CN103833533B - A kind of preparation method of benzo [C] Fluorenone - Google Patents

A kind of preparation method of benzo [C] Fluorenone Download PDF

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CN103833533B
CN103833533B CN201210482394.XA CN201210482394A CN103833533B CN 103833533 B CN103833533 B CN 103833533B CN 201210482394 A CN201210482394 A CN 201210482394A CN 103833533 B CN103833533 B CN 103833533B
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fluorenone
benzo
ketenes
indenes
solvent
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CN103833533A (en
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沈征武
郑书岩
李小平
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Jiangsu beihede Pharmaceutical Technology Co.,Ltd.
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Basilea Pharmaceutica China Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides the preparation method of a kind of benzo [C] Fluorenone.The inventive method for raw material reacting by heating in organic solvent, obtains benzo [C] Fluorenone crude product with 1-indenes ketenes; Crude product is purified through column chromatography or recrystallization and is obtained benzo [C] Fluorenone.The present invention utilizes the 1-indenes ketenes that is conveniently easy to get to prepare benzo [C] Fluorenone for raw material, reacts, de-CO with continuous print Diels-Alder, de-H2 reaction, prepare benzo [C] Fluorenone easily and efficiently, and required reaction conditions is gentle, be suitable for industrial production, have larger using value.

Description

A kind of preparation method of benzo [C] Fluorenone
Technical field
The present invention relates to synthetic pharmacochemistry, be specifically related to pharmaceutical synthesis, particularly relate to a kind of with 1-indenes ketenes for the method for benzo [C] Fluorenone prepared by raw material.
Background technology
Fluorenone (Fluorenone) analog derivative is the compound that a class has compared with strong biological activity, and they are the basic framework of many drug molecules, is also the core texture of a lot of natural product.As natural product dengibsin, dengibsinin, dendroflorin and kinobscurinone etc.Fluorenone analog derivative as photosensitizers in organic photo device, can also have important electricity and optical property.Benzo [C] Fluorenone is an important series in fluorenone derivatives; much there is bioactive compound all using it as core texture; as 5-(dimethyl amine base oxethyl) benzo [C] Fluorenone-VUFB13468(Benfluron; formula 1) and 5-(diethylamide base oxethyl)-6-(diethyl amido ethoxycarbonyl) benzo [C] Fluorenone (VUFB13431; Figure1) and 5-(2-N-oxygen-2-N-dimethyl amine base oxethyl) benzo [C] Fluorenone (benfluronN-oxide) etc. demonstrates very strong antitumour activity.In addition, 5-(4'-N-methylpiperazine base) butane-Isosorbide-5-Nitrae-diamide-dibenzo [C] Fluorenone (formula 2) also has very strong anti-tumor activity.In some natural products, benzo [C] Fluorenone occurs as essential building blocks, as 5-(dimethyl amine base oxethyl)-9-hydroxy benzo [C] Fluorenone (formula 3) (Lycka, A.; Etc.Magn.Reson.Chem., 1987,25,1054 – 1057) and 1,9,11-trimethoxy-2-hydroxyl-6-formyl radical benzo [C] Fluorenone (formula 4) (Kawazoe, K.; Etc.J.Nat.Prod., 2001,64,588 – 591).See following structural:
The bibliographical information synthetic method of multiple benzo [C] Fluorenone.Wherein have and carry out closed loop synthesis (Lee, I.H. by Fu-Ke (Friedel-Crafts) acylation reaction in molecule; Gong, M.S., Bull.KoreanChem.Soc., 2011,32,1475 – 1482; Kim, S.H.; Etc., TetrahedronLett., 2010,51,1592 – 1595); The direct oxidation of 7H-benzofluorene is utilized to synthesize; Have utilize diaryl acetylene substrate to be reacted by intramolecular Diels-Alder and subsequently open loop ring-closure reaction synthesis (see reaction formula 1) (Rodriguez, D.; Etc., J.Org.Chem., 2004,69,3842 – 3848; Rodriguez, D.; Etc., TetrahedronLett., 2002,43,2717 – 2720) etc. method.But these methods above-mentioned all have different shortcomings, if any reaction substrate be difficult to obtain, substrate needs multistep to synthesize, and some reaction preferencies are poor, and target product yield is not satisfactory.
In recent years, the linked reaction of palladium chtalyst obtains significant progress, and in C-C key forming reactions, it has also become a strong instrument.So far; existing several benzo [C] Fluorenone compounds synthetic method relates to the linked reaction (reaction formula 2) of palladium chtalyst; the synthesis of the aryl palladium addition reaction by aromatic aldehyde in continuous print Suzuki coupling between 2-bromobenzeneboronic acid and 2-bromine naphthyl aldehyde and molecule subsequently (approach 1) (Paul, the S. had; Etc., TetrahedronLett., 2010,51,5604 – 5608); Have by the intramolecular formylation reaction synthesis of trifluoro-methanesulfonyl oxy diaryl manthanoate (approach 2) (Bringmann, G.; Etc., Chem.Commun., 1998,1211 – 1212); Have and obtain (approach 3) (Waldo, J.P. by 2-bromine naphthyl aldehyde and the benzyne generation annulation formed online; Etc., J.Org.Chem., 2008,73,6679 – 6685); Also have and obtain (approach 4) (Campo, M.A. by the halid cyclocarbonylization reaction of diaryl; Larock, R.C., Org.Lett., 2000,2,3675 – 3678).The synthetic method of this kind of palladium chtalyst has expanded the preparation scope of benzo [C] Fluorenone compounds, makes substrate have more variation.But in general, this kind of reaction requires all higher to the substituting group of substrate, and the substrate of a lot of reaction needs multistep to synthesize acquisition.In addition, the use of a large amount of expensive metal palladium reagent, makes these methods be difficult to be applied to large-scale production.
Calendar year 2001 and 2008, Balic group doublely refer to the example being obtained benzo [C] Fluorenone compounds by high temperature pyrolysis in two sections of papers.Reaction mechanism is that first identical two molecule 3-bromo-1-indenes ketenes passes through [2+4] cycloaddition, then loses carbon monoxide (CO) and hydrogen bromide (HBr) gas continuously and obtains aromatic nucleus (in reaction formula 3, when R is hydrogen atom, productive rate is 45%; When R is methoxyl group, productive rate is 49%).Then regrettably they fail to further investigate further, and mention as just side reaction.(Tutar,A.;ect.,Tetrahedron,2001,57,9759–9764;Tutar,A.;ect.,Syn.Commun.,2008,38,1333–1345)
Summary of the invention
Instant invention overcomes the weak point of above-mentioned reaction, provide a new reaction conditions gentle, raw material is conveniently easy to get, and is suitable for the method that industrial production prepares benzo [C] Fluorenone.
The invention provides the preparation method of a kind of benzo [C] Fluorenone.
The inventive method prepares benzo [C] Fluorenone by 1-indenes ketenes.
The inventive method specifically comprises the following steps:
(1) with 1-indenes ketenes for raw material reacting by heating in organic solvent, obtain benzo [C] Fluorenone crude product;
(2) crude product is purified through column chromatography or recrystallization and is obtained benzo [C] Fluorenone.
The inventive method step (1) described 1-indenes ketenes is if two different compounds, then the mol ratio of the two is 1:1 ~ 1:2, preferred 1:1.5; Reaction solvent is tetrahydrofuran (THF), 1,2-ethylene dichloride, ethylene glycol monomethyl ether, DMF, toluene, dimethylbenzene or phenyl ether, preferred DMF, and it is 5 ~ 20 milliliters that every mmole substrate need add quantity of solvent, preferably 8 ~ 12 milliliters; Temperature of reaction is 50 ~ 200 DEG C, and optimal reaction temperature is 80 ~ 130 DEG C.Step (2) described column chromatography is normal phase silicagel column, and (silica gel specification is 200 ~ 300 orders) eluting solvent is ethyl acetate/petroleum ether, and the volume proportion of the two is: 1:9 ~ 1:3).
The solvent that the described recrystallization of step (2) uses is acetone and sherwood oil, and the volume ratio of acetone and sherwood oil is 1:10-3:10 solvent temperature is 0 ~ 80 DEG C, and Tc is-20 ° of C ~ 45 DEG C.
Reaction mechanism of the present invention is by two molecule 1s-indenes ketenes Reactive Synthesis benzo [C] Fluorenone compounds, its reaction process is as follows: first two molecule 1s-indenes ketenes passes through [2+4] Diels-Alder reaction and carry out cycloaddition, then loses a part carbon monoxide (CO) and a part hydrogen (H continuously 2) and (in reaction formula 4, R1 with R2 can be identical or not identical to obtain benzo [C] Fluorenone; Being hydrogen, electron-donating group (as methoxyl group, methyl etc.) or electron-withdrawing group (as halogen, ethanoyl etc.) respectively, also can be heterocycle or the aromatic nucleus (as naphthalene nucleus etc.) of benzo):
The present invention utilizes the 1-indenes ketenes that is conveniently easy to get to prepare benzo [C] Fluorenone for raw material, reacts, de-CO, de-H with continuous print diels-aldol 2reaction, prepares benzo [C] Fluorenone easily and efficiently, and required reaction conditions is gentle, is suitable for industrial production, has larger using value.
Accompanying drawing explanation
Fig. 1 compd A molecule stereo structure figure
The molecule structure cell of Fig. 2 compd A molecule piles up sciagraph
Embodiment
Under be classified as the structural formula of compound described in the present embodiment:
Embodiment 1
2,9-dimethoxy benzo [c] Fluorenone (A)
6-methoxyl group-1-indenes ketenes A1(80mg, 0.5mmol) be dissolved in toluene (8ml), reaction solution refluxes 36 hours under argon shield.Be cooled to room temperature, concentration of reaction solution obtains crude product, then obtains Red oil product A (68mg, 85%) by column chromatography purification (ethyl acetate/petroleum ether: 1:8 ~ 1:4), and refrigerator is placed and solidified to obtain red solid.Fusing point 144 ~ 146 ° of C; 1hNMR (400MHz, Acetone-d 6) δ ppm:7.51 (d, J=8.4Hz, 1H), 7.23 (d; J=8.4Hz, 1H), 7.22 (s, 1H); 7.18 (s, 1H), 7.07 (d; J=8.0Hz, 1H), 6.84 (dd; J=8.0and2.0Hz, 1H), 6.40 (dd; J=9.6and2.0Hz, 1H), 5.62 (dd; J=9.2and3.2Hz, 1H), 4.67 (d; J=8.4Hz, 1H), 3.90 (s; 3H), 3.85 (s, 3H); (3.81 dd, J=5.2and3.2Hz, 1H); 13cNMR (100MHz, Acetone-d 6) δ ppm:201.05,179.17,160.14,159.88,148.65,136.30,136.00,128.99,126.98,126.87,124.56,123.64,121.84,115.37,112.50,105.22,55.36,55.07,51.18,40.79; MS-ESI (m/z, %): 291.1 ([M+1] +, 100%); HRMS (ESI +): Calcd.ForC 19h 14na 1o 3([M+Na] +), 313.0835, Found:313.0827.
Embodiment 2
3,9-dichloro benzo [c] Fluorenone (B)
5-chloro-1-indenes ketenes (66mg, 0.40mmol) B1 is dissolved in DMF (5ml), and then reaction solution reacts 5 hours at 80 DEG C.After being cooled to room temperature, removal of solvent under reduced pressure, crude product directly obtains yellow solid B (54mg, 90%) by column chromatography purification (ethyl acetate/petroleum ether: 1:8). 1HNMR(400MHz,CDCl 3)δppm:8.37(d,J=9.2Hz,1H),7.95(d,J=1.6Hz,1H),7.92(d,J=2.0Hz,1H),7.81~7.75(m,2H),7.66~7.60(m,2H),7.36(dd,J=8.0and1.2Hz,1H). 13CNMR(100MHz,CDCl 3)δppm:192.0,145.6,141.1,140.2,138.2,134.2,132.1,131.9,129.3,128.6,128.3,128.0,126.4,125.5,124.6,123.4,120.6.
Embodiment 3
3-methoxyl group-9-chlorobenzene also [c] Fluorenone (C)
5-methoxyl group-1-indenes ketenes C1(32mg, 0.2mmol) and 5-chloro-1-indenes ketenes (34mg, 0.2mmol) be dissolved in dimethylbenzene (6ml), then reaction solution refluxes 20 hours under argon gas.After cooling to room temperature, concentration of reaction solution obtains crude product, obtains yellow solid C (41mg, 70%) by column chromatography purification (ethyl acetate/petroleum ether: 1:8). 1HNMR(400MHz,CDCl 3)δppm:8.07(d,J=8.4Hz,1H),7.88(d,J=1.6Hz,1H),7.81(d,J=2.0Hz,1H),7.72~7.62(m,3H),7.49(s,1H),7.08(dd,J=8.0and1.2Hz,1H). 13CNMR(100MHz,CDCl 3)δppm:191.5,157.6,140.8,138.6,136.2,134.2,132.1,131.9,131.3,130.9,127.8,127.2,126.4,123.5,122.5,118.4,110.6.
Embodiment 4
5-bromo-9-methoxyl group benzo [c] Fluorenone (D)
6-methoxyl group-1-indenes ketenes (32mg, 0.2mmol) and 3-bromo-1-indenes ketenes D1(42mg, 0.2mmol) be dissolved in DMF (6ml), then reaction solution reacts 3 hours at 80 DEG C.After being cooled to room temperature, reaction solution concentrating under reduced pressure obtains crude product, obtains yellow solid D (37mg, 55%) by column chromatography purification (ethyl acetate/petroleum ether: 1:10). 1HNMR(400MHz,CDCl 3)δppm:8.47(dd,J=1.6and6.8Hz,1H),8.37(dd,J=2.4and8.0Hz,1H),8.04(s,1H),7.73~7.66(m,2H),7.57(d,J=2.0),7.45(m,2H). 13CNMR(100MHz,CDCl 3)δppm:191.2,164.6,147.2,146.1,140.2,134.9,132.1,131.9,129.3,128.6,128.3,128.0,126.4,120.2,110.7,110.7,106.8,55.4.MS-ESI(m/z,%):339.1([M+1] +,100%)and341.1([M+3] +,100%).
Embodiment 5
3,10-dimethoxy-5-bromobenzene also [c] Fluorenone (E)
5-methoxyl group-1-indenes ketenes (32mg, 0.2mmol) and 5-methoxyl group-3-bromo-1-indenes ketenes E1(48mg, 0.2mmol) be dissolved in toluene (6ml), then reaction solution refluxes 36 hours under argon gas.After cooling to room temperature, concentration of reaction solution obtains crude product, and re crystallization from toluene obtains yellow solid E (44mg, 60%). 1HNMR(400MHz,CDCl 3)δppm:8.39(d,J=8.4Hz,1H),8.02(s,1H),7.66(d,J=8.4Hz,1H),7.63(d,J=2.8Hz,1H),7.54(d,J=2.4Hz,1H),7.45(dd,J=7.2and2.4Hz,1H),7.34(dd,J=7.2and2.4Hz,1H). 13CNMR(100MHz,CDCl 3)δppm:203.5,164.5,160.0,147.2,137.0,128.5,126.2,125.5,124.9,124.4,120.9,112.0,110.7,110.3,110.0,106.7,55.4,55.1.
MS-ESI(m/z,%):369.2([M+1] +,100%)and371.2([M+3] +,100%)。

Claims (6)

1. a preparation method for benzo [C] Fluorenone, it is characterized in that, the method comprises the following steps:
Wherein, R1 with R2 is identical or not identical, is respectively hydrogen, methoxyl group, methyl, halogen or ethanoyl; Or be benzheterocycle or aromatic nucleus;
(1) with 1-indenes ketenes for raw material reacting by heating in organic solvent, obtain benzo [C] Fluorenone crude product;
(2) crude product is purified through column chromatography or recrystallization and is obtained benzo [C] Fluorenone.
2. a preparation method for benzo [C] Fluorenone, it is characterized in that, the method comprises the following steps:
Wherein, R1 with R2 is identical or not identical, is respectively hydrogen, methoxyl group, methyl, halogen or ethanoyl; Or be naphthalene nucleus;
(1) with 1-indenes ketenes for raw material reacting by heating in organic solvent, obtain benzo [C] Fluorenone crude product;
(2) crude product is purified through column chromatography or recrystallization and is obtained benzo [C] Fluorenone.
3. preparation method according to claim 1 and 2, is characterized in that, described step (1) when 1-indenes ketenes be two different compounds, then the mol ratio of the two is 1:1 ~ 1:2; Reaction solvent is tetrahydrofuran (THF), 1,2-ethylene dichloride, ethylene glycol monomethyl ether, DMF, toluene, dimethylbenzene or phenyl ether, and it is 5 ~ 20 milliliters that every mmole 1-indenes ketenes need add quantity of solvent; Temperature of reaction is 50 ~ 200 DEG C.
4. preparation method according to claim 1 and 2, is characterized in that, described step (1) when 1-indenes ketenes be two different compounds, then the mol ratio of the two is 1:1.5; Reaction solvent is DMF, and it is 8 ~ 12 milliliters that every mmole 1-indenes ketenes need add quantity of solvent; Temperature of reaction is 80 ~ 130 DEG C.
5. preparation method according to claim 1, is characterized in that, described step (2) column chromatography is normal phase silicagel column, and silica gel specification is 200 ~ 300 orders, and eluting solvent is ethyl acetate/petroleum ether, and the volume proportion of the two is: 1:9 ~ 1:3.
6. preparation method according to claim 1, is characterized in that, the solvent that the described recrystallization of described step (2) uses is acetone and sherwood oil, and the volume ratio of acetone and sherwood oil is 1:10 ~ 3:10; Solvent temperature is 0 ~ 80 DEG C, and Tc is-20 DEG C ~ 45 DEG C.
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Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Photobromination of indane: preparation of bromoindenones and ready access to benzo[c]fluorenone skeleton;Ahmet Tutar et al.;《Tetrahedron》;20011231;第57卷(第48期);第9759-9763页 *

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