41g, yield 49.5%.mp?138-139℃； 1H-NMR(500MHz，CDCl 3)：7.54(br，1H)，6.91～7.25(m，3H)，2.66～2.72(m，4H)，2.43(s，3H)，1.85～1.91(m，4H).
Embodiment 3:6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4, the preparation of 9-tetrahydro carbazole (IV)
Get compound III (0.91g, 5mmol, 1equiv) and epoxy chloropropane (3.70g, 40mmol 8equiv) are dissolved among the DMSO 20mL, to wherein add the potassium hydroxide powder (1.12g, 10mmol, 2equiv), stirring at room reaction 2h.After reaction finishes, add water 40mL dilution, with chloroform extraction (40m L * 3).Merge organic layer, use anhydrous Na 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, resistates through purification by silica gel column chromatography (developping agent: hexane: EtOAc=10: 1, v/v), obtain yellow-green colour oily matter 1.14g, yield 95.8%. 1H-NMR(500MHz，CDCl 3)：6.96～7.19(m，3H)，4.17～4.31(m，2H)，4.10～4.17(m，2H)，3.19～3.22(m，1H)，2.71～2.77(m，4H)，2.67(s，3H)，1.84～1.96(m，4H).
Embodiment 4:1-cyclohexylamino-3-(6-methyl-3, the preparation of 4-dihydro-1H-carbazole-9 (2H)-yl)-2-propyl alcohol (compound 1 in the table)
Get compound IV (0.24g, 1mmol, 1equiv) and hexahydroaniline (1.59g, 16mmol 16equiv) are dissolved among the dehydrated alcohol 10mL heating reflux reaction 4h.After reaction finishes, solvent evaporated, resistates is through purification by silica gel column chromatography (developping agent: CH 2Cl 2: MeOH=10: 1, v/v), obtain Off-white solid 0.18g, yield 52.9%.mp?98-99℃； 1H-NMR(500MHz，CDCl 3)：6.94～7.27(m，3H)，4.01～4.08(m，3H)，2.76～2.82(m，1H)，2.68～2.74(m，4H)，2.50～2.57(m，1H)，2.45(s，3H)，1.88～1.95(m，4H)，0.97～2.33(m，13H).
Compound 2-4 is synthesis material with different amine in the table, and is listed as table 1, repeats the step among the embodiment 4, just can synthesize required substituted-tetrahydro carbazole compound.Agents useful for same is commercially available analytical pure among the embodiment.
Embodiment 5:9-(3-bromopropyl)-6-methyl isophthalic acid H-2,3,4, the preparation of 9-tetrahydro carbazole (VI)
(1equiv) with 1, (16.41g, 0.08mol 4equiv) are dissolved among the DMSO 50mL 3-dibromopropane, and (4equiv), stirring at room is reacted 3h for 4.60g, 0.08mol to wherein adding the potassium hydroxide powder for 3.80g, 0.02mol to get compound III.After reaction finishes, add water 50mL dilution, ethyl acetate extraction (100mL * 3).Merge organic layer, wash anhydrous Na with saturated 100mL sodium chloride solution again 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, resistates through purification by silica gel column chromatography (developping agent: hexane: EtOAc=40: 1, v/v), obtain white crystal 2.65g, yield 42.3%. 1H-NMR(500MHz，CDCl 3)：6.95～7.25(m，3H)，4.15(t，J＝6.7Hz，2H)，3.35(t，J＝6.3Hz，2H)，2.67～2.73(m，4H)，2.44(s，3H)，2.27～2.29(m，2H)，1.92～1.95(m，2H)，1.83～1.85(m，2H).
Embodiment 6:N-[3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] preparation of hexahydroaniline (compound 5 in the table)
Get compound VI (0.31g, 1mmol, 1equiv) and hexahydroaniline (0.79g, 8mmol 8equiv) are dissolved among the DMF 10mL, to wherein adding anhydrous K 2CO 3(0.28g, 2mmol 2equiv), are heated to 80 ℃, stirring reaction 4h.After reaction finishes, add ethyl acetate 25mL dilution, washing (10mL * 3).Isolate organic layer, anhydrous Na 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, and resistates is through purification by silica gel column chromatography (developping agent: CH 2Cl 2: MeOH=20: 1, v/v), obtain faint yellow oily thing 0.18g, yield 56.3%. 1H-NMR(500MHz，CDCl 3)：6.94～7.23(m，3H)，4.10(t，J＝6.7Hz，2H)，2.67～2.69(m，4H)，2.61(m，3H)，2.45(s，3H)，1.03～2.05(m，14H).
Compound 6-17 is synthesis material with different amine in the table, and is listed as table 1, repeats the step among the embodiment 6, just can synthesize required substituted-tetrahydro carbazole compound.
Embodiment 7:6-methyl 2,3,4, the preparation of 9-tetrahydrochysene-1H-carbazole-6-carboxylic acid, ethyl ester (VIII)
Get parathesin (34.69g, 0.21mol 3.0equiv) are dissolved among the ethylene glycol ethyl ether 150mL, treat parathesin dissolving after, add Compound I I (12.32g, 0.07mol, 1.0equiv).Feed N 2Under the condition, reflux, stirring reaction 12h.After reaction finishes, solvent evaporated, resistates adds the 250mL ethyl acetate extraction, and filtering insolubles, filtrate water are washed (100mL * 3), and saturated nacl aqueous solution is washed (100mL * 3).Isolate organic layer, use anhydrous Na 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, resistates through purification by silica gel column chromatography (developping agent: hexane: EtOAc=10: 1, v/v), obtain faint yellow solid 7.27g, yield 42.7%. 1H-NMR(500MHz，CDCl 3)：7.25～8.22(m，3H)，7.89(br，1H)，4.39(q，J＝7.1Hz，2H)，2.72～2.75(m，4H)，1.86～1.94(m，4H)，1.42(t，J＝7.1Hz，3H).
Embodiment 8:9-(3-bromopropyl)-2,3,4, the preparation of 9-tetrahydrochysene-1H-carbazole-6-carboxylic acid, ethyl ester (IX)
(1equiv) with 1, (16.41g, 0.08mol 4equiv) are dissolved among the DMSO 50mL 3-dibromopropane, and (4equiv), stirring at room is reacted 3h for 4.60g, 0.08mol to wherein adding the potassium hydroxide powder for 4.87g, 0.02mol to get compound VIII.After reaction finishes, add water 50mL dilution, ethyl acetate extraction (100mL * 3).Merge organic layer, wash anhydrous Na again with the 100mL saturated nacl aqueous solution 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, resistates through purification by silica gel column chromatography (developping agent: hexane: EtOAc=20: 1, v/v), obtain white crystal 2.90g, yield 39.8%. 1H-NMR(500MHz，CDCl 3)：7.29～8.23(m，3H)，4.39(q，J＝7.1Hz，2H)，4.21(t，J＝6.8Hz，2H)，3.37(t，J＝6.2Hz，2H)，2.72～2.76(m，4H)，2.28～2.31(m，2H)，1.95～1.97(m，2H)，1.85～1.88(m，2H)，1.42(t，J＝7.1Hz，3H).
Embodiment 9:9-[3-(benzamido group) propyl group]-2,3,4, the preparation of 9-tetrahydrochysene-1H-carbazole-6-carboxylic acid, ethyl ester (compound 24 in the table)
Get Compound I X (0.36g, 1mmol, 1equiv) and benzylamine (0.86g, 8mmol 8equiv) are dissolved among the DMF 10mL, to wherein adding anhydrous K 2CO 3(0.28g, 2mmol 2equiv), are heated to 80 ℃, stirring reaction 4h.After reaction finishes, add ethyl acetate 25mL dilution, washing (10mL * 3).Isolate organic layer, anhydrous Na 2SO 4Drying is filtered, the evaporated under reduced pressure solvent, and resistates is through silica gel column chromatography (developping agent: CH 2C1 2: MeOH=20: 1, v/v), obtain faint yellow solid 0.25g, yield 64.1%. 1H-NMR(500MHz，CDCl 3)：7.10～8.23(m，8H)，4.20(t，J＝6.7Hz，2H)，4.02(t，J＝6.9Hz，2H)，3.75(s，2H)，2.70～2.76(m，4H)，2.64(t，J＝6.5Hz，2H)，1.86～1.92(m，6H)，1.41(t，J＝6.9Hz，3H)
Embodiment 10:9-[3-(benzamido group) propyl group]-6-methylol-2,3,4, the preparation of 9-1H-tetrahydro carbazole (compound 18 in the table)
Get LiAlH 4(0.76g, 0.020mol 4eq) are dissolved among the exsiccant THF (25mL), and ice bath is cooled to 0 ℃, be dissolved with compound 24 in the table (1.95g, THF solution 25mL 0.005mol) rises to room temperature, stirring reaction 1h naturally to wherein dropwise dripping.After reaction finished, the ice bath cooling was to wherein dropwise adding 1mL H 2O removes excessive LiAlH 4, behind the stirring 1h, add anhydrous Na 2SO 4Dry 30min filters, solvent evaporated, and resistates is through purification by silica gel column chromatography (developping agent: CH 2Cl 2: MeOH=100: 2), obtain white solid 1.09g, yield: 62.6%. 1H-NMR(500MHz，CDCl 3)：6.99～7.31(m，8H)，4.95(br，1H)，4.52(s，2H)，4.08(t，J＝7.0Hz，2H)，3.64(s，2H)，2.67～2.70(m，2H)，2.59～2.62(m，2H)，2.46(t，J＝6.6Hz，2H)，1.83～1.85(m，2H)，1.75～1.78(m，4H).
Embodiment 11: the preparation of benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII)
(3.48g 0.01mol) is dissolved among the methylene dichloride 50mL, adds Et to get compound 18 in the table 3(1.5equiv), ice bath is cooled to 0 ℃ to N for 1.52g, 0.015mol.Be dissolved with Boc to wherein dripping 2O (2.62g, 0.012mol, CH 1.2equiv) 2Cl 2Solution 15mL.Drip and finish stirring reaction 2h under the room temperature.After reaction finishes, washing (10mL * 3), anhydrous Na 2SO 4Drying is filtered, solvent evaporated, and resistates is through purification by silica gel column chromatography (developping agent: Hexane: EtOAc=3: 1), obtain yellow oil 4.25g, yield: 94.9%.1H-NMR(500MHz，CDCl 3)：7.11～7.96(m，8H)，4.71(s，2H)，4.38(br，2H)，3.96(br，2H)，3.26(br，2H)，2.71(t，J＝5.5Hz，2H)，2.59(t，J＝5.5Hz，2H)，1.85～1.90(m，6H)，1.46(s，9H).
Embodiment 12:{9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-preparation of methyl benzoic acid ester (XIV)
Get compounds X III (0.18g, 0.4mmol) and Benzoyl chloride (0.08g, 0.6mmol 1.5equiv) are dissolved among the exsiccant methylene dichloride 15mL, to wherein adding triethylamine (0.08g, 0.8mmol, 2 equiv), stirring reaction 12h under the room temperature.Reaction is washed anhydrous Na with the saturated NaCl solution of 15mL after finishing 2SO 4Drying is filtered, solvent evaporated, and resistates is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=3: 1), obtain yellow oil 0.12g, yield: 54.5%. 1H-NMR(500MHz，CDCl 3)：6.48～7.95(m，13H)，4.71(s，2H)，4.38(s，2H)，3.96(br，2H)，3.26(br，2H)，2.71(br，2H)，2.59(t，2H)，1.84～1.89(m，6H)，1.46(s，9H).
Embodiment 13:{9-[3-(benzyl amino) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-preparation of methyl benzoic acid ester (compound 19 in the table)
Get compounds X IV (0.55g 1mmol) is dissolved among the ethyl acetate solution 10mL, to wherein add the hydrogenchloride ethyl acetate solution (1mol/L, 10mL), stirring reaction 2h under the room temperature.After reaction finishes, to wherein adding saturated sodium carbonate solution 15mL, ethyl acetate extraction (10mL * 3), the organic layer anhydrous sodium sulfate drying, filter, solvent evaporated, residue is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=2: 1), obtain faint yellow oily thing 0.16g, yield 35.6%. 1H-NMR(500MHz，CDCl 3)：6.48～7.96(m，13H)，4.71(s，2H)，4.13(t，J＝6.9Hz，2H)，3.75(s，2H)，2.68～2.72(m，4H)，2.64(t，J＝6.9Hz，2H)，1.85～1.94(m，6H).
Embodiment 14:N-benzyl-3-[6-(4-nitrophenol oxygen base) methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl]-preparation of 1-propylamine (compound 20 in the table)
(1equiv) (0.14g, 1.0mmol 1equiv) are dissolved among the exsiccant THF10mL of prepared fresh, strict control anhydrous and oxygen-free with the 4-nitrophenols for 0.35g, 1.0mmol to get compound 18 in the table.Then, (0.30mL, 1.2mmol 1.2equiv), and are cooled to 0 ℃ with reaction system with ice bath to wherein adding tributylphosphine.At last, (THF solution 5mL 1.2equiv) drips to reaction solution for 0.30g, 1.2mmol will to be dissolved with azo two formyls two piperidines.Naturally rise to room temperature, continue stirring reaction 24h.Reaction adds saturated NaHCO after finishing 3Solution 10mL, ethyl acetate extraction (10mL * 3), organic layer are used anhydrous Na after washing with the 20mL saturated nacl aqueous solution 2SO 4Drying is filtered, solvent evaporated, and resistates is through purification by silica gel column chromatography (developping agent: CH 2Cl 2: MeOH=100: 2), obtain white solid 0.02g, yield: 4.3%. 1H-NMR(500MHz，CDCl 3)：7.03～8.20(m，12H)，5.23(s，2H)，4.08(t，J＝6.6Hz，2H)，3.82(s，2H)，2.65～2.70(m，6H)，2.02～2.07(m，4H)，1.84～1.92(m，2H).
Embodiment 15: the preparation of benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XVI)
(0.45g 1mmol) is dissolved among the methylene dichloride 10mL, under the room temperature, is dissolved with pyridinium chlorochromate (PCC) (0.43g, 2mmol, dichloromethane solution 20mL 2equiv), continuation stirring reaction 2h to wherein dripping to get compounds X III.After reaction finishes, in reaction solution impouring 150mL ether, after stirring 10min, filter, filtrate is washed (15mL * 3) with saturated common salt, anhydrous sodium sulfate drying, filter, solvent evaporated, residue is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=5: 1), obtain yellow oil 0.10g, yield 22.4%. 1H-NMR(500MHz，CDCl 3)：10.01(s，1H)，7.16～8.00(m，8H)，4.39(br，2H)，3.97(br，2H)，3.25(br，2H)，2.73(br，2H)，2.59(br，2H)，1.85～1.93(m，6H)，1.46(s，9H).
Embodiment 16:N-{[9-(3-benzyl aminopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-yl] methyl } preparation of aniline (compound 21 in the table)
Get aniline (0.03g, 0.29mmol) and glacial acetic acid (0.03mL 2equiv) is dissolved among the methyl alcohol 5mL.Feed under the condition of nitrogen gas, add be dissolved with compounds X VI (0.13g, methanol solution 5mL 0.29mmol), add again sodium cyanoborohydride (0.02g, 0.35mmol, 1.2equiv), stirring reaction 12h under the room temperature.After reaction finishes, solvent evaporated, and add water 10mL dilution, dichloromethane extraction (15mL * 3).The organic layer anhydrous sodium sulfate drying filters, and concentrates, and residue is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=10: 1), obtain yellow oil 0.09g, yield 60.0%. 1H-NMR(500MHz，CDCl 3)：6.66～7.45(m，13H)，4.36(br，4H)，3.97(br，2H)，3.24(br，2H)，2.58～2.68(m，4H)，1.85～1.88(m，6H)，1.45(s，9H).
(0.09g 0.17mmol) is dissolved among the ethyl acetate 5mL, to wherein adding 1moL/L hydrogenchloride ethyl acetate solution 5mL, drips and finishes, stirring at room reaction 2h with above yellow oil.After reaction finishes, to wherein adding saturated sodium carbonate solution 10mL, ethyl acetate extraction (10mL * 3), the organic layer anhydrous sodium sulfate drying, filtration, solvent evaporated, residue is through purification by silica gel column chromatography (developping agent: CH 2Cl 2: MeOH=100: 2), obtain white solid 0.06g, yield 85.7%. 1H-NMR(500MHz，CDCl 3)：6.69～7.50(m，13H)，4.40(s，2H)，4.13(t，J＝6.9Hz，2H)，3.77(s，2H)，2.65～2.73(m，6H)，1.89～1.97(m，6H).
Compound 22-23 is synthesis material with different substituted anilines in the table, and is listed as table 1, repeats the step among the embodiment 13, just can synthesize required substituted-tetrahydro carbazole compound.
Embodiment 17:9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4, the preparation of 9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII)
(3.91g 0.01mol) is dissolved in CH to get compound 24 in the table 2Cl 2(50mL), add Et 3(1.5equiv), ice bath is cooled to 0 ℃ to N for 1.52g, 0.015mol.Be dissolved with Boc to wherein dripping 2O (2.62g, 0.012mol, CH 1.2equiv) 2Cl 2Solution 15mL.Drip and finish stirring reaction 2h under the room temperature.After reaction finishes, washing (10mL * 3), anhydrous Na 2SO 4Drying is filtered, solvent evaporated, and resistates is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=10: 1), obtain yellow oil 4.70g, yield: 95.9%. 1H-NMR(500MHz，CDCl 3)：7.10～8.23(m，8H)，4.36～4.44(m，4H)，3.96(br，2H)，3.26(br，2H)，2.74(t，J＝5.5Hz，2H)，2.59(br，2H)，1.86～1.90(m，6H)，1.60(s，9H)，1.40(t，J＝6.9Hz，3H).
Embodiment 18:9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4, the preparation of 9-1H-tetrahydro carbazole-6-carboxylic acid (XIX)
(4.91g 0.01mol) is dissolved among the THF (40mL), and ice bath is cooled to 0 ℃, to wherein adding LiOH.H to get compounds X VIII 2O (2.10g, 0.05mol, 5equiv), H 2O (10mL) and MeOH (20mL) are warming up to 50 ℃ of stirring reaction 24h.Reaction steams THF and MeOH after finishing, and adds saturated NH 4Cl solution 50mL, EtOAc extracts (50mL * 3), organic layer anhydrous Na 2SO 4Drying is filtered, and solvent evaporated obtains white solid 4.02g, yield: 87.1%. 1H-NMR(500MHz，CDCl 3)：12.44(br，1H)，7.16～8.02(m，8H)，4.34(s，2H)，3.99(t，J＝7.0Hz，2H)，3.20(br，2H)，2.61～2.63(m，4H)，1.75～1.82(m，6H)，1.32(s，9H).
Embodiment 19:9-[3-(benzamido group) propyl group]-2,3,4, the preparation of 9-1H-tetrahydro carbazole-6-carboxylic acid phenolic ester (compound 25 in the table)
Get compounds X IX (0.69g, 1.5mmol) and phenol (0.28g, 3.0mmol 2.0equiv) are dissolved among the methylene dichloride 15mL, to wherein add EDC.HCl (0.44g, 2.25mmol, 1.5equiv) and DMAP (0.07g, 0.6mmol, 0.4equiv), stirring reaction 12h under the room temperature.Reaction is washed with 10mL saturated ammonium chloride solution, 10mL saturated sodium carbonate solution and 10mL saturated nacl aqueous solution respectively after finishing, and the organic layer anhydrous sodium sulfate drying filters, and concentrates, and obtains yellow oil.Product need not purifying, can directly carry out next step reaction.
(0.27g 0.5mmol) is dissolved among the ethyl acetate 5mL, to wherein adding 1moL/L hydrogenchloride ethyl acetate solution 10mL, drips and finishes, stirring at room reaction 2h with above yellow oil.After reaction finishes, to wherein adding saturated sodium carbonate solution 15mL, ethyl acetate extraction (10mL * 3), the organic layer anhydrous sodium sulfate drying, filter, solvent evaporated, residue is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=2: 1), obtain white solid 0.18g, yield 82.2%. 1H-NMR(500MHz，CDCl 3)：7.25～8.41(m，13H)，4.18(t，J＝7.0Hz，2H)，3.77(s，2H)，2.72～2.79(m，4H)，2.67(t，J＝6.8Hz，2H)，1.87～1.99(m，6H).
Compound 26-41 is synthesis material with different fortified phenols, alkohol and amine in the table, and is listed as table 1, repeats the step among the embodiment 16, just can synthesize required substituted-tetrahydro carbazole compound.
Embodiment 20: the preparation of benzyl { 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] propyl group } t-butyl carbamate (XXI)
Get compounds X IX (1.05g, 2.27mmol) (0.40g, 4.54mmol 2.0equiv) are dissolved among the methylene dichloride 25mL with the morphine quinoline, to wherein add EDC.HCl (0.67g, 3.40mmol, 1.5equiv) and DMAP (0.11g, 0.91mmol, 0.4equiv), stirring reaction 12h under the room temperature.Reaction is washed with 15mL saturated ammonium chloride solution, 15mL saturated sodium carbonate solution and 15mL saturated nacl aqueous solution respectively after finishing, and the organic layer anhydrous sodium sulfate drying filters, and concentrates, and obtains faint yellow solid 0.86g, yield 71.3%.Product need not purifying, can directly carry out next step reaction. 1H-NMR(500MHz，CDCl 3)：7.12～7.56(m，8H)，4.37(br，2H)，3.95(br，2H)，3.70(br，8H)，3.28(br，2H)，2.69(t，J＝5.8Hz，2H)，2.59(br，2H)，1.83～1.91(m，6H)，1.45(s，9H).
Embodiment 21: the preparation of benzyl [3-(6-oxo picoline-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII)
Get the 2-bromopyridine (0.47g, 3.0mmol, 3equiv) and Tetramethyl Ethylene Diamine (0.45mL, 3.0mmol 3equiv) are dissolved among the exsiccant tetrahydrofuran (THF) 25mL of prepared fresh.Reaction solution is cooled to-78 ℃, and feeds under the nitrogen protection, to wherein add the 2.5N n-Butyl Lithium (1.8mL, 4.5mmol, 4.5equiv), stirring reaction 30min.Then, be dissolved with compounds X XI (0.53g, tetrahydrofuran solution 5mL 1.0mmol), continuation stirring reaction 30min to wherein dripping again.After reaction finishes, add the cancellation of 30mL saturated ammonium chloride solution, ethyl acetate extraction (50mL * 3), organic layer is washed (100mL * 2) with saturated nacl aqueous solution, and anhydrous sodium sulfate drying filters, concentrate, resistates is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=5: 1), obtain yellow oil 0.20g, yield 38.5%. 1H-NMR(500MHz，CDCl 3)：7.15～8.76(m，12H)，4.40(s，2H)，3.97(br，2H)，3.27～3.29(m，2H)，2.68～2.72(m，2H)，2.57～2.59(m，2H)，1.82～1.92(m，6H)，1.49(s，9H).
Other compounds Xs XII is raw material with different bromo heterocycles, and is listed as table 1, repeats the step in the embodiment 21, just can synthesize required benzyl [3-(6-oxo methyl heterocycle-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate.
Embodiment 22:{9-[3-(benzamido group) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl } preparation of (pyridine-2-yl) ketone (compound 42 in the table)
(0.26g 0.5mmol) is dissolved among the ethyl acetate 5mL, to wherein adding 1moL/L hydrogenchloride ethyl acetate solution 10mL, drips and finishes, stirring at room reaction 2h to get compounds X XII.After reaction finishes, to wherein adding the 15mL saturated sodium carbonate solution, ethyl acetate extraction (10mL * 3), the organic layer anhydrous sodium sulfate drying, filter, solvent evaporated, residue is through purification by silica gel column chromatography (developping agent: hexane: EtOAc=2: 1), obtain yellow solid 0.19g, yield 90.4%. 1H-NMR(500MHz，CDCl 3)：7.24～8.73(m，12H)，4.13(t，J＝6.9Hz，2H)，3.73(s，2H)，2.67～2.72(m，4H)，2.62(t，J＝6.7Hz，2H)，1.88～1.93(m，4H)，1.81～1.84(m，2H)； 13C-NMR(500MHz，CDCl 3)：194.21，156.94，148.40，147.52，136.94，136.64，128.39，128.11，127.00，125.23，124.42，123.80，122.96，111.64，108.39，53.97，46.30，40.81，30.57，23.10，22.92，22.14，20.93.
Compound 43-45 is with different benzyls [3-(6-oxo methyl heterocycle-3 in the table, 4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII) is synthesis material, listed as table 1, repeat the step among the embodiment 22, just can synthesize required substituted-tetrahydro carbazole compound.
Embodiment 23: and synthetic N-[3-of the present invention (6-replaces-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] antifungic action of aminated compounds
(1) experimental technique: adopt conventional external bacteriostatic experiment method (to see for details: Antimicrob Agents Chemother 1995,39 (5): 1169)
1. materials and methods
(1) experimental strain
This experiment has selected for use following 7 kinds of important human body cause illness's standard fungal bacterial strains as the screening object, and fungal bacterial strain is provided by Changhai hospital of The 2nd Army Medical College Mycology Lab.
1) Candida albicans (Candida albicans, type strain SC5314);
2) Cryptococcus neoformans (Cryptococcus neoformans, type strain BLS 108);
3) Oidium tropicale (Candida tropicalis, clinical strain);
4) Candida parapsilosis (Candida parapsilosis, clinical strain 0306392);
5) candida krusei (Candida kefyr, clinical strain 0710467);
6) trichophyton (Trichophyton rubrum, clinical strain 0501124);
7) aspergillus fumigatus (Aspergillus fumigatus, clinical strain 0504656).
(2) test method
The bacteria suspension preparation: a. Cryptococcus neoformans and candidiasis were cultivated 16 hours for 35 ℃ through the YEPD liquid nutrient medium, and twice activation with the blood cell counting plate counting, adjusted concentration to 1 * 10 with the RPM1640 liquid nutrient medium 3～5 * 10 3Individual/mL.B. thread fungus (aspergillus fumigatus and trichophyton) is cultivated (35 ℃) one week and (28 ℃) two weeks respectively through the SDA inclined-plane, and twice activation adds the RPM1640 liquid nutrient medium and blow and beat with suction pipe, spore is free in the RPM1640 liquid, through four layers of filtered through gauze, counting is adjusted concentration to 1 * 10 3～5 * 10 3Individual/mL.
Soup preparation: get testing compound of the present invention and be dissolved in methyl-sulphoxide, be made into the medicine storage liquid of 6.4mg/mL, be diluted to 640 μ g/mL with RPM1640 before the experiment.
Inoculation: No. 1 hole of 96 orifice plates adds RPM1640100 μ l and makes blank, the 3-12 hole respectively adds bacteria suspension 100 μ l, No. 2 the hole adds bacteria suspension 180 μ l and soup 20 μ l, the drug level in 2-11 hole is made 10 grade of 2 doubling dilution, and each hole drug level is respectively 64,32,16,8,4,2,1,0.5,0.25,0.125 μ g/mL.No. 12 the hole does not add soup, makes positive control.
Cultivate and detect: establishing positive control hole optical density value (OD value) is 100%, and being lower than 80% lowest concentration of drug with optical density value than positive control hole is minimal inhibitory concentration value (MIC).
(2) experimental result
External bacteriostatic experiment the results are shown in Table 2
The external antimycotic minimal inhibitory concentration value of table 2 part selected objective target compound (MIC, μ g/mL)
Figure BDA0000055496920000301
Figure BDA0000055496920000311
Above-mentioned experimental result shows that compound of the present invention has anti-mycotic activity preferably, illustrates that this compounds can be used for preparing the medicine for the treatment of anti-fungal infection.
Substituted-tetrahydro carbazole compound of the present invention is the anti-mycotic activity compound of a class new texture type, and the present invention is that further investigation and developing novel antifungal medicines have been opened up new approach.

Claims (4)

1. substituted-tetrahydro carbazole compound is characterized in that such structural general formula is:
Figure FDA0000055496910000011
Wherein:
R 1Group is represented the various substituting groups on the aromatic ring, can for low alkyl group ,-CH 2-X-Y, With
(1) low alkyl group is selected from methyl, ethyl, propyl group, sec.-propyl;
(2) X represents O or NH;
(3) Y is hydrogen, low alkyl group, cycloaliphatic ring alkyl, substituted-phenyl, substituted benzyl, heterocyclic substituent, pyridine-3-methyl and benzoyl:
A. low alkyl group nail base, ethyl, propyl group;
B. cycloaliphatic ring alkyl, finger ring hexyl, piperidines-1-base, piperidin-4-yl, N-methyl piperidine-4-base, piperidin-4-one--1-base, morpholine-1-base;
C. the various substituting group positions in substituted-phenyl and the substituted benzyl can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to: hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, nitro, cyano group, trifluoromethyl or halogen; Wherein, halogen is selected from F, Cl, Br, I or 2,4-difluoro;
D. heterocyclic substituent is selected from pyridine-2-base, pyridin-3-yl, 5-picoline-2-base or thiazol-2-yl;
R 2Group is represented hydrogen or hydroxyl;
R 3Group is represented cyclohexyl, pyridine-3-methyl, various substituted-phenyl and substituted benzyl; Various substituting group positions in substituted-phenyl and the substituted benzyl can be positioned at the neighbour,, contraposition, can be single replacement, also can be polysubstituted, substituting group refers to: hydrogen, methyl, ethyl, methoxyl group, oxyethyl group, nitro, cyano group,
Trifluoromethyl or halogen; Wherein, halogen is selected from F, Cl, Br, I or 2,4-dichloro.
2. by the described substituted-tetrahydro carbazole compound of claim 1, it is characterized in that said compound is R 1, R 2And R 3The combination of group is respectively following compound:
(1) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is a cyclohexyl;
(2) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is a phenyl;
(3) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is a benzyl;
(4) R 1Group is a methyl, R 2Group is a hydroxyl, R 3Group is pyridine-3-methyl;
(5) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a cyclohexyl;
(6) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a phenyl;
(7) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(8) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is pyridine-3-methyl;
(9) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 4-luorobenzyl;
(10) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 3-luorobenzyl;
(11) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 2-luorobenzyl;
(12) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a 4-benzyl chloride base;
(13) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a 2-benzyl chloride base;
(14) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is a 3-benzyl chloride base;
(15) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 4-methyl-benzyl;
(16) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is the 4-methoxy-benzyl;
(17) R 1Group is a methyl, R 2Group is a hydrogen, R 3Group is 2, the 4-dichloro benzyl;
(18) R 1Group is-CH 2-X-Y, X group are oxygen, and Y group is a hydrogen, R 2Group is a hydrogen, R 3Group is a benzyl;
(19) R 1Group is-CH 2-X-Y, X group are oxygen, and Y group is a benzoyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(20) R 1Group is-CH 2-X-Y, X group are oxygen, and Y group is the 4-nitrophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(21) R 1Group is-CH 2-X-Y, X group are NH, and Y group is a phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(22) R 1Group is-CH 2-X-Y, X group are NH, and Y group is the 4-bromophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(23) R 1Group is-CH 2-X-Y, X group are NH, and Y group is the 4-aminomethyl phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(24) R 1Group is
Figure FDA0000055496910000031
The X group is an oxygen, and Y group is an ethyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(25) R 1Group is
Figure FDA0000055496910000032
The X group is an oxygen, and Y group is a phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(26) R 1Group is
Figure FDA0000055496910000033
The X group is an oxygen, and Y group is the 4-fluorophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(27) R 1Group is
Figure FDA0000055496910000034
The X group is an oxygen, and Y group is the 4-aminomethyl phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(28) R 1Group is
Figure FDA0000055496910000035
The X group is an oxygen, and Y group is a piperidin-4-yl, R 2Group is a hydrogen, R 3Group is a benzyl;
(29) R 1Group is
Figure FDA0000055496910000036
The X group is an oxygen, and Y group is N-methyl piperidine-4-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(30) R 1Group is
Figure FDA0000055496910000037
The X group is NH, and Y group is a phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(31) R 1Group is
Figure FDA0000055496910000041
The X group is NH, and Y group is the 4-fluorophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(32) R 1Group is
Figure FDA0000055496910000042
The X group is NH, and Y group is the 4-aminomethyl phenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(33) R 1Group is The X group is NH, and Y group is the 4-bromophenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(34) R 1Group is
Figure FDA0000055496910000044
The X group is NH, and Y group is the 4-ethoxyl phenenyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(35) R 1Group is
Figure FDA0000055496910000045
The X group is NH, and Y group is the 2,4 difluorobenzene base, R 2Group is a hydrogen, R 3Group is a benzyl;
(36) R 1Group is
Figure FDA0000055496910000046
The X group is NH, and Y group is a benzyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(37) R 1Group is
Figure FDA0000055496910000047
The X group is NH, and Y group is pyridine-3-methyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(38) R 1Group is
Figure FDA0000055496910000048
The X group is NH, and Y group is a cyclohexyl, R 2Group is a hydrogen, R 3Group is a benzyl;
(39) R 1Group is
Figure FDA0000055496910000049
The X group is NH, and Y group is piperidin-4-one--1-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(40) R 1Group is
Figure FDA00000554969100000410
The X group is NH, and Y group is piperidines-1-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(41) R 1Group is The X group is NH, and Y group is morpholine-1-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(42) R 1Group is
Figure FDA00000554969100000412
Y group is pyridine-2-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(43) R 1Group is
Figure FDA0000055496910000051
Y group is a pyridin-3-yl, R 2Group is a hydrogen, R 3Group is a benzyl;
(44) R 1Group is
Figure FDA0000055496910000052
Y group is 5-picoline-2-base, R 2Group is a hydrogen, R 3Group is a benzyl;
(45) R 1Group is
Figure FDA0000055496910000053
Y group is a thiazol-2-yl, R 2Group is a hydrogen, R 3Group is a benzyl.
3. claim 1 or the 2 described substituted-tetrahydro carbazole compounds application in the preparation antifungal drug.
4. the preparation method of the described substituted-tetrahydro carbazole compound of claim 1, synthetic route is as follows:
Figure FDA0000055496910000054
Figure FDA0000055496910000061
Concrete steps are:
(1) prepares alpha-brominated pimelinketone (II)
Pimelinketone (I) is in anhydrous diethyl ether, and through ammonium acetate catalysis, with the N-bromo-succinimide, at room temperature stirring reaction 0.5h generates alpha-brominated pimelinketone (II);
(2) preparation 6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (III)
Under the nitrogen protection condition, alpha-brominated pimelinketone (II) and para-totuidine reflux in ethylene glycol ethyl ether, reaction 12h generates 6-methyl isophthalic acid H-2, and 3,4,9-tetrahydro carbazole (III);
(3) preparation 6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4,9-tetrahydro carbazole (IV)
6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (III) is an alkali with KOH in DMSO, with epoxy chloropropane room temperature reaction 2h, generates 6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4,9-tetrahydro carbazole (IV);
(4) preparation target compound 1-substituted-amino-3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl)-2-propyl alcohol (V)
6-methyl-9-(epoxy-2-ylmethyl)-1H-2,3,4,9-tetrahydro carbazole (IV) respectively with various amine back flow reaction 4h in ethanol, generate 1-substituted-amino-3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl)-2-propyl alcohol (V);
(5) preparation 9-(3-bromopropyl)-6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (VI)
6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (III) is an alkali with KOH in DMSO, with 1,3-dibromopropane room temperature reaction 3h generates 9-(3-bromopropyl)-6-methyl isophthalic acid H-2, and 3,4,9-tetrahydro carbazole (VI);
(6) preparation target compound N-[3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] replace amine (VII)
9-(3-bromopropyl)-6-methyl isophthalic acid H-2,3,4,9-tetrahydro carbazole (VI) is an alkali with the Anhydrous potassium carbonate in DMF, reacts 4 hours at 80 ℃ with various amine respectively, generation N-[3-(6-methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] replacement amine (VII);
(7) preparation 2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (VIII)
Under the nitrogen protection condition, alpha-brominated pimelinketone (II) and parathesin reflux in ethylene glycol ethyl ether, reaction 12h generates 2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (VIII);
(8) preparation 9-(3-bromopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (IX)
2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (VIII) is an alkali with KOH in DMSO, and with 1,3-dibromopropane room temperature reaction 3h generates 9-(3-bromopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (IX);
(9) preparation target compound 9-[3-(benzamido group) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X)
9-(3-bromopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (IX) they are alkali with the Anhydrous potassium carbonate in DMF, react 4 hours at 80 ℃ with benzylamine, generate 9-[3-(benzamido group) propyl group]-2,3,4, and 9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X);
(10) preparation target compound 9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI)
Lithium Aluminium Hydride is suspended in the tetrahydrofuran (THF), under the ice bath, add 9-[3-(benzamido group) propyl group]-2,3,4, the tetrahydrofuran solution of 9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (X), back room temperature reaction 1h, hydro-reduction generates 9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI);
(11) preparation target compound N-benzyl-3-[6-(4-nitrophenol oxygen base) methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl]-1-propylamine (XII)
At N 2Under the protective condition, 9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI) and 4-nitrophenols and tributylphosphine (TBuP) are in tetrahydrofuran (THF), under the ice bath, the tetrahydrofuran solution that adds azo two formyls, two piperidines (ADDP), back room temperature reaction 24h generates N-benzyl-3-[6-(4-nitrophenol oxygen base) methyl-3,4-dihydro-1H-carbazole-9 (2H)-yl]-1-propylamine (XII);
(12) preparation benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII)
9-[3-(benzamido group) propyl group]-6-methylol-2,3,4,9-1H-tetrahydro carbazole (XI) under the ice bath, is an alkali with the triethylamine in methylene dichloride, add tert-Butyl dicarbonate, back room temperature reaction 2h, and the generation benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII);
(13) preparation 9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl] and-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XIV)
Benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII) is in methylene dichloride, with the triethylamine is alkali, with Benzoyl chloride room temperature reaction 12h, generate 9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XIV);
(14) preparation target compound { 9-[3-(benzyl amino) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XV)
9-[3-benzyl (tertbutyloxycarbonyl) aminopropyl]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XIV) is in the ethyl acetate solution of hydrogenchloride, and room temperature reaction 2h removes the Boc protecting group, generate 9-[3-(benzyl amino) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl }-methyl benzoic acid ester (XV);
(15) preparation benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XVI)
Benzyl [3-(6-methylol-3,4-dihydro-1H-carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XIII) is in methylene dichloride, with pyridinium chlorochromate (PCC) room temperature reaction 2h, the generation benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XVI);
(16) preparation target compound N-{[9-(3-benzyl aminopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-yl] methyl } substituted aniline (XVII)
At N 2Under the protective condition, various substituted anilines and glacial acetic acid are in methyl alcohol, add benzyl [3-(6-formyl radical-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] methanol solution of t-butyl carbamate (XVI), add sodium cyanoborohydride again, stirring at room reaction 12h, product that this reaction is generated is in the ethyl acetate solution of hydrogenchloride, room temperature reaction 2h, remove the Boc protecting group, generate N-{[9-(3-benzyl aminopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-yl] methyl } substituted aniline (XVII);
(17) preparation 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII)
N-{[9-(3-benzyl aminopropyl)-2,3,4,9-1H-tetrahydro carbazole-6-yl] methyl } aniline (XVII) is in methylene dichloride, under the ice bath, with the triethylamine is alkali, adds tert-Butyl dicarbonate, back room temperature reaction 2h, generate 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII)
(18) preparation 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX)
9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid, ethyl ester (XVIII) is at THF: MeOH: H 2In O (4: 2: the 1) solution, react 24h in 50 ℃ with lithium hydroxide, hydrolysis generates 9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX);
(19) preparation target compound 9-[3-(benzamido group) propyl group]-2,3,4, the 9-1H-tetrahydro carbazole-6-carboxylicesters (or acid amides) is (XX)
9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX) respectively with phenol, alcohol or amine in methylene dichloride, use the EDC/DMAP catalyzing and condensing, room temperature reaction 12h, product that this reaction is generated is in the ethyl acetate solution of hydrogenchloride, room temperature reaction 2h, remove the Boc protecting group, generate 9-[3-(benzamido group) propyl group]-2,3,4, the 9-1H-tetrahydro carbazole-6-carboxylicesters (or acid amides) (XX);
(20) preparation benzyl { 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] propyl group } t-butyl carbamate (XXI)
9-{3-[benzyl (tertbutyloxycarbonyl) amido] propyl group }-2,3,4,9-1H-tetrahydro carbazole-6-carboxylic acid (XIX) and morpholine are in methylene dichloride, with using the EDC/DMAP catalyzing and condensing, room temperature reaction 12h, the generation benzyl 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] and propyl group } t-butyl carbamate (XXI);
(21) preparation benzyl [3-(6-oxo methyl heterocycle-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII)
At N 2Under the protective condition, Tetramethyl Ethylene Diamine (TMEDA) exists down, benzyl { 3-[6-(morphine quinoline-4-carbonyl-) 3,4-1H-dihydro carbazole-9 (2H)-yl] propyl group } t-butyl carbamate (XXI) and 2-bromine heterocycle and n-Butyl Lithium react 1h at-78 ℃ in tetrahydrofuran (THF), the generation benzyl [3-(6-oxo methyl heterocycle-3,4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII);
(22) preparation target compound { 9-[3-(benzamido group) propyl group]-2,3,4,9-1H-tetrahydro carbazole-6-yl } (heterocycle) ketone (XXIII)
Benzyl [3-(6-oxo methyl heterocycle-3; 4-1H-dihydro carbazole-9 (2H)-yl) propyl group] t-butyl carbamate (XXII) is in the ethyl acetate solution of hydrogenchloride; room temperature reaction 2h; remove the Boc protecting group; generate 9-[3-(benzamido group) propyl group]-2; 3,4,9-1H-tetrahydro carbazole-6-yl } (heterocycle) ketone (XXIII).
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CN108084082A (en) * 2017-12-25 2018-05-29 南京理工大学 The method for synthesizing [b]-ring annulated indole analog derivative
CN108084082B (en) * 2017-12-25 2021-04-16 南京理工大学 Method for synthesizing [ b ] -cyclized indole derivatives
CN108623585A (en) * 2018-05-22 2018-10-09 中国人民解放军第二军医大学 Beta-tetrahydro carboline class antifungal drug and its preparation method and application

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