CN108707104A - The synthetic method of chloro- -1,4 (the 9H)-diketone of 1H- carbazoles of 2- - Google Patents
The synthetic method of chloro- -1,4 (the 9H)-diketone of 1H- carbazoles of 2- Download PDFInfo
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- CN108707104A CN108707104A CN201810888971.2A CN201810888971A CN108707104A CN 108707104 A CN108707104 A CN 108707104A CN 201810888971 A CN201810888971 A CN 201810888971A CN 108707104 A CN108707104 A CN 108707104A
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- chloro
- carbazoles
- isosorbide
- nitrae
- carbazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
Abstract
The present invention relates to the novel synthesis of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone, include the following steps：The first step, using 3- indolebutyric acids as 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone of Material synthesis；Second step carries out benzyl protection to 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone；Third walks, and double chlorinations, synthesis 9- benzyls -2,2- bis- chloro- 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone occur under the conditions of anhydrous cupric chloride and anhydrous lithium chloride；Elimination reaction occurs under conditions of anhydrous lithium chloride and lithium carbonate for the 4th step, synthesizes the chloro- 9H- carbazoles -1- alcohol of 9- benzyls -2-；5th step removes the benzyl of the chloro- 9H- carbazoles -1- alcohol of 9- benzyls -2-；The chloro- 9H- carbazoles -1- alcohol of 2- is oxidized to the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone by the 6th step.
Description
Technical field
The present invention relates to the synthetic methods of one kind chloro- -1,4 (9H)-diketone of 1H- carbazoles of the 2- of organic synthesis intermediate containing chlorine.
Background technology
The synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone is not reported in patent and non-patent literature, but non-special
The chemical synthesis process that the bromo- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone is reported in sharp document, as Journal of Organic Chemistry (Iqbal N,
Ueno Y.Synthesis of Indolo phenothiazin-6-one derivatives[J].Monatshefte Für
Chemie,1993,124(3):319-321.) report, reaction equation is as follows：
This method uses carbazole-Isosorbide-5-Nitrae-diketone that addition reaction occurs with bromine first, then eliminates under alkaline condition
Reaction, obtains the mixture of the bromo- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone and the bromo- 1H- carbazoles of 3--Isosorbide-5-Nitrae (9H)-diketone.Due to production
The polarity of the bromo- 1H- carbazoles of object 2--Isosorbide-5-Nitrae (9H)-diketone and the bromo- 1H- carbazoles of 3--Isosorbide-5-Nitrae (9H)-diketone is close, leads to target product
The bromo- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone is difficult to purify, and yield is not high.
Invention content
The purpose of the present invention is to provide a kind of synthetic methods of the chloro- 1H- carbazoles of new 2--Isosorbide-5-Nitrae (9H)-diketone, mainly
Solve the technical issues of existing synthetic route is difficult to purify.
Technical scheme of the present invention：The synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone, includes the following steps：
The first step synthesizes 2,3,4,9- tetrahydrochysenes-using 3- indolebutyric acids (1) and polyphosphoric acids as raw material by solvent of toluene
1H- carbazole -1- ketone (2)；
Second step carries out benzyl protection to 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (2), obtains 9- benzyls -2,3, and 4,9-
Tetrahydrochysene -1H- carbazole -1- ketone (3)；
Third walk, 9- benzyls -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (3), anhydrous cupric chloride and anhydrous lithium chloride with
DMF is that chlorination, synthesis 9- benzyls -2,2- bis- chloro- 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (4) occur for solvent；
4th step, with 9- benzyls -2,2- bis- chloro- 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (4) are raw material, in anhydrous chlorine
Elimination reaction occurs under conditions of change lithium and lithium carbonate, synthesizes the chloro- 9H- carbazoles -1- alcohol (5) of 9- benzyls -2-；
5th step, the chloro- 9H- carbazoles -1- alcohol (5) of 9- benzyls -2- and Boron tribromide react under cryogenic, remove benzyl
Obtain the chloro- 9H- carbazoles -1- alcohol (6) of 2-；
6th step, the chloro- 9H- carbazoles -1- alcohol (6) of 2-, nitroso potassium peroxydisulfate and potassium dihydrogen phosphate are in the mixed of water and acetone
Oxidation reaction occurs in bonding solvent, synthesizes 2- chloro- 1H- carbazoles-Isosorbide-5-Nitrae (9H)-diketone (7).
Chemical equation is as follows：
Beneficial effects of the present invention：The present invention provides a kind of effective chloro- -1,4 (9H)-diketone of 1H- carbazoles synthesis of 2-
Route, yield is higher, and is easy to purify.
Specific implementation mode
Following instance helps to understand the content of present invention, and the present invention includes but is not limited to following related content：
The synthesis of 1.2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone
Embodiment 1
3- indolebutyric acids (6.1g, 30mmol) and polyphosphoric acids (152.1g, 72.4mL) are added in 300 mL toluene, mixed
Object is closed to be stirred to react under the conditions of 110 DEG C 5 hours.After reaction, solvent toluene is poured out while hot, after reaction vessel cooling
600mL ice water is added, and stirs one hour.The yellow solid that reaction generates is obtained by filtration, washes until pH=7, then with red
Outer drying box drying, obtains 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (5.19g, yield 93.4%).
1H NMR(400MHz,CDCl3):δ 9.24 (s, 1H, NH), 7.69 (d, J=8.04Hz, 1H, ArH), 7.47 (d, J
=8.32Hz, 1H, ArH), 7.40 (t, 1H, ArH), 7.18 (t, 1H, ArH), 3.05 (t, 2H, ArCH 2), 2.70(t,2H,
COCH 2),2.30(p,2H,CH2CH 2CH2).
13C NMR(100MHz,CDCl3):δ191.48,137.92,131.26,129.55,127.04,125.89,
121.38,120.39,112.59,38.26,25.01,21.42.
The synthesis of 2.9- benzyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone
Embodiment 2
To the acetone of 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (185.0mg, 1mmol) under conditions of ice-water bath
Potassium hydroxide powder (196mg, 3mmol) is added in (10mL) solution.After 15 minutes, into mixture be added dropwise benzyl chloride (0.13mL,
1.1mmol) and it is vigorously stirred.After reaction four hours, another potassium hydroxide powder (203.8mg, 3mmol), mixture is added
It is stirred overnight at ambient temperature.After the completion of reaction, inorganic salts are filtered out, and concentrate filtrate, nothing is obtained with silica gel chromatograph column purification
Color grease (247.5mg, yield 90%).
1H NMR(400MHz,DMSO-d6):δ 7.74 (d, J=8Hz, 1H, ArH), 7.53 (d, J=8.44 Hz, 1H,
), ArH 7.36 (t, 1H, ArH), 7.27-7.12 (m, 4H, ArH), 7.09 (d, J=7.28Hz, 2H, ArH), 5.82 (s, 2H,
PhCH 2),3.02(t,2H,ArCH 2),2.61(t,2H,COCH 2),2.15(p,2H, CH2CH 2CH2).
The synthesis of two chloro- 2,3,4,9- tetrahydrochysenes -1H- carbazole -1- ketone of 3.9- benzyls -2,2-
Embodiment 3
9- benzyls -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone (826.0mg, 3mmol), anhydrous cupric chloride (2.028 g,
15mmol) and anhydrous lithium chloride (388.8mg, 9mmol) is heated to 105 DEG C in 9mL dimethylformamides and reacts 2 hours,
Then heating to 140 DEG C, the reaction was continued 1 hour.It is extracted with ethyl acetate after reaction (25mL*2), merges organic phase and use again
Saturated sodium bicarbonate solution (50mL*2) and saturated salt solution (50mL*1) washing, anhydrous sodium sulfate drying are filtered to remove drying
Filtrate is concentrated after agent, resulting brown oil is directly used in next step.
The synthesis of the chloro- 9H- carbazoles -1- alcohol of 4.9- benzyls -2-
Embodiment 4
Under conditions of nitrogen protection, by embodiment 3 product and anhydrous lithium chloride (386.8mg, 9mmol) and
Lithium carbonate (669.5mg, 9mmol) is heated to 135 DEG C in 10mL dimethylformamides and reacts 40 minutes.It uses after reaction
Ethyl acetate (25mL*2) extracts, and merges organic phase and is washed again with 2N dilute hydrochloric acid (50 mL*2) and saturated salt solution (50mL*1),
Anhydrous sodium sulfate is dried, and concentrates filtrate after being filtered to remove drier, the chloro- 9H- clicks of 9- benzyls -2- are obtained with silica gel chromatograph column purification
Azoles -1- alcohol (white solid, 595mg, yield 64.4%).
1H NMR(400MHz,DMSO-d6):δ 9.76 (s, 1H, OH), 8.12 (d, J=7.64Hz, 1H, ArH), 7.71
(d, J=8.24Hz, 1H, ArH), 7.54 (d, J=8.08Hz, 1H, ArH), 7.40 (t, 1H, ArH), 7.26-7.17 (m, 5H,
), ArH 7.13 (d, J=8Hz, 2H, ArH), 5.96 (s, 2H, PhCH 2).
13C NMR(100MHz,DMSO-d6):δ141.11,139.94,139.44,130.96,128.92, 127.43,
126.91,126.42,123.82,122.75,120.84,120.76,119.93,118.12,113.26, 110.50,47.99.
HRMS(ESI-)m/z calculated for C19H13ClNO(M-H)–306.0686,found 306.0692.
The synthesis of the chloro- 9H- carbazoles -1- alcohol of 5.2-
Embodiment 5
To the dichloromethane of the chloro- 9H- carbazoles -1- alcohol (308.4mg, 1mmol) of 9- benzyls -2- under conditions of subzero 10 DEG C
The dichloromethane solution (1M) of 5mL Boron tribromides is added dropwise in (10mL) solution, mixture stirs 15 under conditions of subzero 10 DEG C
Minute, it is then gradually increased to that 4 hours are stirred at room temperature.After the completion of reaction, 50mL ice water is added and is quenched, with dichloromethane (50mL*
3) it extracts, merges organic phase and washed again with water (50mL*3) and saturated salt solution (50mL*1), anhydrous sodium sulfate drying, filtering
Filtrate is concentrated after removing drier, obtained purple grease is directly used in react in next step.
The synthesis of chloro- -1,4 (the 9H)-diketone of 1H- carbazoles of 6.2-
Embodiment 6
The purple grease obtained in embodiment 5 is dissolved in 46mL acetone, and is slowly dropped to nitroso potassium peroxydisulfate
In the aqueous solution (46mL) of (764.7mg, 1.7mmol) and potassium dihydrogen phosphate (46.2mg, 0.335mmol), mixture is in room temperature
Stirring 15 minutes.After the completion of reaction, peony precipitation is filtered out, is washed with water, is then dried with infrared drying oven, obtain 2-
Chloro- 1H- carbazoles-Isosorbide-5-Nitrae (9H)-diketone (209.4mg, yield 90.4%).
1H NMR(400MHz,DMSO-d6):δ 13.13 (s, 1H, ArH), 8.00 (d, J=7.52Hz, 1H, ArH), 7.55
(d, J=7.92Hz, 1H, ArH), 7.42 (t, 1H, ArH), 7.33 (t, 1H, ArH), 7.10 (s, 1H, ArH)
13C NMR(100MHz,DMSO-d6):δ181.13,172.51,142.09,138.55,135.60, 135.28,
127.36,124.71,123.71,122.20,116.37,114.35.
LC-MS(ESI-)230.1617(M-H)–。
Claims (7)
- The synthetic method of the chloro- 1H- carbazoles of 1.2--Isosorbide-5-Nitrae (9H)-diketone, it is characterized in that including the following steps：The first step, with 3- Yin Diindyl butyric acid is raw material, and in the presence of polyphosphoric acids, 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone are synthesized by solvent of toluene；Second Step, 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone synthesize benzyl -2 9- in the presence of potassium hydroxide and benzyl chloride, by solvent of acetone, 3,4,9- tetrahydrochysene -1H- carbazole -1- ketone；Third walk, 9- benzyls -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone anhydrous cupric chloride with And in the presence of anhydrous lithium chloride, 9- benzyls -2,2- bis- chloro- 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone are synthesized by solvent of DMF； 4th step, 9- benzyls -2,2- bis- chloro- 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone in the presence of anhydrous lithium chloride and lithium carbonate, with DMF is that solvent synthesizes the chloro- 9H- carbazoles -1- alcohol of 9- benzyls -2-；5th step, the chloro- 9H- carbazoles -1- alcohol of 9- benzyls -2- is in tribromide In the presence of boron, the chloro- 9H- carbazoles -1- alcohol of 2- is synthesized by solvent of dichloromethane；6th step, the chloro- 9H- carbazoles -1- of 9- benzyls -2- Alcohol synthesizes the chloro- 1H- carbazoles-Isosorbide-5-Nitraes of 2- in the presence of nitroso potassium peroxydisulfate and potassium dihydrogen phosphate, by mixed solvent of water/acetone (9H)-diketone.
- 2. the synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone according to claim 1, it is characterized in that in the first step Polyphosphoric acids is 2.4 equivalents, and reaction temperature is 110 DEG C, and the reaction time is 5 hours.
- 3. the synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone according to claim 1, it is characterized in that in second step Potassium hydroxide is 6 equivalents, and benzyl chloride is 1.1 equivalents.
- 4. the synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone according to claim 1, it is characterized in that in third step Anhydrous cupric chloride is 5 equivalents, and anhydrous lithium chloride is 3 equivalents, is reacted 2 hours at 105 DEG C, then heats to 140 DEG C of reactions 1 Hour.
- 5. the synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone according to claim 1, it is characterized in that in the 4th step Anhydrous lithium chloride is 3 equivalents, and lithium carbonate is 3 equivalents, and reaction temperature is 135 DEG C, and the reaction time is 40 minutes.
- 6. the synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone according to claim 1, it is characterized in that in the 5th step Boron tribromide is 5 equivalents, is reacted 15 minutes at subzero 10 DEG C, and reaction 4 hours is then warmed to room temperature.
- 7. the synthetic method of the chloro- 1H- carbazoles of 2--Isosorbide-5-Nitrae (9H)-diketone according to claim 1, it is characterized in that in the 6th step Nitroso potassium peroxydisulfate is 1.7 equivalents, and potassium dihydrogen phosphate is 0.335 equivalent, acetone:Water volume ratio=1:1, room temperature reaction 15 minutes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109627254A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | A kind of preparation method of D-biotin |
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| CN1253948A (en) * | 1998-04-17 | 2000-05-24 | 伊莱利利公司 | Substituted tricyclic compound |
| CN1372547A (en) * | 1999-09-07 | 2002-10-02 | 法玛西雅厄普约翰美国公司 | Aminoalkoxy carbazoles for the treatment of CNS diseases |
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| CN1253948A (en) * | 1998-04-17 | 2000-05-24 | 伊莱利利公司 | Substituted tricyclic compound |
| CN1372547A (en) * | 1999-09-07 | 2002-10-02 | 法玛西雅厄普约翰美国公司 | Aminoalkoxy carbazoles for the treatment of CNS diseases |
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| LUCIE MAINGOT ET AL.: "Synthesis of a Calothrixin B Isomer with a Novel 7H-Indolo[2,3-j]phenanthri-dine-7,13(8H)-dione Structure", 《SYNLETT》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109627254A (en) * | 2018-12-13 | 2019-04-16 | 浙江圣达生物药业股份有限公司 | A kind of preparation method of D-biotin |
| CN109627254B (en) * | 2018-12-13 | 2020-04-28 | 浙江圣达生物药业股份有限公司 | Preparation method of d-biotin |
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