CN106316999A - Preparing method and application for coumarone- 2,3- diketone oxime derivative - Google Patents
Preparing method and application for coumarone- 2,3- diketone oxime derivative Download PDFInfo
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Abstract
The invention discloses a preparing method and application for coumarone- 2, 3- diketone oxime derivative. The invention uses 3- formylchromone derivatives as the initiator and the raw materials are easy to get with multiple types and the industrial sodium nitrite as the reaction reagent at low cost; products obtained through the invention are diversified and can be widely applied in drug synthesis of bactericide, sanitizer, drugs for Alzheimer's disease treatment, drugs to restrain hepatitis C virus, SIRT1 and cancer cell proliferation in vitro, etc. In addition, for the method disclosed in the invention, reaction is performed in the air, namely room temperature reaction. The target product has high yield coefficient, low pollution, and simple reaction operation and post-processing, which is suitable for industrial production.
Description
Technical field
The invention belongs to the preparing technical field of organic compound, be specifically related to a kind of benzofuran-2,3-bis-ketoxime spreads out
Biological preparation method and application.
Background technology
In in the past few decades, people to benzofuran-2, the relevant report of 3-bis-ketoximes derivatives seldom (see:
Smith, L. I.; Holmes, R. R. J. Am. Chem. Soc. 1951, 73,4294-4297), its using value
Need further to develop.But, benzofuran-2,3-bis-ketoximes derivatives can be converted into benzo furan easily
Muttering-2,3-derovatives, this compounds is widely used in various medicine, such as antibacterial, disinfectant, treatment Alzheimer
In the synthesis of family name's medicine, suppression hepatitis C virus cytotoxic drug and suppression SIRT1 and cancer cell in vitro hyperproliferation agent etc..
Benzofuran-2,3-derovatives can prepare aurones derivant: has significant bactericidal action；There is anti-gallbladder
Alkali esterase active, can effectively treat Alzheimer；There is the activity well suppressing hepatitis C virus, be treatment
The drug candidate of hepatitis C；Having suppression SIRT1 and the effect of cancer cell in vitro propagation, wherein SIRT1 is to rely on nicotinoyl
The histone deacetylase of amine adenine-dinucleotide (NAD+), phase close with cell proliferation, differentiation, aging, apoptosis and metabolism
Close；Thus can as antibacterial, disinfectant and drug use, the chemical structural formula of aurones derivant following (see:
Smith, L. I.; Holmes, R. R. J. Am. Chem. Soc. 1951, 73, 4294-4297; Nadri, H.
et al. Bioorg. Med. Chem.2010,18, 6360–6366; Manjulatha, K. et al. Bioorg. Med. Chem. Lett. 2012,22, 6160–6165; Haudecoeur, R. et al. J. Med. Chem.2011,54, 5395–5402;Takeuchi, Y.; Choshi, T.; Tomozane, H.; Yoshida, H.; Yamato, M.Chem. Pharm. Bull.1990, 38(8), 2265-2267;Hadj-esfandiari, N. et al. Bioorg. Med. Chem. Lett. 2007. 17).
Existing benzofuran-2, the synthetic route raw material sources difficulty of 3-bis-ketoximes derivatives, with acetic acid for solvent pair
Equipment corrosion is big, affect operator greatly.Therefore a kind of raw material sources of searching are simple, meet Green Chemistry requires, reaction
The preparation method that mild condition, universality are good is necessary effectively to synthesize benzofuran-2,3-two ketoximes derivatives.
Summary of the invention
It is an object of the invention to provide one and prepare benzofuran-2, the method for 3-bis-ketoximes derivatives, it has raw material
Source is simple, reaction condition gentleness, course of reaction environmental protection, post processing simply, productivity advantages of higher.
To achieve the above object of the invention, the technical solution used in the present invention is: one prepares benzofuran-2,3-bis-ketoxime
The method of derivant, comprises the following steps: 3-formacyl chromone derivative, sodium nitrite, potassium peroxydisulfate are dissolved in solvent, in
React under room temperature, it is thus achieved that benzofuran-2,3-bis-ketoximes derivatives；
Described 3-formacyl chromone derivative is as shown in following chemical structure of general formula:
Wherein R is selected from: the one in alkyl, aryl, alkoxyl, halogen, nitro, amide groups；
Described solvent is selected from: the one in acetonitrile, acetone, acetic acid, water, N,N-dimethylformamide；
Shown in described benzofuran-2,3-two ketoximes derivatives following row chemical structure of general formula:
。
In technique scheme, described 3-formacyl chromone derivative is selected from 4-oxo-4H-.alpha.-5:6-benzopyran-3-formaldehyde, 4-
Oxo-4H-6-fluoro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-chloro-.alpha.-5:6-benzopyran-3-formaldehyde, the bromo-benzene of 4-oxo-4H-6-
And pyrans-3-formaldehyde, 4-oxo-4H-6-nitro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-methyl-8-nitro-benzo pyrrole
Mutter-3-formaldehyde, 4-oxo-4H-6-chloro-8-nitro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-isopropyl-.alpha.-5:6-benzopyran-
3-formaldehyde, 4-oxo-4H-7-fluoro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-7-chloro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-
4H-7-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-5-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-first
Epoxide-.alpha.-5:6-benzopyran-3-formaldehyde, 1-oxo-1H-benzo [f] chromone-2-formaldehyde, 4-oxo-4H-benzo also [h] benzo pyrrole
Mutter-3-formaldehyde, 2-formoxyl-N-(3-formoxyl-4-oxo-4H-.alpha.-5:6-benzopyran-6-base) one in butyramide.
In technique scheme, thin layer chromatography (TLC) is utilized to follow the tracks of reaction until being fully completed.
In technique scheme, in molar ratio, 3-formacyl chromone derivative: sodium nitrite: potassium peroxydisulfate is 1: (1 ~ 4)
: (1 ~ 4).
In technique scheme, reaction carries out column chromatography for separation purification processes to product after terminating.
Invention additionally discloses benzofuran-2 prepared according to said method, 3-bis-ketoximes derivatives, can pass through to hydrolyze
To benzofuran-2,3-derovatives, natural product aurones derivant can be readily synthesized by Wittig reaction further；
Have sterilization, sterilization, anticholinesterase activity (can be used for treat Alzheimer), suppression hepatitis C virus cytotoxic activity,
The suppression effect such as SIRT1 and cancer cell in vitro propagation, thus can use as antibacterial, disinfectant and inhibitor medicaments.
The course of reaction of technique scheme is represented by:
Due to the utilization of technique scheme, the present invention compared with prior art has the advantage that
1, the present invention uses 3-formacyl chromone derivative to be starting material, prepares first in the presence of sodium nitrite, potassium peroxydisulfate
Obtain product benzofuran-2,3-bis-ketoximes derivatives, there is the advantage that raw material is easy to get, with low cost, product structure kind is many,
And equipment, personnel are safe from harm by solvent environment safety.
2, benzofuran-2 of preparing disclosed by the invention, in the method for 3-bis-ketoximes derivatives, reaction is carried out in atmosphere,
Reaction condition is gentle, and the response time is short, and the yield of target product is high, and operation and last handling process are simple, are suitable for industry
Metaplasia is produced.
3, benzofuran-2 disclosed by the invention, 3-bis-ketoximes derivatives various structures, can directly use, it is particularly possible to
Obtain benzofuran-2,3-derovatives by hydrolysis, natural product can be readily synthesized by Wittig reaction further
Aurones derivant；Expand its application greatly, also enrich the kind of antibacterial, disinfectant, inhibitor medicaments etc..
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described:
The synthesis of embodiment one: 2-(oxyimino)-benzofuran-3 (2H)-one
Using 4-oxo-4H-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-.alpha.-5:6-benzopyran-3-formaldehyde (0.174 g, 1.0 mmol), sodium nitrite is added in reaction bulb
(0.069 g, 1.0 mmol), potassium peroxydisulfate (0.270 g, 1.0 mmol) and acetone (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 61%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.45 (s, 1H), 7.82
(t, J = 7.4 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.33
(t, J = 7.5 Hz, 1H)。
The synthesis of embodiment two: 2-(oxyimino)-5-fluoro-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-fluorine .alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-6-fluoro-.alpha.-5:6-benzopyran-3-formaldehyde (0.192 g, 1.0 mmol), sodium nitrite is added in reaction bulb
(0.138 g, 2.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and acetone (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 83%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.52 (s, 1H), 7.68
(td, J = 9.0, 2.8 Hz, 1H), 7.58 (dd, J = 6.9, 2.8 Hz, 1H), 7.52 (dd, J = 9.0,
3.7 Hz, 1H)。
The synthesis of embodiment three: 2-(oxyimino)-5-chloro-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-chloro-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-6-chloro-.alpha.-5:6-benzopyran-3-formaldehyde (0.209 g, 1.0 mmol), sodium nitrite is added in reaction bulb
(0.207 g, 3.0 mmol), potassium peroxydisulfate (0.81 g, 3.0 mmol) and acetone (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 86%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.60 (s, 1H), 7.82
(dd, J = 8.8, 2.4 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.8 Hz,
1H)。
The synthesis of embodiment four: 2-(oxyimino)-5-bromo-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-bromo-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-6-bromo-.alpha.-5:6-benzopyran-3-formaldehyde (0.253 g, 1.0 mmol), nitrous acid is added in reaction bulb
Sodium (0.276 g, 4.0 mmol), potassium peroxydisulfate (1.08 g, 4 mmol) and acetonitrile (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 84%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.65 (s, 1H), 7.92
(dd, J = 8.7, 1.9 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 8.7 Hz,
1H)。
The synthesis of embodiment five: 2-(oxyimino)-5-nitro-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-nitro-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-6-nitro-.alpha.-5:6-benzopyran-3-formaldehyde (0.219 g, 1.0 mmol), nitrous acid is added in reaction bulb
Sodium (0.138 g, 2.0 mmol), potassium peroxydisulfate (1.08 g, 4.0 mmol) and acetic acid (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 62%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.76 (d, J = 1.2
Hz, 1H), 8.65 (dd, J = 9.0, 2.5 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H), 7.74 (d, J
= 9.1 Hz, 1H)。
The synthesis of embodiment six: 2-(oxyimino)-5-methyl-7-nitro-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-methyl-8-nitro-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is such as
Under:
In reaction bulb add 4-oxo-4H-6-methyl-8-nitro-.alpha.-5:6-benzopyran-3-formaldehyde (0.233 g, 1.0
Mmol), sodium nitrite (0.138 g, 2.0 mmol), potassium peroxydisulfate (0.81 g, 3.0 mmol) and water (4 milliliters), room temperature is anti-
Should；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 70%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.81 (s, 1H), 8.39
(s, 1H), 8.02 (s, 1H), 2.48 (s, 3H)。
The synthesis of embodiment seven: 2-(oxyimino)-5-chloro-7-nitro-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-chloro-8-nitro-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
Addition 4-oxo-4H-6-chloro-8-nitro-.alpha.-5:6-benzopyran-3-formaldehyde (0.254 g, 1.0 mmol) in reaction bulb,
Sodium nitrite (0.138 g, 2.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and DMF (4 millis
Rise), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 65%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.95 (s, 1H), 8.60
(d, J = 2.2 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H)。
The synthesis of embodiment eight: 2-(oxyimino)-5-isopropyl-benzofuran-3 (2H)-one
Using 4-oxo-4H-6-isopropyl-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-6-isopropyl-.alpha.-5:6-benzopyran-3-formaldehyde (0.216 g, 1.0 mmol), Asia is added in reaction bulb
Sodium nitrate (0.138 g, 2.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and acetone (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 84%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6):δ 12.49 (s, 1H), 7.68
(dd, J = 8.4, 1.2 Hz, 1H), 7.55 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 2.94 (dt,J = 13.6, 6.8 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H)。
Embodiment nine: 2-(oxyimino)-N-(2-(oxyimino)-3-oxo-2,3-Dihydrobenzofuranes-5-
Base) synthesis of butyramide
Using 2-formoxyl-N-(3-formoxyl-4-oxo-4H-.alpha.-5:6-benzopyran-6-base) butyramide, sodium nitrite as raw material, its
Reactions steps is as follows:
2-formoxyl-N-(3-formoxyl-4-oxo-4H-.alpha.-5:6-benzopyran-6-base is added in reaction bulb) butyramide (0.259
G, 1.0 mmol), sodium nitrite (0.138 g, 2.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and acetone (4 millis
Rise), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 73%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.40 (s, 1H), 11.86
(s, 1H), 10.14 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.9, 2.2 Hz,
1H), 7.44 (d, J = 8.9 Hz, 1H), 2.53 (d, J = 7.6 Hz, 2H), 1.03 (t, J = 7.5 Hz,
3H)。
The synthesis of embodiment ten: 2-(oxyimino)-6-fluoro-benzofuran-3 (2H)-one
Using 4-oxo-4H-7-fluoro-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-7-fluoro-.alpha.-5:6-benzopyran-3-formaldehyde (0.192 g, 1.0 mmol), sodium nitrite is added in reaction bulb
(0.207 g, 3.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and acetone (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 81%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.48 (s, 1H), 7.82
(dd, J = 8.5, 5.8 Hz, 1H), 7.44 (dd, J = 9.1, 1.9 Hz, 1H), 7.24 – 7.03 (m,
1H)。
The synthesis of embodiment 11: 2-(oxyimino)-6-chloro-benzofuran-3 (2H)-one
Using 4-oxo-4H-7-chloro-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-7-chloro-.alpha.-5:6-benzopyran-3-formaldehyde (0.209 g, 1.0 mmol), sodium nitrite is added in reaction bulb
(0.207 g, 3.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and water (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 76%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.54 (s, 1H), 7.77
(d, J = 8.2 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 8.2, 1.6 Hz,
1H)。
The synthesis of embodiment 12: 2-(oxyimino)-6-Mehtoxy-Benzofuran-3 (2H)-one
Using 4-oxo-4H-7-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-7-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde (0.204 g, 1.0 mmol), Asia is added in reaction bulb
Sodium nitrate (0.207 g, 3.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and water (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 79%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.56 (s, 1H), 7.64
(d, J = 8.6 Hz, 1H), 7.04 (d, J = 1.2 Hz, 1H), 6.84 (dd, J = 8.5, 1.3 Hz,
1H), 3.91 (s, 3H)。
The synthesis of embodiment 13: 2-(oxyimino)-4-Mehtoxy-Benzofuran-3 (2H)-one
Using 4-oxo-4H-5-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-5-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde (0.204 g, 1.0 mmol), nitrous is added in reaction bulb
Acid sodium (0.207 g, 3.0 mmol), potassium peroxydisulfate (0.59 g, 2.0 mmol) and acetonitrile (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 61%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.23 (s, 1H), 7.75
(t, J = 8.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 3.93
(s, 3H)。
The synthesis of embodiment 14: 2-(oxyimino)-5-Mehtoxy-Benzofuran-3 (2H)-one
Using 4-oxo-4H-6-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
4-oxo-4H-6-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde (0.204 g, 1.0 mmol), nitrous is added in reaction bulb
Acid sodium (0.138 g, 2.0 mmol), potassium peroxydisulfate (0.810 g, 3.0 mmol) and acetonitrile (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 63%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.41 (s, 1H), 7.46-
7.41 (m, 2H), 7.25 (dd, J = 2.2, 0.9 Hz, 1H), 3.84 (s, 3H)。
Embodiment 15: 2-(oxyimino)-naphtho-[1,2-b] furan-3(2H) synthesis of-one
Using 4-oxo-4H-benzo, also [h] .alpha.-5:6-benzopyran-3-formaldehyde, sodium nitrite are as raw material, and its reactions steps is as follows:
4-oxo-4H-benzo also [h] .alpha.-5:6-benzopyran-3-formaldehyde (0.224 g, 1.0 mmol), nitrous is added in reaction bulb
Acid sodium (0.138 g, 2.0 mmol), potassium peroxydisulfate (0.810 g, 3.0 mmol) and acetonitrile (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 72%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.67 (s, 1H), 8.16
(d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.88 – 7.79 (m, 1H), 7.74 (t,J = 7.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 1H)。
The synthesis of embodiment 16: 2-(oxyimino) naphtho-[2,1-b] furan-1 (2H)-one
Using 1-oxo-1H-benzo [f] chromone-2-formaldehyde, sodium nitrite as raw material, its reactions steps is as follows:
1-oxo-1H-benzo [f] chromone-2-formaldehyde (0.224 g, 1.0 mmol), sodium nitrite is added in reaction bulb
(0.138 g, 2.0 mmol), potassium peroxydisulfate (0.810 g, 3.0 mmol) and acetonitrile (4 milliliters), room temperature reaction；
TLC follows the tracks of reaction until being fully completed；
The crude by column chromatography that reaction obtains after terminating separates (petroleum ether: ethyl acetate=4:1), obtains target product
(productivity 75%).The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 12.56 (s, 1H), 8.60
(d, J = 8.3 Hz, 1H), 8.45 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.90
– 7.75 (m, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.62 (ddd, J = 8.2, 7.1, 1.2 Hz,
1H)。
Embodiment 17: 2-(1-5-nitro imidazole-2-methylene)-3 (2HThe conjunction of)-benzofuranone (17-4)
Become
With 2-hydroxyl imido grpup-3 (2H)-benzofuranone (17-1) is as raw material (embodiment one), and its reactions steps is as follows:
(1) compound 17-1(3 g is added in the reactor), acetic acid (50 milliliters), hydrochloric acid (30 milliliters), reacting by heating；
(2) TLC follows the tracks of reaction until being fully completed；
(3) reactant is cooled to room temperature, filters, with benzene and petroleum ether recrystallization, obtains target product 17-2(productivity 87%).
The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 8.22 (d, J = 9.0 Hz,
1H), 8.10 – 7.90 (m, 2H), 7.78 – 7.70 (m, 1H)；
(4) by compound 17-3(0.682 g, 1.7 mmol) it is dissolved in 25 milliliters of dry tetrahydrofuran solutions, at 0 DEG C
It is slowly added dropwise the hexane solution (1.42 mL, 1.8 mmol) of n-BuLi, stirs 30 minutes.It is subsequently adding 17-2 (0.25
G, 1.7 mmol) tetrahydrofuran solution 15 milliliters, stir after half an hour at 0 DEG C, be heated to boiling, react 5 hours.Will
Reactant liquor is poured into water, and is extracted with ethyl acetate, and organic layer washes with water, and anhydrous magnesium sulfate is dried, and concentrates, crude product post layer
Analysis (ethyl acetate: normal hexane=2:3) separating-purifying, obtains faint yellow target product 17-4(productivity 76%).The analytical data of product
As follows:1H NMR (400 MHz, DMSO-d 6): δ 8.22 (d, J = 9.0 Hz, 1H), 8.10 – 7.90 (m,
2H), 7.81 (s, 1H), 7.78 7.70 (m, 1H), 7.05 (s, 1H), 3.72 (s, 3H), compound 17-4
There is significant bactericidal action.
Embodiment 18: 7-methoxyl group-2-(1-5-nitro imidazole-2-methylene)-3 (2H)-benzofuranone
(18-3) synthesis
With 7-methoxyl group-2-hydroxyl imido grpup-3 (2H)-benzofuranone (18-1) is as raw material, and its reactions steps is as follows:
(1) compound 18-1(3.2 g is added in the reactor), acetic acid (50 milliliters), hydrochloric acid (30 milliliters), reacting by heating；
(2) TLC follows the tracks of reaction until being fully completed；
(3) reactant is cooled to room temperature, filters, with benzene and petroleum ether recrystallization, obtains target product 18-2(productivity 84%).
The analytical data of product is as follows:1H NMR (400 MHz, DMSO-d 6): δ 8.22 (d, J = 9.0 Hz,
1H), 8.10 – 7.90 (m, 2H), 7.78 – 7.70 (m, 1H), 3.83 (s, 3H)；
(4) by compound 17-3(0.682 g, 1.7 mmol) it is dissolved in 25 milliliters of dry tetrahydrofuran solutions, at 0 DEG C
It is slowly added dropwise the hexane solution (1.42 mL, 1.8 mmol) of n-BuLi, stirs 30 minutes.It is subsequently adding 17-2 (0.25
G, 1.7 mmol) tetrahydrofuran solution 15 milliliters, stir after half an hour at 0 DEG C, be heated to boiling, react 5 hours.Will
Reactant liquor is poured into water, and is extracted with ethyl acetate, and organic layer washes with water, and anhydrous magnesium sulfate is dried, and concentrates, crude product post layer
Analysis (ethyl acetate: normal hexane=2:3) separating-purifying, obtains faint yellow target product 18-3(productivity 72%).The analytical data of product
As follows:1H NMR (400 MHz, DMSO-d 6): δ 8.23 (d, J = 9.0 Hz, 1H), 8.12 – 7.90 (m,
2H), 7.80 (s, 1H), 7.80 – 7.70 (m, 1H), 7.05 (s, 1H), 3.86 (s, 3H), 3.70 (s,
3H), compound 18-3 has significant bactericidal action.
Embodiment 19: 1-(2-luorobenzyl)-4-((6-methoxyl group-3-oxo benzofuran-2 (3H)-methylene)
Methyl) synthesis of pyridinium chloride salt (19-6)
With 6-methoxyl group-2-hydroxyl imido grpup-3 (2H)-benzofuranone (19-1) is as raw material, and its reactions steps is as follows:
(1) compound 19-1(3.2 g is added in the reactor), acetic acid (50 milliliters), hydrochloric acid (30 milliliters), reacting by heating；
(2) TLC follows the tracks of reaction until being fully completed；
(3) reactant is cooled to room temperature, filters, with benzene and petroleum ether recrystallization, obtains target product 19-2(productivity 79%).Product
Analytical data as follows:1H NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 9.0 Hz, 1H), 8.10-
7.90 (m, 2H), 7.78-7.70 (m, 1H), 3.83 (s, 3H)；
(4) by compound 19-3(0.600 g, 1.7 mmol) it is dissolved in 25 milliliters of dry tetrahydrofuran solutions, at 0 DEG C
It is slowly added dropwise the hexane solution (1.42 mL, 1.8 mmol) of n-BuLi, stirs 30 minutes.It is subsequently adding 19-2
The tetrahydrofuran solution 15 milliliters of (0.303 g, 1.7 mmol), after stirring half an hour, is heated to boiling, reacts 5 at 0 DEG C
Hour.Being poured into water by reactant liquor, be extracted with ethyl acetate, organic layer washes with water, and anhydrous magnesium sulfate is dried, and concentrates, slightly produces
Thing column chromatography (ethyl acetate: normal hexane=2:3) separating-purifying, obtains faint yellow target product 19-4(productivity 83%).Product
Analytical data is as follows:1H NMR (400 MHz, CDCl3), 8.69 (dd, J = 4.5, 2.0 Hz, 2H), 7.71
(dd, J = 5.0, 1.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 1H), 6.77 (dd, J = 8.5, 2.1
Hz, 1H), 6.76 (d, J= 2.1 Hz, 1H), 6.67 (s, 1H), 3.95 (s, 3H)；
(5) compound 19-4(0.25 g, 1 mmol are added in the reactor) and anhydrous acetonitrile (7 milliliters), it is heated to boiling,
Compound 19-5(0.18 g, 1.2 mmol is added in system), stirring reaction 3 hours.Reaction is cooled to room after terminating
Temperature, concentrates, adds 15 ml n-hexanes, filters, and is dried, column chromatography (chloroform: methanol=99:1) separating-purifying, obtains target product
19-6(productivity 90%).The analytical data of product is as follows:1H NMR (DMSO-d 6 , 400 MHz) : δ 9.21 (d, J =
6.0 Hz, 2H), 8.52 (d, J = 6.1 Hz, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.54–7.44
(m, 5H), 7.16 (d, J = 2.2 Hz, 1H), 7.07 (s, 1H), 6.94 (dd, J = 8.3, 2.2 Hz,
1H), 5.86 (s, 2H), 3.95 (s, 3H), compound 19-6 have anticholinesterase activity, can effectively treat A Er
Thatch sea Mo's disease.
Embodiment 20: 2-((N-butyl-1H-indol-3-yl methylene)-4,6-dihydroxy benzofuran-3 (2H)-one
(20-4) synthesis
With 4,6-dihydroxy-2-hydroxyl imido grpup-3 (2H)-benzofuranone (20-1) is as raw material, and its reactions steps is as follows:
(1) compound 20-1(3.2 g is added in the reactor), acetic acid (50 milliliters), hydrochloric acid (30 milliliters), reacting by heating；
(2) TLC follows the tracks of reaction until being fully completed；
(3) reactant is cooled to room temperature, filters, with benzene and petroleum ether recrystallization, obtains target product 20-2(productivity 76%).Product
Analytical data as follows:1H NMR (400 MHz, DMSO-d 6): δ 16.47 (s, 1H), 10.18 (s, 1H), 8.22
(d, J= 9.0 Hz, 1H), 8.10 – 7.90 (m, 2H), 7.78 – 7.70 (m, 1H), 3.83 (s, 3H)；
(4) by compound 20-3(0.760 g, 1.7 mmol) it is dissolved in 25 milliliters of dry tetrahydrofuran solutions, at 0 DEG C
It is slowly added dropwise the hexane solution (1.42 mL, 1.8 mmol) of n-BuLi, stirs 30 minutes.It is subsequently adding 20-2
The tetrahydrofuran solution 15 milliliters of (0.306 g, 1.7 mmol), after stirring half an hour, is heated to boiling, reacts 5 at 0 DEG C
Hour.Being poured into water by reactant liquor, be extracted with ethyl acetate, organic layer washes with water, and anhydrous magnesium sulfate is dried, and concentrates, slightly produces
Thing column chromatography (ethyl acetate: normal hexane=2:3) separating-purifying, obtains faint yellow target product 20-4(productivity 77%).Product
Analytical data is as follows:1H NMR (400 MHz, DMSO- d 6 ): δ 10.75 (s, 2H), 8.13 (s, 1H), 7.97
(d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.18
(t, J = 7.7 Hz, 1H), 6.97 (s, 1H), 6.27 (d, J = 1.2 Hz, 1H), 6.08 (d, J = 1.2
Hz, 1H), 4.28 (t, J = 7.2 Hz, 2H), 1.79–1.73 (m, 2H), 1.30–1.24 (m, 2H), 0.88
(t, J=7.2 Hz, 3H), compound 20-4 has the activity well suppressing hepatitis C virus, is treatment hepatitis C
Drug candidate.
Embodiment 21: 2-(5-bromo-2-phenol methylene) benzofuran-3 (2H) synthesis of-one (21-2)
Using compound 17-2 as raw material, its reactions steps is as follows:
By compound 21-1(0.758 g, 1.7 mmol) it is dissolved in 25 milliliters of dry tetrahydrofuran solutions, at 0 DEG C slowly
The hexane solution (1.42 mL, 1.8 mmol) of dropping n-BuLi, stirs 30 minutes.Be subsequently adding 17-2 (0.252 g,
1.7 mmol) tetrahydrofuran solution 15 milliliters, stir after half an hour at 0 DEG C, be heated to boiling, react 5 hours.Will reaction
Liquid is poured into water, and is extracted with ethyl acetate, and organic layer washes with water, and anhydrous magnesium sulfate is dried, and concentrates, crude product column chromatography
(ethyl acetate: normal hexane=2:3) separating-purifying, obtains faint yellow target product 21-2(productivity 81%).The analytical data of product is such as
Under:1H NMR (400 MHz, CDCl3): d 10.47 (s, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.71–
7.78 (m, 2H), 7.43 (d, J = 8 Hz, 1H) 7.28 (s, 1H), 7.24–7.20 (m, 2H), 6.92
(d, J =8.8 Hz, 1H), compound 21-2 has suppression SIRT1 and the effect of cancer cell in vitro propagation, and wherein SIRT1 is
Depend on the histone deacetylase of nicotinamide adenine dinucleotide (NAD+), with cell proliferation, differentiation, aging, apoptosis and
Metabolism is closely related.
Claims (10)
1. benzofuran-2, the preparation method of 3-bis-ketoximes derivatives, it is characterised in that comprise the following steps: by 3-first
Acyl group chromone derivative, sodium nitrite, potassium peroxydisulfate are dissolved in solvent, react at room temperature, it is thus achieved that benzofuran-2,3-diketone
9 oxime derivate；
Described 3-formacyl chromone derivative is as shown in following chemical structure of general formula:
Wherein R is selected from: the one in alkyl, aryl, alkoxyl, halogen, nitro, amide groups；
Described solvent is selected from: the one in acetonitrile, acetone, acetic acid, water, N,N-dimethylformamide；
Shown in described benzofuran-2,3-two ketoximes derivatives following row chemical structure of general formula:
。
Benzofuran-2 the most according to claim 1, the preparation method of 3-bis-ketoximes derivatives, it is characterised in that: by mole
Ratio, 3-formacyl chromone derivative: sodium nitrite: potassium peroxydisulfate is 1: (1 ~ 4): (1 ~ 4).
Benzofuran-2 the most according to claim 1, the preparation method of 3-bis-ketoximes derivatives, it is characterised in that: reaction knot
After bundle, product is carried out column chromatography for separation purification processes.
Benzofuran-2 the most according to claim 1, the preparation method of 3-bis-ketoximes derivatives, it is characterised in that: described 3-
Formacyl chromone derivative selected from 4-oxo-4H-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-fluoro-.alpha.-5:6-benzopyran-3-formaldehyde,
4-oxo-4H-6-chloro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-bromo-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-nitre
Base-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-methyl-8-nitro-.alpha.-5:6-benzopyran-3-formaldehyde, the chloro-8-of 4-oxo-4H-6-
Nitro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-isopropyl-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-7-fluoro-benzo pyrrole
Mutter-3-formaldehyde, 4-oxo-4H-7-chloro-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-7-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde,
4-oxo-4H-5-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, 4-oxo-4H-6-methoxyl group-.alpha.-5:6-benzopyran-3-formaldehyde, 1-oxo-
1H-benzo [f] chromone-2-formaldehyde, 4-oxo-4H-benzo also [h] .alpha.-5:6-benzopyran-3-formaldehyde, 2-formoxyl-N-(3-formyl
Base-4-oxo-4H-.alpha.-5:6-benzopyran-6-base) one in butyramide.
Benzofuran-2 the most according to claim 1, the preparation method of 3-bis-ketoximes derivatives, it is characterised in that: utilize thin
Layer chromatography follows the tracks of reaction until being fully completed.
Benzofuran-the 2,3-that the most according to claim 1, prepared by the preparation method of benzofuran-2,3-two ketoximes derivatives
Two ketoximes derivatives.
7. benzofuran-2,3-two ketoximes derivatives described in claim 6 is in preparing benzofuran-2,3-derovatives
Application.
8. the application in preparation disinfectant of benzofuran-2,3-two ketoximes derivatives described in claim 6.
9. benzofuran-2,3-two ketoximes derivatives application in preparing antibacterial described in claim 6.
10. benzofuran-2,3-two ketoximes derivatives application in preparing inhibitor described in claim 6.
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