WO2015090122A1 - 苯基苄基醚类衍生物及其制备方法和应用 - Google Patents

苯基苄基醚类衍生物及其制备方法和应用 Download PDF

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WO2015090122A1
WO2015090122A1 PCT/CN2014/090510 CN2014090510W WO2015090122A1 WO 2015090122 A1 WO2015090122 A1 WO 2015090122A1 CN 2014090510 W CN2014090510 W CN 2014090510W WO 2015090122 A1 WO2015090122 A1 WO 2015090122A1
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group
compound
ether derivative
substituted
och
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French (fr)
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张志勇
崔孟超
林春平
刘伯里
国毓智
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北京智博高科生物技术有限公司
张志勇
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Priority to US15/101,385 priority Critical patent/US20170037008A1/en
Priority to JP2016559482A priority patent/JP6560689B2/ja
Publication of WO2015090122A1 publication Critical patent/WO2015090122A1/zh

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Definitions

  • the present invention relates to the field of pharmaceutical compounds, and in particular to a phenylbenzyl ether derivative and a process for the preparation thereof, wherein a part of the compound is labeled with a radionuclide as an A ⁇ plaque imaging agent, and the phenyl benzyl ether
  • a radionuclide as an A ⁇ plaque imaging agent
  • the phenyl benzyl ether The use of derivatives in the preparation of a medicament for the diagnosis and treatment of Alzheimer's disease.
  • AD Alzheimer's Disease
  • AD is a progressive developmental fatal neurodegenerative disease with clinical manifestations of decreased cognitive and memory function, decreased daily living ability, and various neuropsychiatric symptoms. And behavioral disorders. AD is more common in the elderly population. Statistics show that the prevalence of AD in China is 6.6% among people over 65 years old. It has become one of the major diseases that seriously threaten the physical and mental health of the elderly after cancer, heart disease and stroke. At present, China is rapidly entering an aging society. It is estimated that by 2030, China's population over 65 will surpass Japan and become the country with the highest degree of aging population in the world. At present, an AD patient is added every 7 seconds, and 4.6 million new cases are reported each year. It is expected that this number will exceed 100 million by 2050. It can be seen that the task of prevention and treatment of AD is arduous. It is extremely important to study the early diagnosis methods and therapeutic drugs of AD.
  • senile plaques SPs
  • NFTs neurofibrillary tangles
  • a ⁇ plaque deposition in the brain has begun 10 to 20 years before the onset of AD (Braak, H et al. Acta Neuropathol., 1991, 82: 239-259). Therefore, using A ⁇ plaques in the brain as targets, molecular probes with high affinity and selectivity have been developed, and nuclear medicine images such as single photon scanning (SPECT) or positron emission tomography (PET) have been developed. Techniques can be used to diagnose AD early on the molecular level without trauma (Cai L S et al. Curr Med Chem., 2007, 14: 19-52).
  • SPECT single photon scanning
  • PET positron emission tomography
  • a ⁇ plaque imaging agents for nuclear medicine PET imaging have developed rapidly. Many molecules have been modified by the two dyes, Thioflavin-T (ThT) and Congo Red (CR). Entered the clinical trial phase.
  • the 2-phenyl-benzothiazole-based compounds representative of [11 C] PIB (Pittsburgh Compound B) is currently the most widely used imaging agent A ⁇ plaques (Klunk WE et al.Annals of Neurology. , 2004,55 :306-319), its analogue [ 18 F]GE-067 may have a greater clinical application prospect due to the 18 F label (Koole M et al. J. Nucl.
  • a ⁇ plaque imaging agents for SPECT imaging in which 123 I-labeled 2-phenylimidazopyridine derivatives [ 123 I] IMPY is the first SPECT to enter the clinical stage.
  • the agent (Newberg, AB et al. J. Nucl. Med. 2006, 47: 748-754), but was quickly eliminated due to its poor stability in vivo.
  • Other radioactive iodine-labeled A ⁇ plaque imaging agents also have the disadvantages of high fat solubility, slow brain clearance, and decellularized iodine in the body.
  • an A ⁇ plaque imaging agent that can be used for early diagnosis of AD can be obtained. It is bound to have great application prospects and economic value.
  • Another object of the present invention is to provide a process for producing the phenylbenzyl ether derivative.
  • Another object of the present invention is to provide an A? plaque imaging agent prepared by using the phenylbenzyl ether derivative.
  • Another object of the present invention is to provide an application of the A ⁇ plaque imaging agent for the preparation of a medicament for diagnosing an amyloidosis disease, including early diagnosis of AD.
  • Another object of the present invention is to provide the use of the phenylbenzyl ether derivative for the preparation of a medicament for the diagnosis and treatment of AD.
  • the present invention provides a phenylbenzyl ether derivative having a structural formula of the formula (I):
  • X may be O, NH or S; Y 1 and Y 2 each independently represent -CH- or nitrogen;
  • R 1 and R 2 each independently represent hydrogen, halogen, hydroxy, decyl, alkoxy, alkyl, carbocycloalkyl, heterocycloalkyl, nitro, amino, alkylamino, cyano, carboxy, aryl, Heteroaryl, arylalkoxy, substituted arylalkoxy, aryloxy, substituted aryloxy, arylalkenyl, substituted arylalkenyl, -O(CH 2 )mNRaRb, -CO- NRaRb, -NHCO-Ra, -Sn (alkyl) 3, - (CH 2) mZ, -O (CH 2) mZ, - (CH 2) m- aryl or - (OCH 2 CH 2) nZ ;
  • Ra and Rb each independently represent hydrogen, alkyl or -(CH 2 )m-aryl
  • Z represents a halogen, a hydroxyl group, a trifluoromethylsulfonyl group, a methylsulfonyl group or a p-toluenesulfonyl group;
  • any one of m and n is an integer of 1 to 6, and m and n are each preferably an integer of 1 to 3.
  • Y 1 and Y 2 may be simultaneously -CH- or nitrogen.
  • Y 1 and Y 2 may be -CH- or nitrogen, respectively, or Y 1 and Y 2 may be nitrogen or -CH-, respectively.
  • -(CH 2 )m-aryl is -(CH 2 )m-phenyl, including R 1 and R 2 and -(CH 2 )m-aryl represented by Ra and Rb.
  • R 1 and R 2 are both ortho, meta or para substituents.
  • halogen is fluorine, chlorine, bromine or iodine, and includes a halogen represented by R 1 and R 2 and a halogen represented by Z.
  • alkoxy group is a C 1 -C 12 alkoxy group, preferably a C 1 -C 6 alkoxy group.
  • alkoxy group is a methoxy group, an ethoxy group, a propoxy group or a butoxy group.
  • alkyl group is a C 1 -C 12 alkyl group, preferably a C 1 -C 6 alkyl group.
  • alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group or a tert-butyl group.
  • carbocyclic alkyl group is a 3- to 6-membered carbocyclic alkyl group.
  • carbocyclic alkyl group is a cyclopropyl group, a cyclopentyl group or a cyclohexane group.
  • heterocycloalkyl group is a 3- to 6-membered heterocycloalkyl group.
  • heteroalkyl ring group is piperidinyl, piperazinyl or morpholine ring.
  • alkylamino group is a C 1 -C 12 alkylamino group, preferably a C 1 -C 6 alkylamino group.
  • alkylamino group is N-methylamino, dimethylamino, diethylamino, dipropylamino or diisopropylamino.
  • aryl group is a phenyl group or a naphthyl group.
  • heteroaryl group is a pyridyl group, a furyl group, a thienyl group, a benzothiazolyl group, a benzofuranyl group or a benzoxazolyl group.
  • arylalkoxy group is a C 5 -C 7 aryl C 1 -C 12 alkoxy group.
  • arylalkoxy group is a phenylmethoxy group or a phenylethoxy group.
  • substituted arylalkoxy group is a substituted C 5 -C 7 aryl C 1 -C 12 alkoxy group.
  • substituted arylalkoxy group is a substituted phenylmethoxy group or a substituted phenylethoxy group.
  • aryloxy group is a C 5 -C 7 aryloxy group.
  • aryloxy group is a cyclopentadienyloxy group or a phenyloxy group.
  • substituted aryloxy group is a substituted C 5 -C 7 aryloxy group.
  • substituted aryloxy group is a substituted cyclopentadienyloxy group or a substituted phenyloxy group.
  • arylalkenyl group is a C 5 -C 7 aryl C 2 -C 6 alkenyl group.
  • arylalkenyl group is a phenylvinyl group.
  • substituted arylalkenyl group is a substituted C 5 -C 7 aryl C 2 -C 6 alkenyl group.
  • substituted arylalkenyl group is a substituted phenylvinyl group.
  • aryl group in the substituted arylalkoxy group is substituted by a halogen, a hydroxyl group, an alkoxy group, a nitro group, an amino group or an alkylamino group.
  • the aryl group in the substituted aryloxy group is substituted by a halogen, a hydroxyl group, an alkoxy group, a nitro group, an amino group or an alkylamino group.
  • aryl group in the substituted arylalkenyl group is substituted by a halogen, a hydroxyl group, an alkoxy group, a nitro group, an amino group or an alkylamino group.
  • the halogen in the substituted arylalkoxy group, the substituted aryloxy group and the substituted arylalkenyl group is fluorine, chlorine, bromine or iodine; wherein the alkoxy group is a methoxy group, an ethoxy group, a propoxy group Or a butoxy group; wherein the alkylamino group is N-methylamino, dimethylamino, diethylamino, dipropylamino or diisopropylamino.
  • the phenylbenzyl ether derivative provided by the present invention further has a structural formula represented by the formula (I-1):
  • R 1 is nitro, methoxy, hydroxy, fluoro, chloro, bromo, iodo, hydrogen, tert-butyl, amino, methylamino, dimethylamino, -OCH 2 CH 2 F, -Sn(butyl) 3 , -OCH 2 CH 2 OH, -(OCH 2 CH 2 ) 3 OH, -OCH 2 CH 2 OTs, -(OCH 2 CH 2 ) 3 OTs or -(OCH 2 CH 2 ) 3 F;
  • R 2 is iodine, methoxy, bromo, hydrogen, -OCH 2 CH 2 F, -Sn(butyl) 3 , -OCH 2 CH 2 Br, -OCH 2 CH 2 OTs or dimethylamino.
  • R 1 and R 2 are respectively:
  • R 1 and R 2 are both ortho, meta or para substituents.
  • R 1 , R 2 and X are respectively:
  • the phenylbenzyl ether derivative provided by the present invention further has a structural formula represented by the formula (I-2):
  • R 1 is hydrogen, bromine, iodine, nitro, amino, methylamino or dimethylamino;
  • R 2 is iodine, methoxy or -OCH 2 CH 2 F.
  • R 1 and R 2 are respectively:
  • R 1 and R 2 are both ortho, meta or para substituents.
  • R 1 , R 2 and X are respectively:
  • the phenylbenzyl ether derivative provided by the present invention further has a structural formula represented by the formula (I-3):
  • R 1 is chlorine, bromine or iodine; and R 2 is iodine, methoxy or -OCH 2 CH 2 F.
  • R 1 and R 2 are respectively:
  • R 1 and R 2 are both ortho, meta or para substituents.
  • R 1 , R 2 and X are respectively:
  • phenyl benzyl ether derivative provided by the present invention, further, when it contains a fluorine atom, F is 18 F or 19 F; when it contains an iodine atom, I takes 123 I, 124 I, 125 I, 127 I or 131 I; when it contains methyl, methoxy, N-methylamino or dimethylamino, -CH 3 takes - 11 CH 3 , -OCH 3 takes -O 11 CH 3 , -NHCH 3 takes -NH 11 CH 3 , -N(CH 3 ) 2 takes -N( 11 CH 3 ) 2 or -N(CH 3 )( 11 CH 3 ).
  • the obtained phenylbenzyl ether derivative can be used as an A ⁇ plaque imaging agent, especially as a PET-based A ⁇ plaque imaging agent.
  • the obtained phenylbenzyl ether derivative can be used as an A ⁇ plaque imaging agent, especially as a PET-based A ⁇ plaque imaging agent.
  • the obtained phenylbenzyl ether derivative can be used as an A ⁇ plaque imaging agent, particularly as a SPECT-like A ⁇ plaque imaging agent.
  • the preparation method of the phenylbenzyl ether derivative provided by the invention has the reaction equation:
  • Y 3 is bromine or chlorine; and R 1 , R 2 , X, Y 1 and Y 2 are as defined corresponding to a phenylbenzyl ether derivative of any one of the above formulas (I).
  • the preparation method of the phenylbenzyl ether derivative provided by the invention has the reaction equation:
  • Y 3 is bromine or chlorine; and R 1 , R 2 and X are as defined correspondingly to the phenylbenzyl ether derivative represented by the above formula (I-1).
  • the preparation method of the phenylbenzyl ether derivative provided by the invention has the reaction equation:
  • Y 3 is bromo or chloro; defining respective R 1, R 2 and X are any of the above structural formula as a formula (I-2) phenyl benzyl ether derivative of FIG.
  • the preparation method of the phenylbenzyl ether derivative provided by the invention has the reaction equation:
  • Y 3 is bromine or chlorine; and R 1 , R 2 and X are as defined corresponding to a phenylbenzyl ether derivative represented by any one of the above structural formulas (I-3).
  • the present invention also provides an A? plaque imaging agent prepared by using the phenylbenzyl ether derivative.
  • a compound containing a radionuclide F-18 is prepared, that is, as an A ⁇ plaque imaging agent, especially as a PET-like A ⁇ plaque Image agent.
  • a compound containing radionuclide I-124 is prepared, that is, as an A ⁇ plaque imaging agent, especially as a PET-like A ⁇ plaque. Image agent.
  • any of the above phenylbenzyl ether derivatives contains a methyl group, a methoxy group, an N-methylamino group or a dimethylamino group
  • the radionuclide C-11 (- 11 CH 3 , - a compound of O 11 CH 3 , -NH 11 CH 3 , -N( 11 CH 3 ) 2 or -N(CH 3 )( 11 CH 3 )), as an A ⁇ plaque imaging agent, especially as a PET-like A ⁇ plaque Block imaging agent.
  • a compound containing radionuclide I-123, I-125 or I-131 is prepared, that is, as an A ⁇ plaque imaging agent, Especially as a SPECT-like A ⁇ plaque imaging agent.
  • any one of the above phenylbenzyl ether derivatives contains two or more of fluorine, iodine, methyl, methoxy, N-methylamino and dimethylamino groups, Only one of the substituents is prepared into the above-mentioned corresponding radionuclide to obtain an A ⁇ plaque imaging agent.
  • the A ⁇ plaque imaging agent is a single photon or positron A ⁇ plaque imaging agent.
  • the A ⁇ plaque imaging agent can be used for PET imaging or SPECT imaging.
  • the A ⁇ plaque imaging agent provided by the invention can be used for early diagnosis of amyloidosis in AD.
  • the present invention also provides the use of the phenylbenzyl ether derivative for the preparation of a medicament for the diagnosis and treatment of Alzheimer's disease.
  • the invention prepares a novel structure of phenyl benzyl ether compounds, and the in vitro competition binding experiments show that the molecules have high affinity with A ⁇ 1-42 aggregates; in vitro autoradiography experiments show that I-125 or F-18
  • the labeled molecules can specifically bind to A ⁇ plaques in the brain of AD human brain slices or AD transgenic mice; biodistribution experiments in normal mice indicate that some I-125 or F-18 labeled imaging agents have It has the advantages of high initial brain uptake and rapid clearance; it is expected to become a new single photon or positron A ⁇ plaque imaging agent for clinical imaging.
  • the present inventors have developed a new class of phenylbenzyl ether derivatives having a high affinity for A[beta] plaques in the brain of AD patients, the chemical structure differs from the compounds disclosed in the prior art, especially Thioflavin-T and Congo. Red, is a brand new compound for the diagnosis and treatment of Alzheimer's disease; the obtained A ⁇ plaque imaging agent has good stability in vivo, low fat solubility, fast brain clearance, and no problem of denuclear radionuclide in vivo. Has a huge application prospect and market value.
  • FIG. 1 is a reaction route diagram of the first embodiment and the first part of the fifth embodiment.
  • Fig. 2 is a reaction route diagram of the second embodiment of Example 2 and Example 5.
  • Example 3 is a reaction route diagram of Example 3.
  • Example 4 is a reaction route diagram of Example 4.
  • 5 and 6 are graphs showing the results of the autoradiography experiment in Experimental Example 2.
  • the [ 125 I]NaI solution used in the present invention was purchased from China Tongfu Co., Ltd.
  • the room temperature in the present invention is 25 °C.
  • the concentration (%) of each material is a mass concentration.
  • the synthesis reaction route is shown in Fig. 1.
  • the compound numbers in this example are all unified with the numbers in the reaction route of the figure.
  • the reagents and conditions are as follows: (a) K 2 CO 3 , DMF, 90 ° C; (b) SnCl 2 ⁇ 2H 2 O, EtOH, HCl, reflux; (c) 1: NaOMe , (CH 2 O) n , MeOH, reflux; 2: NaBH 4 , reflux; (d) (CH 2 O) n , NaBH 3 CN, HAc, rt; (e) 1-bromo-2-fluoroethane, KOH, ethanol, reflux; (f) 10% Pd/C, 1 atm H 2 , 50 ° C; (g) NaBH 4 , MeOH, 0 ° C; (h) PBr 3 , CH 2 Cl 2 , rt; (i) ( Bu 3 Sn) 2 , (PPh 3 ) 4 Pd, toluene, Et 3 N, reflux; (j) [ 125 I]NaI, HCl (1M), H 2 O
  • the compound 29 (2.08 g, 8.44 mmol) was dissolved in 10 mL of anhydrous methanol, and a palladium carbon catalyst (89.4 mg, 0.84 mmol) was added, and the reaction was stirred at 50 ° C for 4 h under 1 atm H 2 .
  • the compound 33 (2.73 g, 16.0 mmol) was dissolved in 25 mL of anhydrous CH 2 Cl 2 and slowly stirred at room temperature with 25 ml of LPBr 3 (4.33 g, 16.0 mmol) in CH 2 Cl 2 , and the reaction was continued for 0.5 h, TLC monitoring end of the reaction, 20mL of deionized water was added to quench the reaction, then 1g NaHCO 3 was added and stirring was continued 0.5H,, The combined organic phases were dried and extracted CH 2 Cl 2 (3 ⁇ 10mL) dried over anhydrous MgSO 4, filtered off with suction and removed under reduced pressure The solvent gave a colorless oily liquid 34 (3.54 g, 95.0%).
  • the synthesis reaction route is shown in Fig. 2.
  • the compound numbers in this example are all unified with the numbers in the reaction route of the figure.
  • the synthesis reaction route is shown in Fig. 3.
  • the compound numbers in this example are all unified with the numbers in the reaction route of the figure.
  • the reagents and conditions are as follows: (a) K 2 CO 3 , DMF, 90 ° C; (b) SnCl 2 ⁇ 2H 2 O, EtOH, HCl, reflux; (c) CH 3 I , K 2 CO 3 , rt
  • the synthesis reaction route is shown in Fig. 4, and the compound numbers in this example are all unified with the numbers in the reaction route of the figure.
  • the synthetic reaction route is shown in Figure 2.
  • 1.0 mg of the corresponding labeled precursors (compounds 48, 52a and 52b, respectively) were dissolved in 0.8 mL of anhydrous acetonitrile and added to the water-containing K 222 containing a certain activity.
  • a /F 2 CO 3 18 F - reaction tube mark at 100 ° C for 5 min, and after cooling, add 10 mL of deionized water to dilute the reaction mixture.
  • the mixture was purified by pre-treated Sep-Pak Plus C-18 solid phase extraction cartridge, and the column was washed with 10 mL of deionized water to remove unreacted [ 18 F]F - and inorganic salts, and N 2 was dried.
  • the labeled compound and the labeled precursor adsorbed on the column were eluted with 2 ⁇ 1 mL of anhydrous acetonitrile, and concentrated and purified by HPLC.
  • the retention time of the 18 F-labeled ligand and the reference compound was analyzed by HPLC, and the analysis conditions were the same as those of the separation conditions.
  • 125 I-labeled ligands were prepared by classical tin-halogen exchange methods.
  • the labeling rates of [ 125I ]4, [ 125I ]24, [ 125I ]22, [ 125I ]31a and [ 125I ]35a were 86.2%, 94.9%, 92.9%, 67.3% and 27.1%, respectively.
  • the radiochemical purity was greater than 95%, and consistent with the retention time of stable iodo ligands (see Table 1).
  • the 18 F-labeled compound was prepared by a one-step process.
  • the labeling rates of [ 18 F]44a, [ 18 F]53a and [ 18 F]53b were 13.8%, 13.4% and 23.9%, respectively.
  • the radiochemical purity was greater than 98% and consistent with the retention time of the stable ligand (see Table 1).
  • a certain concentration of A ⁇ 1-42 aggregate protein is bound to a certain concentration of radioligand [ 125 I]IMPY, and different concentrations of the test compound are added to the reaction system (compounds 4-25, 31a, 35a, respectively).
  • 44a, 46, 47, 53a, 55, 57-59, 65 and 67) and IMPY and PIB compete with [ 125I ]4, and the equilibrium complex is separated to calculate the inhibition constant (Ki) by measuring the radioactivity.
  • Radioligand [ 125 I] IMPY is prepared according to the prior art; [ 125 I] IMPY is formulated into an aqueous solution of 100000 cpm/100 ⁇ L;
  • test compound is formulated into a 10 -3 to 10 -9 mol/L serially diluted ethanol solution
  • the receptor A ⁇ 1-42 protein was prepared according to a conventional method. Dilute it into an aqueous solution of about 30 nM;
  • the glass fiber filter membrane is immersed in a PBS solution containing 0.1% (by volume fraction) of polyethyleneimine for 0.5 h;
  • the multi-head cell harvester collects the reaction solution and rinses three times with PBS for 3 mL each time;
  • a certain concentration of 18 F or 125 I-labeled compound was combined with plaques in brain slices of AD transgenic mice and AD patients, and then exposed through a phosphor screen, and then analyzed using a phosphor screen system.
  • the wrap film was placed under a phosphor screen for 120 minutes, and the image was analyzed by a phosphorus storage screen system.
  • Fig. 5 and Fig. 6 The experimental results are shown in Fig. 5 and Fig. 6, which fully demonstrate that the compound of the present invention can be used as an imaging agent for brain A ⁇ plaque after being labeled with a radionuclide, and is used in clinical diagnosis.
  • Figure 5 shows: [125 I] 4, [ 125 I] 24 and [125 I] 23, respectively, in human brain slices ((A, E, and I) AD, 64 years old, female; (B, F and J) normal, 74 years old, male) and rat brain slices ((C, G and K) transgenic mice, APPswe/PSEN1, November; (D, H and L) normal, C57BL6, November) autoradiography results. Same slice Controlled by Thioflavin-S staining.
  • Figure 6 shows that [ 18 F]53a and [ 18 F]53b are in human brain slices ((A, E) AD, 64 years old, female; (B, F) normal, 74 years old, male) and rat brain slices ( (C, G) Transgenic mice, APPswe/PSEN1, November; (D, H) normal, C57BL6, November) Autoradiography results, the same sections were stained with Thioflavin-S for comparison.
  • mice The pharmacokinetic properties of 18 F or 125 I-labeled compounds in mice, especially initial brain uptake and brain clearance, were investigated by in vivo distribution experiments.
  • the experimental results are shown in Table 3.
  • the 18 F or 125 I-labeled compounds of the present invention can smoothly pass through the blood-brain barrier, and the brain intake peaks at 2 minutes and clears in the brain of normal mice.
  • the ratio of minutes to 60 minutes brain uptake reached about 10.
  • prior art (known) compounds such as [ 125I ]IMPY revealed that the phenylbenzyl ether compounds of the present invention have significantly better clearance rates in normal mouse brains than they are.

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Abstract

本发明涉及一种苯基苄基醚类衍生物及其制备方法，其部分化合物被放射性核素标记后作为Aβ斑块显像剂，以及所述苯基苄基醚类衍生物在制备诊断和治疗阿尔茨海默症的药物中的应用。苯基苄基醚类衍生物，其结构式如式(I)所示；本发明研发出一类全新的与AD病人脑内Aβ斑块具有高亲和力的苯基苄基醚衍生物，化学结构不同于现有技术所公开的化合物，属于诊断和治疗阿尔茨海默症的全新的化合物；得到的Aβ斑块显像剂，体内稳定性好，脂溶性低、脑清楚速度快，并且不存在体内脱放射性核素的问题，具有巨大的应用前景和市场价值。

Description

苯基苄基醚类衍生物及其制备方法和应用 技术领域
本发明涉及药物化合物领域，具体地，涉及苯基苄基醚类衍生物及其制备方法，其部分化合物被放射性核素标记后作为Aβ斑块显像剂，以及所述苯基苄基醚类衍生物在制备诊断和治疗阿尔茨海默症的药物中的应用。
背景技术
阿尔茨海默症(Alzheimer′s Disease，AD)是一种进行性发展的致死性神经退行性疾病，临床表现为认知和记忆功能下降，日常生活能力减退，并伴有各种神经精神症状和行为障碍。AD多发于老年人群，统计资料显示，我国AD的患病率在65岁以上人群中平均为6.6％，已成为继肿瘤、心脏病和中风之后，严重威胁老年人身心健康的主要疾病之一。目前我国正在快速步入老龄化社会，预计到2030年，我国65岁以上人口占比将超过日本，成为全球人口老龄化程度最高的国家。目前全球每7秒钟便新增一名AD患者，每年新发病例460万例；预计到2050年，这一数字将过亿。可见，AD的防治工作任务艰巨，研究AD的早期诊断方法及治疗药物具有极其重要的意义。
研究表明，AD脑内沉积在神经细胞外的老年斑(SPs)和神经细胞内的神经纤维缠结(NFTs)是AD的两大主要病理特征。且脑内的Aβ斑块沉积在AD发病前的10～20年就已经开始(Braak,H et al.Acta Neuropathol.,1991,82:239-259)。因此，利用脑内的Aβ斑块为靶点，开发与之具有高亲和性和选择性的分子探针，通过单光子计算机扫描(SPECT)或正电子发射断层扫描(PET)等核医学影像技术，可以无创伤的从分子水平上早期诊断AD(Cai L S et al.Curr Med Chem.,2007,14:19-52)。
在过去的研究里，用于核医学PET显像的Aβ斑块显像剂发展迅速，通过对硫磺素-T(ThT)和刚果红(CR)这两种染料进行修饰，已经有不少分子进入了临床试验阶段。如2-苯基苯并噻唑类的代表化合物[11C]PIB(匹茨堡化合物B)是目前使用最为广泛的Aβ斑块显像剂(Klunk W E et al.Annals of Neurology.,2004,55:306-319)，它的类似物[18F]GE-067由于采用了18F标记，临床应用前景可能更大(Koole M et al.J.Nucl.Med.,2009,50:818-22)；二苯乙烯衍生物[18F]BAY94-9172正在积极的开展三期临床试验(Rowe C C et al.Lancet Neurol.,2008,7:129-35)，[18F]AV-45已经获得美国FDA批准(Wong D F et al.J.Nucl.Med.,2010,51:913-20)。
然而，用于SPECT显像的Aβ斑块显像剂还没有获得突破性进展，其中123I标记的2-苯基咪唑并吡啶衍生物[123I]IMPY是第一个进入临床阶段的SPECT显像剂(Newberg,A B et al.J.Nucl.Med.2006,47:748-754)，但由于其体内稳定性差而很快被淘汰。其他放射性碘标记的Aβ斑块显像剂也普遍存在脂溶性高、脑清除缓慢、体内脱放射性碘的缺点。
因此，若能开发出一类全新的与脑内Aβ斑块具有高亲和力的化合物，并对其进行放射性核素标记，从而得到一种能够用于AD的早期诊断的Aβ斑块显像剂，势必将会有巨大的应用前景和经济价值。
发明内容
为了解决上述技术问题，本发明的目的之一在于，提供苯基苄基醚类衍生物。该类化合物与AD病人脑内Aβ斑块具有高亲和力，属于诊断和治疗AD的全新化合物。
本发明的另一目的在于，提供所述苯基苄基醚类衍生物的制备方法。
本发明的另一目的在于，提供一种利用所述苯基苄基醚类衍生物制备得到的Aβ斑块显像剂。
本发明的另一目的在于，提供所述Aβ斑块显像剂在制备诊断淀粉样病变疾病的药物中的应用，包括AD的早期诊断。
本发明的另一目的在于，提供所述苯基苄基醚类衍生物在制备诊断和治疗AD的药物中的应用。
为了实现上述目的，本发明提供的苯基苄基醚类衍生物，其结构式如式(I)所示：
Figure PCTCN2014090510-appb-000001
其中，X可以为O，NH或S；Y1和Y2各自独立地表示-CH-或氮；
R1和R2各自独立地表示氢、卤素、羟基、巯基、烷氧基、烷基、碳环烷基、杂环烷基、硝基、氨基、烷氨基、氰基、羧基、芳基、杂芳基、芳基烷氧基、取代芳基烷氧基、芳基氧基、取代芳基氧基、芳基烯基、取代芳基烯基、-O(CH2)mNRaRb、-CO-NRaRb、-NHCO-Ra、-Sn(烷基)3、-(CH2)m-Z、-O(CH2)m-Z、-(CH2)m-芳基或-(OCH2CH2)n-Z；
其中，Ra和Rb各自独立地表示氢、烷基或-(CH2)m-芳基；
其中，Z表示卤素、羟基、三氟甲基磺酰基、甲基磺酰基或对甲苯磺酰基；
其中，上述任意一个m和n分别取1～6的整数，m和n均分别优选1～3的整数。
进一步地，Y1和Y2可同时为-CH-或氮。
进一步地，Y1和Y2可以分别为-CH-或氮，或者Y1和Y2可以分别为氮或-CH-。
进一步地，-(CH2)m-芳基为-(CH2)m-苯基，包括R1和R2以及Ra和Rb所代表的-(CH2)m-芳基。
其中，R1和R2均为邻位、间位或对位取代基。
其中，所述卤素为氟、氯、溴或碘，包括R1和R2所表示的卤素，Z所表示的卤素。
其中，所述烷氧基为C1～C12烷氧基，优选C1～C6烷氧基。
进一步地，所述烷氧基为甲氧基、乙氧基、丙氧基或丁氧基。
其中，所述烷基为C1～C12烷基，优选C1～C6烷基。
进一步地，所述烷基为甲基、乙基、丙基、异丙基或叔丁基。
其中，所述碳环烷基为3～6元碳环烷基。
进一步地，所述碳环烷基为环丙烷基、环戊烷基或环己烷基。
其中，所述杂环烷基为3～6元杂环烷基。
进一步地，所述杂烷环基为哌啶基、哌嗪基或吗啉环基。
其中，所述烷氨基为C1～C12烷氨基，优选C1～C6烷氨基。
进一步地，所述烷氨基为N-甲氨基、二甲氨基、二乙氨基、二丙氨基或二异丙氨基。
其中，所述芳基为苯基或萘基。
其中，所述杂芳基为吡啶基、呋喃基、噻吩基、苯并噻唑基、苯并呋喃基或苯并恶唑基。
其中，所述芳基烷氧基为C5～C7芳基C1～C12烷氧基。
进一步地，所述芳基烷氧基为苯基甲氧基或苯基乙氧基。
其中，所述取代芳基烷氧基为取代C5～C7芳基C1～C12烷氧基。
进一步地，所述取代芳基烷氧基为取代苯基甲氧基或取代苯基乙氧基。
其中，所述芳基氧基为C5～C7芳基氧基。
进一步地，所述芳基氧基为环戊二烯基氧基或苯基氧基。
其中，所述取代芳基氧基为取代C5～C7芳基氧基。
进一步地，所述取代芳基氧基为取代环戊二烯基氧基或取代苯基氧基。
其中，所述芳基烯基为C5～C7芳基C2～C6烯基。
进一步地，所述芳基烯基为苯基乙烯基。
其中，所述取代芳基烯基为取代C5～C7芳基C2～C6烯基。
进一步地，所述取代芳基烯基为取代苯基乙烯基。
进一步地，所述取代芳基烷氧基中的芳基被卤素、羟基、烷氧基、硝基、氨基或烷氨基所取代。
进一步地，所述取代芳基氧基中的芳基被卤素、羟基、烷氧基、硝基、氨基或烷氨基所取代。
进一步地，所述取代芳基烯基中的芳基被卤素、羟基、烷氧基、硝基、氨基或烷氨基所取代。
更进一步地，取代芳基烷氧基、取代芳基氧基和取代芳基烯基中的卤素为氟、氯、溴或碘；其中的烷氧基为甲氧基、乙氧基、丙氧基或丁氧基；其中的烷氨基为N-甲氨基、二甲氨基、二乙氨基、二丙氨基或二异丙氨基。
本发明提供的苯基苄基醚类衍生物，进一步地，其结构式如式(I-1)所示：
Figure PCTCN2014090510-appb-000002
其中，X为O，NH或S；
R1为硝基、甲氧基、羟基、氟、氯、溴、碘、氢、叔丁基、氨基、甲氨基、二甲氨基、-OCH2CH2F、-Sn(丁基)3、-OCH2CH2OH、-(OCH2CH2)3OH、-OCH2CH2OTs、-(OCH2CH2)3OTs或-(OCH2CH2)3F；
R2为碘、甲氧基、溴、氢、-OCH2CH2F、-Sn(丁基)3、-OCH2CH2Br、-OCH2CH2OTs或二甲 氨基。
进一步地，R1和R2分别为：
Figure PCTCN2014090510-appb-000003
Figure PCTCN2014090510-appb-000004
其中，R1和R2均为邻位、间位或对位取代基。
更进一步地，R1、R2和X分别为：
Figure PCTCN2014090510-appb-000005
Figure PCTCN2014090510-appb-000006
本发明提供的苯基苄基醚类衍生物，进一步地，其结构式如式(I-2)所示：
Figure PCTCN2014090510-appb-000007
其中，X为O，NH或S；
R1为氢、溴、碘、硝基、氨基、甲氨基或二甲氨基；
R2为碘、甲氧基或-OCH2CH2F。
进一步地，R1和R2分别为：
Figure PCTCN2014090510-appb-000008
其中，R1和R2均为邻位、间位或对位取代基。
更进一步地，R1、R2和X分别为：
R1         R2      X
p-H        I       O
p-I        I       O。
本发明提供的苯基苄基醚类衍生物，进一步地，其结构式如式(I-3)所示：
Figure PCTCN2014090510-appb-000009
其中，X为O，NH或S；
R1为氯、溴或碘；R2为碘、甲氧基或-OCH2CH2F。
进一步地，R1和R2分别为：
Figure PCTCN2014090510-appb-000010
其中，R1和R2均为邻位、间位或对位取代基。
更进一步地，R1、R2和X分别为：
Figure PCTCN2014090510-appb-000011
本发明提供的上述任意一项苯基苄基醚类衍生物，进一步地，当其中含有氟原子时，F取18F或19F；当其中含有碘原子时，I取123I、124I、125I、127I或131I；当其中含有甲基、甲氧基、N-甲氨基或二甲氨基时，-CH3取-11CH3、-OCH3取-O11CH3、-NHCH3取-NH11CH3、-N(CH3)2取-N(11CH3)2或-N(CH3)(11CH3)。
更进一步地，当F取18F或I取124I时，得到的苯基苄基醚类衍生物可作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
更进一步地，当-CH3取-11CH3、-OCH3取-O11CH3、-NHCH3取-NH11CH3、-N(CH3)2取-N(11CH3)2或-N(CH3)(11CH3)时，得到的苯基苄基醚类衍生物可作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
更进一步地，当I取125I，123I或131I时，得到的苯基苄基醚类衍生物可作为Aβ斑块显像剂，尤其作为SPECT类Aβ斑块显像剂。
本发明提供的上述任意一项苯基苄基醚类衍生物，更进一步地，当其中同时含有氟、碘、甲基、甲氧基、N-甲氨基和二甲氨基中的两种及两种以上的取代基时，只将其中的一种取代基制备成上述相应的放射性核素，得到Aβ斑块显像剂。
本发明提供的所述苯基苄基醚类衍生物的制备方法，其反应方程式为：
Figure PCTCN2014090510-appb-000012
其中，Y3为溴或氯；R1、R2、X、Y1和Y2同上述任意一项结构式如式(I)所示的苯基苄基醚类衍生物的相应的定义。
本发明提供的所述苯基苄基醚类衍生物的制备方法，其反应方程式为：
Figure PCTCN2014090510-appb-000013
其中，Y3为溴或氯；R1、R2和X同上述任意一项结构式如式(I-1)所示的苯基苄基醚类衍生物的相应限定。
本发明提供的所述苯基苄基醚类衍生物的制备方法，其反应方程式为：
Figure PCTCN2014090510-appb-000014
其中，Y3为溴或氯；R1、R2和X同上述任意一项结构式如式(I-2)所示的苯基苄基醚类衍生物的相应的限定。
本发明提供的所述苯基苄基醚类衍生物的制备方法，其反应方程式为：
Figure PCTCN2014090510-appb-000015
其中，Y3为溴或氯；R1、R2和X同上述任意一项结构式如式(I-3)所示的苯基苄基醚类衍生物的相应的限定。
本发明还提供利用所述苯基苄基醚类衍生物制备得到的Aβ斑块显像剂。
其中，当上述任意一项苯基苄基醚类衍生物中含有氟原子时，制备得到含有放射性核素F-18的化合物，即作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
或者，当上述任意一项苯基苄基醚类衍生物中含有碘原子时，制备得到含有放射性核素I-124的化合物，即作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
或者，当上述任意一项苯基苄基醚类衍生物中含有甲基、甲氧基、N-甲氨基或二甲氨基时，制备得到含有放射性核素C-11(-11CH3、-O11CH3、-NH11CH3、-N(11CH3)2或-N(CH3)(11CH3))的化合物，即作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂。
或者，当上述任意一项苯基苄基醚类衍生物中含有碘原子时，制备得到含有放射性核素I-123、I-125或I-131的化合物，即作为Aβ斑块显像剂，尤其作为SPECT类Aβ斑块显像剂。
进一步地，当上述任意一项苯基苄基醚类衍生物中同时含有氟、碘、甲基、甲氧基、N-甲氨基和二甲氨基中的两种及两种以上的取代基时，只将其中的一种取代基制备成上述相应的放射性核素，得到Aβ斑块显像剂。
其中，所述Aβ斑块显像剂为单光子或正电子Aβ斑块显像剂。
其中，所述Aβ斑块显像剂可用于PET显像或SPECT显像。
本发明提供的Aβ斑块显像剂可用于AD中淀粉样病变的早期诊断。
本发明还提供所述苯基苄基醚类衍生物在制备诊断和治疗阿尔茨海默症的药物中的应用。
本发明制备了一类全新结构的苯基苄基醚化合物，体外竞争结合实验表明，该类分子与Aβ1-42聚集体的亲和力很高；体外放射自显影实验表明I-125或F-18标记的该类分子可以特异性地与AD人脑切片或AD转基因小鼠脑内的Aβ斑块结合；正常小鼠体内生物分布实验表明，部分I-125或F-18标记的显像剂具有初始脑摄取高，清除快的优点；有望成为一种新的用于临床显像的单光子或正电子Aβ斑块显像剂。
总之，本发明研发出一类全新的与AD病人脑内Aβ斑块具有高亲和力的苯基苄基醚衍生物，化学结构不同于现有技术所公开的化合物，尤其是硫磺素-T和刚果红，属于诊断和治疗阿尔茨海默症的全新的化合物；得到的Aβ斑块显像剂，体内稳定性好，脂溶性低、脑清除速度快，并且不存在体内脱放射性核素的问题，具有巨大的应用前景和市场价值。
附图说明
图1为实施例1和实施例5第1)部分的反应路线图。
图2为实施例2和实施例5第2)部分的反应路线图。
图3为实施例3的反应路线图。
图4为实施例4的反应路线图。
图5和图6为实验例2中，放射自显影实验的显示图。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
本发明中未提及的操作均为本领域的常规操作，
本发明中所使用的[125I]NaI溶液购自中国同辐股份有限公司。
本发明中所使用的其他物料均为可以从市场上购买得到的常规物料，或者能够通过现有方法制备得到(如4-羟基-N,N-二甲基苯胺)。
本发明中的室温均为25℃。
本发明中，各物料的浓度(％)均为质量浓度。
实施例1：碘代化合物的合成
合成反应路线如图1所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图1所示的合成路线中，试剂与条件如下：(a)K2CO3,DMF,90℃；(b)SnCl2·2H2O,EtOH,HCl,回流；(c)1:NaOMe,(CH2O)n,MeOH,回流；2:NaBH4,回流；(d)(CH2O)n,NaBH3CN,HAc,r.t.；(e)1-溴-2-氟乙烷,KOH,乙醇,回流；(f)10％Pd/C,1atm H2,50℃；(g)NaBH4,MeOH,0℃；(h)PBr3,CH2Cl2,r.t.；(i)(Bu3Sn)2,(PPh3)4Pd,甲苯,Et3N,回流；(j)[125I]NaI,HCl(1M),H2O2(3％).
1)1-碘-4-((4-硝基苄氧基)甲基)苯(1-iodo-4-((4-nitrophenoxy)methyl)benzene，化合物1)的合成
将4-硝基苯酚(2.78g，20mmol)、4-碘溴苄(5.00g，20mmol)溶于5mL无水DMF中，加入K2CO3(5.53g，40mmol)。90℃回流搅拌反应2h，TLC监测反应结束，减压除去溶剂，加入50mL去离子水，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到白色固体 1(1.69g,95.2％)。HPLC:7.51min,99.8％；mp 147.4-148.1℃；1H NMR(400MHz,CDCl3)δ8.21(d,J＝9.2Hz,2H),7.75(d,J＝8.3Hz,2H),7.18(d,J＝8.3Hz,2H),7.01(d,J＝9.2Hz,2H),5.10(s,2H).
2)1-(4-碘苄氧基)-3-硝基苯(1-(4-iodobenzyloxy)-3-nitrobenzene，化合物2)的合成
按照化合物1的方法制备(反应物用3-硝基苯酚代替4-硝基苯酚)，得到白色固体2(345.5mg,97.3％)。HPLC:8.53min,99.9％；mp 75.2-75.9℃；1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.0Hz,1H),7.80(s,1H),7.74(d,J＝8.2Hz,2H),7.45(t,J＝8.2Hz,1H),7.30–7.26(m,1H),7.19(d,J＝8.1Hz,2H),5.09(s,2H).
3)1-(4-碘苄氧基)-2-硝基苯(1-(4-iodobenzyloxy)-2-nitrobenzene，化合物3)的合成
按照化合物1的方法制备(反应物用2-硝基苯酚代替4-硝基苯酚)，得到黄色固体3(238.9mg,67.3％)。HPLC:6.03min,99.5％；mp 70.6-71.5℃；1H NMR(400MHz,CDCl3)δ7.87(dd,J＝8.1,1.4Hz,1H),7.73(d,J＝8.2Hz,2H),7.56–7.46(m,1H),7.22(d,J＝8.1Hz,2H),7.09–7.04(m,2H),5.18(s,2H).
4)1-碘-4-((4-甲氧基苄氧基)甲基)苯(1-iodo-4-((4-methoxyphenoxy)methyl)benzene，化合物4)的合成
按照化合物1的方法制备(反应物用4-甲氧基苯酚代替4-硝基苯酚)，得到白色固体4(255.3mg,75.1％)。HPLC:8.28min,99.5％；mp 128.9-130.2℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.2Hz,2H),7.17(d,J＝8.2Hz,2H),6.89(d,J＝9.2Hz,2H),6.83(d,J＝9.2Hz,2H),4.96(s,2H),3.77(s,3H).13C NMR(101MHz,CDCl3)δ154.18,152.68,137.63,137.08,129.25,115.92,114.72,93.30,70.07,55.72.
5)1-(4-碘苄氧基)-3-甲氧基苯(1-(4-iodobenzyloxy)-3-methoxybenzene，化合物5)的合成
按照化合物1的方法制备(反应物用3-甲氧基苯酚代替4-硝基苯酚)，得到白色固体5(211.7mg,62.2％)。HPLC:8.68min,98.5％；mp 77.4-78.7℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.1Hz,2H),7.21–7.17(m,3H),6.57–6.50(m,2H),4.99(s,2H),3.79(s,3H).
6)1-(4-碘苄氧基)-2-甲氧基苯(1-(4-iodobenzyloxy)-2-methoxybenzene，化合物6)的合成
按照化合物1的方法制备(反应物用2-甲氧基苯酚代替4-硝基苯酚)，得到白色固体6(288.1mg,84.7％)。HPLC:6.63min,98.7％；mp 110.4-110.8℃；1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.1Hz,2H),7.19(d,J＝8.0Hz,2H),6.97–6.91(m,2H),6.85(d,J＝3.8Hz,2H),5.10(s,2H),3.89(s,3H).
7)4-(4-碘苄氧基)苯酚(4-(4-iodobenzyloxy)phenol，化合物7)的合成
将对苯二酚(110.1mg,1.0mmol)、4-碘溴苄(296.9mg,1.0mmol)溶于5mL无水DMF中，加入K2CO3(276.4mg,2.0mmol)。90℃回流搅拌反应2h，TLC监测反应结束，减压除去溶剂，加入50mL去离子水，CH2Cl2萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝4/1)得白色固体7(49.3mg,15.1％)。HPLC:3.75min,99.3％；mp 152.2-153.7℃；1H NMR(400MHz,CDCl3) δ7.71(d,J＝8.3Hz,2H),7.17(d,J＝8.2Hz,2H),6.85–6.81(m,2H),6.78–6.74(m,2H),4.95(s,2H),4.41(s,1H).
8)3-(4-碘苄氧基)苯酚(3-(4-iodobenzyloxy)phenol，化合物8)的合成
按照化合物7的方法制备(反应物用间苯二酚代替对苯二酚)，得到白色固体8(93.1mg,28.5％)。HPLC:3.95min,98.6％；mp 109.9-110.6℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝7.9Hz,2H),7.17(d,J＝8.2Hz,2H),7.16–7.09(m,1H),6.54(d,J＝8.6Hz,1H),6.46–6.44(m,2H),4.98(s,2H),4.74(s,1H).
9)2-(4-碘苄氧基)苯酚(2-(4-iodobenzyloxy)phenol，化合物9)的合成
按照化合物7的方法制备(反应物用邻苯二酚代替对苯二酚)，得到黄色油状化合物9(109.8mg,33.7％)。HPLC:4.25min,99.9％；mp 62.1-63.4℃；1H NMR(400MHz,CDCl3)δ7.74(d,J＝8.2Hz,2H),7.17(d,J＝8.0Hz,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).
10)1-氟-4-(4-碘苄氧基)苯(1-fluoro-4-(4-iodobenzyloxy)benzene，化合物10)的合成
按照化合物1的方法制备(反应物用4-氟苯酚代替4-硝基苯酚)，得到白色固体10(253.1mg,77.1％)。HPLC:8.92min,98.0％；mp 62.3-62.8℃；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.17(d,J＝8.2Hz,2H),7.00–6.95(m,2H),6.91–6.85(m,2H),4.97(s,2H).
11)1-氯-4-(4-碘苄氧基)苯(1-chloro-4-(4-iodobenzyloxy)benzene，化合物11)的合成
按照化合物1的方法制备(反应物用4-氯苯酚代替4-硝基苯酚)，得到白色固体11(136.2mg,79.0％)。HPLC:12.86min,99.6％；mp 107.5-108.1℃；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.24(d,J＝8.9Hz,2H),7.16(d,J＝8.2Hz,2H),6.87(d,J＝8.9Hz,2H),4.98(s,2H).
12)1-溴-4-(4-碘苄氧基)苯(1-bromo-4-(4-iodobenzyloxy)benzene，化合物12)的合成
按照化合物1的方法制备(反应物用4-溴苯酚代替4-硝基苯酚)，得到白色固体12(302.5mg,77.8％)。HPLC:14.61min,99.3％；mp 122.6-123.5℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.2Hz,2H),7.37(d,J＝9.0Hz,2H),7.16(d,J＝8.2Hz,2H),6.82(d,J＝8.9Hz,2H),4.97(s,2H).
13)1-碘-4-(4-碘苄氧基)苯(1-iodo-4-(4-iodobenzyloxy)benzene，化合物13)的合成
按照化合物1的方法制备(反应物用4-碘苯酚代替4-硝基苯酚)，得到白色固体13(436.0mg,89.3％)。HPLC:17.49min,98.2％；mp 135.0-135.9℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.2Hz,2H),7.56(d,J＝8.7Hz,2H),7.15(d,J＝8.1Hz,2H),6.72(d,J＝8.8Hz,2H),4.97(s,2H).
14)1-碘-4-(苄氧基甲基)苯(1-iodo-4-(phenoxymethyl)benzene，化合物14)的合成
按照化合物1的方法制备(反应物用苯酚代替4-硝基苯酚)，得到白色固体 14(310.1mg,72.1％)。HPLC:9.59min,99.2％；mp 96.7-97.6℃；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.32–7.27(m,2H),7.19(d,J＝8.1Hz,2H),6.99–6.94(m,3H),5.02(s,2H).
15)1-叔丁基-4-(4-碘苄氧基)苯(1-tert-butyl-4-(4-iodobenzyloxy)benzene，化合物15)的合成
按照化合物1的方法制备(反应物用4-叔丁基苯酚代替4-硝基苯酚)，得到白色固体15(366.2mg,87.4％)。HPLC:27.14min,98.3％；mp 91.9-93.0℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.2Hz,2H),7.31(d,J＝8.8Hz,2H),7.18(d,J＝8.2Hz,2H),6.89(d,J＝8.8Hz,2H),4.99(s,2H),1.30(s,9H).
16)4-(4-碘苄氧基)苯胺(4-(4-iodobenzyloxy)aniline，化合物16)的合成
将化合物1(1.42g,4.0mmol)和SnCl2·2H2O(1.66g,8.0mmol)溶于25mL乙醇中，滴加2mL浓盐酸，80℃下回流搅拌反应2h,冷却至室温，加入30mL 1M NaOH水溶液中和盐酸及沉淀SnCl2，乙酸乙酯萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝2/1)得粉色固体16(643.3mg,49.5％)。HPLC:4.16min,98.4％；mp 138.6-140.0℃；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.2Hz,2H),7.16(d,J＝7.9Hz,2H),6.78(d,J＝8.7Hz,2H),6.64(d,J＝8.8Hz,2H),4.93(s,2H),3.44(s,2H).
17)3-(4-碘苄氧基)苯胺(3-(4-iodobenzyloxy)aniline，化合物17)的合成
按照化合物16的方法制备(反应物用化合物2代替化合物1)，得到白色固体17(695.5mg,73.1％)。HPLC:4.50min,99.4％；mp 153.9-154.8℃；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.1Hz,2H),7.17(d,J＝8.0Hz,2H),7.07(t,J＝8.0Hz,1H),6.40–6.34(m,3H),4.97(s,2H).
18)2-(4-碘苄氧基)苯胺(2-(4-iodobenzyloxy)aniline，化合物18)的合成
按照化合物16的方法制备(反应物用化合物3代替化合物1)，得到白色固体18(99.3mg,11.4％)。HPLC:4.88min,99.1％；mp 99.1-100.1℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.3Hz,2H),7.19(d,J＝8.3Hz,2H),6.85–6.78(m,3H),6.75–6.71(m,1H),5.03(s,2H).
19)4-(4-碘苄氧基)-N-甲基苯胺(4-(4-iodobenzyloxy)-N-methylaniline，化合物19)的合成
将化合物16(162.6mg,0.5mmol)和多聚甲醛(60.0mg,2.0mmol)溶于30mL无水甲醇中，逐滴加入5mL NaOCH3(54.0mg,1.0mmol)的甲醇溶液，回流搅拌反应2h。冷却至室温后，缓慢加入NaBH4(75.6mg,2.0mmol)，继续回流搅拌反应2h。减压除去溶剂，加入50mL 1M NaOH溶液，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到粉色固体19(152.4mg,89.9％)。HPLC:6.34min,99.2％；mp 93.9-95.2℃；1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.2Hz,2H),7.17(d,J＝8.1Hz,2H),6.84(d,J＝8.7Hz,2H),6.58(d,J＝8.5Hz,2H),4.94(s,2H),2.81(s,3H).
20)3-(4-碘苄氧基)-N-甲基苯胺(3-(4-iodobenzyloxy)-N-methylaniline，化合物20)的合成
将化合物17(162.6mg,0.5mmol)和多聚甲醛(60.0mg,2.0mmol)溶于30mL无水甲 醇中，逐滴加入5mL NaOCH3(54.0mg,1.0mmol)的甲醇溶液，回流搅拌反应2h。冷却至室温后，缓慢加入NaBH4(75.6mg,2.0mmol)，继续回流搅拌反应2h。减压除去溶剂，加入50mL 1M NaOH溶液，CH2Cl2萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝4/1)得无色油状化合物20(71.0mg,41.8％)。HPLC:6.60min,99.9％；mp 45.3-46.6℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.1Hz,2H),7.19(d,J＝8.0Hz,2H),7.09(t,J＝8.0Hz,1H),6.32(d,J＝8.0Hz,1H),6.27(d,J＝7.9Hz,1H),6.24(s,1H),4.99(s,2H),2.83(s,3H).
21)2-(4-碘苄氧基)-N-甲基苯胺(2-(4-iodobenzyloxy)-N-methylaniline，化合物21)的合成
按照化合物19的方法制备(反应物用化合物18代替化合物16)，反应完成后，用CH2Cl2萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝4/1)得黄色油状化合物21(34.2mg,67.2％)。HPLC:8.19min,98.1％；1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.1Hz,2H),7.19(d,J＝8.0Hz,2H),6.94(t,J＝7.6Hz,1H),6.80(d,J＝7.3Hz,1H),6.72–6.64(m,2H),5.02(s,2H),2.87(s,3H).
22)4-(4-碘苄氧基)-N,N-二甲基苯胺(4-(4-iodobenzyloxy)-N,N-dimethyla niline，化合物22)的合成
将化合物16(162.6mg,0.5mmol)与多聚甲醛(150.0mg,5.0mmol)溶于20mL醋酸中，缓慢加入NaBH3CN(157.0mg,2.5mmol)，室温下搅拌反应24h。加入20mL1M NaOH溶液，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得白色固体22(168.4mg,95.4％)。HPLC:10.63min,98.4％；mp 128.2-129.3℃；1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.2Hz,2H),7.17(d,J＝8.0Hz,2H),6.88(d,J＝8.9Hz,2H),6.82–6.68(s,2H),4.95(s,2H),2.87(s,6H).
23)3-(4-碘苄氧基)-N,N-二甲基苯胺(3-(4-iodobenzyloxy)-N,N-dimethyla niline，化合物23)的合成
按照化合物22的方法制备(反应物用化合物17代替化合物16)，得到白色固体23(171.3mg,97.1％)。HPLC:11.30min,99.9％；mp 68.8-70.1℃；1H NMR(400MHz,CDCl3)δ7.71(d,J＝8.2Hz,2H),7.19(d,J＝8.2Hz,2H),7.15(t,J＝8.1Hz,1H),6.43–6.30(m,3H),5.00(s,2H),2.94(s,6H).13C NMR(101MHz,CDCl3)δ150.92,145.99,137.59,137.41,129.28,115.95,114.77,93.19,70.16,41.73.
24)1-碘-4-(4-甲氧基苄氧基)苯(1-iodo-4-(4-methoxybenzyloxy)benzene，化合物24)的合成
按照化合物1的方法制备(反应物用4-碘苯酚代替4-硝基苯酚，用4-甲氧基溴苄代替4-碘溴苄)，得到白色固体24(906.3mg,88.9％)。HPLC:8.55min,99.7％；mp130.3-131.5℃；1H NMR(400MHz,CDCl3)δ7.55(d,J＝9.0Hz,2H),7.33(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),6.74(d,J＝8.9Hz,2H),4.95(s,2H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ159.59,158.71,138.22,129.19,128.55,117.36,114.08,82.95,69.91,55.31.
25)(4-碘苄基)(4-甲氧基苯基)硫醚((4-iodobenzyl)(4-methoxyphenyl)sulfane，化合物25)的合成
按照化合物1的方法制备(反应物用4-甲氧基苯硫酚代替4-硝基苯酚)，得到 白色固体25(712.4mg,94.7％)。1H NMR(400MHz,CDCl3)δ7.56(d,J＝8.3Hz,2H),7.23(d,J＝8.8Hz,2H),6.90(d,J＝8.3Hz,2H),6.79(d,J＝8.8Hz,2H),3.89(s,2H),3.78(s,3H).13C NMR(101MHz,CDCl3)δ159.43,138.01,137.40,134.36,130.81,125.45,114.54,92.31,55.31,40.77.
26)1-溴-4-((4-甲氧基苯氧基)甲基)苯(1-bromo-4-((4-methoxyphenoxy)methyl)benzene，化合物26)的合成
按照化合物1的方法制备(反应物用4-甲氧基苯酚代替4-硝基苯酚，用对溴溴苄代替4-碘溴苄)，得到白色固体26(2.93g,93.2％)。mp 105.3-106.7℃；1H NMR(400MHz,CDCl3)δ7.51(d,J＝8.3Hz,2H),7.30(d,J＝8.3Hz,2H),6.89(d,J＝9.2Hz,2H),6.83(d,J＝9.2Hz,2H),4.97(s,2H),3.77(s,3H).
27)1-溴-4-(4-甲氧基苄氧基)苯(1-bromo-4-(4-methoxybenzyloxy)benzene，化合物27)的合成
按照化合物1的方法制备(反应物用4-溴苯酚代替4-硝基苯酚，用4-甲氧基溴苄代替4-碘溴苄)，得到白色固体27(681.4mg,77.8％)。mp 122.1-122.9℃；1H NMR(400MHz,CDCl3)δ7.37(d,J＝9.0Hz,2H),7.33(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),6.84(d,J＝9.0Hz,2H),4.96(s,2H),3.82(s,3H).
28)4-(4-溴苄氧基)-N,N-二甲基苯胺(4-(4-bromobenzyloxy)-N,N-dimethyl aniline，化合物28)的合成
按照化合物1的方法制备(反应物用4-羟基-N,N-二甲基苯胺代替4-硝基苯酚，用对溴溴苄代替4-碘溴苄)，得白色固体28(303.5mg,99.1％)。mp 125.8-127.1℃；1H NMR(400MHz,CDCl3)δ7.52–7.48(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).
29)1-(苄氧基)-4-(2-氟乙氧基)苯(1-(benzyloxy)-4-(2-fluoroethoxy)benzene，化合物29)的合成
将4-苄氧基苯酚(2.00g,10.0mmol)和KOH(0.56g,10.0mmol)溶于30mL无水乙醇中，80℃加热回流30min，缓慢滴入20mL1-溴-2-氟乙烷(1.52g,12.0mmol)的乙醇溶液，继续回流搅拌反应1h，TLC监测反应基本结束，减压除去溶剂，加入50mL1M NaOH溶液，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到白色晶体29(2.23g,90.4％)。1H NMR(400MHz,CDCl3)δ7.46–7.28(m,5H),6.91(d,J＝9.2Hz,2H),6.86(d,J＝9.3Hz,2H),5.02(s,2H),4.81–4.64(m,2H),4.22–4.10(m,2H).
30)4-(2-氟乙氧基)苯酚(4-(2-fluoroethoxy)phenol，化合物30)的合成
将化合物29(2.08g,8.44mmol)溶于10mL无水甲醇中，加入钯炭催化剂(89.4mg,0.84mmol)，1atm H2条件下，50℃搅拌反应4h，TLC监测反应结束，抽滤除去钯炭催化剂，减压除去溶剂得白色固体30(1.32g,57.4％)。1H NMR(400MHz,CDCl3)δ6.83(d,J＝8.9Hz,2H),6.77(d,J＝9.0Hz,2H),4.80–4.64(m,2H),4.42(s,1H),4.23–4.09(m,2H).
31)1-(2-氟乙氧基)-4-(4-碘苄氧基)苯(1-(2-fluoroethoxy)-4-((4-iodob enzyl)oxy)benzene，化合物31a)的合成
将化合物30(468.5mg，3.0mmol)、4-碘溴苄(890.8mg，3.0mmol)溶于5mL无水DMF中，加入K2CO3(414.6mg，3.0mmol)。90℃回流搅拌反应0.5h，TLC监测反应结束，减 压除去溶剂，加入50mL去离子水，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到白色固体31a(986.8mg,88.4％)。1H NMR(400MHz,CDCl3)δ7.70(d,J＝8.3Hz,2H),7.16(d,J＝8.2Hz,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(101MHz,CDCl3)δ153.11,152.93,137.62,136.94,129.24,115.89,115.79,93.35,82.86,81.17,69.96,67.97,67.76.
32)1-溴-4-((4-(2-氟乙氧基)苯氧基)甲基)苯(1-bromo-4-((4-(2-fluoroethoxy)phenoxy)methyl)benzene，化合物31b)的合成
按照化合物31a的方法制备(反应物用对溴溴苄代替4-碘溴苄)，得白色固体31b(1.55g,95.2％)。1H NMR(400MHz,CDCl3)δ7.50(d,J＝8.4Hz,2H),7.29(d,J＝8.4Hz,2H),6.90–6.84(m,4H),4.97(s,2H),4.80–4.65(m,2H),4.21–4.11(m,2H).
33)4-(2-氟乙氧基)苯甲醛(4-(2-fluoroethoxy)benzaldehyde，化合物32)的合成
将对羟基苯甲醛(2.44g，20mmol)、1-溴-2-氟乙烷(2.54g，20mmol)溶于5mL无水DMF中，加入K2CO3(5.53g，40mmol)。90℃回流搅拌反应2h，TLC监测反应结束，减压除去溶剂，加入50mL去离子水，乙酸乙酯萃取(3×10mL)，无水MgSO4干燥，抽滤并减压除去溶剂得黄色油状液体32(2.95g,87.8％)。1H NMR(400MHz,CDCl3)δ9.90(s,1H),7.86(d,J＝8.7Hz,2H),7.04(d,J＝8.6Hz,2H),4.88–4.71(m,2H),4.37–4.24(m,2H).
34)(4-(2-氟乙氧基)苯基)甲醇((4-(2-fluoroethoxy)phenyl)methanol，化合物33)的合成
将化合物32(2.95g,17.6mmol)溶于10mL无水甲醇中，0℃搅拌下缓慢加入NaBH4(1.33g,35.2mmol)，继续反应0.5h，TLC监测反应结束，加入10mL去离子水淬灭反应，减压除去甲醇，适量1M HCl中和至pH＝7，CH2Cl2萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂得黄色油状液体33(2.73g,91.1％)。1H NMR(400MHz,CDCl3)δ7.31(d,J＝8.5Hz,2H),6.93(d,J＝8.5Hz,2H),4.84–4.68(m,2H),4.63(s,2H),4.27–4.17(m,2H).
35)1-(溴甲基)-4-(2-氟乙氧基)苯(1-(bromomethyl)-4-(2-fluoroethoxy)benzene，化合物34)的合成
将化合物33(2.73g,16.0mmol)溶于25mL无水CH2Cl2中，室温搅拌下缓慢滴加25mLPBr3(4.33g,16.0mmol)的CH2Cl2溶液，继续反应0.5h，TLC监测反应结束，加入20mL去离子水淬灭反应，再加入1g NaHCO3并继续搅拌0.5h，CH2Cl2萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂得无色油状液体34(3.54g,95.0％)。1H NMR(400MHz,CDCl3)δ7.33(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),4.84–4.68(m,2H),4.50(s,2H),4.27–4.16(m,2H).
36)1-(2-氟乙氧基)-4-((4-碘苯氧基)甲基)苯(1-(2-fluoroethoxy)-4-((4-iodophenoxy)methyl)benzene，化合物35a)的合成
按照化合物31a的方法制备(反应物用化合物34代替4-碘溴苄，用4-碘苯酚代替化合物30)，得白色固体35a(623.4mg,94.1％)。1H NMR(400MHz,CDCl3)δ7.55(d,J＝8.9Hz,2H),7.34(d,J＝8.6Hz,2H),6.94(d,J＝8.6Hz,2H),6.74(d,J＝8.9Hz,2H),4.95(s,2H),4.83–4.68(m,2H),4.27–4.16(m,2H).13C NMR(101MHz,CDCl3)δ158.65,158.39,138. 23,129.24,129.21,117.34,114.81,83.00,82.72,81.03,69.80,67.31,67.10.
37)1-溴-4-(4-(2-氟乙氧基)苄氧基)苯(1-bromo-4-((4-(2-fluoroethoxy)benzyl)oxy)benzene，35b)的合成
按照化合物31a的方法制备(反应物用化合物34代替4-碘溴苄，用4-溴苯酚代替化合物30)，得白色固体35b(1.03g,76.1％)。1H NMR(400MHz,CDCl3)δ7.35(7.39–7.31,4H),6.94(d,J＝8.0Hz,2H),6.84(d,J＝8.2Hz,2H),4.96(s,2H),4.76(d,J＝47.3Hz,2H),4.22(d,J＝27.8Hz,2H).
38)三丁基(4-((4-甲氧基苯氧基)甲基)苯基)锡(tributyl(4-((4-methoxyphenoxy)methyl)phenyl)stannane，化合物36)的合成
将化合物26(146.6mg,0.5mmol)、六正丁基二锡(580.1mg,1.0mmol)和四(三苯基磷)钯(57.8mg,0.05mmol)溶于10mL甲苯中(含1mL三乙胺)，回流搅拌反应过夜。减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝15/1)得无色油状化合物36(89.5mg,35.6％)。1HNMR(400MHz,CDCl3)δ7.49(d,J＝7.9Hz,2H),7.39(d,J＝7.8Hz,2H),6.93(d,J＝9.1Hz,2H),6.85(d,J＝9.1Hz,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＝7.3Hz,9H).
39)三丁基(4-(4-甲氧基苄氧基)苯基)锡(tributyl(4-(4-methoxybenzyloxy)phenyl)stannane，化合物37)的合成
按照化合物36的方法制备(反应物用化合物27代替化合物26)，得无色油状化合物37(75.0mg,29.8％)。1H NMR(400MHz,CDCl3)δ7.40–7.32(m,3H),7.31–7.27(m,1H),6.99–6.95(m,2H),6.91(d,J＝8.4Hz,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＝7.3Hz,9H).
40)N,N-二甲基-4-(4-(三丁基锡)苄氧基)苯胺(N,N-dimethyl-4-(4-(tribu tylstannyl)benzyloxy)aniline，化合物38)的合成
按照化合物36的方法制备(反应物用化合物28代替化合物26)，得无色油状化合物36(56.2mg,21.8％)。1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.7Hz,2H),7.39(d,J＝7.6Hz,2H),6.92(d,J＝9.0Hz,2H),6.76(d,J＝8.7Hz,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＝7.4Hz,9H).
41)三丁基(4-((4-(2-氟乙氧基)苯氧基)甲基)苯基)锡(tributyl(4-((4-(2-fluoroethoxy)phenoxy)methyl)phenyl)stannane，化合物39)的合成
按照化合物36的方法制备(反应物用化合物31b代替化合物26)，得无色油状化合物39(325.6mg,30.4％)。1H NMR(400MHz,CDCl3)δ7.54–7.41(m,2H),7.37(d,J＝7.8Hz,2H),6.92(d,J＝9.3Hz,2H),6.87(d,J＝9.3Hz,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＝7.3Hz,9H).
42)三丁基(4-(4-(2-氟乙氧基)苄氧基)苯基)锡(tributyl(4-((4-(2-fluoroethoxy)benzyl)oxy)phenyl)stannane，化合物40)的合成
按照化合物36的方法制备(反应物用化合物35b代替化合物26)，得无色透明油状化合物40(134.6mg,25.1％)。1H NMR(400MHz,CDCl3)δ7.37(d,J＝8.7Hz,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＝7.3Hz,9H).
实施例2：氟代化合物的合成
合成反应路线如图2所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图2所示的合成路线中，试剂与条件如下：
(a)1-bromo-2-fluoroethane(1-溴-2-氟乙烷)or1,2-二溴乙烷(1,2-dibromoethane),K2CO3,DMF,90℃；(b)NaBH4,MeOH,0℃；(c)PBr3,CH2Cl2,r.t.；(d)4-methoxyphenol(4-甲氧基苯酚)or4-nitrophenol(4-硝基苯酚),K2CO3,DMF,90℃；(e)SnCl2·2H2O,EtOH,HCl,回流；(f)1:NaOMe,(CH2O)n,MeOH,回流；2:NaBH4,回流；(g)(CH2O)n,NaBH3CN,HAc,r.t.；(h)AgOTs,MeCN,回流；(i)18F-,K2CO3,Kryptofix-2.2.2(即K222,氨基聚醚),乙腈,100℃；(j)2-chloroethanol(2-氯乙醇)or2-(2-(2-chloroethoxy)ethoxy)ethanol(2-(2-(2-氯乙氧基)乙氧基)乙醇代替2-氯乙醇),KOH,EtOH,回流；(k)10％Pd/C,1atm H2,50℃；(l)1-(chloromethyl)-4-methoxybenzene(1-(氯甲基)-4-甲氧基苯，即4-甲氧基苄氯),K2CO3,DMF,90℃；(m)TsCl,CH2Cl2,Et3N,0℃～rt；(n)TBAF(1M in THF),THF,回流.
1)4-(2-溴乙氧基)苯甲醛(4-(2-bromoethoxy)benzaldehyde，化合物41)的合成
将对羟基苯甲醛(2.44g，20mmol)、1,2-二溴乙烷(7.51g，40mmol)溶于5mL无水DMF中，加入K2CO3(5.53g，40mmol)。90℃回流搅拌反应2h，TLC监测反应结束，减压除去溶剂，加入50mL去离子水，CH2Cl2萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝4/1)得白色固体41(1.32g,28.9％)。1H NMR(400MHz,CDCl3)δ9.90(s,1H),7.85(d,J＝8.8Hz,2H),7.02(d,J＝8.7Hz,2H),4.38(t,J＝6.2Hz,2H),3.67(t,J＝6.2Hz,2H).
2)(4-(2-溴乙氧基)苯基)甲醇((4-(2-bromoethoxy)phenyl)methanol，化合物42)的合成
按照化合物33的方法制备(反应物用化合物41代替化合物32)，得白色固体42(1.14g,95.8％)。1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.5Hz,2H),6.91(d,J＝8.6Hz,2H),4.63(s,2H),4.30(t,J＝6.3Hz,2H),3.64(t,J＝6.3Hz,2H).
3)1-(2-溴乙氧基)-4-(溴甲基)苯(1-(2-bromoethoxy)-4-(bromomethyl)benzene，化合物43)的合成
按照化合物34的方法制备(反应物用化合物42代替化合物33)，得白色固体43(1.29g,99.0％)。1H NMR(400MHz,CDCl3)δ7.33(d,J＝8.7Hz,2H),6.87(d,J＝8.7Hz,2H),4.49(s,2H),4.29(t,J＝6.3Hz,2H),3.63(t,J＝6.3Hz,2H).
4)1-(2-氟乙氧基)-4-((4-甲氧基苯氧基)甲基)苯(1-(2-fluoroethoxy)-4-((4-methoxyphenoxy)methyl)benzene，化合物44a)的合成
将化合物34(411.3mg，1.76mmol)、4-甲氧基苯酚(218.5mg，1.76mmol)溶于5mL无水DMF中，加入K2CO3(243.2mg，1.76mmol)。90℃回流搅拌反应0.5h，TLC监测反应结 束，减压除去溶剂，加入50mL去离子水，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到白色固体44a(136.5mg,28.1％)。1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.5Hz,2H),6.97–6.87(m,4H),6.83(d,J＝9.1Hz,2H),4.94(s,2H),4.84–4.67(m,2H),4.28–4.15(m,2H),3.77(s,3H).13C NMR(101MHz,CDCl3)δ158.24,154.01,152.99,130.09,129.20,115.95,114.74,114.67,82.74,81.04,70.45,67.31,67.10,55.71.
5)1-(2-溴乙氧基)-4-((4-甲氧基苯氧基)甲基)苯(1-(2-bromoethoxy)-4-((4-methoxyphenoxy)methyl)benzene，化合物44b)的合成
按照化合物44a的方法制备(反应物用化合物43代替化合物34)，得白色固体44b(242.8mg,68.1％)。1H NMR(400MHz,CDCl3)δ7.35(d,J＝8.6Hz,2H),6.94–6.87(m,4H),6.83(d,J＝9.2Hz,2H),4.94(s,2H),4.30(t,J＝6.3Hz,2H),3.77(s,3H),3.63(t,J＝6.3Hz,2H).
6)1-(2-氟乙氧基)-4-((4-硝基苯氧基)甲基)苯(1-(2-fluoroethoxy)-4-((4-nitrophenoxy)methyl)benzene，化合物44c)的合成
按照化合物44a的方法制备(反应物用4-硝基苯酚代替4-甲氧基苯酚)，得白色固体44c(2.35g,78.6％)。1H NMR(400MHz,CDCl3)δ8.20(d,J＝9.2Hz,2H),7.36(d,J＝8.5Hz,2H),7.02(d,J＝9.2Hz,2H),6.96(d,J＝8.5Hz,2H),5.09(s,2H),4.86–4.67(m,2H),4.31–4.17(m,2H).
7)4-(4-(2-氟乙氧基)苄氧基)苯胺(4-(4-(2-fluoroethoxy)benzyloxy)aniline，化合物45)的合成
将化合物44c(1.94g,6.67mmol)和SnCl2·2H2O(3.01g,13.34mmol)溶于25mL乙醇中，滴加2mL浓盐酸，80℃下回流搅拌反应2h,冷却至室温，加入30mL 1M NaOH水溶液中和盐酸及沉淀SnCl2，乙酸乙酯萃取(3×10mL)，合并有机相，无水MgSO4干燥，抽滤并减压除去溶剂得白色固体45(1.26g,72.5％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.4Hz,2H),6.92(d,J＝8.5Hz,2H),6.80(d,J＝8.6Hz,2H),6.63(d,J＝8.6Hz,2H),4.91(s,2H),4.84–4.67(m,2H),4.27–4.15(m,2H),3.42(s,2H).
8)4-(4-(2-氟乙氧基)苄氧基)-N-甲基苯胺(4-(4-(2-fluoroethoxy)benzyloxy)-N-methylaniline，化合物46)的合成
将化合物45(522.6mg,2.0mmol)和多聚甲醛(240.0mg,8.0mmol)溶于30mL无水甲醇中，逐滴加入5mL NaOCH3(216.1mg,4.0mmol)的甲醇溶液，回流搅拌反应2h。冷却至室温后，缓慢加入NaBH4(302.4mg,8.0mmol)，继续回流搅拌反应2h。减压除去溶剂，加入50mL1M NaOH溶液，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到淡黄色晶体46(423.6mg,76.9％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝4.8Hz,2H),6.92(d,J＝4.8Hz,2H),6.85(d,J＝5.0Hz,2H),6.57(d,J＝4.9Hz,2H),4.92(s,2H),4.75(d,J＝47.4Hz,2H),4.22(d,J＝27.6Hz,2H),3.49(s,1H),2.80(s,3H).
9)4-(4-(2-氟乙氧基)苄氧基)-N,N-二甲基苯胺(4-(4-(2-fluoroethoxy)benzyloxy)-N,N-dimethylaniline，化合物47)的合成
将化合物45(261.3mg,1.0mmol)与多聚甲醛(300.0mg,10.0mmol)溶于20mL醋酸中，缓慢加入NaBH3CN(314.0mg,5.0mmol)，室温下搅拌反应24h。加入20mL1M NaOH溶液，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得淡黄色晶体47(213.9mg,75.8％)。1H  NMR(400MHz,CDCl3)δ7.35(d,J＝8.0Hz,2H),6.96–6.87(m,4H),6.77(s,2H),4.94(s,2H),4.75(d,J＝47.7Hz,2H),4.22(d,J＝27.7Hz,2H),2.88(s,6H).
10)2-(4-((4-甲氧基苯氧基)甲基)苯氧基)乙基-4-甲基苯磺酸(2-(4-((4-methoxyphenoxy)methyl)phenoxy)ethyl-4-methylbenzenesulfonate，化合物48)的合成
将化合物44b(137.2mg,0.41mmol)和对甲苯磺酸银(227.1mg,0.82mg)溶于20mL乙腈中，90℃回流搅拌反应12h，TLC监测反应基本结束，减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝4/1)得白色固体48(174.4mg,60.6％)。1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.3Hz,2H),7.34(d,J＝8.1Hz,2H),7.31(d,J＝8.6Hz,2H),6.89(d,J＝9.2Hz,2H),6.82(d,J＝9.2Hz,2H),6.78(d,J＝8.6Hz,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(101MHz,CDCl3)δ157.80,154.01,152.94,144.94,132.96,130.21,129.86,129.12,127.99,115.92(overlapped),114.66,70.39,68.09,65.52,55.72,21.62.
11)2-(4-(苄氧基)苯氧基)乙醇(2-(4-(benzyloxy)phenoxy)ethanol，化合物49a)的合成
将4-苄氧基苯酚(4.00g,20.0mmol)和KOH(1.12g,20.0mmol)溶于30mL无水乙醇中，80℃加热回流30min，缓慢滴入20mL2-氯乙醇(2.01g,25mmol)的乙醇溶液，继续回流搅拌反应1h，TLC监测反应基本结束，减压除去溶剂，加入50mL1M NaOH溶液，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到白色晶体49a(2.35g,48.1％)。1H NMR(400MHz,CDCl3)δ7.46–7.30(m,5H),6.91(d,J＝9.1Hz,2H),6.85(d,J＝9.0Hz,2H),5.02(s,2H),4.08–3.99(m,2H),3.97–3.87(m,2H),1.95(s,1H).
12)2-(2-(2-(4-(苄氧基)苯氧基)乙氧基)乙氧基)乙醇(2-(2-(2-(4-(benzyloxy)phenoxy)ethoxy)ethoxy)ethanol，化合物49b)的合成
按照化合物49a的方法制备(反应物用2-(2-(2-氯乙氧基)乙氧基)乙醇代替2-氯乙醇)，得白色固体49b(2.55g,38.3％)。1H NMR(400MHz,CDCl3)δ7.46–7.29(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).
13)4-(2-羟乙氧基)苯酚(4-(2-hydroxyethoxy)phenol，化合物50a)的合成
将化合物49a(2.15g,8.79mmol)溶于10mL无水甲醇中，加入钯炭催化剂(93.6mg,0.88mmol)，1atm H2条件下，50℃搅拌反应4h，TLC监测反应结束，抽滤除去钯炭催化剂，减压除去溶剂得白色固体50a(1.35g,100％)。1H NMR(400MHz,DMSO)δ8.86(s,1H),6.74(d,J＝8.6Hz,2H),6.66(d,J＝8.8Hz,2H),4.78(t,J＝5.2Hz,1H),3.90–3.80(m,2H),3.70–3.61(m,2H).
14)4-(2-(2-(2-羟乙氧基)乙氧基)乙氧基)苯酚(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenol，化合物50b)的合成
按照化合物50a的方法制备(反应物用化合物49b代替化合物49a)，得无色透明油状化合物50b(1.78g,98.6％)。1H NMR(400MHz,CDCl3)δ7.26(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).
15)2-(4-(4-甲氧基苄氧基)苯氧基)乙醇(2-(4-(4-methoxybenzyloxy)phenoxy)ethanol，化合物51a)的合成
将化合物50a(235.3mg，1.53mmol)、4-甲氧基苄氯(239.6mg，1.53mmol)溶于5mL无水DMF中，加入K2CO3(211.6mg，1.53mmol)。90℃回流搅拌反应0.5h，TLC监测反应结束，减压除去溶剂，加入50mL去离子水，有白色沉淀析出，抽滤，水洗沉淀，甲醇重结晶得到白色固体51a(282.8mg,67.4％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.6Hz,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).
16)2-(2-(2-(4-(4-甲氧基苄氧基)苯氧基)乙氧基)乙氧基)乙醇(2-(2-(2-(4-(4-methoxybenzyloxy)phenoxy)ethoxy)ethoxy)ethanol，化合物51b)的合成
按照化合物51a的方法制备(反应物用化合物50b代替化合物50a)，得白色固体51b(369.7mg,66.9％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.0Hz,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).
17)2-(4-(4-甲氧基苄氧基)苯氧基)乙基-4-甲基苯磺酸(2-(4-(4-methoxybenzyloxy)phenoxy)ethyl-4-methylbenzenesulfonate，化合物52a)的合成
将化合物51a(137.2mg,0.5mmol)溶于10mL CH2Cl2中，加入10mL三乙胺，冰浴搅拌下缓慢加入对甲苯磺酰氯(143.0mg,0.75mmol)，继续搅拌反应4h，TLC监测反应结束，减压除去溶剂，加入50mL去离子水，CH2Cl2萃取(3×10mL)，无水MgSO4干燥，抽滤并减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝4/1)得白色固体52a(214.3mg,77.2％)。1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.1Hz,2H),7.33(d,J＝8.1Hz,4H),6.91(d,J＝8.4Hz,2H),6.85(d,J＝8.7Hz,2H),6.72(d,J＝8.9Hz,2H),4.92(s,2H),4.37–4.31(m,2H),4.12–4.07(m,2H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ159.46,153.57,152.32,144.89,133.01,129.84,129.18,128.00,115.88,115.76,114.00,70.45,68.27,66.26,55.29,21.62.
18)2-(2-(2-(4-(4-甲氧基苄氧基)苯氧基)乙氧基)乙氧基)乙基-4-甲基苯磺酸(2-(2-(2-(4-(4-methoxybenzyloxy)phenoxy)ethoxy)ethoxy)ethyl-4-methylbenzenesulfonate，化合物52b)的合成
按照化合物52a的方法制备(反应物用化合物51b代替化合物51a)，得无色透明油状液体52b(225.4mg,83.9％)。1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.9Hz,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(101MHz,CDCl3)δ159.44,153.25,153.12,144.76,133.17,129.81,129.36,129.18,127.96,115.91,115.66,113.99,70.81,70.75,70.52,69.93,69.25,68.74,68.13,55.29,21.59.
19)1-(2-氟乙氧基)-4-(4-甲氧基苄氧基)苯(1-(2-fluoroethoxy)-4-(4-me thoxybenzyloxy)benzene，化合物53a)的合成
将化合物52a(128.6mg,0.3mmol)溶于5mL无水THF中，滴加0.6mL四丁基氟化铵的四氢呋喃溶液(1M)。80℃回流搅拌反应2h，TLC监测反应结束，减压除去溶剂，残余物经硅胶柱层析分离(石油醚/乙酸乙酯＝2/1)得白色固体53a(70.7mg,85.3％)。 1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.2Hz,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(101MHz,CDCl3)δ159.48,153.56,152.80,129.31,129.19,115.99,115.82,114.02,82.90,81.20,70.52,68.06,67.85,55.30.
20)1-(2-(2-(2-氟乙氧基)乙氧基)乙氧基)-4-(4-甲氧基苄氧基)苯(1-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-4-(4-methoxybenzyloxy)benzene，化合物53b)的合成
按照化合物53a的方法制备(反应物用化合物52b代替化合物52a)，得无色透明油状液体53b(87.5mg,73.7％)。1H NMR(400MHz,CDCl3)δ7.34(d,J＝8.2Hz,2H),6.94–6.82(m,4H),4.93(s,2H),4.56(d,J＝47.8Hz,2H),4.09(s,2H),3.85–3.70(m,11H).13C NMR(101MHz,CDCl3)δ159.42,153.21,153.13,129.34,129.18,115.87,115.64,113.97,83.97,82.29,70.85,70.84,70.54,70.49,70.34,69.93,68.12,55.28.
实施例3：吡啶衍生物的合成
合成反应路线如图3所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图3所示的合成路线中，试剂与条件如下：(a)K2CO3,DMF,90℃；(b)SnCl2·2H2O,EtOH,HCl,回流；(c)CH3I,K2CO3,r.t.
1)2-(4-碘苄氧基)吡啶(2-((4-iodobenzyl)oxy)pyridine，化合物54)的合成
按照化合物1的方法制备(反应物用2-羟基吡啶代替4-硝基苯酚)，得到白色固体54(187.5mg,60.3％)。1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.2Hz,2H),7.34(ddd,J＝8.8,6.7,1.8Hz,1H),7.26–7.24(m,1H),7.06(d,J＝8.2Hz,3H),6.66(d,J＝9.1Hz,1H),6.19(t,J＝6.7Hz,1H),5.09(s,2H).
2)2-氯-5-(4-碘苄氧基)吡啶(2-chloro-5-((4-iodobenzyl)oxy)pyridine，化合物55)的合成
按照化合物1的方法制备(反应物用2-氯-5-羟基吡啶代替4-硝基苯酚)，得到白色固体55(635.7mg,92.0％)。1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.73(d,J＝8.2Hz,2H),7.24–7.21(m,2H),7.16(d,J＝8.1Hz,2H),5.04(s,2H).
3)5-溴-2-(4-碘苄氧基)吡啶(5-bromo-2-((4-iodobenzyl)oxy)pyridine，化合物56)的合成
按照化合物1的方法制备(反应物用5-溴-2-羟基吡啶代替4-硝基苯酚)，得到白色固体56(346.5mg,88.8％)。1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.3Hz,2H),7.36–7.32(m,2H),7.06(d,J＝8.2Hz,2H),6.54(d,J＝10.5Hz,1H),5.03(s,2H).
4)2-溴-5-(4-碘苄氧基)吡啶(2-bromo-5-((4-iodobenzyl)oxy)pyridine，化合物57)的合成
按照化合物1的方法制备(反应物用2-溴-5-羟基吡啶代替4-硝基苯酚)，得到白色固体57(361.7mg,92.7％)。1H NMR(400MHz,CDCl3)δ8.11(d,J＝3.1Hz,1H),7.73(d,J＝8.2Hz,2H),7.37(d,J＝8.7Hz,1H),7.17–7.11(m,3H),5.03(s,2H).
5)5-碘-2-(4-碘苄氧基)吡啶(5-iodo-2-((4-iodobenzyl)oxy)pyridine，化合物58)的合成
按照化合物1的方法制备(反应物用2-羟基-5-碘吡啶代替4-硝基苯酚)，得到白色固体58(321.5mg,73.6％)。1H NMR(400MHz,CDCl3)δ7.69(d,J＝8.3Hz,2H),7.45(d,J＝2.2Hz,1H),7.42(dd,J＝9.5,2.4Hz,1H),7.05(d,J＝8.2Hz,2H),6.44(d,J＝9.5Hz,1H),5.02(s,2H).
6)2-碘-5-(4-碘苄氧基)吡啶(2-iodo-5-((4-iodobenzyl)oxy)pyridine，化合物59)的合成
按照化合物1的方法制备(反应物用2-碘-5-羟基吡啶代替4-硝基苯酚)，得到白色固体59(289.8mg,48.8％)。1H NMR(400MHz,CDCl3)δ8.06–8.02(m,1H),7.75(d,J＝8.2Hz,2H),7.24(d,J＝8.4Hz,2H),7.21–7.15(m,1H),7.03–6.98(m,1H),5.12(s,2H).
7)2-(4-碘苄氧基)-5-硝基吡啶(2-((4-iodobenzyl)oxy)-5-nitropyridine，化合物60)的合成
按照化合物1的方法制备(反应物用2-羟基-5-硝基吡啶代替4-硝基苯酚)，得到黄色固体60(343.0mg,96.3％)。1H NMR(400MHz,CDCl3)δ8.58(d,J＝3.0Hz,1H),8.08(dd,J＝10.1,3.0Hz,1H),7.73(d,J＝8.2Hz,2H),7.11(d,J＝8.2Hz,2H),6.60(d,J＝10.1Hz,1H),5.12(s,2H).
8)6-(4-碘苄氧基)吡啶-3-胺(6-((4-iodobenzyl)oxy)pyridin-3-amine，化合物61)的合成
按照化合物16的方法制备(反应物用化合物60代替化合物1)，得到蓝色固体61(203.4mg,82.0％)。1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.2Hz,2H),7.06–7.02(m,3H),6.70(d,J＝2.9Hz,1H),6.57(d,J＝9.6Hz,1H),5.01(s,2H).
9)6-(4-碘苄氧基)-N,N-二甲基氨基吡啶-3-胺(6-((4-iodobenzyl)oxy)-N,N-dimethylpyridin-3-amine，化合物62)的合成
按照化合物21的方法制备(反应物用化合物61代替化合物18)，得到蓝色固体61(66.8mg,35.6％)。1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.3Hz,3H),7.34(d,J＝9.7Hz,1H),7.09(d,J＝8.0Hz,2H),6.67(d,J＝9.8Hz,1H),5.06(s,2H),2.82(s,6H).
10)2-碘-5-(4-甲氧基苄氧基)吡啶(2-iodo-5-((4-methoxybenzyl)oxy)pyridine，化合物63)的合成
按照化合物1的方法制备(反应物用2-碘-5-羟基吡啶代替4-硝基苯酚，用4-甲氧基溴苄代替4-碘溴苄)，得到白色固体63(569.1mg,83.4％)。1H NMR(400MHz,CDCl3)δ8.01(dd,J＝4.6,1.4Hz,1H),7.39(d,J＝8.6Hz,2H),7.16(dd,J＝8.1,4.6Hz,1H),7.05–7.01(m,1H),6.93(d,J＝8.7Hz,2H),5.11(s,2H),3.82(s,3H).
11)5-碘-2-(4-甲氧基苄氧基)吡啶(5-iodo-2-((4-methoxybenzyl)oxy)pyridine，化合物64)的合成
按照化合物1的方法制备(反应物用2-羟基-5-碘吡啶代替4-硝基苯酚，用4-甲氧基溴苄代替4-碘溴苄)，得到白色固体64(297.4mg,87.2％)。1H NMR(400MHz,CDCl3)δ7.46(d,J＝2.4Hz,1H),7.40(dd,J＝9.5,2.4Hz,1H),7.26(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),6.45(d,J＝9.5Hz,1H),5.02(s,2H),3.80(s,3H).
12)5-(4-(2-氟乙氧基)苄氧基)-2-碘吡啶(5-((4-(2-fluoroethoxy)benzyl)oxy)-2-iodopyridine，化合物65)的合成
按照化合物1的方法制备(反应物用2-碘-5-羟基吡啶代替4-硝基苯酚，用化合物34代替4-碘溴苄)，得到白色固体65(357.4mg,73.1％)。1H NMR(400MHz,CDCl3)δ8.05(d,J＝4.7Hz,1H),7.40(d,J＝8.6Hz,2H),7.21(dd,J＝8.0,4.8Hz,1H),7.07(d,J＝8.2Hz,1H),6.96(d,J＝8.7Hz,2H),5.13(s,2H),4.85–4.68(m,2H),4.29–4.18(m,2H).
13)2-(4-(2-氟乙氧基)苄氧基)-5-碘吡啶(2-((4-(2-fluoroethoxy)benzyl)oxy)-5-iodopyridine，化合物66)的合成
按照化合物1的方法制备(反应物用2-羟基-5-碘吡啶代替4-硝基苯酚，用化合物34代替4-碘溴苄)，得到白色固体66(297.8mg,79.8％)。1H NMR(400MHz,CDCl3)δ7.47(s,1H),7.43(d,J＝9.5Hz,1H),7.29–7.26(m,2H),6.92(d,J＝8.6Hz,2H),6.51(dd,J＝9.4,3.6Hz,1H),5.04(s,2H),4.83–4.68(m,2H),4.27–4.15(m,2H).
实施例4：苄基胺衍生物的合成
合成反应路线如图4所示，本实施例中的化合物编号均与该图反应路线中的编号统一。
在图4所示的合成路线中，试剂与条件如下：(a)EtOH,回流；(b)NaBH4,MeOH,回流.
1)4-(((4-碘苯基)氨基)甲基)-N，N-二甲氨基苯胺(4-(((4-iodophenyl)amino)methyl)-N,N-dimethylaniline，化合物67)的合成
将4-碘苯胺(876.1mg，4.0mmol)和4-二甲氨基苯甲醛(596.8mg，4.0mmol)溶于25mL无水乙醇中，90℃回流搅拌反应15min，有大量白色晶体析出，冷却后抽滤，冷乙醇洗涤，干燥后溶于50mL甲醇中，并缓慢加入NaBH4(453.6mg，12.0mmol)，90℃回流搅拌反应30min。TLC监测反应基本完成，减压除去甲醇，加入50mL去离子水，有大量白色固体析出，抽滤，水洗，干燥得白色固体产物(821.1mg,58.3％)。1H NMR(400MHz,CDCl3)δ7.41(d,J＝8.5Hz,2H),7.22(d,J＝8.1Hz,2H),6.74(s,2H),6.42(d,J＝8.6Hz,2H),4.17(s,2H),2.95(s,6H).
实施例5：125I和18F标记配体的制备
一、实验步骤：
1)化合物[125I]4、[125I]24、[125I]22、[125I]31a和[125I]35a的制备
合成反应路线见图1，称取0.1mg各相应锡前体(分别为化合物36、37、38、39和40)于玻璃反应瓶中，加入100μL乙醇溶解，再依次加入1μL[125]NaI溶液(200μCi，2200Ci/mmol)，100μL1M盐酸和50μL H2O2水溶液(3％)。密闭后室温下反应15min，加入20μL饱和亚硫酸氢钠溶液终止反应，适量NaHCO3调节至中性。反应液经HPLC分离，分离条件：Venusil MP C18反向柱(5μm,4.6×250mm)；CH3CN:H2O＝80％:20％；流速1.0mL/min。[125]22的分离条件为：Venusil MP C18反向柱(5μm,4.6×250mm)；CH3CN:10mMAcNH4＝80％:20％；流速1.0mL/min。并通过HPLC分析125I标记配体与参比化合物的保留时间。所得125I标记配体置于-20℃下储存待用。
2)化合物[18F]44a、[18F]53a和[18F]53b的制备
合成反应路线见图2，将1.0mg相应标记前体(分别为化合物48、52a和52b)溶于0.8mL无水乙腈中，并将其加入到已除水的含一定活度的含K222/K2CO3的18F-的反应管中，在100℃的条件下标记5min，冷却后加入10mL去离子水稀释反应混合物。混合液通过 经预处理的Sep-Pak Plus C-18固相萃取小柱纯化，再用10mL去离子水淋洗柱子除去未反应的[18F]F-及无机盐类，N2吹干柱子后，用2×1mL无水乙腈将吸附在柱子上的标记化合物及标记前体洗脱下来，浓缩后通过HPLC分离纯化，分离条件：Venusil MP C18反向柱(5μm,10×250mm)；CH3CN:H2O＝70％:30％；流速4.0mL/min。并通过HPLC分析18F标记配体与参比化合物的保留时间，分析条件与分离条件相同。
二、实验结果：
125I标记配体由经典的锡卤交换法制备。[125I]4、[125I]24、[125I]22、[125I]31a和[125I]35a的标记率依次为86.2％、94.9％、92.9％、67.3％和27.1％。经HPLC分离纯化后，放射性化学纯度都大于95％，且与稳定碘代配体的保留时间一致(见表1)。
18F标记化合物由一步法制备。[18F]44a、[18F]53a和[18F]53b的标记率依次为13.8％、13.4％和23.9％。经HPLC分离纯化后，放射性化学纯度都大于98％，且与稳定配体的保留时间一致(见表1)。
表1：125I、18F标记配体及其稳定配体的保留时间和纯度
Figure PCTCN2014090510-appb-000016
实验例1：生物评价
化合物4～25，31a，35a，44a，46，47，53a，55，57～59，65，67，IMPY和PIB与Aβ1-42聚集体体外竞争结合实验(Ki测定)：
一定浓度的Aβ1-42聚集体蛋白与一定浓度的放射性配基[125I]IMPY发生结合反应，反应***中同时加入不同浓度的待测化合物(分别制备的化合物4～25，31a，35a，44a，46，47，53a，55，57～59，65和67)以及IMPY和PIB与[125I]4发生竞争反应，平衡后分离复合物通过测定放射性来计算抑制常数(Ki)。
1、实验步骤：
(1)配制pH＝7.4的PBS(0.2M)缓冲液4L；
(2)放射配基[125I]IMPY按照已有方法制备；将[125I]IMPY配制成100000cpm/100μL的水溶液；
(3)将待测化合物配制成10-3至10-9mol/L连续稀释的乙醇溶液；
(4)受体Aβ1-42蛋白按照已有方法制备。将其稀释成约30nM的水溶液；
(5)玻璃纤维滤膜用含0.1％(体积分数)聚乙烯亚胺的PBS溶液浸泡0.5h；
(6)在12×75mm高硼硅玻璃管中分别加入100μL不同浓度待测化合物溶液和100μL[125I]IMPY溶液、700μL PBS及100μL Aβ1-42溶液。用封口膜封好，涡旋；
(7)在37℃恒温水浴中振荡孵育2h；
(8)多头细胞收集器收集反应液，用PBS冲洗三遍，每次3mL；
(9)用γ计数仪测量计数；
(10)数据处理。
2、实验结果：
由竞争结合实验得到的半抑制常数(IC50)以及进一步根据公式计算出的抑制常数Ki见表2。
Figure PCTCN2014090510-appb-000017
表2：化合物4～25，31a，35a，44a，46，47，53a
和53b与Aβ1-42聚集体的亲和力常数
Figure PCTCN2014090510-appb-000018
Figure PCTCN2014090510-appb-000019
通过上述的竞争结合实验可知，本发明所述的化合物中4、11、12、13、22、31a、35a及47具有与Aβ1-42聚集体较高的亲和力，相比已知化合物IMPY和PIB要高。
本实验例中，已知化合物IMPY和PIB的结构式分别为：
Figure PCTCN2014090510-appb-000020
实验例2：放射自显影实验
分别让一定浓度的18F或125I标记的化合物与AD转基因小鼠及AD病人脑切片中的斑块结合后，通过磷屏曝光，后用储磷屏***分析图像。
1、实验步骤：
(1)预处理AD转基因小鼠脑切片和AD人脑切片；
(2)分别在AD转基因小鼠脑切片或AD人脑切片上覆盖5μCi的18F或125I标记的化合物溶液100μL，室温下孵育60分钟；
(3)依次用碳酸锂饱和的40％乙醇溶液冲洗5分钟，流水冲洗5分钟；
(4)晾干后，保鲜膜包覆置于磷屏下曝光120分钟，用储磷屏***分析图像。
2、实验结果：
实验结果如图5和图6所示，充分说明本发明的化合物被放射性核素标记后，可以作为脑Aβ斑块的显像剂，在临床诊断中应用。
图5显示：[125I]4、[125I]24和[125I]23分别在人脑切片((A、E和I)AD，64岁，女性；(B、F和J)正常，74岁，男性)和鼠脑切片((C、G和K)转基因小鼠，APPswe/PSEN1，11月；(D、H和L)正常，C57BL6,11月)的放射自显影结果.相同切片经过硫磺素-S染色加以对照。
图6显示：[18F]53a和[18F]53b分别在人脑切片((A、E)AD，64岁，女性；(B、F)正常，74岁，男性)和鼠脑切片((C、G)转基因小鼠，APPswe/PSEN1，11月；(D、H)正常，C57BL6,11月)的放射自显影结果，相同切片经过硫磺素-S染色加以对照。
实验例3：正常小鼠体内生物分布实验
通过体内分布实验研究了18F或125I标记的化合物在小鼠体内的药代动力学性质，特别是初始脑摄取和脑清除情况。
1、实验步骤
将5-10μCi标记化合物(100μL生理盐水溶液，含5％乙醇)由尾静脉注射入正常小鼠(ICR，male，20-22g，5周龄)体内(n＝5)，分别于注射后2分钟、10分钟、30分钟和60分钟将其断头处死，解剖取出相关脏器，测量湿重及放射性计数。数据表示为脏器中放射性百分剂量(％ID/organ)和每克脏器中放射性百分剂量(％ID/g)。
2、实验结果
实验结果如表3所示，本发明所述的18F或125I标记的化合物都可以顺利的通过血脑屏障，2分钟时脑部摄取达到峰值且在正常小鼠脑部清除很快，2分钟与60分钟脑摄取比值达到10左右。再进一步与现有技术(已知)化合物如[125I]IMPY对比可以发现，本发明的苯基苄基醚类化合物在正常小鼠脑部的清除速率显著优于它们。
本实验例中，已知化合物[125I]IMPY的结构式为：
Figure PCTCN2014090510-appb-000021
表3：[125I]4、[125I]24、[125I]22、[125I]31a、[125I]35a、
[125I]IMPY、[18F]44a、[18F]53a及[18F]53b
在正常小鼠体内生物分布结果a
Figure PCTCN2014090510-appb-000022
Figure PCTCN2014090510-appb-000023
a表示为％ID/g，n＝4-5
b表示为％ID/organ(器官)
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (15)

  1. 一种苯基苄基醚类衍生物，其结构式如式(I)所示：
    Figure PCTCN2014090510-appb-100001
    其中，X为O，NH或S；Y1和Y2各自独立地表示-CH-或氮；
    R1和R2各自独立地表示氢、卤素、羟基、巯基、烷氧基、烷基、碳环烷基、杂环烷基、硝基、氨基、烷氨基、氰基、羧基、芳基、杂芳基、芳基烷氧基、取代芳基烷氧基、芳基氧基、取代芳基氧基、芳基烯基、取代芳基烯基、-O(CH2)mNRaRb、-CO-NRaRb、-NHCO-Ra、-Sn(烷基)3、-(CH2)m-Z、-O(CH2)m-Z、-(CH2)m-芳基或-(OCH2CH2)n-Z；
    Ra和Rb各自独立地表示氢、烷基或-(CH2)m-芳基；Z表示卤素、羟基、三氟甲基磺酰基、甲基磺酰基或对甲苯磺酰基；m和n分别取1～6的整数，均分别优选1～3的整数。
  2. 根据权利要求1所述的苯基苄基醚类衍生物，其特征在于，R1和R2均为邻位、间位或对位取代基。
  3. 根据权利要求1或2所述的苯基苄基醚类衍生物，其特征在于，所述卤素为氟、氯、溴或碘；所述烷氧基为C1～C12烷氧基，优选为C1～C6烷氧基；所述烷基为C1～C12烷基，优选为C1～C6烷基；所述碳环烷基为3～6元碳环烷基，优选为环丙烷基、环戊烷基或环己烷基；所述杂环烷基为3～6元杂环烷基，优选为哌啶基、哌嗪基或吗啉环基；所述烷氨基为C1～C12烷氨基，优选为C1～C6烷氨基，更优选为N-甲氨基、二甲氨基、二乙氨基、二丙氨基或二异丙氨基；所述芳基为苯基或萘基；所述杂芳基为吡啶基、呋喃基、噻吩基、苯并噻唑基、苯并呋喃基或苯并恶唑基；所述芳基烷氧基为C5～C7芳基C1～C12烷氧基，优选为苯基甲氧基或苯基乙氧基；所述取代芳基烷氧基为取代C5～C7芳基C1～C12烷氧基，优选为取代苯基甲氧基或取代苯基乙氧基；所述芳基氧基为C5～C7芳基氧基，优选为环戊二烯基氧基或苯基氧基；所述取代芳基氧基为取代C5～C7芳基氧基，优选为取代环戊二烯基氧基或取代苯基氧基；所述芳基烯基为C5～C7芳基C2～C6烯基，优选为苯基乙烯基；所述取代芳基烯基为取代C5～C7芳基C2～C6烯基，优选为取代苯基乙烯基。
  4. 根据权利要求1～3任意一项所述的苯基苄基醚类衍生物，其特征在于，其结构式如式(I-1)所示：
    Figure PCTCN2014090510-appb-100002
    其中，X为O，NH或S；
    R1为硝基、甲氧基、羟基、氟、氯、溴、碘、氢、叔丁基、氨基、甲氨基、二甲氨基、-OCH2CH2F、-Sn(丁基)3、-OCH2CH2OH、-(OCH2CH2)3OH、-OCH2CH2OTs、-(OCH2CH2)3OTs或-(OCH2CH2)3F；
    R2为碘、甲氧基、溴、氢、-OCH2CH2F、-Sn(丁基)3、-OCH2CH2Br、-OCH2CH2OTs或二甲氨基；优选地，R1和R2分别为：
    Figure PCTCN2014090510-appb-100003
    Figure PCTCN2014090510-appb-100004
    更优选地，R1、R2和X分别为：
    Figure PCTCN2014090510-appb-100005
  5. 根据权利要求1～3任意一项所述的苯基苄基醚类衍生物，其特征在于，其结构式如式(I-2)所示：
    Figure PCTCN2014090510-appb-100006
    其中，X为O，NH或S；
    R1为氢、溴、碘、硝基、氨基、甲氨基或二甲氨基；
    R2为碘、甲氧基或-OCH2CH2F；
    优选地，R1和R2分别为：
    Figure PCTCN2014090510-appb-100007
    更优选地，R1、R2和X分别为：
    R1      R2     X
    p-H    I      O
    p-I    I      O。
  6. 根据权利要求1～3任意一项所述的苯基苄基醚类衍生物，其特征在于，其结构式如式(I-3)所示：
    Figure PCTCN2014090510-appb-100008
    其中，X为O，NH或S；R1为氯、溴或碘；R2为碘、甲氧基或-OCH2CH2；
    优选地，R1和R2分别为：
    Figure PCTCN2014090510-appb-100009
    更优选地，R1、R2和X分别为：
    Figure PCTCN2014090510-appb-100010
  7. 根据权利要求1～6任意一项所述的苯基苄基醚类衍生物，其特征在于，当其中含有氟原子时，F取18F或19F；当其中含有碘原子时，I取123I、124I、125I、127I或131I；当其 中含有甲基、甲氧基、N-甲氨基或二甲氨基时，-CH3取-11CH3、-OCH3取-O11CH3、-NHCH3取-NH11CH3、-N(CH3)2取-N(11CH3)2或-N(CH3)(11CH3)。
  8. 权利要求1～3任意一项所述的苯基苄基醚类衍生物的制备方法，其反应方程式为：
    Figure PCTCN2014090510-appb-100011
    其中，Y3为溴或氯；R1、R2、X、Y1和Y2同权利要求1～3中任意一项结构式如式(I)所示的苯基苄基醚类衍生物的相应的定义。
  9. 权利要求4所述的苯基苄基醚类衍生物的制备方法，其反应方程式为：
    Figure PCTCN2014090510-appb-100012
    其中，Y3为溴或氯；R1、R2和X同权利要求4中结构式如式(I-1)所示的苯基苄基醚类衍生物的相应的定义。
  10. 权利要求5所述的苯基苄基醚类衍生物的制备方法，其反应方程式为：
    Figure PCTCN2014090510-appb-100013
    其中，Y3为溴或氯；R1、R2和X同权利要求5中结构式如式(I-2)所示的苯基苄基醚类衍生物的相应的定义。
  11. 权利要求6所述的苯基苄基醚类衍生物的制备方法，其反应方程式为：
    Figure PCTCN2014090510-appb-100014
    其中，Y3为溴或氯；R1、R2和X同权利要求6中结构式如式(I-3)所示的苯基苄基醚类衍生物的相应的定义。
  12. 利用权利要求1～7任意一项所述的苯基苄基醚类衍生物制备得到的Aβ斑块显 像剂；
    其中，当所述任意一项苯基苄基醚类衍生物中含有氟原子时，制备得到含有F-18的化合物，作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂；
    或者，当所述任意一项苯基苄基醚类衍生物中含有碘原子时，制备得到含有I-124的化合物，作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂；
    或者，当所述任意一项苯基苄基醚类衍生物中含有甲基、甲氧基、N-甲氨基或二甲氨基时，制备得到含有C-11的化合物，作为Aβ斑块显像剂，尤其作为PET类Aβ斑块显像剂；
    或者，当所述任意一项苯基苄基醚类衍生物中含有碘原子时，制备得到含有I-123、I-125或I-131的化合物，作为Aβ斑块显像剂，尤其作为SPECT类Aβ斑块显像剂。
  13. 根据权利要求12所述的Aβ斑块显像剂，其特征在于，其为单光子或正电子Aβ斑块显像剂。
  14. 权利要求12或13所述的Aβ斑块显像剂在制备诊断淀粉样病变疾病的药物中的应用。
  15. 权利要求1～7任意一项所述的苯基苄基醚类衍生物在制备诊断和治疗阿尔茨海默症的药物中的应用。
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