CN103172612B - Dibenzo iodonium salts and anticancer application thereof - Google Patents
Dibenzo iodonium salts and anticancer application thereof Download PDFInfo
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- CN103172612B CN103172612B CN201310070771.3A CN201310070771A CN103172612B CN 103172612 B CN103172612 B CN 103172612B CN 201310070771 A CN201310070771 A CN 201310070771A CN 103172612 B CN103172612 B CN 103172612B
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Abstract
The invention relates to dibenzo iodonium salts represented by the following structural formula (I), and discloses a preparation method and an application thereof. In in-vitro experiments, the iodonium salts substantially inhibit the growths of cells of human-sourced pancreatic cancer, stomach cancer, colon cancer and other malignant tumors, and provide substantially killing effects against cells of ovarian cancer, lung cancer, liver cancer, leukemia, glioma, bone marrow cancer and other malignant tumors. In animal experiments, with the salts, the growths of human pancreatic cancer and colon cancer xenografts in nude mice can be substantially inhibited. The compounds can be used in developing novel antitumor medicines. (I) is shown below.
Description
Technical field
the present invention relates to salt compounded of iodine, more specifically, relate to a kind of dibenzo salt compounded of iodine and its similar compound and anti-cancer applications thereof.
Background technology
cancer has a strong impact on global human life and health, and it instead of cardiovascular disorder becomes the first disease causing human death in the world.For many years, although the research of scientific circles on formation of cancer and development mechanism achieves great progress, the effective methods for the treatment of up to now for cancer still compares shortage.Nearly all antitumor drug shortcomings such as all ubiquity onset is slow, side effect is developed immunity to drugs greatly and easily on current domestic and international market, thus their Clinical practice receives certain restriction.Find new anticancer target spot and research and development are current important tasks of sciences for the high-efficiency low-toxicity cancer therapy drug of these novel targets.
Summary of the invention
The object of the invention is to be to provide a kind of novel cpd, dibenzo salt compounded of iodine.
First the present invention provides a kind of dibenzo salt compounded of iodine, shown in following structural formula (I):
（I）
Described R
1for hydrogen, fluorine, methoxyl group, trifluoromethoxy, cyano group, methyl, trifluoromethyl, ethyl, propyl group, butyl or phenyl;
Described Y
-for chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion or tosic acid ion,
When described structural formula is as Suo Shi structural formula (II),
(II),
Described-R is-R
2-R
3, described-R
2-be-O-or-NH-, described R
3for methyl, trifluoromethyl, ethyl, propyl group, butyl, phenyl, benzyl, acetyl or benzoyl base;
When described structural formula is as Suo Shi structural formula (III),
(III),
Described-R is-NO
2,-R
2-R
3,
or-CO-R
2-R
3, described-R
2-be-O-or-NH-, described R
3for methyl, trifluoromethyl, ethyl, propyl group, butyl, phenyl, benzyl, acetyl or benzoyl base;
When described-R connects two charcoal atomic time,
Described structural formula as shown in structural formula (IV),
(IV).
Being preferably described-R is-NO
2, described R
1for fluorine, methoxyl group, trifluoromethoxy, cyano group, methyl, trifluoromethyl, ethyl, propyl group, butyl or phenyl; Described Y
-for chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion or tosic acid ion.
Another is preferably described-R is-CO-R
2-R
3, described R
1for hydrogen.
Described-R
2-be-NH-, described-R
3for methyl, ethyl, propyl group or butyl.
Described Y
-be preferably trifluoromethanesulfonic acid ion or tosic acid ion.
Described dibenzo salt compounded of iodine most preferably is following 18 kinds of compounds, 18 kinds of described compounds structural formula as follows:
。
According to demand, reoffer a kind of cancer therapy drug, comprise above-mentioned arbitrary described dibenzo salt compounded of iodine.
Described cancer therapy drug, preferably comprises following compounds
。
Cancer in described cancer therapy drug is carcinoma of the pancreas, cancer of the stomach or intestinal cancer.
In order to understand the present invention better, do further explaination to the present invention program's association reaction formula below, listed reaction formula is only theory deduction gained, and it can not as the restriction of scope.
There is notable difference in most of malignant cell and normal cell, main manifestations is that glycolysis-is abnormal to be increased in energy metabolism.Normal cell mainly relies on aerobic repiration to produce ATP kinetomeres, but tumour cell is because respiratory chain is impaired and aerobic repiration functional disorder now mainly relies on the abnormal glycolysis-increased to provide ATP.Whole glycolytic cycle consumes two molecular oxidation type Reduced nicotinamide-adenine dinucleotide (NAD
+), corresponding generation two molecule nicotinamide adenine dinucleotide reduced (NADH, reduced form of nicotinamide-adenine dinucleotide).Tumour cell will maintain glycolysis-, and to continue one of key condition carried out be NAD
+constantly supplemented.The nearest research work of contriver finds the NAD that the nadh oxidase in tumour cell produces
+nAD needed for glycolysis-
+one of main source (
pLoS Biol. 2012, 10 (5), e1001326.).We propose accordingly by suppressing nadh oxidase to block the generation of NAD+ and effectively kill tumour cell.
Based on the research work of this team at nadh oxidase and inhibitor DPI thereof, we are a series of dibenzo salt compounded of iodine of Design and synthesis in working in the past, finds that they have certain antitumous effect (number of patent application 201210057259.0).On this result basis, we carry out composition optimizes to these dibenzo [b, d]-5-salt compounded of iodine again further, have found 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate with more high anti-tumor activity of series of novel
1deng aromatic iodonium salt.
Invention has 3-methyl-7-nitro dibenzo [b, d]-5-salt compounded of iodine of molecular formula I.Y in molecular formula I is chlorion (Cl
-), bromide anion (Br
-), iodide ion (I
-), acetate moiety (AcO
-), trifluoroacetic acid root (CF
3cO
2 -), bisulfate ion (HSO
4 -), trifluoromethanesulfonic acid ion (TfO
-or
-and tosic acid ion (TsO OTf)
-or
-oTs).When Y is tosic acid ion, this compound is 3-methyl-7-nitro dibenzo [b, d]-5-toluene iodide sulfonate
1.
Invention has the compound of molecular formula II.X in molecular formula II is fluorine (F), methoxyl group (MeO), trifluoromethoxy (CF
3o), cyano group (CN), methyl (Me), trifluoromethyl (CF
3), ethyl (Et), n-propyl (Pr), sec.-propyl (i-Pr), normal-butyl (Bu), isobutyl-(i-Bu), the tertiary butyl (t-Bu) and phenyl (Ph); Y is chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion and tosic acid ion.
Invention has the compound of molecule formula III.X in III
1can be but be not limited to oxygen (O) and nitrogen hydrogen (NH); X
2can be but be not limited to methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and benzyl (Bn); X
3for fluorine, methoxyl group, trifluoromethoxy, cyano group, methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and nitro (NO
2); Y is chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion and tosic acid ion.
Invention has the compound of molecular formula IV.X in IV
1can be but be not limited to oxygen and nitrogen hydrogen; X
2can be but be not limited to methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and benzyl; X
3for fluorine, methoxyl group, trifluoromethoxy, cyano group, methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and nitro; Y is chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion and tosic acid ion.
Invention has the compound of molecular formula V.X in molecular formula V
1can be but be not limited to oxygen and nitrogen hydrogen; X
2can be but be not limited to methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and benzyl; X
3can be but be not limited to fluorine, methoxyl group, trifluoromethoxy, cyano group, methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and nitro; Y is chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion and tosic acid ion.
Invention has the compound of molecular formula VI.X in molecular formula VI can be but is not limited to hydrogen, fluorine, methoxyl group, trifluoromethoxy, cyano group, methyl, trifluoromethyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, phenyl and nitro; Y can be but is not limited to chlorion, bromide anion, iodide ion, acetate moiety, trifluoroacetic acid root, bisulfate ion, trifluoromethanesulfonic acid ion and tosic acid ion.
Invention compound
1-
18.
3-methyl-7-nitro dibenzo [b that this patent finds, d]-5-iodomethyl benzene sulfonate 1 and analogue 2-18 thereof have obvious fragmentation effect to (but being not limited to) human pancreatic cancer cell Panc-1, cancer of the stomach HGC-27 cell and intestinal cancer DLD1, HCT116 and HT29 cell.This patent also finds 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1 and analogue 2-4 thereof be to (but being not limited to) ovarian cancer cell A2780, lung carcinoma cell NCI-H460, liver cancer cell SK-Hep1, leukemia cell Molm13, brain glioblastoma cell U87, myeloma cell U266, and people source pancreatic cancer cell Canpan2, Aspc1 and Bxpc3 etc. have obvious fragmentation effect.Therefore, this kind of compounds is expected to be used for the treatment of human pancreatic adenocarcinoma, cancer of the stomach, intestinal cancer, ovarian cancer, lung cancer, liver cancer, cerebral glioma, the malignant disease such as leukemia and myelomatosis.
Accompanying drawing explanation
Fig. 1 is in the present invention after 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1 and similar compound 2-4 administration thereof, and human pancreas cancer Panc1 inoculates Balb/c transplanted tumor in nude mice volume over time.
Fig. 2 is that in the present invention, 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1 and analogue 2-4 administration thereof are after 4 weeks, and human pancreas cancer Panc1 inoculates Balb/c transplanted tumor in nude mice weight.
Fig. 3 is in the present invention after 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1 and analogue 2-4 administration thereof, and people intestinal cancer DLD1 inoculates Balb/c transplanted tumor in nude mice volume over time.
Fig. 4 is that in the present invention, 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1 and analogue 2-4 administration thereof are after 4 weeks, and people intestinal cancer DLD1 inoculates Balb/c transplanted tumor in nude mice weight.
Embodiment
The present invention is further described below in conjunction with the drawings and specific embodiments.Unless stated otherwise, the present invention adopts reagent, equipment and method are conventional commercial reagent, equipment and the conventional method used of the art.
embodiment 1, the synthesis of 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1:
4'-methyl-4-nitro-[1,1'-biphenyl]-2-amine (1b): toward adding the bromo-5-N-methyl-p-nitroaniline of 2-(300 mg, 1.38 mmol) to the ethanolic soln (10mL) of methylphenylboronic acid (226 mg, 1.66 mmol), K
3pO
4(734 mg, 3.4 6 mmol), Pd (PPh
3)
4(80 mg, 69.12 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 1b (236 mg, 75% productive rate).
1H NMR (400 MHz, DMSO) δ 7.61 (d,
J= 2.4 Hz, 1H), 7.41 (d,
J= 2.4 Hz, 1H), 7.32 (q,
J= 8.2 Hz, 4H), 7.19 (d,
J= 8.3 Hz, 1H), 5.43 (s, 2H), 2.36 (s, 3H).
The iodo-4'-methyl of 2--4-nitro-1,1'-biphenyl (1a): toward 1b(236 mg, 1.03 mmol) tetrahydrofuran solution (5 mL) in add the aqueous hydrochloric acid (2.5 mL) of 4M.Under ice-water bath, drip the aqueous solution (3 mL) of Sodium Nitrite (85.6 mg, 1.24 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (429.1 mg, 2.58 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow solid 1a(260 mg, 74% productive rate).
3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate (1): toward 1a(80 mg, 235.9 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (81.4mg, 353.9 umol) and tosic acid (121.9 mg, 707.7 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add ethyl acetate (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid with ethyl acetate washs 3 times, finally obtains white solid 1(91 mg, 76% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.01 (s, 1H), 8.61 (s, 2H), 8.48 (d,
J= 8.0 Hz, 1H), 8.05 (s, 1H), 7.73 (d,
J= 7.9 Hz, 1H), 7.49 (d,
J= 7.9 Hz, 2H), 7.11 (d,
J= 7.8 Hz, 2H), 2.49 (s, 3H), 2.27 (s, 3H)ppm；LR-MS (ESI,
m/z): 338 (M
+)。
The synthesis of embodiment 2,3-fluoro-7-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (2):
The fluoro-4-nitro of 4'--[1,1'-biphenyl]-2-amine (2b): toward adding the bromo-5-N-methyl-p-nitroaniline of 2-(700 mg, 3.23 mmol) to the ethanolic soln (15 mL) of fluorobenzoic boric acid (524 mg, 3.87 mmol), K
3pO
4(1.71 g, 8.06 mmol), Pd (PPh
3)
4(186.36 mg, 161.28 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 2b (676 mg, 90% productive rate).
The iodo-4'-of 2-fluoro-4-nitro-1,1'-biphenyl (2a): toward 2b(676 mg, 2.91 mmol) tetrahydrofuran solution (10 mL) in add the aqueous hydrochloric acid (7.28 mL) of 4M.Under ice-water bath, drip the aqueous solution (3 mL) of Sodium Nitrite (241.03 mg, 3.49 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (1.21 g, 7.28 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow solid 2a(739 mg, 74% productive rate).
3 – fluoro-7-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (2): toward 2a(50 mg, 145.73 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (50.3 mg, 218.6 umol) and trifluoromethanesulfonic acid (38.6 uL, 437.2 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 2(57 mg, 80% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.01 (d,
J= 1.7 Hz, 1H), 8.67 (qd,
J= 8.9, 3.3 Hz, 3H), 8.07 (dd,
J= 7.8, 2.4 Hz, 1H), 7.87 (td,
J= 8.7, 2.4 Hz, 1H) ppm；LR-MS (ESI, m/z): 342 (M
+)。
Embodiment 3, the synthesis of compound 3-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (3):
4-nitro-[1,1'-biphenyl]-2-amine (3b): the ethanolic soln (5 mL) toward phenylo boric acid (300 mg, 2.46 mmol) adds the bromo-5-N-methyl-p-nitroaniline of 2-(640.76 mg, 2.95 mmol), K
3pO
4(1.31 g, 6.15 mmol), Pd (PPh
3)
4(142.16 mg, 123.02 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow liquid 3b (515 mg, 98% productive rate).
2-iodo-4-nitro-1,1'-biphenyl (3a): toward 3b(515 mg, 2.40 mmol) tetrahydrofuran solution (10 mL) in add the aqueous hydrochloric acid (6.0 mL) of 4M.Under ice-water bath, drip the aqueous solution (3 mL) of Sodium Nitrite (199.04 mg, 2.88 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (997.71 mg, 6.01 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains orange solids 3a(605 mg, 77% productive rate).
3-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (3): toward 3a(100 mg, 307.60 umol) anhydrous methylene chloride solution (5 mL) add 75% metachloroperbenzoic acid (106.16 mg, 461.39 umol) and trifluoromethanesulfonic acid (81.46 uL, 922.79 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains brown solid 3(98 mg, 67% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.03 (d,
J= 1.9 Hz, 1H), 8.72 (d,
J= 8.7 Hz, 1H), 8.68 – 8.62 (m, 2H), 8.29 (d,
J= 8.2 Hz, 1H), 7.94 (t,
J= 7.6 Hz, 1H), 7.84 (t,
J= 7.7 Hz, 1H) ppm；
13C NMR (100 MHz,
d 6 -DMSO) δ 147.4, 147.3, 139.5, 132.7, 131.0, 130.7, 128.5, 127.3, 126.1, 125.7, 123.6, 121.8 ppm；LR-MS (ESI, m/z): 324 (M
+)。
Embodiment 4, the synthesis of compound 3-nitro dibenzo [b, d]-5-iodine toluenesulfonate (4):
To implement compound 3a in 4 for raw material, adopt the similarity condition synthetic compound 4 from compound 1a synthesis-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1.
1H NMR (400 MHz,
d 6 -DMSO) δ 9.05 (d,
J= 2.1 Hz, 1H), 8.71 (d,
J= 8.8 Hz, 1H), 8.68 – 8.61 (m, 2H), 8.31 (d,
J= 8.2 Hz, 1H), 7.93 (t,
J= 7.5 Hz, 1H), 7.83 (t,
J= 7.7 Hz, 1H), 7.50 (d,
J= 8.0 Hz, 2H), 7.12 (d,
J= 7.9 Hz, 2H), 2.28 (s, 3H) ppm；
13C NMR (100 MHz,
d 6 -DMSO) δ 147.4, 145.0, 139.6, 138.0, 132.6, 131.0, 130.8, 128.4, 128.2, 127.2, 126.2, 125.7, 125.4, 123.8, 121.9, 20.7 ppm；LR-MS (ESI, m/z): 324 (M
+)。
The synthesis of embodiment 5,3-nitro-7-trifluoromethoxy dibenzo [b, d]-5-iodine fluoroform sulphonate (5)
4-nitro-4'-trifluoromethoxy-[1,1'-biphenyl]-2-amine (5b): the ethanolic soln (8 mL) toward 4-trifluoromethoxy phenylo boric acid (300 mg, 1.46 mmol) adds the bromo-5-N-methyl-p-nitroaniline of 2-(380 mg, 1.75 mmol), K
3pO
4(773 mg, 3.64 mmol), Pd (PPh
3)
4(84 mg, 73 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains orange liquid 5b (403 mg, 93% productive rate).
The iodo-4-nitro of 2--4'-trifluoromethoxy-1,1'-biphenyl (5a): toward 5b(403 mg, 1.35 mmol) tetrahydrofuran solution (5 mL) in add the aqueous hydrochloric acid (3.38 mL) of 4M.Under ice-water bath, drip the aqueous solution (5 mL) of Sodium Nitrite (111.89 mg, 1.62 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (560.83 mg, 3.38 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 5a(436 mg, 79% productive rate).
3-nitro-7-trifluoromethoxy dibenzo [b, d]-5-iodine fluoroform sulphonate (5): toward 5a(80mg, 195.55 umol) anhydrous methylene chloride solution (5 mL) add 75% metachloroperbenzoic acid (67.49 mg, 293.33 umol) and trifluoromethanesulfonic acid (86.32 uL, 977.76 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 3(73 mg, 67% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.02 (d, J = 2.1 Hz, 1H), 8.81 – 8.72 (m, 2H), 8.68 (dd, J = 8.7, 2.0 Hz, 1H), 8.25 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 149.6, 147.7, 145.9, 138.9, 129.9, 127.9, 126.0, 125.9, 124.7, 124.1, 122.7, 122.5, 99.5 ppm; LR-MS (ESI, m/z): 408 (M
+); IR(KBr) 1591, 1526, 1347, 1266 cm
-1。
The synthesis of embodiment 6,3-nitro-7-trifluoromethyl dibenzo [b, d]-5-iodine fluoroform sulphonate (6)
4-nitro-4'-trifluoromethyl-[1,1'-biphenyl]-2-amine (6b): the ethanolic soln (8 mL) toward 4-trifluoromethylbenzene boronic acid (300 mg, 1.58 mmol) adds the bromo-5-N-methyl-p-nitroaniline of 2-(411 mg, 1.90 mmol), K
3pO
4(838 mg, 3.95 mmol), Pd (PPh
3)
4(91 mg, 79 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 6b (383 mg, 86% productive rate).
The iodo-4-nitro of 2--4'-Trifluoromethyl-1,1'-biphenyl (6a): toward 6b(383 mg, 1.36 mmol) tetrahydrofuran solution (5 mL) in add the aqueous hydrochloric acid (3.39 mL) of 4M.Under ice-water bath, drip the aqueous solution (5 mL) of Sodium Nitrite (112.36 mg, 1.63 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (563.21 mg, 3.39 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 6a(481 mg, 90% productive rate).
3-nitro-7-trifluoromethyl dibenzo [b, d]-5-iodine fluoroform sulphonate (6): toward 6a(80mg, 203.51 umol) anhydrous methylene chloride solution (5 mL) add 75% metachloroperbenzoic acid (70.24 mg, 305.27 umol) and trifluoromethanesulfonic acid (89.83 uL, 1.02 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 6(65 mg, 59% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.06 (s, 1H), 8.92 – 8.82 (m, 2H), 8.71 (d, J = 8.5 Hz, 1H), 8.59 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 148.7, 146.3, 144.0, 129.7, 128.94, 128.4, 128.0, 126.6, 126.4, 124.8, 123.8 ppm; LR-MS (ESI, m/z): 392 (M
+); IR(KBr) 1654, 1527, 1268, 1178 cm
-1.
The synthesis of embodiment 7,3-cyano group-7-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (7)
2-amino-4'-nitro-[1,1'-biphenyl]-4-nitrile (7b): the ethanolic soln (8 mL) toward 4-cyanophenylboronic acid (300 mg, 2.04 mmol) adds the bromo-5-N-methyl-p-nitroaniline of 2-(532 mg, 2.45 mmol), K
3pO
4(1.08 g, 5.10 mmol), Pd (PPh
3)
4(118 mg, 102 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 7b (340 mg, 70% productive rate).
2-amino-4'-nitro-[1,1'-biphenyl]-4-nitrile (7a): toward 7b(340 mg, 1.42 mmol) tetrahydrofuran solution (5 mL) in add the aqueous hydrochloric acid (3.55 mL) of 4M.Under ice-water bath, drip the aqueous solution (5 mL) of Sodium Nitrite (117.69 mg, 1.71 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (589.82 mg, 3.55 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=6/1-3/1) purifying, obtains white solid 7a(363 mg, 73% productive rate).
3-cyano group-7-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (7): toward 7a(80 mg, 228.50 umol) anhydrous methylene chloride solution (5 mL) add 75% metachloroperbenzoic acid (78.86 mg, 342.75 umol) and trifluoromethanesulfonic acid (100.86 uL, 1.14 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 7(101 mg, 89% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.04 (d, J = 2.0 Hz, 1H), 8.84 (dd, J = 8.5, 4.7 Hz, 2H), 8.71 (dd, J = 8.7, 2.0 Hz, 1H), 8.60 (s, 1H), 8.42 (d, J = 8.2 Hz, 1H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 148.3, 145.7, 143.7, 134.5, 134.2, 128.7, 126.0, 123.8, 123.6, 117.2, 113.9 ppm; LR-MS (ESI, m/z): 349 (M
+); IR(KBr) 1648, 1526, 1347, 1272 cm
-1。
The synthesis of embodiment 8, the 3-tertiary butyl-7-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (8)
4-nitro-4'-the tertiary butyl-[1,1'-biphenyl]-2-amine (8b): the ethanolic soln (8 mL) toward 4-tert-butylbenzeneboronic acid (300 mg, 1.69 mmol) adds the bromo-5-N-methyl-p-nitroaniline of 2-(403 mg, 1.85 mmol), K
3pO
4(894 mg, 4.21 mmol), Pd (PPh
3)
4(97 mg, 84 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 8b (389 mg, 85% productive rate).
Iodo-4 nitros of the 4'-tertiary butyl-2--[1,1'-biphenyl] (8a): toward 8b(50 mg, 184.96 umol) tetrahydrofuran solution (3 mL) in add the aqueous hydrochloric acid (462.40 uL) of 4M.Under ice-water bath, drip the aqueous solution (2 mL) of Sodium Nitrite (15.31 mg, 221.95 umol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (3 mL) of potassiumiodide (76.76 mg, 462.40 umol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow solid 8a(63 mg, 89% productive rate).
The 3-tertiary butyl-7-nitro dibenzo [b, d]-5-iodine fluoroform sulphonate (8): toward 8a(63 mg, 165.26 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (57.04 mg, 247.90 umol) and trifluoromethanesulfonic acid (43.77 uL, 495.79 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 8(64 mg, 73% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.00 (s, 1H), 8.64 (d, J = 8.8 Hz, 2H), 8.54 (d, J = 8.2 Hz, 1H), 8.27 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 1.39 (s, 9H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 156.8, 147.8, 147.6, 137.6, 129.2, 128.7, 127.6, 127.3, 126.7, 126.3, 124.8, 122.1, 36.2, 31.2 ppm; LR-MS(ESI): 380(M
+); IR(KBr) 2969, 1621, 1526, 1454, 1228 cm
-1。
The synthesis of embodiment 9,3-fluoro-7-methoxyl group dibenzo [b, d]-5-iodine fluoroform sulphonate (9)
The fluoro-4-methoxyl group of 4'--2-nitro-[1,1'-biphenyl] (9c): the ethanolic soln (8 mL) toward 4-fluorobenzoic boric acid (250 mg, 1.79 mmol) adds 3-nitro-4-bromoanisole (497 mg, 2.14 mmol), K
3pO
4(948 mg, 4.47 mmol), Pd (PPh
3)
4(103 mg, 89 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 9c (423 mg, 96% productive rate).
The fluoro-4-methoxyl group of 4'--[1,1'-biphenyl]-2-amine (9b): toward 9a(420 mg, 1.70 mmol) methanol solution (5 mL) in add Pd/C(42 mg).Under room temperature, stir 1 hour in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Obtain brown solid 9b(368 mg, 100% productive rate).
The iodo-4-methoxyl group of the fluoro-2-of 4'--[1,1'-biphenyl] (9a): toward 9b(368 mg, 1.69 mmol) tetrahydrofuran solution (10 mL) in add the aqueous hydrochloric acid (4.37 mL) of 4M.Under ice-water bath, drip the aqueous solution (5 mL) of Sodium Nitrite (140.25 mg, 2.03 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5 mL) of potassiumiodide (703.02 mg, 4.23 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 9a(460 mg, 83% productive rate).
3-fluoro-7-methoxyl group dibenzo [b, d]-5-iodine fluoroform sulphonate (9): toward 9a(150 mg, 457.15 umol) anhydrous methylene chloride solution (5 mL) add 75% metachloroperbenzoic acid (157.78 mg, 685.72 umol) and trifluoromethanesulfonic acid (201.79 uL, 2.29 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (5 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains yellow solid 9(173 mg, 79% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.42 – 8.24 (m, 2H), 7.95 (d, J = 7.8 Hz, 1H), 7.72 (s, 2H), 7.42 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 160.5, 138.3, 133.2, 127.5, 123.0, 121.1, 118.7, 117.9, 117.7, 117.4, 114.7, 99.4, 56.0 ppm; LR-MS (ESI, m/z): 327 (M
+); IR(KBr) 3054, 1649, 1598, 1270 cm
-1。
The synthesis of embodiment 10,3-methoxyl group-7-methyldiphenyl also [b, d]-5-iodine fluoroform sulphonate (10)
4'-methyl-4-methoxyl group-2-nitro-[1,1'-biphenyl] (10c): the ethanolic soln (8 mL) toward 4-methylphenylboronic acid (300 mg, 2.21 mmol) adds 3-nitro-4-bromoanisole (614 mg, 2.65 mmol), K
3pO
4(1.17 g, 5.52 mmol), Pd (PPh
3)
4(128 mg, 110 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 10c (521 mg, 97% productive rate).
4'-methyl-4-methoxyl group-[1,1'-biphenyl]-2-amine (10b): toward 10c(521 mg, 2.14 mmol) methanol solution (10 mL) in add Pd/C(52 mg).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Obtain yellow liquid 10b(456 mg, 100% productive rate).
The iodo-4'-methyl of 2--4-methoxyl group-[1,1'-biphenyl] (10a): toward 10b(456 mg, 2.14 mmol) tetrahydrofuran solution (10 mL) in add the aqueous hydrochloric acid (5.35 mL) of 4M.Under ice-water bath, drip the aqueous solution (5 mL) of Sodium Nitrite (177.02 mg, 2.57 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5 mL) of potassiumiodide (887.32 mg, 5.35 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 10a(504 mg, 73% productive rate).
3-methoxyl group-7-methyldiphenyl also [b, d]-5-iodine fluoroform sulphonate (10): toward 10a(80 mg, 246.79 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (85.18 mg, 370.19 umol) and trifluoromethanesulfonic acid (108.94 uL, 1.23 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (5 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 10(86 mg, 74% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.29 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.7, 2.4 Hz, 1H), 3.90 (s, 3H), 2.49 (d, J = 11.3 Hz, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 160.4, 140.1, 138.9, 134.3, 131.6, 130.1, 127.2, 125.9, 122.3, 121.0, 117.8, 114.7, 99.5, 56.0, 21.1 ppm; LR-MS (ESI, m/z): 323 (M
+); IR(KBr) 1647, 1600, 1469, 1268 cm
-1。
The synthesis of embodiment 11,3-methoxyl group-7-trifluoromethoxy dibenzo [b, d]-5-iodine fluoroform sulphonate (11)
4'-trifluoromethyl-4-methoxyl group-2-nitro-[1,1'-biphenyl] (11c): the ethanolic soln (5 mL) toward 4-trifluoromethylbenzene boronic acid (300 mg, 1.58 mmol) adds 3-nitro-4-bromoanisole (403 mg, 1.74 mmol), K
3pO
4(832 mg, 3.95 mmol), Pd (PPh
3)
4(91 mg, 79 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains brown solid 11c (422 mg, 90% productive rate).
4'-trifluoromethyl-4-methoxyl group-[1,1'-biphenyl]-2-amine (11b): toward 11c(422 mg, 1.42 mmol) methanol solution (5 mL) in add Pd/C(40 mg).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=10/1-5/1) purifying obtained, obtains yellow solid 11b (345 mg, 91% productive rate).
The iodo-4'-trifluoromethyl of 2--4-methoxyl group-[1,1'-biphenyl] (11a): toward 11b(244 mg, 913.02 umol) tetrahydrofuran solution (5 mL) in add the aqueous hydrochloric acid (2.28 mL) of 4M.Under ice-water bath, drip the aqueous solution (3 mL) of Sodium Nitrite (75.59 mg, 1.10 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5 mL) of potassiumiodide (378.91 mg, 2.28 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 11a(269.29 mg, 78% productive rate).
3-methoxyl group-7-trifluoromethoxy dibenzo [b, d]-5-iodine fluoroform sulphonate (11): toward 11a(30 mg, 79.34 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (21.91 mg, 95.21 umol) and trifluoromethanesulfonic acid (21.01 uL, 238.01 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains yellow solid 11(30 mg, 72% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.52 (d, J = 8.3 Hz, 1H), 8.45 (d, J = 5.6 Hz, 2H), 8.15 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.46 (d, J = 8.7 Hz, 1H), 3.93 (s, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 161.59, 145.38, 132.71, 128.59, 127.55, 127.30, 126.70, 124.14, 121.15, 117.99, 114.83, 56.16 ppm; LR-MS (ESI, m/z): 377.0 (M
+); IR(KBr) 1596, 1476, 1326, 1230 cm
-1。
The synthesis of embodiment 12,3-methoxyl group-7-phenyl dibenzo [b, d]-5-iodine fluoroform sulphonate (12)
4'-phenyl-4-methoxyl group-2-nitro-[1,1'-biphenyl] (12c): the ethanolic soln (8 mL) toward 4-phenyl phenylo boric acid (300 mg, 1.51 mmol) adds 3-nitro-4-bromoanisole (422 mg, 1.82 mmol), K
3pO
4(804 mg, 3.79 mmol), Pd (PPh
3)
4(88 mg, 76 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains orange liquid 12c (384 mg, 83% productive rate).
4'-tolyl-4-methoxyl group-[1,1'-biphenyl]-2-amine (12b): toward 12c(175 mg, 573.16 umol) methanol solution (5 mL) in add Pd/C(18 mg).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Obtain yellow solid 12b(157 mg, 100% productive rate).
The iodo-4'-phenyl of 2--4-methoxyl group-[1,1'-biphenyl] (12a): toward 12b(157 mg, 570.2 umol) tetrahydrofuran solution (5 mL) in add the aqueous hydrochloric acid (1.43 mL) of 4M.Under ice-water bath, drip the aqueous solution (3 mL) of Sodium Nitrite (47.21 mg, 684.23 umol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5 mL) of potassiumiodide (236.63 mg, 1.43 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow solid 10a(172 mg, 78% productive rate).
3-methoxyl group-7-phenyl dibenzo [b, d]-5-iodine fluoroform sulphonate (12): toward 12a(80 mg, 207.13 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (71.49 mg, 310.70 umol) and trifluoromethanesulfonic acid (91.43 uL, 1.04 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (5 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains black solid 12(79 mg, 71% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.37 (m, J = 8.7, 6.7 Hz, 3H), 8.08 (dd, J = 8.2, 1.5 Hz, 1H), 7.74 (dd, J = 4.9, 2.4 Hz, 3H), 7.56 (t, J = 7.6 Hz, 2H), 7.50 – 7.39 (m, 2H), 3.91 (s, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 160.7, 141.4, 140.4, 138.1, 133.8, 129.4, 129.1, 128.5, 128.0, 127.6, 126.7, 126.5, 122.9, 121.9, 117.9, 114.9, 56.0 ppm; LR-MS (ESI, m/z): 385 (M
+); IR(KBr) 1599, 1466, 1389, 1274 cm
-1。
The synthesis of embodiment 13,3-phenoxy group dibenzo [b, d]-5-iodine tosilate (13)
2'-nitro-3-hydroxyl-[1,1'-biphenyl] (13d): the ethanolic soln (5 mL) toward 3-hydroxybenzene boric acid (246 mg, 2.41 mmol) adds o-iodonitrobenzene (370 mg, 2.01 mmol), K
3pO
4(1.07 g, 5.02 mmol), Pd (PPh
3)
4(116 mg, 100 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=6/1-3/1) purifying obtained, obtains brown liquid 13d (280 mg, 88% productive rate).
2-nitro-3'-phenoxy group-[1,1'-biphenyl] (13c): toward 13d(280 mg, 1.30 mmol) aqueous isopropanol (5 mL) in add iodobenzene (292mg, 1.43 mmol), cuprous iodide (12.39 mg, 65.05 umol), ethylene glycol (2.6 mmol), K
2cO
3(360 mg, 2.60 mmol).Reaction solution is under argon shield 80
0c reacts 6 hours, then decompression removing Virahol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains green liquid 13c (154 mg, 90% productive rate).
3'-phenoxy group-[1,1'-biphenyl]-2-amine (13b): toward 13c(97 mg, 332.99 umol) methanol solution (3 mL) in add Pd/C(10 mg).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=10/1-5/1) purifying obtained, obtains yellow liquid 13b (73 mg, 84% productive rate).
The iodo-3'-phenoxy group of 2--[1,1'-biphenyl] (13a): toward 13b(73 mg, 279.35 umol) tetrahydrofuran solution (3 mL) in add the aqueous hydrochloric acid (698.38 uL) of 4M.Under ice-water bath, drip the aqueous solution (1 mL) of Sodium Nitrite (23.13 mg, 335.22 umol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (3 mL) of potassiumiodide (115.93 mg, 698.38 umol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 10a(80 mg, 78% productive rate).
3-phenoxy group dibenzo [b, d]-5-iodine tosilate (13): toward 13a(40 mg, 107.47 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (37.09 mg, 161.20 umol) and tosic acid (55.52 mg, 322.41 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add ethyl acetate (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid with ethyl acetate washs 3 times, finally obtains white solid 13(22 mg, 70% productive rate)
1h NMR (400 MHz,
d 6 -DMSO) δ 8.45 (d, J=7.7 Hz, 1H), 8.28 – 8.13 (m; 3H), 7.82 (t, J=7.5 Hz, 1H); 7.71 (t, J=7.8 Hz, 1H), 7.48 (dd; J=13.7,7.8 Hz, 4H), 7.33 – 7.21 (m; 2H), 7.13 (t, J=8.5 Hz; 4H), 2.28 (s, 3H) ppm;
13c NMR (101 MHz,
d 6 -DMSO) δ 159.3,155.8,145.2,143.9,141.0,137.9,132.1; 131.3,130.7,130.7,130.3,128.1,127.3,125.5; 124.4,121.9,121.0,119.1,116.7,113.9,20.7 ppm; LR-MS (ESI, m/z): 371 (M
+). IR (KBr) 1654,1218 cm
-1.
The synthesis of embodiment 14,3-benzyloxy dibenzo [b, d]-5-iodine tosilate (14)
3'-benzyloxy-[1,1'-biphenyl]-2-amine (14b): the ethanolic soln (10mL) toward 3-benzyloxy phenylo boric acid (300 mg, 1.32 mmol) adds adjacent Iodoaniline (346 mg, 1.58 mmol), K
3pO
4(698 mg, 3.29 mmol), Pd (PPh
3)
4(76 mg, 65.6 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains brown liquid 14b (309 mg, 85% productive rate).
3'-benzyloxy-2-iodo-[1,1'-biphenyl] (14a): toward 14b(305 mg, 1.11 mmol) tetrahydrofuran solution (8 mL) in add the aqueous hydrochloric acid (2.77 mL) of 4M.Under ice-water bath, drip the aqueous solution (3 mL) of Sodium Nitrite (91.71 mg, 1.33 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5mL) of potassiumiodide (459.70 mg, 2.77 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 14a(355 mg, 82% productive rate).
3-benzyloxy dibenzo [b, d]-5-iodine tosilate (14): toward 14a(30 mg, 77.67 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (26.81 mg, 116.51 umol) and tosic acid (66.88 mg, 388.37 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add ethyl acetate (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid with ethyl acetate washs 3 times, finally obtains white solid 14(33 mg, 76% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.55 (d, J = 7.8 Hz, 1H), 8.20 (dd, J = 17.0, 5.3 Hz, 2H), 8.07 (d, J = 9.0 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.50 (dd, J = 16.0, 7.7 Hz, 4H), 7.40 (dt, J = 25.9, 7.1 Hz, 4H), 7.11 (d, J = 7.8 Hz, 2H), 5.32 (s, 2H), 2.28 (s, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 160.6, 145.3, 143.3, 141.5, 137.9, 136.3, 131.4, 131.1, 130.6, 130.6, 128.5, 128.1, 128.0, 127.2, 125.5, 121.8, 118.9, 112.5, 110.7, 70.0, 20.7 ppm; LR-MS (ESI, m/z): 385 (M
+); IR(KBr) 1651, 1569, 1196 cm
-1。
The synthesis of embodiment 15,2-(benzamido) dibenzo [b, d]-5-iodine tosilate (15)
3'-nitro-[1,1'-biphenyl]-2-amine (15d): the ethanolic soln (15 mL) toward 3-nitrobenzene boronic acid (1.0 g, 5.99 mmol) adds adjacent Iodoaniline (1.57 g, 7.19 mmol), K
3pO
4(3.18 g, 14.98 mmol), Pd (PPh
3)
4(346 mg, 300 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 15d (1.19 g, 93% productive rate).
The iodo-3'-nitro of 2--[1,1'-biphenyl] (15c): toward 15d(1.19 g, 5.6 mmol) tetrahydrofuran solution (15 mL) in add the aqueous hydrochloric acid (14 mL) of 4M.Under ice-water bath, drip the aqueous solution (5 mL) of Sodium Nitrite (463.79 mg, 6.72 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (5 mL) of potassiumiodide (2.32 g, 14 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow liquid 15c(1.31 g, 72% productive rate).
2'-iodo-[1,1'-biphenyl]-3-amine (15b): toward 15c(1.03 g, 3.61 mmol) methanol solution (15 mL) add Raney-Ni (100 mg), NH
2nH
2-H
2o (80%, 548.64 uL, 9.03 mmol).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=10/1-5/1) purifying obtained, obtains yellow solid 15b (832 mg, 89% productive rate).
3'-benzoylamino-2-iodo-[1,1'-biphenyl] (15a): toward 15b(100 mg, 339 umol) dichloromethane solution (3 mL) add Benzoyl chloride (71.45mg, 508.27umol), DMAP(2 mg, 17 umol), triethylamine (678 umol).Under room temperature, react one hour.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=6/1-3/1) purifying, obtains yellow liquid 15a(114 mg, 84% productive rate).
2-(benzamido) dibenzo [b, d]-5-iodine tosilate (15): toward 15a(42 mg, 105.2 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (36.31 mg, 157.81 umol) and tosic acid (54.35 mg, 315.61 mmol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add ethyl acetate (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid with ethyl acetate washs 3 times, finally obtains white solid 15(40 mg, 69% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 10.74 (s, 1H), 8.84 (s, 1H), 8.25 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 8.9 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.89 (t, J = 7.7 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 7.0 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.48 (d, J = 7.7 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 2.28 (s, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 166.1, 145.2, 142.1, 141.7, 141.4, 137.9, 134.2, 132.0, 131.1, 130.8, 130.8, 130.8, 128.5, 128.1, 127.8, 126.4, 125.5, 123.1, 121.9, 117.6, 114.0, 20.7 ppm; LR-MS (ESI, m/z): 398 (M
+); 1660, 1531, 1199 cm
-1。
Embodiment 16,3-(third carbamyl) synthesis of dibenzo [b, d]-5-iodine fluoroform sulphonate (16)
2'-nitro-4-carboxyl-[1,1'-biphenyl] (16d): the ethanolic soln (15 mL) toward 4-Carboxybenzeneboronic acid (500 mg, 3.01 mmol) adds o-iodonitrobenzene (900 mg, 3.62 mmol), K
3pO
4(1.60 g, 7.53 mmol), Pd (PPh
3)
4(174 mg, 151 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 16d (601 mg, 82% productive rate).
2'-nitro-N-n-propyl-[1,1'-biphenyl]-4-methane amide (16c): toward 16d(100 mg, 411 umol) dichloromethane solution (5 mL) add Tri N-Propyl Amine (494 umol), EDCI(115 mg, 617 umol), DMAP(2.5 mg, 20.56 umol).Under room temperature, react four hours.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=6/1-3/1) purifying, obtains yellow solid 16c(79 mg, 68% productive rate).
2'-amino-N-n-propyl-[1,1'-biphenyl]-4-methane amide (16b): toward 16c(79 mg, 277.87 umol) methanol solution (3 mL) add Raney-Ni (10 mg), NH
2nH
2-H
2o (80%, 33.76 uL, 694.66 umol).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Obtain yellow liquid 16b (71 mg, 100% productive rate).
The iodo-N-n-propyl of 2'--[1,1'-biphenyl]-4-methane amide (16a): toward 16b(71 mg, 279.17 umol) tetrahydrofuran solution (3 mL) in add the aqueous hydrochloric acid (697.92 uL) of 4M.Under ice-water bath, drip the aqueous solution (1 mL) of Sodium Nitrite (23.11 mg, 335.0 umol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (3 mL) of potassiumiodide (115.86 mg, 697.92 umol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=4/1-2/1) purifying, obtains yellow liquid 16a(67 mg, 66% productive rate).
3-(third carbamyl) dibenzo [b; d]-5-iodine fluoroform sulphonate (16): toward 16a (67 mg; 183.46 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (63.32 mg; 275.19 umol) and trifluoromethanesulfonic acid (80.98 uL, 917.28 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid washed with ether 3 times, finally obtains white solid 16(68 mg, 72% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.81 (t, J = 5.5 Hz, 1H), 8.67 (d, J = 1.1 Hz, 1H), 8.56 (dd, J = 7.7, 4.5 Hz, 2H), 8.30 – 8.21 (m, 2H), 7.89 (t, J = 7.5 Hz, 1H), 7.80 – 7.72 (m, 1H), 3.28 (dd, J = 13.1, 6.6 Hz, 2H), 1.63 – 1.51 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 164.3 , 143.9 , 140.9, 136.5, 131.6, 130.8, 130.7, 130.2, 128.6, 127.6, 126.5, 122.3, 121.8, 41.2, 22.2, 11.4 ppm; LR-MS (ESI, m/z): 364 (M
+); IR(KBr) 1648, 1544, 1274 cm
-1。
The synthesis of embodiment 17,3-(morphine-4-carbonyl) dibenzo [b, d]-5-iodine tosilate (17)
17c: toward 16d(210 mg, 617 umol) dichloromethane solution (5 mL) add morpholine (925 umol), EDCI(248 mg, 915 umol), DMAP(5.3 mg, 30.84 umol).Under room temperature, react four hours.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=2/1-1/1) purifying, obtains yellow solid 17c(222 mg, 82% productive rate).
17b: toward 17c(222 mg, 704.41 umol) methanol solution (5 mL) add Pd/C (20 mg).Under room temperature, stir 2 hours in atmosphere of hydrogen.This mixed solution diatomite filtration, removal of solvent under reduced pressure.Obtain yellow solid 17b (198 mg, 100% productive rate)
17a: toward 17b(168 mg, 595.03 umol) tetrahydrofuran solution (3 mL) in add the aqueous hydrochloric acid (1.49 mL) of 4M.Under ice-water bath, drip the aqueous solution (1 mL) of Sodium Nitrite (49.27 mg, 714.04 umol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (3 mL) of potassiumiodide (246.94 mg, 1.49 mmol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=4/1-2/1) purifying, obtains yellow liquid 17a(189 mg, 81% productive rate).
3-(morphine-4-carbonyl) dibenzo [b, d]-5-iodine tosilate (17): toward 17a (40 mg, 101.72 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (35.11 mg, 152.59 umol) and tosic acid (52.55 mg, 305.17 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add ethyl acetate (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid with ethyl acetate washs 3 times, finally obtains white solid 17(44 mg, 79% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 8.54 (d, J = 8.0 Hz, 2H), 8.27 (d, J = 5.1 Hz, 2H), 7.89 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 3.64(brs, 8H), 2.29 (s, 3H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 167.0, 145.3, 142.8, 141.0, 137.8, 137.2, 131.5, 130.8, 130.7, 129.4, 128.1, 127.3, 126.7, 125.5, 122.2, 121.7, 66.0, 20.7 ppm; LR-MS (ESI, m/z): 392 (M
+); IR(KBr) 1629, 1189 cm
-1。
The synthesis of embodiment 18,9-nitro benzo [b] naphtho-[2,1-d]-11-iodine fluoroform sulphonate (18)
2-(2'-naphthyl)-5-nitro-analine (18b): the ethanolic soln (8 mL) toward 2-naphthalene boronic acids (300 mg, 1.74 mmol) adds the bromo-5-N-methyl-p-nitroaniline of 2-(416 mg, 1.92 mmol), K
3pO
4(927 mg, 4.36 mmol), Pd (PPh
3)
4(101 mg, 87 umol).Reaction solution reflux 6 hours under argon shield, then decompression removing ethanol.Residue with Ethyl acetate dissolves, and respectively washs once successively, anhydrous sodium sulfate drying with water and saturated aqueous common salt, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: the ethyl acetate=20/1-10/1) purifying obtained, obtains yellow solid 18b (363 mg, 79% productive rate).
The iodo-4-nitrophenyl of 2-(2-)-naphthalene (18a): toward 18b(50 mg, 189.19 umol) tetrahydrofuran solution (3 mL) in add the aqueous hydrochloric acid (472.99 uL) of 4M.Under ice-water bath, drip the aqueous solution (2 mL) of Sodium Nitrite (15.66 mg, 227.03 mmol) toward above-mentioned solution.Stir after 20 minutes, under ice-water bath, drip the aqueous solution (3 mL) of potassiumiodide (78.52 mg, 472.99 umol).Stir after 10 minutes, solution slowly rises to room temperature, then stirs 1 hour.Finally, the sodium thiosulfate solution of 1M is dripped until reaction solution color is constant.Separatory, aqueous phase ethyl acetate extracts (15 mL x 3).Merge organic phase, use water (5 mL x 2) and saturated aqueous common salt (5 mL) washing successively, anhydrous sodium sulfate drying, filters, removal of solvent under reduced pressure.Residue silica gel column chromatography (elutriant sherwood oil: ethyl acetate=20/1-10/1) purifying, obtains yellow solid 18a(58 mg, 82% productive rate).
9-nitro benzo [b] naphtho-[2,1-d]-11-iodine fluoroform sulphonate (18): toward 18a(58mg, 154.6 umol) anhydrous methylene chloride solution (3 mL) add 75% metachloroperbenzoic acid (53.36 mg, 231.9 umol) and trifluoromethanesulfonic acid (4094 uL, 463.8 umol).Reaction solution at room temperature stirs 1 hour, then removal of solvent under reduced pressure.Add diethyl ether (3 mL) toward residue, mixture stirs 20 minutes, and filter, solid with ethyl acetate washs 3 times, finally obtains white solid 1(63 mg, 78% productive rate).
1H NMR (400 MHz,
d 6 -DMSO) δ 9.13 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J = 8.2 Hz, 1H), 8.42 (s, 2H), 8.21 (d, J = 6.1 Hz, 1H), 7.85 (s, 2H) ppm;
13C NMR (100 MHz,
d 6 -DMSO) δ 148.5, 147.2, 139.2, 134.4, 131.8, 131.2, 129.6, 129.4, 129.1, 128.2, 128.1, 126.8, 126.1, 124.2, 122.0, 99.5 ppm; LR-MS (ESI, m/z): 374 (M
+); IR(KBr) 1621, 1552, 1345, 1240 cm
-1。
The antitumous effect of embodiment 19 compound:
External MTT method measures drug molecule to the fragmentation effect of tumour cell: the human tumor cells of phase growth of taking the logarithm, digests centrifugal and count, making cell density at 3x10
4individual left and right, cell is seeded in 96 orifice plates, namely 3000 cells are inoculated in every hole, after cell attachment, (each drug level establishes three secondary orifices to add the nutrient solution of the DPI analogue containing different concns, blank well is separately established to return to zero, 3-methyl-7-nitro dibenzo [b, d] in the solution such as-5-iodomethyl benzene sulfonate DMSO concentration control within 0.1%), hatch in CO2gas incubator 72 little after, add the MTT of 5mg/ml, after acting on 4 hours, add the first Zan (quantity of viable cell is directly proportional to the turnout of first Zan) of 200ul DMSO dissolve purple, after room temperature shaker shakes 10 minutes, be the absorbance of 570 nanometers at wavelength with microplate reader detection 96-orifice plate, experiment in triplicate.The calculation formula of cells survival rate is: the mean absorbance values x100% of the mean absorbance values/control group of medication therapy groups, IC
50for drug level when 3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate 1 and analogue thereof cause 50% death of neoplastic cells, calculate IC with prism Software on Drawing cells survival graphic representation
50value.
3-methyl-7-nitro dibenzo [b, d]-5-iodomethyl benzene sulfonate that embodiment 1 obtains and the similar compound 2-18 that embodiment 2-18 obtains respectively have have significantly killed and wounded (tables one) such as people source pancreatic cancer cell Panc-1, colon-cancer cell DLD1 and stomach cancer cell HGC-27 in MTT experiment in vitro.
Table one: representative compound 1-18 causes drug level IC during 50% death of neoplastic cells
50(unit is micromole uM).
Embodiment 1 obtains 3-methyl-7-nitro dibenzo [b, d] the similar compound 2(dq278 that obtains of-5-iodomethyl benzene sulfonate (dq285) and embodiment 2), the similar compound 3(dq265 that embodiment 3 obtains) and the similar compound 4(dq266 that obtains of embodiment 4) significantly kill and wound people's colon-cancer cell HCT116 and HT29 in MTT experiment in vitro, ovum cancer A2780, lung cancer NCI-H460, liver cancer cell SK-Hep1, leukemia Molm13, cerebral glioma U87, bone marrow cancer U266, and people source pancreatic cancer cell Canpan2, Aspc1 and Bxpc3 etc. (table two).
Table two: representative compound 1-4 is to the inhibit activities IC of other people source cancer cells
50(unit is micromole uM).
These compounds also embody antitumous effect to a certain degree in experimentation on animals.3-methyl-7-nitro dibenzo [b is obtained with embodiment 1, d] the similar compound 2(dq278 that obtains of-5-iodomethyl benzene sulfonate (dq285) and embodiment 2), the similar compound 3(dq265 that obtains of embodiment 3) and the similar compound 4(dq266 that obtains of embodiment 4) be that example is described for the fragmentation effect of human pancreas cancer transplanted tumor in nude mice and people's intestinal cancer transplanted tumor in nude mice, dosage is 1.5 milligrams of per kilogram nude mices, dosage regimen is abdominal injection, secondary on every Fridays, observe surrounding or three weeks.The blank group of contrast DMSO, significantly can see that compound 1-4 suppresses human pancreas cancer transplanted tumor in nude mice growth (Fig. 1,2) and people's intestinal cancer transplanted tumor in nude mice growth (Fig. 3,4).
Claims (1)
1. dibenzo salt compounded of iodine is preparing the application in ovarian cancer resistance or leukemia medicine, it is characterized in that, described dibenzo salt compounded of iodine is structural formula (I), (II) or (III):
（I） （II） （III）。
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| CN108164391A (en) * | 2018-01-19 | 2018-06-15 | 李现伟 | A kind of biphenyl compound and its application in 1,3- dibromo pyrenes are prepared |
| CN108250034A (en) * | 2018-01-19 | 2018-07-06 | 李现伟 | A kind of biphenyl compound and its application in 1,3,6- tribromo pyrenes are prepared |
| CN108976248B (en) * | 2018-06-04 | 2021-04-16 | 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） | Heterocyclic ring-containing high-valence iodine compound and preparation method and application thereof |
| CN114177302B (en) * | 2021-11-12 | 2023-07-18 | 中山大学 | Glycosaminoglycan modified substance for antitumor drug delivery, and preparation method and application thereof |
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