Patent Application
20170037008
Field of Invention
The present invention relates to a field of medicine compounds, in particular to a phenyl benzyl ether derivative, a preparation method thereof and application of the phenyl benzyl ether derivative to preparation of medicine for diagnosing and treating an Alzheimer's disease (AD), wherein parts of compounds, after being labeled by radionuclide, of the phenyl benzyl ether derivative, are used as an Aβ plaque imaging agent.
Description of Related Arts
Alzheimer's disease (AD) is a progressively developed lethal neurodegenerative disease, which is clinically featured by decrease in cognition and memory functions and decrease in daily living ability and is accompanied by various neuropsychiatric symptoms and behavior disorders. The AD mostly strikes old people. According to statistical information, the AD prevalence rate of people at age above 65 years in China is averagely 6.6%, and it has become one of major diseases after tumors, heart diseases and stroke, which seriously threaten the physical and psychological health of the old people. At present, China is quickly stepping into an aging society. It is predicted that, by the year 2030, the proportion of population at age above 65 in China will exceed that in Japan and China will become a country with the highest degree of population aging in the world. At present, one AD patient is newly added every seven seconds around the world and 4.6 million new cases occur each year; and it is predicted that, by the year 2050, the number will exceed a hundred million. As you see, the task of AD prevention and control is difficult. Therefore, it has a very great significance to carry studies on the early-stage diagnosis method and the treatment medicine of the AD.
According to studies, senile plaques (SPs) deposited outside nerve cells in the brain due to the AD and nerve fiber tangles (NFTs) inside the nerve cells are two major pathological features. Moreover, deposition of Aβ plaques in the brain has already started 10-20 years before the AD comes on (Braak, H et. al. Acta Neuropathol., 1991, 82: 239-259). Therefore, by using the Aβ plaques in the brain as targets, developing molecular probes which have high affinity and selectivity with the Aβ plaques and adopting nuclear medicine imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET), the AD can be non-invasively diagnosed at an early stage from the molecular level (Cai L S, et. al. Curr Med Chem., 2007, 14: 19-52).
In the past studies, the Aβ plaque imaging agent for nuclear medicine PET imaging is developed quickly. By modifying two kinds of dyestuffs, i.e., thioflavin-T (ThT) and Congo red (CR), a wide variety of molecules have already entered a clinical test stage. For example, 2-phenylbenzothiazole representative compound [11C]PIB (Pittsburgh compound B) is the most commonly used Aβ plaque imaging agent at present (Klunk W E, et. al. Annals of Neurology., 2004, 55: 306-319), and since the analogue [18F] thereof is labeled by adopting 18F, the clinical application prospect of the analogue [18F] may be greater (Koole M, et. al. J. Nucl. Med., 2009, 50: 818-22); and for diphenylethene derivative [18F] BAY94-9172, phase-III clinical tests are being actively carried out now (Rowe C C, et. al. Lancet Neurol., 2008, 7:129-35), and [18F] AV-45 has already been approved by FDA of the United States.
However, no breakthrough has made in the Aβ plaque imaging agent for SPECT imaging, wherein 2-phenyl imidazopyridine derivative [123I] IMPY is the first SPECT imaging agent which enters the clinical stage (Newberg. A B, et. al. J. Nucl. Med. 2006, 47: 748-754). However, due to the in-vivo stability thereof is poor, it is weeded out quickly. Other Aβ plaque imaging agents which are labeled by radioactive iodine have the common disadvantages of high fat solubility, slow brain removing speed and in-vivo radioactive iodine removal.
Therefore, if a kind of brand new compounds which have high affinity with the Aβ plaques in the brain can be developed and are subjected to radionuclide labeling, an Aβ plaque imaging agent which can be used for the early-stage diagnosis of the AD can be obtained and the application prospect and the economic value will be great without any doubt.
In order to solve the above-mentioned technical problems, one purpose of the present invention is to provide a phenyl benzyl ether derivative. Compounds thereof have high affinity with Aβ plaques in brains of AD patients and belong to brand new compounds for diagnosing and treating the AD.
Another purpose of the present invention is to provide a preparation method of the phenyl benzyl ether derivative.
Another purpose of the present invention is to provide an Aβ plaque imaging agent prepared by using the phenyl benzyl ether derivative.
Another purpose of the present invention is to provide application of the Aβ plaque imaging agent to preparation of a medicine for diagnosing an amyloidosis disease, including early-stage diagnosis of the AD.
Another purpose of the present invention is to provide application of the phenyl benzyl ether derivative to preparation of a medicine for diagnosing and treating the AD.
In order to realize the above-mentioned purposes, a phenyl benzyl ether derivative is provided by the present invention, wherein a structural formula thereof is shown by a formula (I):
wherein X is O, NH or S; Y1 and Y2 respectively and independently denote —CH— or nitrogen;
R1 and R2 respectively and independently denote nitrogen, halogen, hydroxyl, hydrosulfuryl, alkoxy, alkyl, carbocyclic alkyl, heterocyclic alkyl, nitro, amino, alkylamino, cyan, carboxyl, aryl, heteraryl, arylalkoxy, substituted arylalkoxy, aryloxy, substituted aryloxy, arylalkenyl, substituted arylalkenyl, —O(CH2)mNRaRb, —CO—NRaRb, —NHCO—Ra, —Sn(alkyl)3, —(CH2)m-Z, —O(CH2)m-Z, —(CH2)m- aryl or —(OCH2CH2)n-Z;
wherein Ra and Rb respectively and independently denote hydrogen, alkyl or —(CH2)m- aryl;
wherein Z denotes halogen, hydroxyl, trifluoromethylsulfonyl, methylsulfonyl or tolylsulfonyl;
wherein the above-mentioned any m and n are respectively integers from 1 to 6, preferably integers from 1 to 3 respectively.
More preferably, Y1 and Y2 are simultaneously —CH— or nitrogen.
More preferably, Y1 and Y2 are respectively —CH— or nitrogen, or Y1 and Y2 are respectively nitrogen or —CH—.
More preferably, —(CH2)m-aryl is —(CH2)m-phenyl, including —(CH2)m-aryl denoted by R1, R2, Ra and Rb.
Preferably, R1 and R2 are o-substituents, m-substituents or p-substituents.
Preferably, the halogen is fluorine, chlorine, bromine or iodine, including halogen denoted by R1 and R2 and halogen denoted by Z.
Preferably, the alkoxy is C1-C12 alkoxy, preferably C1-C6 alkoxy.
More preferably, the alkoxy is methoxy, ethyoxyl, propoxy or butoxy.
Preferably, the alkyl is C1-C12 alkyl, preferably C1-C6 alkyl.
More preferably, the alkyl is methyl, ethyl, propyl, isopropyl or tert-butyl.
Preferably, the carbocyclic alkyl is three-membered to six-membered carbocyclic alkyl.
More preferably, the carbocyclic alkyl is cyclopropyl, cyclopentyl or cyclohexyl.
Preferably, the heterocyclic alkyl is three-membered to six-membered heterocyclic alkyl.
More preferably, the heterocyclic alkyl is piperidyl, piperazinyl or morpholine cyclic group.
Preferably, the alkylamino is C1-C12 alkylamino, preferably C1-C6 alkylamino.
More preferably, the alkylamino is N-methylamino, dimethylamino, diethylamino, dipropylamino or diisopropylamino.
Preferably, the aryl is phenyl or naphthyl.
Preferably, the heteraryl is pyridyl, furyl, thienyl, benzothiazolyl, benzofuryl or benzoxazolyl.
Preferably, the arylalkoxy is C5-C7 aryl C1-C12 alkoxy.
More preferably, the arylalkoxy is phenylmethoxyl or phenylethyoxyl.
Preferably, the substituted arylalkoxy is substituted C5-C7 aryl C1-C12 alkoxy.
More preferably, the substituted arylalkoxy is substituted phenylmethoxyl or substituted phenylethyoxyl.
Preferably, the aryloxy is C5-C7 aryloxy.
More preferably, the aryloxy is cyclopentadienyloxy or phenyloxy.
Preferably, the substituted aryloxy is substituted C5-C7 aryloxy.
More preferably, the substituted aryloxy is substituted cyclopentadienyloxy or substituted phenyloxy.
Preferably, the arylalkenyl is C5-C7 aryl C2-C6 alkenyl.
More preferably, the arylalkenyl is phenylvinyl.
Preferably, the substituted arylalkenyl is substituted C5-C7 aryl C2-C6 alkenyl.
Moreover preferably, the substituted arylalkenyl is substituted phenylvinyl.
More preferably, the aryl in the substituted arylalkoxy is substituted by halogen, hydroxyl, alkoxy, nitro, amino or alkylamino.
More preferably, the aryl in the substituted aryloxy is substituted by halogen, hydroxyl, alkoxy, nitro, amino or alkylamino.
More preferably, the aryl in the substituted aryalkenyl is substituted by halogen, hydroxyl, alkoxy, nitro, amino or alkylamino.
More preferably, the halogen in the substituted arylalkoxy, the substituted aryloxy and the substituted arylalkenyl is fluorine, chlorine, bromine or iodine, wherein the alkoxy is methoxy, ethyoxyl, propoxy or butoxy; wherein the alkylamino is N-methylamino, dimethylamino, diethylamino, dipropylamino or diisopropylamino.
The phenyl benzyl ether derivative is provided by the present invention, wherein more preferably, the structural formula thereof is shown by a formula (I-1):
wherein X is O, NH or S;
R1 is nitro, methoxy, hydroxyl, fluorine, chorine, bromine, iodine, hydrogen, tert-butyl, amino, methylamino, dimethylamino, —OCH2CH2F, —Sn(butyl)3, —OCH2CH2OH, —(OCH2CH2)3OH, —OCH2CH2OTs, —(OCH2CH2)3OTs or —(OCH2CH2)3F;
R2 is iodine, methoxy, bromine, hydrogen, —OCH2CH2F, —Sn(butyl)3, —OCH2CH2Br, —OCH2CH2OTs or dimethylamino.
More preferably, R1 and R2 are respectively:
Preferably, R1 and R2 are o-substituents, m-substituents or p-substituents.
More preferably, R1, R2 and X are respectively:
The phenyl benzyl ether derivative is provided by the present invention, wherein more preferably, the structural formula thereof is shown by a formula (I-2):
wherein X is O, NH or S;
R1 is hydrogen, bromine, iodine, nitro, amino, methylamino or dimethylamino;
R2 is iodine, methoxy or —OCH2CH2F;
More preferably, R1 and R2 are respectively:
wherein R1 and R2 are o-substituents, m-substituents or p-substituents.
More preferably, R1 and R2 are respectively:
The phenyl benzyl ether derivative is provided by the present invention, wherein more preferably, the structural formula thereof is shown by formula (I-3):
wherein X is O, NH or S;
R1 is chlorine, bromine or iodine; and R2 is iodine, methoxy or —OCH2CH2.
More preferably, R1 and R2 are respectively:
wherein R1 and R2 are o-substituents, m-substituents or p-substituents.
More preferably, R1, R2 and X are respectively:
The phenyl benzyl ether derivative is provided by the present invention, wherein more preferably, when the phenyl benzyl ether derivative contains fluorine atoms, F is 18F or 19F; when the phenyl benzyl ether derivative contains iodine atoms, I is 123I, 124I, 125I, 127I or 131I; and when the phenyl benzyl ether derivative contains methyl, methoxy, N-methylamino or dimethylamino, —CH3 is —11CH3, —OCH3 is —O11CH3, —NHCH3 is —NH11CH3, and —N(CH3)2 is —N(11CH3)2 or —N(CH3)(11CH3).
More preferably, when F is 18F or I is 124I, the obtained phenyl benzyl ether derivative is able to be used as the Aβ plaque imaging agent, especially a PET Aβ plaque imaging agent.
More preferably, when —CH3 is —11CH3, —OCH3 is —O11CH3, —NHCH3 is —NH11CH3 and —N(CH3)2 is —N(11CH3)2 or —N(CH3)(11CH3), the obtained phenyl benzyl ether derivative is able to be used as the Aβ plaque imaging agent, especially the PET Aβ plaque imaging agent.
More preferably, when I is 125I, 123I, or 131I, the obtained phenyl benzyl ether derivative is able to be used as the Aβ plaque imaging agent, especially a SPECT Aβ plaque imaging agent.
The phenyl benzyl ether derivative is provided by the present invention, wherein more preferably, when the phenyl benzyl ether derivative simultaneously contains two and more than two substituents of fluorine, iodine, methyl, methoxy, N-methylamino and dimethylamino, only one substituent is prepared into the above-corresponding radionuclide to obtain the Aβ plaque imaging agent.
A preparation method of the phenyl benzyl ether derivative is provided by the present invention, wherein a reaction equation is:
wherein Y3 is bromine or chlorine; and R1, R2, X, Y1 and Y2 are correspondingly defined as that in the phenyl benzyl ether derivative shown by the structural formula such as the formula (I).
Another preparation method of the phenyl benzyl ether derivative provided by the present invention, wherein a reaction equation is:
wherein Y3 is bromine or chlorine; R1, R2 and X are correspondingly defined as that in the phenyl benzyl ether derivative shown by the structural formula such as the formula (I-1).
Another preparation method of the phenyl benzyl ether derivative provided by the present invention, wherein a reaction equation is:
wherein Y3 is bromine or chlorine; R1, R2 and X are correspondingly defined as that in the phenyl benzyl ether derivative shown by the structural formula such as the formula (I-2).
Another preparation method of the phenyl benzyl ether derivative provided by the present invention, wherein a reaction equation is:
wherein Y3 is bromine or chlorine; R1, R2 and X are correspondingly defined as that in the phenyl benzyl ether derivative shown by the structural formula such as the formula (I-3).
The present invention further provides an Aβ plaque imaging agent prepared by using the phenyl benzyl ether derivative.
wherein, when the phenyl benzyl ether derivative contains fluorine atoms, the prepared compounds containing radionuclide F-18 are used as the Aβ plaque imaging agent, especially the PET Aβ plaque imaging agent.
Or when the phenyl benzyl ether derivative contains iodine atoms, the prepared compounds containing radionuclide I-124 are used as the Aβ plaque imaging agent, especially the PET Aβ plaque imaging agent.
Or when the phenyl benzyl ether derivative contains methyl, methoxy, N-methylamino or dimethylamino, the prepared compounds containing radionuclide C-11 (—11CH3, —O11CH3, —NH11CH3—N(11CH3)2 or —N(CH3)(11CH3)) are used as the Aβ plaque imaging agent, especially the PET Aβ plaque imaging agent.
Or when the phenyl benzyl ether derivative contains iodine atoms, the prepared compounds containing radionuclide I-123, I-125 or I-131 are used as the Aβ plaque imaging agent, especially the SPECT Aβ plaque imaging agent.
More preferably, when the phenyl benzyl ether derivative simultaneously contains two and more than two substituents of fluorine, iodine, methyl, methoxy, N-methylamino and dimethylamino, only one substituent is prepared into the above-mentioned corresponding radionuclide to obtain the Aβ plaque imaging agent.
Preferably, the Aβ plaque imaging agent is a single photon or positron AP plaque imaging agent.
Preferably, the Aβ plaque imaging agent is able to be used for PET imaging or SPECT imaging.
The Aβ plaque imaging agent provided by the present invention is able to be used for the early-stage diagnosis of amyloidosis in the AD.
The present invention further provides application of the phenyl benzyl ether derivative to the preparation of the medicine for diagnosing and treating the AD.
The present invention prepares a kind of phenyl benzyl ether compounds with brand new structures. According to in-vitro competitive binding experiments, this kind of molecules has very high affinity with Aβ1-42 aggregates; according to in-vitro autoradiography experiments, this kind of molecules labeled by I-125 or F-18 can be specifically bound with Aβ plaques in AD human brain sections or brains of AD transgenic mice; according to in-vivo biological distribution experiments carried to normal mice, part of imaging agent labeled by I-125 or F-18 has the advantages of high initial brain intake and fast removing speed; and it is expected to become a new single photon or positron Aβ plaque imaging agent for clinical imaging.
In conclusion, the present invention develops a kind of brand new phenyl benzyl ether derivatives which have high affinity with Aβ plaques in brains of AD patients, the chemical structures are different from that of the compounds disclosed by the prior art, especially thioflavin-T and Congo red, and the brand new phenyl benzyl ether derivatives belong to brand new compounds for diagnosing and treating the AD; and the obtained Aβ plaque imaging agent has the advantages that the in-vivo stability is good, the fat solubility is low, the brain removing speed is fast, the problem of removing the radionuclide in vivo does not exist, and the application prospect and the market value are great.
The following embodiments are used for describing the present invention instead of limiting the scope of the present invention.
Operations which are not mentioned in the present invention are conventional operations in the field.
[125I] NaI solution used in the present invention is bought from China Isotope & Radiation Corporation.
Other materials used in the present invention are conventional materials which can be bought from the market or can be prepared by adopting the existing methods (for example, 4-hydroxy-N,N-dimethylaniline).
A Room temperature in the present invention is 25° C.
Concentration (%) of each material in the present invention is mass concentration.
A synthesis reaction route is shown in
In the synthesis route shown in
4-nitrophenol (2.78 g, 20 mmol) and 4-iodobenzyl bromide (5.00 g, 20 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 (5.53 g, 40 mmol) is added. Reaction is conducted for 5 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water and methanol recrystallization is conducted to obtain white solid 1 (1.69 g, 95.2%). HPLC: 7.51 min, 99.8%; mp 147.4-148.1° C.; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=9.2 Hz, 2H), 7.75 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 7.01 (d, J=9.2 Hz, 2H), 5.10 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 3-nitrophenol) to obtain white solid 2 (345.5 mg, 97.3%). HPLC: 8.53 min, 99.9%; mp 75.2-75.9° C.; 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.45 (t, J=8.2 Hz, 1H), 7.30-7.26 (m, 1H), 7.19 (d, J=8.1 Hz, 2H), 5.09 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-nitrophenol) to obtain yellow solid 3 (238.9 mg, 67.3%). HPLC: 6.03 min, 99.5%; mp 70.6-71.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J=8.1, 1.4 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.56-7.46 (m, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.09-7.04 (m, 2H), 5.18 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-methoxyphenol) to obtain white solid 4 (255.3 mg, 75.1%). HPLC: 8.28 min, 99.5%; mp 128.9-130.2° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.89 (d, J=9.2 Hz, 2H), 6.83 (d, J=9.2 Hz, 2H), 4.96 (s, 2H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.18, 152.68, 137.63, 137.08, 129.25, 115.92, 114.72, 93.30, 70.07, 55.72.
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 3-methoxyphenol) to obtain white solid 5 (211.7 mg, 62.2%). HPLC: 8.68 min, 98.5%; mp 77.4-78.7° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.1 Hz, 2H), 7.21-7.17 (m, 3H), 6.57-6.50 (m, 2H), 4.99 (s, 2H), 3.79 (s, 3H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-methoxyphenol) to obtain white solid 6 (288.1 mg, 84.7%). HPLC: 6.63 min, 98.7%; mp 110.4-110.8° C.; 1H NMR (400 MHz, CDCl3) 87.69 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.97-6.91 (m, 2H), 6.85 (d, J=3.8 Hz, 2H), 5.10 (s, 2H), 3.89 (s, 3H).
P-dihydroxybenzene (110.1 mg, 1.0 mmol) and 4-iodobenzyl bromide (296.9 g, 1.0 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 (276.4 mg, 2.0 mmol) is added. Reaction is conducted for 2 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, extraction is conducted by using CH2Cl2 (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain white solid 7 (49.3 mg, 15.1%). HPLC: 3.75 min, 99.3%; mp 152.2-153.7° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 6.85-6.81 (m, 2H), 6.78-6.74 (m, 2H), 4.95 (s, 2H), 4.41 (s, 1H).
Preparation is conducted according to the preparation method of the compound 7 (reactant p-dihydroxybenzene is replaced by m-dihydroxybenzene) to obtain white solid 8 (93.1 mg, 28.5%). HPLC: 3.95 min, 98.6%; mp 109.9-110.6° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.9 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.16-7.09 (m, 1H), 6.54 (d, J=8.6 Hz, 1H), 6.46-6.44 (m, 2H), 4.98 (s, 2H), 4.74 (s, 1H).
Preparation is conducted according to the preparation method of the compound 7 (reactant p-dihydroxybenzene is replaced by o-dihydroxybenzene) to obtain white solid 9 (109.8 mg, 33.7%). HPLC: 4.25 min, 99.9%; mp 62.1-63.4° C.; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 6.98-6.95 (m, 1H), 6.93-6.88 (m, 2H), 6.85-6.81 (m, 1H), 5.62 (s, 1H), 5.06 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-fluorophenol) to obtain white solid 10 (253.1 mg, 77.1%). HPLC: 8.92 min, 98.0%; mp 62.3-62.8° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.00-6.95 (m, 2H), 6.91-6.85 (m, 2H), 4.97 (s, 2H). [0148]
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-chlorophenol) to obtain white solid 11 (136.2 mg, 79.0%). HPLC: 12.86 min, 99.6%; mp 107.5-108.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.9 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 4.98 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-bromophenol) to obtain white solid 12 (302.5 mg, 77.8%). HPLC: 14.61 min, 99.3%; mp 122.6-123.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 6.82 (d, J=8.9 Hz, 2H), 4.97 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-iodophenol) to obtain white solid 13 (436.0 mg, 89.3%). HPLC: 17.49 min, 98.2%; mp 135.0-135.9° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 4.97 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by phenol) to obtain white solid 14 (310.1 mg, 72.1%). HPLC: 9.59 min, 99.2%; mp 96.7-97.6 C; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.2 Hz, 2H), 7.32-7.27 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 6.99-6.94 (m, 3H), 5.02 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-tert-butylphenol) to obtain white solid 15 (366.2 mg, 87.4%). HPLC: 27.14 min, 98.3%; mp 91.9-93.0° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2H, 7.31 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.99 (s, 2H), 1.30 (s, 9H).
The compound 1 (1.42 g, 4.0 mmol) and SnCl2.2H2O (1.66 g, 8.0 mmol) are dissolved in 25 ml of ethanol, 2 ml of concentrated hydrochloric acid is dripped, reaction is conducted for 2 h at 80° C. under a reflux and stirring state, cooling to room temperature is conducted, 30 ml of 1M NaOH water solution is added to neutralize the hydrochloric acid and precipitate SnCl2, extraction is conducted by using ethyl acetate (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain white solid 16 (643.3 mg, 49.5%). HPLC: 4.16 min, 98.4%; mp 138.6-140.0° C.; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.2 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 6.78 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.8 Hz, 2H), 4.93 (s, 2H), 3.44 (s, 2H).
Preparation is conducted according to the preparation method of the compound 16 (reactant compound 1 is replaced by the compound 2) to obtain white solid 17 (695.5 mg, 73.1%). HPLC: 4.50 min, 99.4%; mp 153.9-154.8° C.; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.1 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.07 (t, J=8.0 Hz, 1H), 6.40-6.34 (m, 3H), 4.97 (s, 2H).
Preparation is conducted according to the preparation method of the compound 16 (reactant compound 1 is replaced by the compound 3) to obtain white solid 18 (99.3 mg, 11.4%). HPLC: 4.88 min, 99.1%; mp 99.1-100.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 6.85-6.78 (m, 3H), 6.75-6.71 (m, 1H), 5.03 (s, 2H).
The compound 16 (162.6 mg, 0.5 mmol) and paraformaldehyde (60.0 mg, 2.0 mmol) are dissolved in 30 ml of anhydrous methanol, 5 ml of NaOCH3 (54.0 mg, 1.0 mmol) methanol solution is added drop by drop, and reaction is conducted for 2 h under a reflux and stirring state. After cooling to room temperature is conducted, NaBH4 (75.6 mg, 2.0 mmol) is slowly added and continuously reaction is conducted for 2 h under a reflex and stirring state. Depressurization is conducted to remove solvent, 50 ml of 1M NaOH solution is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water, and methanol recrystallization is conducted to obtain pink solid 19 (152.4 mg, 89.9%). HPLC: 6.34 min, 99.2%; mp 93.9-95.2° C.; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 6.84 (d, J=8.7 Hz, 2H), 6.58 (d, J=8.5 Hz, 2H), 4.94 (s, 2H), 2.81 (s, 3H).
The compound 17 (162.6 mg, 0.5 mmol) and paraformaldehyde (60.0 mg, 2.0 mmol) are dissolved in 30 ml of anhydrous methanol, 5 ml of NaOCH3 (54.0 mg, 1.0 mmol) methanol solution is added drop by drop, and reaction is conducted for 2 h under a reflux and stirring state. After cooling to room temperature is conducted, NaBH4 (75.6 mg, 2.0 mmol) is slowly added and continuously reaction is conducted for 2 h under a reflex and stirring state. Depressurization is conducted to remove solvent, 50 ml of 1M NaOH solution is added, extraction is conducted by using CH2Cl2 (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain a colorless oily compound 20 (71.0 mg, 41.8%). HPLC: 6.60 min, 99.9%; mp 45.3-46.6° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 6.27 (d, J=7.9 Hz, 1H), 6.24 (s, 1H), 4.99 (s, 2H), 2.83 (s, 3H).
Preparation is conducted according to the preparation method of the compound 19 (reactant compound 16 is replaced by the compound 18), extraction is conducted by using CH2Cl2 (3×10 ml) after reaction is completed, organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain a yellow oily compound 21 (34.2 mg, 67.2%). HPLC: 8.19 min, 98.1%; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.94 (t, J=7.6 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.72-6.64 (m, 2H), 5.02 (s, 2H), 2.87 (s, 3H).
The compound 16 (162.6 mg, 0.5 mmol) and paraformaldehyde (150.0 mg, 5.0 mmol) are dissolved in 20 ml of acetic acid, NaBH3CN (157.0 mg, 2.5 mmol) is slowly added, and reaction is conducted for 24 h at room temperature under a stirring state. 20 ml of 1M NaOH solution is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water and methanol recrystallization is conducted to obtain white solid 22 (168.4 mg, 95.4%). HPLC: 10.63 min, 98.4%; mp 128.2-129.3° C.; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.9 Hz, 2H), 6.82-6.68 (s, 2H), 4.95 (s, 2H), 2.87 (s, 6H).
Preparation is conducted according to the preparation method of the compound 22 (reactant compound 16 is replaced by the compound 17) to obtain white solid 23 (171.3 mg, 97.1%). HPLC: 11.30 min, 99.9%; mp 68.8-70.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 7.15 (t, J=8.1 Hz, 1H), 6.43-6.30 (m, 3H), 5.00 (s, 2H), 2.94 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 150.92, 145.99, 137.59, 137.41, 129.28, 115.95, 114.77, 93.19, 70.16, 41.73.
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-iodophenol and reactant 4-iodobenzyl bromide is replaced by 4-methoxybenzyl bromide) to obtain white solid 24 (906.3 mg, 88.9%). HPLC: 8.55 min, 99.7%; mp 130.3-131.5° C.; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.74 (d, J=8.9 Hz, 2H), 4.95 (s, 2H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.59, 158.71, 138.22, 129.19, 128.55, 117.36, 114.08, 82.95, 69.91, 55.31.
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-methoxythiophenol) to obtain white solid 25 (712.4 mg, 94.7%). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.3 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.3 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 3.89 (s, 2H), 3.78 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.43, 138.01, 137.40, 134.36, 130.81, 125.45, 114.54, 92.31, 55.31, 40.77.
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-methoxyphenol and reactant 4-iodobenzyl bromide is replaced by p-bromobenzyl bromide) to obtain white solid 26 (2.93 g, 93.2%). mp 105.3-106.7° C.; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 6.89 (d, J=9.2 Hz, 2H), 6.83 (d, J=9.2 Hz, 2H), 4.97 (s, 2H), 3.77 (s, 3H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-bromophenol and reactant 4-iodobenzyl bromide is replaced by 4-methoxybenzyl bromide) to obtain white solid 27 (681.4 mg, 77.8%). mp 122.1-122.9° C.; 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.96 (s, 2H), 3.82 (s, 3H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 4-hydroxy-N,N-dimethylaniline and reactant 4-iodobenzyl bromide is replaced by p-bromobenzyl bromide) to obtain white solid 28 (303.5 mg, 99.1%). mp 125.8-127.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.52-7.48 (m, 2H), 7.32-7.28 (m, 2H), 6.92-6.85 (m, 2H), 6.76 (s, 2H), 4.96 (s, 2H), 2.88 (s, 6H).
4-benzyloxyphenol (2.00 g, 10.0 mmol) and KOH (0.56 g, 10.0 mmol) are dissolved in 30 ml of anhydrous ethanol, reflux is conducted for 30 min by heating at 80° C., 20 ml of 1-bromo-2-fluoroethane (1.52 g, 12.0 mmol) ethanol solution, continuously reaction is conducted for 1 h under a reflux and stirring state, reaction is monitored through TLC till basic completion, depressurization is conducted to remove solvent, 50 ml of 1M NaOH solution is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water and methanol recrystallization is conducted to obtain white crystal 29 (2.23 g, 90.4%). 1H NMR (400 MHz, CDCl3) δ 7.46-7.28 (m, 5H), 6.91 (d, J=9.2 Hz, 2H), 6.86 (d, J=9.3 Hz, 2H), 5.02 (s, 2H), 4.81-4.64 (m, 2H), 4.22-4.10 (m, 2H).
The compound 29 (2.08 g, 8.44 mmol) is dissolved in 10 ml of anhydrous methanol, palladium-carbon catalyst (89.4 mg, 0.84 mmol) is added, reaction is conducted for 4 h at 50° C. under a stirring state under the condition of 1 atm H2, reaction is monitored through TLC till completion, suction filtration is conducted to remove the palladium-carbon catalyst, and depressurization is conducted to remove solvent to obtain white solid 30 (1.32 g, 57.4%). 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J=8.9 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 4.80-4.64 (m, 2H), 4.42 (s, 1H), 4.23-4.09 (m, 2H).
The compound 30 (468.5 mg, 3.0 mmol) and 4-iodobenzyl bromide (890.8 mg, 3.0 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 (414.6 mg, 3.0 mmol) is added. Reaction is conducted for 0.5 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water, and methanol recrystallization is conducted to obtain white solid 31a (986.8 mg, 88.4%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 6.90-6.84 (m, 4H), 4.96 (s, 2H), 4.79-4.65 (m, 2H), 4.21-4.11 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 153.11, 152.93, 137.62, 136.94, 129.24, 115.89, 115.79, 93.35, 82.86, 81.17, 69.96, 67.97, 67.76.
Preparation is conducted according to the preparation method of the compound 31a (reactant 4-iodobenzyl bromide is replaced by p-bromobenzyl bromide) to obtain white solid 31b (1.55 g, 95.2%). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 6.90-6.84 (m, 4H), 4.97 (s, 2H), 4.80-4.65 (m, 2H), 4.21-4.11 (m, 2H).
P-hydroxybenzaldehyde (2.44 g, 20 mmol) and 1-bromo-2-fluoroethane (2.54 g, 20 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 (5.53 g, 40 mmol) is added. Reaction is conducted for 2 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, extraction is conducted by using ethyl acetate (3×10 ml), drying is conducted by using anhydrous MgSO4, suction filtration is conducted, and depressurization is conducted to remove solvent to obtain yellow oily liquid 32 (2.95 g, 87.8%). 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.86 (d, J=8.7 Hz, 2H), 7.04 (d, J=8.6 Hz, 2H), 4.88-4.71 (m, 2H), 4.37-4.24 (m, 2H).
The compound 32 (2.95 g, 17.6 mmol) is dissolved in 10 ml of anhydrous methanol, NaBH4 (1.33 g, 35.2 mmol) is slowly added at 0° C. under a stirring state, continuously reaction is conducted for 0.5 h, reaction is monitored through TLC till completion, 10 ml of deionized water is added to quench the reaction, depressurization is conducted to remove methanol, a proper amount of 1M HCl is added to neutralize to pH=7, extraction is conducted by using CH2Cl2 (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, and depressurization is conducted to remove solvent to obtain yellow oily liquid 33 (2.73 g, 91.1%). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5 Hz, 2H), 4.84-4.68 (m, 2H), 4.63 (s, 2H), 4.27-4.17 (m, 2H).
The compound 33 (2.73 g, 16.0 mmol) is dissolved in 25 ml of anhydrous CH2Cl2, 25 ml of PBr3 (4.33 g, 16.0 mmol) CH2Cl2 solution is slowly added at room temperature under a stirring state, continuously reaction is conducted for 0.5 h, reaction is monitored through TLC till completion, 20 ml of deionized water is added to quench the reaction, then 1 g of NaHCO3 is added, stirring is continuously conducted for 0.5 h, extraction is conducted by using CH2Cl2 (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, and depressurization is conducted to remove solvent to obtain colorless oily liquid 34 (3.54 g, 95.0%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 4.84-4.68 (m, 2H), 4.50 (s, 2H), 4.27-4.16 (m, 2H).
Preparation is conducted according to the preparation method of the compound 31a (reactant 4-iodobenzyl bromide is replaced by the compound 34 and reactant compound 30 is replaced by 4-iodophenol) to obtain white solid 35a (623.4 mg, 94.1%). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=8.9 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 6.74 (d, J=8.9 Hz, 2H), 4.95 (s, 2H), 4.83-4.68 (m, 2H), 4.27-4.16 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 158.65, 158.39, 138.23, 129.24, 129.21, 117.34, 114.81, 83.00, 82.72, 81.03, 69.80, 67.31, 67.10.
Preparation is conducted according to the preparation method of the compound 31a (reactant 4-iodobenzyl bromide is replaced by the compound 34 and reactant compound 30 is replaced by 4-bromophenol) to obtain white solid 35b (1.03 g, 76.1%). 1H NMR (400 MHz, CDCl3) δ 7.35 (7.39-7.31, 4H), 6.94 (d, J=8.0 Hz, 2H), 6.84 (d, J=8.2 Hz, 2H), 4.96 (s, 2H), 4.76 (d, J=47.3 Hz, 2H), 4.22 (d, J=27.8 Hz, 2H).
The compound 26 (146.6 mg, 0.5 mmol), hexabutyldistannane (580.1 mg, 1.0 mmol) and Tetrakis (triphenylphosphine) palladium (57.8 mg, 0.05 mmol) are dissolved in 10 ml of methylbenzene (containing 1 ml of triethylamine), and reaction is conducted over a night under a reflux and stirring state. Depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to obtain a colorless oily compound 36 (89.5 mg, 35.6%). 1HNMR (400 MHz, CDCl3) δ 7.49 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 6.93 (d, J=9.1 Hz, 2H), 6.85 (d, J=9.1 Hz, 2H), 5.00 (s, 2H), 3.78 (s, 3H), 1.59-1.51 (m, 6H), 1.39-1.29 (m, 6H), 1.15-0.97 (m, 6H), 0.90 (t, J=7.3 Hz, 9H).
Preparation is conducted according to the preparation method of the compound 36 (reactant compound 26 is replaced by the compound 27) to obtain a colorless oily compound 37 (75.0 mg, 29.8%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 3H), 7.31-7.27 (m, 1H), 6.99-6.95 (m, 2H), 6.91 (d, J=8.4 Hz, 2H), 4.98 (s, 2H), 3.82 (s, 3H), 1.69-1.60 (m, 6H), 1.41-1.30 (m, 12H), 0.92 (t, J=7.3 Hz, 9H).
Preparation is conducted according to the preparation method of the compound 36 (reactant compound 26 is replaced by the compound 28) to obtain a colorless oily compound 38 (56.2 mg, 21.8%). 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.7 Hz, 2H), 7.39 (d, J=7.6 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 6.76 (d, J=8.7 Hz, 2H), 4.98 (s, 2H), 2.87 (s, 6H), 1.58-1.49 (m, 6H), 1.38-1.28 (m, 12H), 0.89 (t, J=7.4 Hz, 9H).
Preparation is conducted according to the preparation method of the compound 36 (reactant compound 26 is replaced by the compound 31b) to obtain a colorless oily compound 39 (325.6 mg, 30.4%). 1H NMR (400 MHz, CDCl3) δ 7.54-7.41 (m, 2H), 7.37 (d, J=7.8 Hz, 2H), 6.92 (d, J=9.3 Hz, 2H), 6.87 (d, J=9.3 Hz, 2H), 4.99 (s, 2H), 4.80-4.65 (m, 2H), 4.22-4.11 (m, 2H), 1.58-1.50 (m, 6H), 1.39-1.27 (m, 6H), 1.14-0.96 (m, 6H), 0.88 (t, J=7.3 Hz, 9H).
Preparation is conducted according to the preparation method of the compound 36 (reactant compound 26 is replaced by the compound 35b) to obtain a colorless oily compound 40 (134.6 mg, 25.1%). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.7 Hz, 2H), 7.32-7.26 (m, 2H), 6.99-6.93 (m, 4H), 5.00 (s, 2H), 4.83-4.68 (m, 2H), 4.28-4.17 (m, 2H), 1.58-1.50 (m, 6H), 1.39-1.27 (m, 6H), 1.14-0.96 (m, 6H), 0.88 (t, J=7.3 Hz, 9H).
A synthesis reaction route is shown in
In the synthesis route shown in
(a) 1-bromo-2-fluoroethane or 1, 2-dibromoethane, K2CO3, DMF, 90° C.; (b) NaBH4, MeOH, 0° C.; (c) PBr3, CH2Cl2, r. t.; (d) 4-methoxyphenol or 4-nitrophenol, K2CO3, DMF, 90° C.; (e) SnCl2.2H2O, EtOH, HCl, reflux; (f) 1: Na0Me, (CH2O)n, MeOH, reflux; 2: NaBH4, reflux; (g) (CH2O)n, NaBH3CN, HAc, r.t.; (h) AgOTs, MeCN, reflux; (i) 18F−, K2CO3, Kryptofix-2.2.2 (i.e., K222, aminopolyether), acetonitrile, 100° C.; (j) 2-chloroethanol or 2-(2-(2-chloroethoxy) ethoxy) ethanol), KOH, EtOH, reflux; (k) 10% Pd/C, 1 atm H2, 50° C.; (l) 1-(chloromethyl)-4-methoxybenzene (i.e., 4-methoxybenzyl chloride), K2CO3, DMF, 90° C.; (m) TsCl, CH2Cl2, Et3N, 0° C.-rt; (n) TBAF (1M in THF), THF, reflux.
P-hydroxybenzaldehyde (2.44 g, 20 mmol) and 1, 2-dibromoethane (7.51 g, 40 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 (5.53 g, 40 mmol) is added. Reaction is conducted for 2 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, extraction is conducted by using CH2Cl2 (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain white solid 41 (1.32 g, 28.9%). 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 4.38 (t, J=6.2 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H).
Preparation is conducted according to the preparation method of the compound 33 (reactant compound 32 is replaced by the compound 41) to obtain white solid 42 (1.14 g, 95.8%). 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=8.5 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 4.63 (s, 2H), 4.30 (t, J=6.3 Hz, 2H), 3.64 (t, J=6.3 Hz, 2H).
Preparation is conducted according to the preparation method of the compound 34 (reactant compound 33 is replaced by the compound 42) to obtain white solid 43 (1.29 g, 99.0%).1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.49 (s, 2H), 4.29 (t, J=6.3 Hz, 2H), 3.63 (t, J=6.3 Hz, 2H).
The compound 34 (411.3 mg, 1.76 mmol) and 4-methoxyphenol (218.5 mg, 1.76 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 (243.2 mg, 1.76 mmol) is added. Reaction is conducted for 0.5 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water and methanol recrystallization is conducted to obtain white solid 44a (136.5 mg, 28.1%). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.5 Hz, 2H), 6.97-6.87 (m, 4H), 6.83 (d, J=9.1 Hz, 2H), 4.94 (s, 2H), 4.84-4.67 (m, 2H), 4.28-4.15 (m, 2H), 3.77 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.24, 154.01, 152.99, 130.09, 129.20, 115.95, 114.74, 114.67, 82.74, 81.04, 70.45, 67.31, 67.10, 55.71.
Preparation is conducted according to the preparation method of the compound 44a (reactant compound 34 is replaced by the compound 43) to obtain white solid 44b (242.8 mg, 68.1%). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.6 Hz, 2H), 6.94-6.87 (m, 4H), 6.83 (d, J=9.2 Hz, 2H), 4.94 (s, 2H), 4.30 (t, J=6.3 Hz, 2H), 3.77 (s, 3H), 3.63 (t, J=6.3 Hz, 2H).
Preparation is conducted according to the preparation method of the compound 44a (reactant 4-methoxyphenol is replaced by 4-nitrophenol) to obtain white solid 44c (2.35 g, 78.6%). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=9.2 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.02 (d, J=9.2 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 5.09 (s, 2H), 4.86-4.67 (m, 2H), 4.31-4.17 (m, 2H).
The compound 44c (1.94 g, 6.67 mmol) and SnCl2.2H2O (3.01 g, 13.34 mmol) are dissolved in 25 ml of ethanol, 2 ml of concentrated hydrochloric acid is dripped, reaction is conducted for 2 h at 80° C. under a reflux and stirring state, cooling to room temperature is conducted, 30 ml of 1M NaOH water solution is added to neutralize the hydrochloric acid and precipitate SnCl2, extraction is conducted by using ethyl acetate (3×10 ml), organic phases are combined, drying is conducted by using anhydrous MgSO4, suction filtration is conducted, and depressurization is conducted to remove solvent to obtain white solid 45 (1.26 g, 72.5%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 6.63 (d, J=8.6 Hz, 2H), 4.91 (s, 2H), 4.84-4.67 (m, 2H), 4.27-4.15 (m, 2H), 3.42 (s, 2H).
The compound 45 (522.6 mg, 2.0 mmol) and paraformaldehyde(240.0 mg, 8.0 mmol) are dissolved in 30 ml of anhydrous methanol, 5 ml of NaOCH3 (216.1 mg, 4.0 mmol) methanol solution is added drop by drop, and reaction is conducted for 2 h under a reflux and stirring state. After cooling to room temperature is conducted, NaBH4 (302.4 mg, 8.0 mmol) is slowly added and continuously reaction is conducted for 2 h under a reflex and stirring state. Depressurization is conducted to remove solvent, 50 ml of 1M NaOH solution is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water, and methanol recrystallization is conducted to obtain light yellow crystal 46 (423.6 mg, 76.9%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=4.8 Hz, 2H), 6.92 (d, J=4.8 Hz, 2H), 6.85 (d, J=5.0 Hz, 2H), 6.57 (d, J=4.9 Hz, 2H), 4.92 (s, 2H), 4.75 (d, J=47.4 Hz, 2H), 4.22 (d, J=27.6 Hz, 2H), 3.49 (s, 1H), 2.80 (s, 3H).
The compound 45 (261.3 mg, 1.0 mmol) and paraformaldehyde (300.0 mg, 10.0 mmol) are dissolved in 20 ml of acetic acid, NaBH3CN (314.0 mg, 5.0 mmol) is slowly added and reaction is conducted for 24 h at room temperature under a stirring state. 20 ml of 1M NaOH solution is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water, and methanol recrystallization is conducted to obtain light yellow crystal 47 (213.9 mg, 75.8%). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=8.0 Hz, 2H), 6.96-6.87 (m, 4H), 6.77 (s, 2H), 4.94 (s, 2H), 4.75 (d, J=47.7 Hz, 2H), 4.22 (d, J=27.7 Hz, 2H), 2.88 (s, 6H).
The compound 44b (137.2 mg, 0.41 mmol) and silver p-methylbenzene sulfonate (227.1 mg, 0.82 mg) are dissolved in 20 ml of acetonitrile, reaction is conducted for 12h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till basic completion, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain white solid 48 (174.4 mg, 60.6%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 6.89 (d, J=9.2 Hz, 2H), 6.82 (d, J=9.2 Hz, 2H), 6.78 (d, J=8.6 Hz, 2H), 4.92 (s, 2H), 4.39-4.35 (m, 2H), 4.17-4.13 (m, 2H), 3.77 (s, 3H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.80, 154.01, 152.94, 144.94, 132.96, 130.21, 129.86, 129.12, 127.99, 115.92 (overlapped), 114.66, 70.39, 68.09, 65.52, 55.72, 21.62.
The 4-benzyloxyphenol (4.00 g, 20.0 mmol) and KOH (1.12 g, 20.0 mmol) are dissolved in 30 ml of anhydrous ethanol, reflux is conducted for 30 min by heating at 80° C., 20 ml of 2-chloroethanol (2.01 g, 25 mmol) ethanol solution, continuously reaction is conducted for 1 h under a reflux and stirring state, reaction is monitored through TLC till basic completion, depressurization is conducted to remove solvent, 50 ml of 1M NaOH solution is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water and methanol recrystallization is conducted to obtain white crystal 49a (2.35 g, 48.1%). 1H NMR (400 MHz, CDCl3) δ 7.46-7.30 (m, 5H), 6.91 (d, J=9.1 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 5.02 (s, 2H), 4.08-3.99 (m, 2H), 3.97-3.87 (m, 2H), 1.95 (s, 1H).
Preparation is conducted according to the preparation method of the compound 49a (reactant 2-chloroethanol is replaced by 2-(2-(2-chloroethoxy) ethoxy) ethanol) to obtain white solid 49b (2.55 g, 38.3%). 1H NMR (400 MHz, CDCl3) δ 7.46-7.29 (m, 5H), 6.93-6.81 (m, 4H), 5.01 (s, 2H), 4.12-4.02 (m, 2H), 3.86-3.79 (m, 2H), 3.75-3.67 (m, 6H), 3.64-3.59 (m, 2H), 2.16 (s, 1H).
The compound 49a (2.15 g, 8.79 mmol) is dissolved in 10 ml of anhydrous methanol, palladium-carbon catalyst (93.6 mg, 0.88 mmol) is added, reaction is conducted for 4 h at 50° C. under a stirring state under the condition ofl atm H2, reaction is monitored through TLC till completion, suction filtration is conducted to remove the palladium-carbon catalyst, and depressurization is conducted to remove solvent to obtain white solid 50a (1.35 g, 100%). 1HNMR (400 MHz, DMSO) δ 8.86 (s, 1H), 6.74 (d, J=8.6 Hz, 2H), 6.66 (d, J=8.8 Hz, 2H), 4.78 (t, J=5.2 Hz, 1H), 3.90-3.80 (m, 2H), 3.70-3.61 (m, 2H).
Preparation is conducted according to the preparation method of the compound 50a (reactant compound 49a is replaced by the compound 49b) to obtain a colorless transparent oily compound 50b (1.78 g, 98.6%). 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 6.81-6.67 (m, 4H), 4.08-4.01 (m, 2H), 3.86-3.79 (m, 2H), 3.77-3.68 (m, 6H), 3.66-3.59 (m, 2H).
The compound 50a (235.3 mg, 1.53 mmol) and 4-methoxybenzyl chloride (239.6 mg, 1.53 mmol) are dissolved in 5 ml of anhydrous DMF, and K2CO3 ((211.6 mg, 1.53 mmol) is added. Reaction is conducted for 0.5 h at 90° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, deionized water is added, white precipitate is separated out, suction filtration is conducted, the precipitate is washed with water, and methanol recrystallization is conducted to obtain white solid 51a (282.8 mg, 67.4%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.6 Hz, 2H), 6.94-6.82 (m, 6H), 4.94 (s, 2H), 4.06-4.01 (m, 2H), 3.96-3.90 (m, 2H), 3.81 (s, 3H).
Preparation is conducted according to the preparation method of the compound 51a (reactant compound 50a is replaced by the compound 50b) to obtain white solid 51b (369.7 mg, 66.9%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.0 Hz, 2H), 6.94-6.82 (m, 2H), 4.93 (s, 2H), 4.12-4.05 (m, 2H), 3.88-3.83 (m, 2H), 3.81 (s, 3H), 3.76-3.68 (m, 6H), 3.65-3.58 (m, 2H), 2.08 (s, 1H).
The compound 51a (137.2 mg, 0.5 mmol) is dissolved in 10 ml of CH2Cl2, 10 ml of triethylamine is added, p-toluensulfonyl chloride (143.0 mg, 0.75 mmol) is slowly added under an ice-bath stirring state, continuously reaction is conducted for 4 h under a stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, 50 ml of deionized water is added, extraction is conducted by using CH2Cl2 (3×10 ml), drying is conducted by using anhydrous MgSO4, suction filtration is conducted, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to obtain white solid 52a (214.3 mg, 77.2%). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 4H), 6.91 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.72 (d, J=8.9 Hz, 2H), 4.92 (s, 2H), 4.37-4.31 (m, 2H), 4.12-4.07 (m, 2H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.46, 153.57, 152.32, 144.89, 133.01, 129.84, 129.18, 128.00, 115.88, 115.76, 114.00, 70.45, 68.27, 66.26, 55.29, 21.62.
Preparation is conducted according to the preparation method of the compound 52a (reactant compound 51a is replaced by the compound 51b) to obtain colorless transparent oily liquid 52b (225.4 mg, 83.9%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.9 Hz, 2H), 7.37-7.30 (m, 4H), 6.93-6.82 (m, 6H), 4.93 (s, 2H), 4.19-4.13 (m, 2H), 4.08-4.02 (m, 2H), 3.83-3.76 (m, 5H), 3.71-3.58 (m, 6H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.44, 153.25, 153.12, 144.76, 133.17, 129.81, 129.36, 129.18, 127.96, 115.91, 115.66, 113.99, 70.81, 70.75, 70.52, 69.93, 69.25, 68.74, 68.13, 55.29, 21.59.
The compound 52a (128.6 mg, 0.3 mmol) is dissolved in 5 ml of anhydrous THF, 0.6 ml of tetrabutylammonium fluoride tetrahydrofuran solution (1M) is added. Reaction is conducted for 2 h at 80° C. under a reflux and stirring state, reaction is monitored through TLC till completion, depressurization is conducted to remove solvent, and residues are separated through silica gel column chromatography (petroleum ether/ethyl acetate=2/1) to obtain white solid 53a (70.7 mg, 85.3%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.2 Hz, 2H), 6.94-6.84 (m, 6H), 4.94 (s, 2H), 4.81-4.64 (m, 2H), 4.23-4.11 (m, 2H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.48, 153.56, 152.80, 129.31, 129.19, 115.99, 115.82, 114.02, 82.90, 81.20, 70.52, 68.06, 67.85, 55.30.
Preparation is conducted according to the preparation method of the compound 53a (reactant compound 52a is replaced by the compound 52b) to obtain colorless transparent oily liquid 53b (87.5 mg, 73.7%). 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.2 Hz, 2H), 6.94-6.82 (m, 4H), 4.93 (s, 2H), 4.56 (d, J=47.8 Hz, 2H), 4.09 (s, 2H), 3.85-3.70 (m, 11H). 13C NMR (101 MHz, CDCl3) δ 159.42, 153.21, 153.13, 129.34, 129.18, 115.87, 115.64, 113.97, 83.97, 82.29, 70.85, 70.84, 70.54, 70.49, 70.34, 69.93, 68.12, 55.28.
A synthesis reaction route is shown in
In the synthesis route shown in
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-hydroxypyridine) to obtain white solid 54 (187.5 mg, 60.3%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.2 Hz, 2H), 7.34 (ddd, J=8.8, 6.7, 1.8 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (d, J=8.2 Hz, 3H), 6.66 (d, J=9.1 Hz, 1H), 6.19 (t, J=6.7 Hz, 1H), 5.09 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-chloro-5-hydroxypyridine) to obtain white solid 55 (635.7 mg, 92.0%). 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.24-7.21 (m, 2H), 7.16 (d, J=8.1 Hz, 2H), 5.04 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 5-bromo-2-hydroxypyridine) to obtain white solid 56 (346.5 mg, 88.8%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.3 Hz, 2H), 7.36-7.32 (m, 2H), 7.06 (d, J=8.2 Hz, 2H), 6.54 (d, J=10.5 Hz, 1H), 5.03 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-bromo-5-hydroxypyridine) to obtain white solid 57 (361.7 mg, 92.7%). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=3.1 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.7 Hz, 1H), 7.17-7.11 (m, 3H), 5.03 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-hydroxy-5-iodopyridine) to obtain white solid 58 (321.5 mg, 73.6%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=8.3 Hz, 2H), 7.45 (d, J=2.2 Hz, 1H), 7.42 (dd, J=9.5, 2.4 Hz, 1H), 7.05 (d, J=8.2 Hz, 2H), 6.44 (d, J=9.5 Hz, 1H), 5.02 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-iodo-5-hydroxypyridine) to obtain white solid 59 (289.8 mg, 48.8%). 1H NMR (400 MHz, CDCl3) δ 8.06-8.02 (m, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.21-7.15 (m, 1H), 7.03-6.98 (m, 1H), 5.12 (s, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-hydroxy-5-nitropyridine) to obtain yellow solid 60 (343.0 mg, 96.3%). 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=3.0 Hz, 1H), 8.08 (dd, J=10.1, 3.0 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.11 (d, J=8.2 Hz, 2H), 6.60 (d, J=10.1 Hz, 1H), 5.12 (s, 2H).
Preparation is conducted according to the preparation method of the compound 16 (reactant compound 1 is replaced by the compound 60) to obtain blue solid 61 (203.4 mg, 82.0%). 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.2 Hz, 2H), 7.06-7.02 (m, 3H), 6.70 (d, J=2.9 Hz, 1H), 6.57 (d, J=9.6 Hz, 1H), 5.01 (s, 2H).
Preparation is conducted according to the preparation method of the compound 21 (reactant compound 18 is replaced by the compound 61) to obtain blue solid 62 (66.8 mg, 35.6%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.3 Hz, 3H), 7.34 (d, J=9.7 Hz, 1H), 7.09 (d, J=8.0 Hz, 2H), 6.67 (d, J=9.8 Hz, 1H), 5.06 (s, 2H), 2.82 (s, 6H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-iodo-5-hydroxypyridine and reactant 4-iodobenzyl bromide is replaced by 4-methoxybenzyl bromide) to obtain white solid 63 (569.1 mg, 83.4%). 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J=4.6, 1.4 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 7.16 (dd, J=8.1, 4.6 Hz, 1H), 7.05-7.01 (m, 1H), 6.93 (d, J=8.7 Hz, 2H), 5.11 (s, 2H), 3.82 (s, 3H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-hydroxy-5-iodopyridine and reactant 4-iodobenzyl bromide is replaced by 4-methoxybenzyl bromide) to obtain white solid 64 (297.4 mg, 87.2%). 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=2.4 Hz, 1H), 7.40 (dd, J=9.5, 2.4 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 6.45 (d, J=9.5 Hz, 1H), 5.02 (s, 2H), 3.80 (s, 3H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-iodo-5-hydroxypyridine and reactant 4-iodobenzyl bromide is replaced by the compound 34) to obtain white solid 65 (357.4 mg, 73.1%). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=4.7 Hz, 1H), 7.40 (d, J=8.6 Hz, 2H), 7.21 (dd, J=8.0, 4.8 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.96 (d, J=8.7 Hz, 2H), 5.13 (s, 2H), 4.85-4.68 (m, 2H), 4.29-4.18 (m, 2H).
Preparation is conducted according to the preparation method of the compound 1 (reactant 4-nitrophenol is replaced by 2-hydroxy-5-iodopyridine and reactant 4-iodobenzyl bromide is replaced by the compound 34) to obtain white solid 66 (297.8 mg, 79.8%). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.43 (d, J=9.5 Hz, 1H), 7.29-7.26 (m, 2H), 6.92 (d, J=8.6 Hz, 2H), 6.51 (dd, J=9.4, 3.6 Hz, 1H), 5.04 (s, 2H), 4.83-4.68 (m, 2H), 4.27-4.15 (m, 2H).
A synthesis reaction route is shown in
In the synthesis route shown in
4-iodoaniline (876.1 mg, 4.0 mmol) and 4-dimethylaminobenzaldehyde (596.8 mg, 4.0 mmol) are dissolved in 25 ml of anhydrous ethanol, reaction is conducted for 15 min at 90° C. under a reflux and stirring state, a great amount of white crystals are separated out, suction filtration is conducted after cooling, the crystals are washed with cold ethanol, the crystals are dried and then are dissolved in 50 ml of methanol, NaBH4 (453.6 mg, 12.0 mmol) is slowly added, and reaction is conducted for 30 min at 90° C. under a reflux and stirring state. Reaction is monitored through TLC till basic completion, depressurization is conducted to remove methanol, 50 ml of deionized water is added, a great amount of white solid is separated out, suction filtration is conducted, the solid is washed with water and drying is conducted to obtain a white solid product (821.1 mg, 58.3%). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 6.74 (s, 2H), 6.42 (d, J=8.6 Hz, 2H), 4.17 (s, 2H), 2.95 (s, 6H).
I. Experiment Steps:
1) Preparation of Compounds [125I] 4, [125I] 24, [125I] 22, [125I] 31a and [125I] 35a
See
2) Preparation of Compounds [18F] 44a, [18F] 53a and [18F] 53b
See
II. Experiment Results:
125I labeled ligands are prepared through a classic tin-halogen exchange method. Labeling rates of [125I] 4, [125I] 24, [125I] 22, [125I] 31a and [125I] 35a are sequentially 86.2%, 94.9%, 92.9%, 67.3% and 27.1%. After separation and purification are conducted through HPLC, radiochemical purity is higher than 95% and the retention time is consistent with the retention time of stable iodo ligands (see Table 1).
18F labeled compounds are prepared through a one-step method. Labelling rates of [18F] 44a, [18F] 53a and [18F] 53b are sequentially 13.8%, 13.4% and 23.9%. After separation and purification are conducted through HPLC, radiochemical purity is higher than 98% and the retention time is consistent with the retention time of stable ligands (see Table 1).
In-vitro competitive binding experiments (Ki determination) of compounds 4-25, 31a, 35a, 44a, 46, 47, 53a, 55, 57-59, 65 and 67, IMPY and PIB with Aβ1-42 aggregates:
Binding reaction occurs between Aβ1-42 aggregate proteins with certain concentration and radioactive ligands [125I] IMPY, compounds (respectively prepared compounds 4-25, 31a, 35a, 44a, 46, 47, 53a, 55, 57-59, 65 and 67) with different concentration and to be determined, IMPY and PM are simultaneously added into the reaction system to competitively react with [125I] 4, the compounds are separated after balancing, and the inhibition constant (Ki) is calculated by determining radioactivity.
1. Experiment Steps:
(1) Preparing 4 l of PBS (0.2M) buffer solution with pH=7.4;
(2) Preparing radioligand [125] IMPY according to the existing method; preparing the [125I] IMPY into 100000 cpm/100 μL water solution;
(3) Preparing the compounds to be determined into 10−3 to 10−9 mol/L continuously diluted ethanol solution;
(4) Preparing receptor Aβ1-42 proteins according to the existing method and diluting the proteins into 30 nM water solution;
(5) Soaking a glass fiber filter membrane in PBS solution containing 0.1% (volume fraction) polyethyleneimine for 0.5 h;
(6) Respectively adding 100 μl of solution of compounds with different concentration and to be determined, 100 μl of [125I] IMPY solution, 700 μl of PBS and 100 μl of Aβ1-42 solution in a 12×75 mm high borosilicate glass tube; sealing the tube by using a sealing film and whirling;
(7) Oscillating and incubating for 2 h in 37° C. constant-temperature water bath;
(8) Collecting reaction liquid by using a multi-head cell collector, and washing the reaction liquid for three times by using PBS, 3 ml per time;
(9) Measuring and counting by using a γ counter; and
(10) Processing data.
2. Experiment Results
See Table 2 for half inhibition constants (IC50) which are obtained through the competitive binding experiment and the inhibition constants Ki which are further calculated according to a formula.
1060 ± 130.0
According to the above-mentioned competitive binding experiments, it can be known that the compounds 4, 11, 12, 13, 22, 31a, 35a and 47 of the compounds described in the present invention have higher affinity with the Aβ1-42 aggregates, and the affinity of the compounds is higher than that of the known compounds IMPY and PIB.
In this experiment example, the structural formulas of the known compounds IMPY and PM are respectively:
After 18F or 125I labeled compounds with certain concentration are respectively bound with plaques in AD transgenic mouse and AD patient brain sections, exposure is conducted through a phosphor screen and then images are analyzed by using a storage phosphor screen system.
1. Experiment Steps:
(1) Pretreating the AD transgenic mouse brain section and the AD patient brain section;
(2) Respectively covering the AD transgenic mouse brain section or the AD patient brain section with 100 μl of 5μ, Ci 18F or 125I labeled compounds, and incubating for 60 min at room temperature;
(3) Sequentially washing the section with lithium carbonate saturated 40% ethanol solution for 5 min and then washing the section with flowing water for 5 min; and
(4) After being air-dried, wrapping the section with a preservative film, placing the section under the phosphor screen for exposure for 120 min and analyzing the images by using the storage phosphor screen system.
2. Experiment Results:
Experiment results are shown in
Through in-vivo distribution experiments, pharmacokinetic features, especially initial bran intake and brain removal situations of 18F or 125I labeled compounds in the bodies of mice are studied.
1. Experiment Steps
5-10μ Ci labeled compounds (1000 of normal saline solution, containing 5% ethanol) are injected into the bodies of normal mice (ICR, male, 20-22 g, 5-week old) from caudal veins, the mice are beheaded respectively at the moment of 2 min, 10 min, 30 min and 60 min after injection, relevant organs are taken out through dissection, wet weight is measured and radioactive counting is conducted. Data are expressed in radioactive percentage dosage per organ (% ID/organ) and radioactive percentage dosage per gram of organ (% ID/g).
2. Experiment Results
Experiment results are shown in Table 3. The 18F or 125I labeled compounds of the present invention can smoothly pass through blood brain barriers, brain intake reaches a peak at the moment of 2 min, the removing speed in the brains of normal mice is very fast and the ratio of brain intake at the moment of 2 min to brain intake at the moment of 60 min reaches approximate 10. Through further comparison with the known compounds such as [125I] IMPY in the prior art, it can be found that the removing speed of the phenyl benzyl ether compounds in the brains of the normal mice is obviously superior to that of the known compounds.
In this experiment example, the structural formula of the known compound [125I] IMPY is:
ais expressed in % ID/g, n = 4-5.
bis expressed in % ID/organ.
Although the present invention has been described above in details by using general description and specific embodiments, some modifications or improvements can be made on the basis of the present invention and it is obvious for one skilled in the art. Therefore, any modifications or improvements made without departing from the spirit of the present invention belong to the protection scope claimed by the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201310714057.3 | Dec 2013 | CN | national |
This is a U.S. National Stage under 35 U.S.C 371 of the International Application PCT/CN2014/090510, filed Nov. 6, 2014, which claims priority under 35 U.S.C. 119(a-d) to CN 201310714057.3, filed Dec. 20, 2013.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2014/090510 | 11/6/2014 | WO | 00 |
