CN101805247A - Fluorine marking cyclofenil derivative as well as reference compound, midbody, preparation method and application thereof - Google Patents

Fluorine marking cyclofenil derivative as well as reference compound, midbody, preparation method and application thereof Download PDF

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CN101805247A
CN101805247A CN200910197712A CN200910197712A CN101805247A CN 101805247 A CN101805247 A CN 101805247A CN 200910197712 A CN200910197712 A CN 200910197712A CN 200910197712 A CN200910197712 A CN 200910197712A CN 101805247 A CN101805247 A CN 101805247A
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沈玉梅
朱华
黄立梁
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Shanghai Institute of Applied Physics of CAS
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Abstract

The invention discloses a fluorine marking cyclofenil derivative as well as a reference compound, a midbody, a preparation method and application thereof. The fluorine marking cyclofenil derivative is shown as a formula V, wherein a radical R is shown as a formula in the specification of the invention; 18 F is radioactive fluorine-18; a radical R1 and a radical R2 are independent H, CH3 or C2H5; and n is 0-5. The fluorine marking cyclofenil derivative has the regulation action of an estrogen receptor, very good targeting property for the ER (estrogen receptor), lower toxic side effect and good development effect on cancer cell accumulating tissues, is very suitable for PET (positron emission tomography) development and is a potential estrogen drug.

Description

Fluorine marked cyclofenil derivative and reference compound thereof and intermediate, and preparation method and application
Technical field
The present invention relates to a kind of fluorine marked cyclofenil derivative and reference compound thereof and intermediate, reach preparation method and application.
Background technology
(estrogen receptor ER) is steroid receptor to estrogen receptor, belongs to transcription factor nuclear receptor superfamily member, is divided into two kinds of hypotypes of ER α and ER β.Oestrogenic hormon is brought into play its physiological action by the mediation of ER in vivo just.Mammary cancer is the malignant tumour of serious threat women's health, in the U.S., has 1 people among per 8 women and suffers from breast cancer.Along with improving constantly of China's living standards of the people, the sickness rate of mammary cancer also is the trend that rises year by year, and annual growth reaches 2%.In the city, mammary cancer has become the modal malignant tumour of women especially.The expression of estrogen receptor is arranged in patient with breast cancer's the cancer cells, and the ratio of ER α and ER β is different in optimum and malignant breast tumor, in benign tissue, is expressed as the master, and in malignant tissue, preponderates with ER α with ER β.Therefore, estrogen receptor is an important indicator of endocrinotherapy for breast cancer and prognosis evaluation, in the existing method mainly the expression by detecting estrogen receptor to mammary cancer diagnose, treatment and prognosis evaluation.The detection method of mammary cancer is mainly methods such as nuclear magnetic resonance, ultrasonic examination, positron emission computerized tomography and flicker mammary gland radiography at present.
F-18 is the isotropic substance of natural fluorine, easily by accelerator by nuclear reaction 18O (p, n) 18F and 20Ne (d, α) 18F obtains.Its main mode of decay is that the generation energy is β+(96.73%) of 0.635MeV, and the transformation period is 109.7min, has determined F-18 to have following characteristics thus: the rate ratio of (1) F-18 is higher, and conventional production all reaches Curie's magnitude; (2) in positron radionuclide commonly used, the positron energy of F-18 is minimum, and consequent radiation injury is also minimum; (3) transformation period of F-18 is 109.7min, the synthetic and videograph process that may reach several hrs is finished fast, thereby helped dynamics research; (4) F-18 is that the positron emission computerized tomograph of using always that utilizes is implemented the radiohalogen of the emission positron of diagnosis; (5) the positron energy of F-18 is minimum, and the range in tissue is the shortest, so the resolving power of its video picture is the highest; (6) F-18 is when carrying out metabolism and plasma analysis (all require quantize), with respect to other Short-lived radionuclide commonly used (as C-11 etc.), carries out, can carry out the research of long period easily because of its counting rate height, statistics, and advantage is very obvious.
In oncology, (Positron Emission Computed Tomography, application PET) is very extensive for the positron emission computerized tomograph.PET be mainly used in lesion detection, by stages, classification and prognostic evaluation.Along with the popularization of PET with popularize, and PET and robot calculator x-ray tomography technology (computed tomography, CT) and Magnetic resonance imaging (nuclear magnetic resonance imaging, MRI) combination, its advantage is more obvious, PET will constantly increase the demand of positron emitting tracer, and its quantity and kind all will enlarge and renovate day by day.
Now, Chang Yong positron radionuclide mainly is 11C, 13N, 15O and 18F etc.Wherein, because 18F has transformation period the longest (109.7min) and the minimum good nucleic character such as (0.635MeV) of positron beta maximum energy, no matter is in clinical application, or in fundamental research, 18The radiopharmaceuticals of F mark is more and more paid close attention to.(Single-PhotonEmission Computed Tomography SPECT) can carry out quantitative assay to ER α and ER β by PET and SPECT (single photon emission computed tomography).And use the prerequisite that PET and SPECT carry out video picture is to synthesize the molecular probe that is fit to video picture by chemical process.Cyclofenil (Cyclofenil) belongs to the non-steroidal estrogen receptor antagon, is 2～3 times of steroidal class estradiol to the estrogen receptor selectivity, and its structure is shown below.
Figure B2009101977126D0000021
People such as Bigott pass through 94mTc Marking ring Pfennig parent compound because its structure itself has very big difference with cyclofenil, can not embody the advantage of cyclofenil compound self.People such as Seo once passed through 18F Marking ring Pfennig is used for the estrogen receptor video picture, because fluorine is substituted on the six-ring of cyclofenil, though cyclofenil derivative and estrogen receptor bonding properties are fine, the video picture result is unsatisfactory.People such as Gao have carried out this compound 11The mark of C, its video picture result is undesirable equally.Therefore, demand seeking a kind of advantage that can embody cyclofenil compound self urgently, can reach the molecular probe of better phenomenon effect again; Further research to the cyclofenil compound is also imperative.
Summary of the invention
Technical problem to be solved by this invention is to have overcome defectives such as the relatively poor or imaging results of the selectivity of existing radio-labeling cyclofenil compound mark estrogen receptor is undesirable, and a kind of fluorine marked cyclofenil derivative and reference compound thereof and intermediate, and preparation method and application are provided.This fluorine marked cyclofenil derivative has certain anti-breast cancer activity, has the regulating effect of estrogen receptor, and the ER acceptor is had good target, toxic side effect is lower, good to cancer cells aggregate structure imaging results, be well suited for the PET video picture, also be a kind of potential estrogenic.
The inventor finds that through lot of experiments selection does not change the structure on the cyclofenil cycloalkyl, only one in two reciprocity phenolic hydroxyl groups is carried out but the replacement of tosic acid fluorine ethyl ester, just can keep to ER avidity and to ER β has highly selective more, develops in the hope of later stage PET video picture.
The present invention solves the problems of the technologies described above by following technical proposals.
The present invention relates to a kind of suc as formula the fluorine marked cyclofenil derivative shown in the V;
Figure B2009101977126D0000031
Wherein, radicals R is shown below, 18F is a radioactive fluorine-18.
Figure B2009101977126D0000032
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
The invention still further relates to the preparation method suc as formula the compound shown in the V, it comprises the following step: in the solvent, with compound shown by formula I with 18The tosic acid fluorine ethyl ester of F mark reacts, and gets final product.
Figure B2009101977126D0000041
Wherein, radicals R is shown below, 18F is a radioactive fluorine-18.
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Wherein, the method for described reaction and condition all can be the ordinary method and the condition of this type of reaction of this area, preferred especially following method of the present invention and condition: in the solvent, in ultrasound reactor, with compound shown by formula I with 18The tosic acid fluorine ethyl ester of F mark reacts, and promptly makes compound V.
Wherein, described compound shown by formula I is commercially available gets; Described 18The tosic acid fluorine ethyl ester of F mark can be synthetic with reference to following document: Journal of Fluorine Chemistry, 129 (2008): 210～216.
Wherein, described solvent is the conventional solvent that uses in this area, is generally the NaCl aqueous solution; But for to make the mark rate of reaction higher, the mixed solution of the preferred especially organic inert solvent of the present invention and the NaCl aqueous solution is as reaction solvent.Described organic inert solvent is preferable is in methyl alcohol, acetonitrile, acetone and the ethanol one or more, and better is ethanol.What the consumption volume ratio of the described organic inert solvent and the NaCl aqueous solution was preferable is 3: 1～1: 3.Wherein, to be generally mass percent be 0.9% to the concentration of the described NaCl aqueous solution.
Wherein, the volume mass of described solvent and Compound I than preferable be 20～200ml/g; Described 18That the radioactive activity of the tosic acid fluorine ethyl ester of F mark and the molar ratio of Compound I are preferable is 0.05mCi:1mmol～100mCi:1mmol, and that better is 0.5mCi:1mmol～5mCi:1mmol; What the rotating speed of described ultrasound reactor was preferable is 500～2000 rev/mins; What the temperature of described reaction was preferable is 40 ℃～120 ℃, and better is 60 ℃; The time of described reaction preferable with detection reaction fully till, better is 50 minutes.
Wherein, after described reaction is finished, generally can handle by the conventional post processing mode in this area, preferable separates purification with HPLC, can obtain more highly purified product.
The invention still further relates to a kind of reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV;
Figure B2009101977126D0000051
Wherein, radicals R is shown below, and F is a fluorine.
Figure B2009101977126D0000052
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Preferably, the compound suc as formula shown in the IV among the present invention is preferably following compound:
(1) 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene, wherein, radicals R is shown in the following formula, n is 1.
Figure B2009101977126D0000053
(2) 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene hexanaphthene, wherein, radicals R is shown in the following formula, n is 2.
Figure B2009101977126D0000061
(3) 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene suberane, wherein, radicals R is shown in the following formula, n is 3.
Figure B2009101977126D0000062
(4) 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene-3-methylcyclohexane, radicals R is shown in the following formula, and R 1Be H, R 2Be CH 3
Figure B2009101977126D0000063
(5) 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene-4-methylcyclohexane, radicals R is shown in the following formula, and R 1Be CH 3, R 2Be H.
Figure B2009101977126D0000064
The invention still further relates to the preparation method suc as formula the compound shown in the IV, it comprises the following step: in the solvent, compound shown by formula I and tosic acid fluorine ethyl ester are reacted, get final product.
Figure B2009101977126D0000065
Wherein, radicals R is shown below, and F is a fluorine.
Figure B2009101977126D0000071
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Wherein, the method of described reaction and condition all can be the ordinary method and the condition of this type of reaction of this area, preferred especially following method of the present invention and condition: in organic inert solvent, under catalyst action, compound shown by formula I and tosic acid fluorine ethyl ester are reacted, promptly make compound IV.
Wherein, described compound shown by formula I and tosic acid fluorine ethyl ester is all commercially available gets.
Wherein, described organic inert solvent is preferable is in methyl alcohol, ethanol, acetonitrile and the acetone one or more, and better is acetone; What described catalyzer was preferable is salt of wormwood; The volume mass of described organic inert solvent and Compound I than preferable be 20～200ml/g; Described catalyst consumption is preferable is 0.01～0.5 times of molar weight of Compound I, and better is 0.1 times; The consumption of described tosic acid fluorine ethyl ester is preferable is 0.5～5 times of Compound I molar weight, and better is 0.8 times; What the temperature of described reaction was preferable is 40 ℃～70 ℃, and better is 55 ℃～60 ℃; The time of described reaction preferable with detection reaction fully till, better is 1 hour.
Wherein, preferablely in above-mentioned preparation method's reactant also can add KI, it can further increase speed of reaction, and described catalyst consumption is preferable is 0.001～0.2 times of molar weight of Compound I, and better is 0.05 times.
The invention still further relates to another preparation method suc as formula the compound shown in the IV, it comprises the following step: in the solvent, compound and HCl shown in formula III are reacted, get final product.
Figure B2009101977126D0000072
Wherein, radicals R is shown below, and F is a fluorine.
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Wherein, the method for described reaction and condition all can be the ordinary method and the condition of this type of reaction of this area, preferred especially following method of the present invention and condition: in organic inert solvent, compound and HCl shown in formula III are reacted, promptly make compound IV.
Wherein, described organic inert solvent is preferable is in acetone, methyl alcohol, acetonitrile, ethanol and the tetrahydrofuran (THF) one or more, and better is acetone; The volume mass of described organic inert solvent and Compound I than preferable be 20～200ml/g; Described HCl plays catalyzer, and what the mol ratio of HCl and compound III was preferable is 0.1: 1～0.5: 1, and better is 0.2: 1; What the temperature of described reaction was preferable is 40 ℃～70 ℃, and better is 50 ℃; The time of described reaction preferable with detection reaction fully till, the better time is 30min.
Among the present invention, described compound III can be made by following method: in the solvent, will carry out nucleophilic substitution reaction suc as formula compound shown in the II and tosic acid fluorine ethyl ester, and get final product.
Figure B2009101977126D0000082
Wherein, radicals R is shown below, and F is a fluorine.
Figure B2009101977126D0000083
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Wherein, but the method for described reaction and condition be the ordinary method and the condition of this type of reaction of this area all, preferred especially following method of the present invention and condition: in organic inert solvent, under the basic catalyst effect, to carry out nucleophilic substitution reaction suc as formula compound shown in the II and tosic acid fluorine ethyl ester, promptly make compound III.
Wherein, described organic inert solvent is preferable is in acetone, methyl alcohol, acetonitrile and the tetrahydrofuran (THF) one or more, and better is acetone; What described basic catalyst was preferable is sodium hydroxide and/or salt of wormwood, and better is salt of wormwood; The volume mass of described organic inert solvent and Compound I I than preferable be 10～100ml/g; What the mol ratio of described basic catalyst and Compound I I was preferable is 0.1: 1～12.5: 1, and better is 1.2: 1; What the mol ratio of described Compound I I and tosic acid fluorine ethyl ester was preferable is 0.5: 1～10: 1, and better is 2: 1; What the temperature of described reaction was preferable is 50 ℃～70 ℃, and better is 60 ℃; The time of described reaction preferable with detection reaction fully till, better is 2 hours.
Wherein, preferablely in above-mentioned preparation method's reactant also can add KI, its can with tosic acid fluorine ethyl ester generation replacement(metathesis)reaction, further increase speed of reaction.What the consumption of described KI was preferable is 5%～30% of Compound I I molar weight, and better is 10～15%.
Among the present invention, described Compound I I can be made by following method: in the solvent, Compound I and chloromethyl methyl ether carry out nucleophilic substitution reaction, get final product.
Figure B2009101977126D0000091
Wherein, radicals R is shown below.
Figure B2009101977126D0000092
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Wherein, the method of described reaction and condition are the ordinary method and the condition of this type of reaction of this area, preferred especially following method of the present invention and condition: in organic inert solvent, under the basic catalyst effect, Compound I and chloromethyl methyl ether carry out nucleophilic substitution reaction, promptly make Compound I I.
Wherein, described Compound I and chloromethyl methyl ether are all commercially available gets; Described Compound I also can be synthesized by reference: " Fluorine-Substituted Cyclofenil Derivatives as Estrogen Receptor Ligands:Synthesis and Structure-Affinity Relationship Study of Potential Positron Emission Tomography Agents for Imaging Estrogen Receptors in Breast Cancer " (Katzenellenbogen, J.A.; J Med Chem, 2006,49,2496).
Wherein, described organic inert solvent is preferable is in acetone, methyl alcohol, acetonitrile and the tetrahydrofuran (THF) one or more, and better is acetone; What described basic catalyst was preferable is sodium hydroxide and/or salt of wormwood, and better is salt of wormwood; The volume mass of described organic inert solvent and Compound I than preferable be 20～200ml/g; What the mol ratio of described basic catalyst and Compound I was preferable is 1: 1～12.5: 1, and better is 2: 1; Described Compound I with to the mol ratio of chloromethyl methyl ether preferable be 0.5: 1～1: 1, better is 0.8: 1; What the temperature of described reaction was preferable is-10 ℃～20 ℃, and better is 5 ℃; What the time of described reaction was preferable is complete with detection reaction, and better is 1 hour.
The invention still further relates to a kind of intermediate compound III for preparing compound IV.
Figure B2009101977126D0000101
Wherein, radicals R is shown below, and F is a fluorine.
Figure B2009101977126D0000102
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Preferably, the compound shown in formula III among the present invention is preferably following compound:
(1) 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene pentamethylene, wherein, radicals R is shown in the following formula, n is 1.
Figure B2009101977126D0000103
(2) 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene hexanaphthene, wherein, radicals R is shown in the following formula, n is 2.
Figure B2009101977126D0000111
(3) 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene suberane, wherein, radicals R is shown in the following formula, n is 3.
Figure B2009101977126D0000112
(4) 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene-3-methylcyclohexane, radicals R is shown in the following formula, and R 1Be H, R 2Be CH 3
(5) 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methylene-4-methylcyclohexane, radicals R is shown in the following formula, and R 1Be CH 3, R 2Be H.
Figure B2009101977126D0000114
The invention still further relates to a kind of midbody compound II for preparing compound IV.
Figure B2009101977126D0000115
Wherein, radicals R is shown below, and F is a fluorine.
Figure B2009101977126D0000116
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
Preferably, the compound suc as formula shown in the II among the present invention is preferably following compound:
(1) 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene pentamethylene, wherein, radicals R is shown in the following formula, n is 1.
Figure B2009101977126D0000121
(2) 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene hexanaphthene, wherein, radicals R is shown in the following formula, n is 2.
Figure B2009101977126D0000122
(3) 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene suberane, wherein, radicals R is shown in the following formula, n is 3.
Figure B2009101977126D0000123
(4) 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene-3-methylcyclohexane, radicals R is shown in the following formula, and R 1Be H, R 2Be CH 3
Figure B2009101977126D0000124
(5) 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene-4-methylcyclohexane, radicals R is shown in the following formula, and R 1Be CH 3, R 2Be H.
Figure B2009101977126D0000125
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
The invention still further relates to suc as formula the marked cyclofenil derivative shown in the V and preparing with the application in the radiopharmaceuticals of monitoring of estrogen receptor therapy and/or treatment disease; Further, also can be used for monitoring and/or treat the application of the radiopharmaceuticals of mammary cancer in preparation.
Positive progressive effect of the present invention is: the invention provides a kind of fluorine marked cyclofenil derivative and reference compound thereof and intermediate, reach preparation method and application.This fluorine marked cyclofenil derivative is a non-steroidal estrogenic agents cyclofenil of using radionuclide selectivity fluoro list phenolic hydroxyl group mark by the method for indirect labelling.Wherein, 18Part in the F marker can guide nucleic to arrive tumour cell, nucleic 18F can the kill tumor cell, has certain anti-breast cancer activity; Although radionuclide can cause damage to healthy tissues inevitably in the kill tumor cell, cyclofenil derivative has the regulating effect of estrogen receptor, and the ER acceptor is had good target, 18The F-cyclofenil derivative has lower toxic side effect, and is good to cancer cells aggregate structure imaging results, is well suited for the PET video picture, further, also is a kind of potential estrogenic.
Description of drawings
The F-NMR spectrogram of the compound IV a that Fig. 1 makes for embodiment 4.
The F-NMR spectrogram of the compound IV b that Fig. 2 makes for embodiment 5.
The F-NMR spectrogram of the compound IV c that Fig. 3 makes for embodiment 6.
The F-NMR spectrogram of the compound IV d that Fig. 4 makes for embodiment 7.
The F-NMR spectrogram of the compound IV e that Fig. 5 makes for embodiment 8.
The F-NMR spectrogram of the compound IV f that Fig. 6 makes for embodiment 9.
Fig. 7 is the radioactivity high-efficient liquid phase chromatogram of embodiment 10 synthetic compound tosic acid fluorine ethyl esters.
Fig. 8 is the embodiment 10 radioactivity high-efficient liquid phase chromatogram that synthetic compound 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene is not purified.
Fig. 9 is the radioactivity high-efficient liquid phase chromatogram behind embodiment 10 synthetic compound 4-fluorine ethoxyl phenenyls-4-hydroxy phenyl methene pentamethylene purifying.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
Embodiment 1 synthetic 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene pentamethylene (IIa)
Figure B2009101977126D0000141
(1) in there-necked flask, add Compound I a (500mg, 1.79mmol), anhydrous K 2CO 3(1.20g 8.8mmol), vacuumizes logical N 2Displacement, reciprocal three times.To wherein injecting 30ml acetone, 0 ℃ of temperature control stirs 0.5h then; (120mg 1.5mmol), under the uniform temp condition, continues reaction 1 hour, gets pink muddy shape solution to wherein slowly dripping chloromethyl methyl ether more afterwards.Filter, wash with saturated NaCl, (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Again with the volume ratio sherwood oil: ethyl acetate is that 10: 1 mixed solution is a leacheate, obtains faint yellow thick product 225.2mg, productive rate 35% fast through the flash post.
Its appraising datum is as follows:
IR(KBr)：ν3320，2941，1610，1585，1214，1165，1018，916，766cm -1；
1H?NMR(CDCl 3)δ：7.09(2H，d，J＝8.7Hz，aromatic)，7.04(2H，d，J＝7.8Hz，aromatic)，6.94(2H，d，J＝8.7Hz，aromatic)，6.84(2H，d，J＝8.6Hz，aromatic)，5.18(2H，s，-OCH 2O-)，3.49(3H，s，-OCH 3)，2.37-2.38(4H，m，C 2-H)，1.60-1.70(4H，m，C 3-H).
Wherein, Compound I cyclofenil and derivative reference literature (Katzenellenbogen, J.A.; JMed Chem, 2006,49,2496) synthetic, concrete steps are as follows:
In there-necked flask, add 1.2g (18.5mmol) zinc powder, vacuumize logical N 2Displacement, reciprocal three times; Add the anhydrous THF of 15ml then, the cryosel cooling is slowly to wherein adding TiCl 4(1.64g 8.62mmol), has yellow smog to emit after the adding, reaction system becomes yellow-green colour.Remove ice bath, be warming up to 100 ℃, refluxed 2 hours; Be cooled to room temperature, contain 4,4 to wherein injecting '-(500mg's dihydroxy benaophenonel 2.33mmol) and the mixing solutions of the anhydrous THF (15ml) of all kinds of cyclic ketones (2.33mmol), refluxed 2 hours, used NaHCO afterwards 3Saturated solution cancellation reaction.Dichloromethane extraction (3 * 20mL), anhydrous sodium sulfate drying filters, and is spin-dried for solvent, get or with normal hexane/methylene dichloride recrystallization through flash post wash-out, a white solid, productive rate 70%.
Below be respectively cyclopentanone, pimelinketone, suberone, the 3-methylcyclohexanone, the 4-methylcyclohexanone, isobutyric aldehyde participates in the cyclofenil compound that reaction makes, and uses Ia respectively, Ib, Ic, Id, Ie, If represent that its structural formula is as follows:
Figure B2009101977126D0000151
(2) adjust reaction conditions and prepare Compound I Ia, the concrete operations step is as follows:
(500mg, 1.79mmol), no water sodium hydroxide (1.79mmol) vacuumizes logical N to add Compound I a in there-necked flask 2Displacement, reciprocal three times.Then to wherein injecting 30ml methyl alcohol and acetonitrile mixed solution, temperature control-10 ℃ stirs 0.5h; Again to wherein slowly dripping chloromethyl methyl ether (3.58mmol), under the uniform temp condition, continue to react completely afterwards, get pink muddy shape solution.Filter, wash with saturated NaCl, (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Again with the volume ratio sherwood oil: ethyl acetate is that 10: 1 mixed solution is a leacheate, obtains faint yellow thick product fast through the flash post.
(3) adjust reaction conditions and prepare Compound I Ia, the concrete operations step is as follows:
(500mg, 1.79mmol), Anhydrous potassium carbonate (22.375mmol) vacuumizes logical N to add Compound I a in there-necked flask 2Displacement, reciprocal three times.To wherein injecting the 30ml tetrahydrofuran (THF), 20 ℃ of temperature controls stir 0.5h then; Again to wherein slowly dripping chloromethyl methyl ether (1.79mmol), under the uniform temp condition, continue to react completely afterwards, get pink muddy shape solution.Filter, wash with saturated NaCl, (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Again with the volume ratio sherwood oil: ethyl acetate is that 10: 1 mixed solution is a leacheate, obtains faint yellow thick product fast through the flash post.
(4) by the method for synthetic compound IIa in aforementioned (1), with Ib, Ic, Id, Ie and If replace Compound I a respectively, prepare synthetic compound IIb respectively, IIc, IId, IIe and IIf, its structural formula is as follows respectively:
Figure B2009101977126D0000161
Embodiment 2 synthetic 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene pentamethylene (IIIa)
Figure B2009101977126D0000162
(1) concrete steps are as follows: and adding Compound I Ia in there-necked flask (300mg, 0.97mmol), anhydrous K 2CO 3(0.20g 1.45mmol), vacuumizes logical N 2Displacement, reciprocal three times; To wherein injecting 15ml acetone, room temperature stirs 0.5h then.Then to wherein slowly drip tosic acid fluorine ethyl ester (400mg, 1.83mmol), then temperature control is 60 ℃, reacts 1 hour, filters afterwards, with saturated NaCl washing, (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Again with the volume ratio sherwood oil: ethyl acetate is that 10: 1 mixed solution is a leacheate, arrives faint yellow thick product 317mg, productive rate 93% fast through the flash post.
Its appraising datum is as follows:
UV(EtOH)：λ205，232nm；
IR(KBr)：ν2954，1607，1508，1241，1175，1008，924，775cm -1；
1H?NMR(CDCl 3)δ：7.05-7.15(4H，m，aromatic)，6.94(2H，d，J＝8.7Hz，aromatic)，6.84(2H，d，J＝8.6Hz，aromatic)，5.16(2H，s，-OCH 2O-)，4.74(2H，dt， 2J H-F＝47.36Hz， 2J H-H＝4.18Hz，-CH 2F)，4.20(2H，dt， 3J H-F＝27.65Hz， 2J H-H＝4.17Hz，-OCH 2-)，3.49(3H，s，-OCH 3)，2.36-2.38(4H，m，C 2-H)，1.62-1.72(4H，m，C 3-H)； 19F?NMR(CDCl 3)δ：-223.09(1F，tt， 2J F-H＝50.10Hz， 3J F-H＝23.08Hz).
(2) adjust reaction conditions and prepare compound III a, the concrete operations step is as follows:
Adding Compound I Ia in there-necked flask (300mg, 0.97mmol), no water sodium hydroxide (0.097mmol), KI (0.291mmol) vacuumizes logical N 2Displacement, reciprocal three times; To the mixed solution that wherein injects 15ml methyl alcohol and acetonitrile, room temperature stirs 0.5h then.Then to wherein slowly dripping tosic acid fluorine ethyl ester (0.097mmol), then temperature control is 50 ℃, reacts completely, and filters afterwards, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Again with the volume ratio sherwood oil: ethyl acetate is that 10: 1 mixed solution is a leacheate, arrives faint yellow thick product fast through the flash post.
(3) adjust reaction conditions and prepare compound III a, the concrete operations step is as follows:
Adding Compound I Ia in there-necked flask (300mg, 0.97mmol), Anhydrous potassium carbonate (12.125mmol), KI (0.0485mmol) vacuumizes logical N 2Displacement, reciprocal three times; To wherein injecting the 15ml tetrahydrofuran (THF), room temperature stirs 0.5h then.Then to wherein slowly dripping tosic acid fluorine ethyl ester (0.194mmol), then temperature control is 70 ℃, reacts completely, and filters afterwards, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Again with the volume ratio sherwood oil: ethyl acetate is that 10: 1 mixed solution is a leacheate, arrives faint yellow thick product fast through the flash post.
(4) by the method for synthetic compound IIIa in aforementioned (1), with IIb, IIc, IId, IIe and IIf replace Compound I Ia respectively, prepare synthetic compound IIIb respectively, IIIc, IIId, IIIe and IIIf, its structural formula is as follows respectively:
Figure B2009101977126D0000181
Embodiment 3 synthetic 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene (IVa)
Figure B2009101977126D0000182
(1) concrete steps are as follows: (100mg 0.28mmol), dissolves in the 10ml methyl alcohol, then adds the 0.4ml concentrated hydrochloric acid, and reaction is 12 hours under room temperature, adds saturated NaHCO then to add compound III a in there-necked flask 3Stopped reaction is with dichloromethane extraction.Need not further separation and can obtain the 86.7mg product, productive rate 99%.This reaction also can be reacted 10min down at 60 ℃, and productive rate is 95%.
Its appraising datum is as follows:
UV(EtOH)：λ208，225，265nm；
IR(KBr)：ν3350，2953，2864，1605，1164，829，575cm -1；
1H?NMR(CDCl 3)δ：7.09(2H，d，J＝8.3Hz，aromatic)，7.03(2H，d，J＝8.2Hz，aromatic)，6.84(2H，d，J＝8.3Hz，aromatic)，6.74(2H，d，J＝8.4Hz，aromatic)，4.7(2H，dt， 2J H-F＝47.44Hz， 2J H-H＝3.88Hz，-CH 2F)，4.39(2H，dt， 3J H-F＝27.79Hz， 2J H-H＝5.98Hz，-OCH 2-)，2.40-2.45(4H，m，C 2-H)，1.60-1.70(4H，m，C 3-H)；
19F?NMR(CDCl 3)δ：-223.83(1F，tt， 2J F-H＝50.55Hz， 3J H-H＝24.45Hz)；
ESI-HRMS?calcd.for?C 20H 22O 2F[M+1] +313.1604，found?313.1604.
(2) adjust reaction conditions and prepare compound IV a, the concrete operations step is as follows:
(100mg 0.28mmol), dissolves in 10ml acetone and the alcoholic acid mixed solution, then adds 0.14mmol HCl (form with concentrated hydrochloric acid adds), reacts completely under 40 ℃, adds saturated NaHCO then to add compound III a in there-necked flask 3Stopped reaction is with dichloromethane extraction.Need not further separation and can obtain product.
(3) adjust reaction conditions and prepare compound IV a, the concrete operations step is as follows:
(100mg 0.28mmol), dissolves in the mixed solution of 10ml acetonitrile and tetrahydrofuran (THF), then adds 0.028mmol HCl (form with concentrated hydrochloric acid adds), reacts completely under 70 ℃, adds saturated NaHCO then to add compound III a in there-necked flask 3Stopped reaction is with dichloromethane extraction.Need not further separation and can obtain product.
(4) by the method for synthetic compound IVa in aforementioned (1), with IIIb, IIIc, IIId, IIIe and IIIf replace compound III a respectively, prepare synthetic compound IVb respectively, IVc, IVd, IVe and IVf, its structural formula is as follows respectively:
Figure B2009101977126D0000191
Embodiment 4 synthetic 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene (IVa)
(1) concrete steps are as follows: and adding Compound I a in there-necked flask (270mg, 1.0mmol), anhydrous K 2CO 3(0.0205g, 0.15mol), (1.7mg, 0.02mmol), (23mg 1.1mol), connects reflux condensing tube to KI, vacuumizes logical N to add tosic acid fluorine ethyl ester 2Displacement, reciprocal three times; To wherein injecting 10ml acetone, 60 ℃ of temperature controls refluxed 6 hours then.Stopped reaction filters, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Arrive faint yellow thick product 200mg fast through the flash post, productive rate is 65%.
Its appraising datum is as follows:
UV(EtOH)：λ208，225，265nm；
IR(KBr)：ν3350，2953，2864，1605，1164，829，575cm -1；
1H?NMR(CDCl 3)δ：7.09(2H，d，J＝8.3Hz，aromatic)，7.03(2H，d，J＝8.2Hz，aromatic)，6.84(2H，d，J＝8.3Hz，aromatic)，6.74(2H，d，J＝8.4Hz，aromatic)，4.7(2H，dt， 2J H-F＝47.44Hz， 2J H-H＝3.88Hz，-CH 2F)，4.39(2H，dt， 3J H-F＝27.79Hz， 2J H-H＝5.98Hz，-OCH 2-)，2.40-2.45(4H，m，C 2-H)，1.60-1.70(4H，m，C 3-H)；
19F NMR (CDCl 3) δ :-223.83 (1F, tt, 2J F-H=50.55Hz, 3J F-H=24.45Hz), visible accompanying drawing 1.
ESI-HRMS?calcd.for?C 20H 22O 2F[M+1] +313.1604，found?313.1604.
(2) adjust reaction conditions and prepare compound IV a, the concrete operations step is as follows:
Adding Compound I a in there-necked flask (270mg, 1.0mmol), anhydrous K 2CO 3(0.01mmol), KI (0.001mmol), tosic acid fluorine ethyl ester (0.5mmol) connects reflux condensing tube, vacuumizes logical N 2Displacement, reciprocal three times; Then to wherein injecting 10ml methyl alcohol and alcoholic acid mixed solution, 70 ℃ of temperature controls are back to and react completely, filter, wash with saturated NaCl, and dichloromethane extraction (3 * 20mL), anhydrous sodium sulfate drying, filter, be spin-dried for solvent, arrive faint yellow thick product fast through the flash post.
(3) adjust reaction conditions and prepare compound IV a, the concrete operations step is as follows:
Adding Compound I a in there-necked flask (270mg, 1.0mmol), anhydrous K 2CO 3(0.5mmol), KI (0.001mmol), tosic acid fluorine ethyl ester (5mmol) connects reflux condensing tube, vacuumizes logical N 2Displacement, reciprocal three times; Then to wherein injecting the 10ml acetonitrile, 40 ℃ of temperature controls are back to and react completely, and filter, with saturated NaCl washing, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent, arrives faint yellow thick product fast through the flash post.
Embodiment 5 synthetic 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene hexanaphthenes (IVb)
Figure B2009101977126D0000211
Concrete steps are as follows: in there-necked flask, add compounds ib (280mg, 1.0mmol), anhydrous K 2CO 3(0.0205g, 0.15mmol), (1.7mg, 0.02mmol), (23mg 1.1mol), connects reflux condensing tube to KI, vacuumizes logical N to add tosic acid fluorine ethyl ester 2Displacement, reciprocal three times; Then to wherein injecting 10ml acetone, 60 ℃ of temperature controls, backflow 6h.Stopped reaction filters, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Arrive faint yellow thick product 200mg fast through the flash post, productive rate is 61%.
Its appraising datum is as follows:
UV(EtOH)：λ207，253nm；
IR(KBr)：ν3259，2921，1707，1609，1169，833，575cm -1；
1H?NMR(CDCl 3)δ：7.01(2H，d，J＝8.9Hz，aromatic)，6.92(2H，d，J＝8.9Hz，aromatic)，6.83(2H，d，J＝7.4Hz，aromatic)，6.73(2H，d，J＝7.3Hz，aromatic)，4.7(2H，dt， 2J H-F＝47.46Hz， 2J H-H＝2.66Hz，-CH 2F)，4.18(2H，dt， 3J H-F＝27.72Hz， 2J H-H＝2.84Hz，-OCH 2-)，2.10-2.25(4H，m，C 2-H)，1.50-1.70(6H，m，C 3，4-H)；
19F NMR (CDCl 3) δ :-223.03 (tt, 1F, 2J F-H=49.35Hz, 3J F-H=24.55Hz), visible accompanying drawing 2.
ESI-HRMS?calcd.for?C 21H 24O 2F[M+1] +327.1760，found?327.1765.
Embodiment 6 synthetic 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene suberane (IVc)
Figure B2009101977126D0000221
Concrete steps are as follows: and adding Compound I c in there-necked flask (295mg, 1.0mmol), anhydrous K 2CO 3(0.0205g, 0.15mmol), (1.7mg, (230mg 1.1mol), connects reflux condensing tube to KI, vacuumizes logical N 0.02mmol) to add tosic acid fluorine ethyl ester 2Displacement, reciprocal three times; To wherein injecting 10ml acetone, 60 ℃ of temperature controls refluxed 6 hours then.Stopped reaction filters, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Arrive faint yellow thick product 190mg fast through the flash post, productive rate is 56%.
Its appraising datum is as follows:
UV(EtOH)：λ209，225nm；
IR(KBr)：ν3293，2913，1605，1507，1180，608cm -1；
1H?NMR(CDCl 3)δ：7.06(2H，d，J＝8.6Hz，aromatic)，7.00(2H，d，J＝8.4Hz，aromatic)，6.83(2H，d，J＝8.5Hz，aromatic)，6.72(2H，d，J＝8.4Hz，aromatic)，4.72(2H，dt， 2J H-F＝47.37Hz， 2J H-H＝4.13Hz，-CH 2F)，4.18(2H，dt， 3J H-F＝27.65Hz， 2J H-H＝4.1Hz，-OCH 2-)，2.30-2.45(4H，m，C 2-H)，1.50-1.70(8H，m，C 3，4-H)；
19F NMR (CDCl 3) δ :-223.16 (1F, tt, 2J F-H=50.55Hz, 3J F-H=23.03Hz), visible accompanying drawing 3.
ESI-HRMS?calcd.for?C 22H 26O 2F[M+1] +341.1917，found?341.1928.
Embodiment 7 synthetic 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene-4-methylcyclohexanes (IVd)
Figure B2009101977126D0000231
Concrete steps are as follows: and adding Compound I d in there-necked flask (295mg, 1.0mmol), anhydrous K 2CO 3(0.0205g, 0.15mmol), (1.7mg, 0.02mmol), (23mg 1.1mol), connects reflux condensing tube to KI, vacuumizes logical N to add tosic acid fluorine ethyl ester 2Displacement, reciprocal three times; To wherein injecting 10ml acetone, 60 ℃ of temperature controls refluxed 6 hours then.Stopped reaction filters, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Arrive faint yellow thick product 200mg fast through the flash post, productive rate is 59%.
Its appraising datum is as follows:
UV(EtOH)：λ225nm；
IR(KBr)：ν3245，2958，1598，1359，1177，921，554cm -1；
1H?NMR(CDCl 3)δ：7.02(2H，d，J＝7.5Hz，aromatic)，6.96(2H，d，J＝8.4Hz，aromatic)，6.83(2H，d，J＝7.5Hz，aromatic)，6.73(2H，d，J＝6.9Hz，aromatic)，4.76(2H，dt， 2J H-F＝47.2Hz， 2J H-H＝4.1Hz，-CH 2F，)，4.20(2H，dt， 3J H-F＝27.1Hz， 2J H-H＝4.1Hz，-OCH 2)，2.52(2H，bd，J＝11.1Hz，C 2-H)，1.77(2H，bd，J＝14.4Hz，C 2’-H)，1.40-1.70(4H，m，C 3’，4-H)，1.20-1.30(1H，m，C 3-H)，0.87(3H，d，J＝5.7Hz，-CH 3，)；
19F NMR (CDCl 3) δ :-223.74 (1F, tt, 2J F-H=50.25Hz, 3J F-H=23.50Hz), visible accompanying drawing 4.
ESI-HRMS?calcd.for?C 22H 26O 2F[M+1] +341.1917，found?341.1892.
Embodiment 8 synthetic 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene-4-methylcyclohexanes (IVe)
Figure B2009101977126D0000241
Concrete steps are as follows: and adding Compound I e in there-necked flask (295mg, 1.0mmol), anhydrous K 2CO 3(0.0205g, 0.15mmol), (1.7mg, 0.02mmol), (23mg 1.1mol), connects reflux condensing tube to KI, vacuumizes logical N to add tosic acid fluorine ethyl ester 2Displacement, reciprocal three times; To wherein injecting 10ml acetone, 60 ℃ of temperature controls refluxed 6 hours then.Stopped reaction filters, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Arrive faint yellow thick product 210mg fast through the flash post, productive rate is 61%.
Its appraising datum is as follows:
UV(EtOH)：λ225nm；
IR(KBr)：ν3270，2810，1599，1359，1178，922，555cm -1；
1H?NMR(CDCl 3)δ：7.02(2H，d，J＝8.7Hz，aromatic)，6.96(2H，d，J＝8.4Hz，aromatic)，6.83(2H，d，J＝8.7Hz，aromatic)，6.72(2H，d，J＝8.1Hz，aromatic)，4.81(2H，dt， 2J H-F＝47.1Hz， 2J H-H＝4.42Hz，-CH 2F)，4.18(2H，dt， 3J H-F＝27.6Hz， 2J H-H＝4.1Hz，-OCH 2-)，2.54(2H，bd，J＝15.2Hz，C 2-H)，1.93(2H，td，J＝13.0Hz，C 2-H)，1.70-1.80(2H，m，C 3-H)，1.55-1.65(1H，m，C 4-H)，0.99-1.1(2H，m，C 3-H)，0.93(3H，d，J＝8.0Hz，-CH 3)；
19F NMR (CDCl 3) δ :-223.09 (1F, tt, 2J F-H=50.40Hz, 3J F-H=25.90Hz), visible accompanying drawing 5.
ESI-HRMS?calcd.for?C 22H 26O 2F[M+1] +341.1917，found?341.1911.
Embodiment 9 synthetic 4-fluorine ethoxyl phenenyl-different propane of 4-hydroxy phenyl methene (IVf)
Figure B2009101977126D0000251
Concrete steps are as follows: and adding Compound I f in there-necked flask (255mg, 1.0mmol), anhydrous K 2CO 3(0.0205g, 0.15mmol), (1.7mg, 0.02mmol), (23mg 1.1mol), connects reflux condensing tube to KI, vacuumizes logical N to add tosic acid fluorine ethyl ester 2Displacement, reciprocal three times; To wherein injecting 10ml acetone, 60 ℃ of temperature controls refluxed 6 hours then.Stopped reaction filters, washs with saturated NaCl, and (3 * 20mL), anhydrous sodium sulfate drying filters dichloromethane extraction, is spin-dried for solvent.Arrive faint yellow thick product 210mg fast through the flash post, productive rate is 69%.
Its appraising datum is as follows:
UV(EtOH)：λ224，265nm；
IR(KBr)：ν3212，2955，1519，1269，1169，918，552cm -1；
1H?NMR(CDCl 3)δ：7.15(2H，d，J＝8.7Hz，aromatic)，7.04(2H，d，J＝8.4Hz，aromatic)，6.93(2H，d，J＝8.7Hz，aromatic)，6.72(2H，d，J＝8.4Hzaromatic，)，5.76(1H，d，J＝10.2Hz，alkene-H)，4.73(2H，dt， 2J H-F＝47.1Hz， 2J H-H＝2.1Hz，-CH 2F)，4.20(2H，dt， 3J H-F＝28.2Hz， 2J H-H＝3.45Hz，-OCH 2-)，2.42(1H，m，C-H)，1.00(6H，d，J＝6.9Hz，-CH 3)；
19F NMR (CDCl 3) δ :-223.03 (1F, tt, 2J F-H=50.55Hz, 3J F-H=23.65Hz), visible accompanying drawing 6.
ESI-HRMS?calcd.for?C 19H 22O 2F[M+1] +301.1604，found?301.1616.
Embodiment 10 synthetic 4-fluorine (F-18) ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene (Va)
1, tosic acid fluorine (F-18) ethyl ester is synthetic
Figure B2009101977126D0000252
After activation, contain in the fluoro-18 ionic reaction flasks, add and be dissolved with 1 of 6-8mg, the 0.4ml acetonitrile of 2-two tosic acid ethylene glycol, airtight, 110 ℃ of oil bath reacting by heating 10 minutes, point sample launches, and radioactivity thin layer chromatograph (radio-TLC) scanning and sampling are carried out the radioactivity high performance liquid phase and measured (Radio-HPLC) sign as shown in Figure 7, its retention time t=8.10min.
2,4-fluorine (F-18) ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene is synthetic
(1) will contain [ 18F] FCH 2CH 2The whole solution concentration of the reaction of OTs adds the 2mL distilled water diluting to about 20 μ L, and mixed solution passes through in advance with the little column purification of water saturated C18Sep-Pak.Pillar dries up with nitrogen, with the drip washing of 2 * 1mL ethyl acetate, organic phase is collected in the v-vial bottle, and nitrogen slowly dries up under 60 ℃ of situations.Add 3mg 4,4 ' dihydroxy phenyl methene pentamethylene (being dissolved in the 200 μ L acetone), the K of 20 μ L1mol/L 2CO 3Solution, and the acetonitrile of 400 μ L are to react 20 minutes under 1000 rev/mins of conditions at 110 ℃ of ultrasound reactor rotating speeds.Product identifies that through radio-TLC and radio-HPLC HPLC identifies as shown in Figure 8.React whole solution after concentrating by partly preparing the HPLC purifying, measurement result as shown in Figure 9, its retention time t=24.55min.
(2) adjust reaction conditions and prepare compound Va, the concrete operations step is as follows:
To contain [ 18F] FCH 2CH 2The whole solution concentration of the reaction of OTs adds the 2mL distilled water diluting to about 20 μ L, and mixed solution passes through in advance with the little column purification of water saturated C18Sep-Pak.Pillar dries up with nitrogen, with the drip washing of 2 * 1mL ethyl acetate, organic phase is collected in the v-vial bottle, and nitrogen slowly dries up under 60 ℃ of situations.' (be dissolved in the 200 μ L ethanol, its consumption is dihydroxy phenyl methene pentamethylene to add 4,4 18The radioactive activity of the tosic acid fluorine ethyl ester of F mark and the molar ratio of Compound I are 0.05mCi:1mmol), the K of 20 μ L 1mol/L 2CO 3Solution, and the acetonitrile of 400 μ L is at 120 ℃, the ultrasound reactor rotating speed is to react completely under 500 rev/mins of conditions.Product is identified through radio-TLC and radio-HPLC, reacts whole solution and gets final product by partly preparing the HPLC purifying after concentrating.
(3) adjust reaction conditions and prepare compound Va, the concrete operations step is as follows:
To contain [ 18F] FCH 2CH 2The whole solution concentration of the reaction of OTs adds the 2mL distilled water diluting to about 20 μ L, and mixed solution passes through in advance with the little column purification of water saturated C18Sep-Pak.Pillar dries up with nitrogen, with the drip washing of 2 * 1mL ethyl acetate, organic phase is collected in the v-vial bottle, and nitrogen slowly dries up under 60 ℃ of situations.' (be dissolved in the 200 μ L methyl alcohol, its consumption is dihydroxy phenyl methene pentamethylene to add 4,4 18The radioactive activity of the tosic acid fluorine ethyl ester of F mark and the molar ratio of Compound I are 100mCi:1mmol), the K of 20 μ L 1mol/L 2CO 3Solution, and the acetonitrile of 400 μ L is at 60 ℃, the ultrasound reactor rotating speed is to react completely under 2000 rev/mins of conditions.Product is identified through radio-TLC and radio-HPLC, reacts whole solution and gets final product by partly preparing the HPLC purifying after concentrating.

Claims (18)

1. one kind suc as formula the fluorine marked cyclofenil derivative shown in the V;
Wherein, radicals R is shown below, 18F is a radioactive fluorine-18;
Figure F2009101977126C0000012
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
2. the preparation method of a fluorine marked cyclofenil derivative as claimed in claim 1, it is characterized in that: it comprises the following step: in the solvent, with compound shown by formula I with 18The tosic acid fluorine ethyl ester of F mark reacts, and gets final product;
Figure F2009101977126C0000013
Wherein, radicals R is shown below, 18F is a radioactive fluorine-18;
Figure F2009101977126C0000014
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
3. preparation method as claimed in claim 2 is characterized in that: describedly made by following method suc as formula the fluorine marked cyclofenil derivative shown in the V: in the solvent, in ultrasound reactor, with compound shown by formula I with 18The tosic acid fluorine ethyl ester of F mark reacts, and promptly makes compound V; Wherein, described solvent is the mixed solution of the organic inert solvent and the NaCl aqueous solution, and described organic inert solvent is one or more in methyl alcohol, acetonitrile, acetone and the ethanol; Described 18The radioactive activity of the tosic acid fluorine ethyl ester of F mark and the molar ratio of Compound I are 0.05mCi:1mmol～100mCi:1mmol; The rotating speed of described ultrasound reactor is 500～2000 rev/mins; The temperature of described reaction is 40 ℃～120 ℃; The time of described reaction with detection reaction fully till.
4. reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV;
Figure F2009101977126C0000021
Wherein, radicals R is shown below, and F is a fluorine;
Figure F2009101977126C0000022
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
5. the reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV as claimed in claim 4, it is characterized in that: described reference compound is 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene pentamethylene, 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene hexanaphthene, 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene suberane, 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene-3-methylcyclohexane, perhaps 4-fluorine ethoxyl phenenyl-4-hydroxy phenyl methene-4-methylcyclohexane.
6. the preparation method of the reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV as claimed in claim 4, it is characterized in that: it comprises the following step: in the solvent, compound shown by formula I and tosic acid fluorine ethyl ester are reacted, get final product;
Figure F2009101977126C0000031
Wherein, radicals R is shown below, and F is a fluorine;
Figure F2009101977126C0000032
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
7. preparation method as claimed in claim 6, it is characterized in that: the reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV is made by following method: in organic inert solvent, under catalyst action, compound shown by formula I and tosic acid fluorine ethyl ester are reacted, promptly make compound IV; Wherein, described organic inert solvent is one or more in methyl alcohol, ethanol, acetonitrile and the acetone; Described catalyzer is a salt of wormwood; Described catalyst consumption is 0.01～0.5 times of molar weight of Compound I; The consumption of described tosic acid fluorine ethyl ester is 0.5～5 times of Compound I molar weight; The temperature of described reaction is 40 ℃～70 ℃; The time of described reaction with detection reaction fully till.
8. preparation method as claimed in claim 6 is characterized in that: also add KI in described preparation method's the reactant; The consumption of described KI is 0.001～0.2 times of molar weight of Compound I.
9. the preparation method of the reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV as claimed in claim 4, it is characterized in that: it comprises the following step: in the solvent, with compound shown in formula III and HCl reaction, get final product;
Figure F2009101977126C0000041
Wherein, radicals R is shown below, and F is a fluorine;
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
10. preparation method as claimed in claim 9, it is characterized in that: the reference compound suc as formula the fluorine marked cyclofenil derivative V shown in the IV is made by following method: in organic inert solvent, compound and HCl shown in formula III are reacted, promptly make compound IV; Described organic inert solvent is one or more in acetone, methyl alcohol, acetonitrile, ethanol and the tetrahydrofuran (THF); The mol ratio of described HCl and compound III is 0.1: 1～0.5: 1; The temperature of described reaction is 40 ℃～70 ℃; The time of described reaction with detection reaction fully till.
11. preparation method as claimed in claim 9 is characterized in that: described compound III is made by following method: in the solvent, will carry out nucleophilic substitution reaction suc as formula compound shown in the II and tosic acid fluorine ethyl ester, and get final product;
Figure F2009101977126C0000043
Wherein, radicals R is shown below, and F is a fluorine;
Figure F2009101977126C0000051
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
12. preparation method as claimed in claim 11, it is characterized in that: described compound III is made by following method: in organic inert solvent, under the basic catalyst effect, will carry out nucleophilic substitution reaction, promptly make compound III suc as formula compound shown in the II and tosic acid fluorine ethyl ester; Wherein, described organic inert solvent is one or more in acetone, methyl alcohol, acetonitrile and the tetrahydrofuran (THF); Described basic catalyst is sodium hydroxide and/or salt of wormwood; The mol ratio of described basic catalyst and Compound I I is 0.1: 1～12.5: 1; The mol ratio of described Compound I I and tosic acid fluorine ethyl ester is 0.5: 1～10: 1; The temperature of described reaction is 50 ℃～70 ℃; The time of described reaction with detection reaction fully till.
13. preparation method as claimed in claim 11 is characterized in that: also add KI in described preparation method's the reactant; The consumption of described KI is 5%～30% of a Compound I I molar weight.
14. preparation method as claimed in claim 11 is characterized in that: described Compound I I is made by following method: in the solvent, compound shown by formula I and chloromethyl methyl ether are carried out nucleophilic substitution reaction, get final product;
Figure F2009101977126C0000052
Wherein, radicals R is shown below;
Figure F2009101977126C0000053
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
15. preparation method as claimed in claim 14, it is characterized in that: described Compound I I is made by following method: in organic inert solvent, under the basic catalyst effect, compound shown by formula I and chloromethyl methyl ether are carried out nucleophilic substitution reaction, promptly make Compound I I; Wherein, described organic inert solvent is one or more in acetone, methyl alcohol, acetonitrile and the tetrahydrofuran (THF); Described basic catalyst is sodium hydroxide and/or salt of wormwood; The mol ratio of described basic catalyst and Compound I is 1: 1～12.5: 1; The mol ratio of described Compound I and chloromethyl methyl ether is 0.5: 1～1: 1; The temperature of described reaction is-10 ℃～20 ℃; The time of described reaction is complete with detection reaction.
A 16. midbody compound II or compound III for preparing compound IV;
Figure F2009101977126C0000061
Wherein, radicals R is shown below, and F is a fluorine;
Figure F2009101977126C0000062
Wherein, radicals R 1And radicals R 2Independently be H, CH separately 3Or C 2H 5This n is 0～5.
17. midbody compound II as claimed in claim 16 or compound III, it is characterized in that: described Compound I I is: 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene pentamethylene, 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene hexanaphthene, 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene suberane, 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene-3-methylcyclohexane, perhaps 4-methoxyl group methoxy phenyl-4-hydroxy phenyl methene-4-methylcyclohexane; Described compound shown in formula III is: 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene pentamethylene, 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene hexanaphthene, 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene suberane, 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methene-3-methylcyclohexane, perhaps 4-fluorine ethoxyl phenenyl-4-methoxyl group methoxy phenyl methylene-4-methylcyclohexane.
18. one kind suc as formula the application of the marked cyclofenil derivative shown in the V in preparing the radiopharmaceuticals of monitoring and/or treating disease with the estrogen receptor therapy.
CN200910197712A 2009-10-27 2009-10-27 Fluorine marking cyclofenil derivative as well as reference compound, midbody, preparation method and application thereof Pending CN101805247A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786394A (en) * 2012-07-30 2012-11-21 中国医学科学院医药生物技术研究所 Substituent bis-aryl methylene naphthenic base derivative as well as preparation method and application thereof
CN109705124A (en) * 2018-12-14 2019-05-03 上海健康医学院 A kind of labeled with radioactive fluorine Larotrectinib compound and preparation method thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102786394A (en) * 2012-07-30 2012-11-21 中国医学科学院医药生物技术研究所 Substituent bis-aryl methylene naphthenic base derivative as well as preparation method and application thereof
CN102786394B (en) * 2012-07-30 2017-03-01 中国医学科学院医药生物技术研究所 Replace double aryl methylene cycloalkyl derivatives and its preparation method and application
CN109705124A (en) * 2018-12-14 2019-05-03 上海健康医学院 A kind of labeled with radioactive fluorine Larotrectinib compound and preparation method thereof
WO2020119205A1 (en) * 2018-12-14 2020-06-18 上海健康医学院 Radioactive fluorine-labeled larotrectinib compound and preparation method therefor
CN109705124B (en) * 2018-12-14 2021-09-24 上海健康医学院 Radioactive fluorine labeled Larotrectinib compound and preparation method thereof

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