CN106278963B - Target sulfonamides compound, intermediate and the preparation and application of carbonic anhydrase Ⅸ - Google Patents
Target sulfonamides compound, intermediate and the preparation and application of carbonic anhydrase Ⅸ Download PDFInfo
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Abstract
The present invention relates to a kind of sulfonamides compound, intermediate and preparation and application for targetting carbonic anhydrase Ⅸ.Wherein, the sulfonamides compound of carbonic anhydrase Ⅸ is targetted, its structural formula is as follows：Wherein, n=0~6, R1For H, C1~C4Straight chained alkyl, C3~C4Branched alkyl, C3~C6Cycloalkyl or phenyl C1~C4Alkyl.Compared with prior art, radiolabeled precursor synthesis step is used in the present invention simple, yield height, it is easy to a large amount of to prepare.The sulfonamides compound preparation method of the targeting carbonic anhydrase Ⅸ of the present invention is simple, and the reaction time is short, is more suitable for radiopharmaceuticals clinical practice, prepares18F labeled compounds radiochemical purity is more than 99%.Used reagent is commercial reagents in the present invention, and raw material is conveniently easy to get.
Description
Technical field
The present invention relates to sulfonamides compound, more particularly, to a kind of sulfonamides compound for targetting carbonic anhydrase Ⅸ, in
Mesosome and preparation method thereof.
Background technology
Carbonic anhydrase Ⅸ (carbonic anhydrase Ⅸ, abbreviation CA Ⅸ) is the different of carbonic anhydrase family (CAs)
One of structure body.The transmembrane glycoprotein that it is made up of acidic amino acid, is distributed in cell membrane and nucleus, relative molecular mass point
Wei not 58kD and 54kD (Opavsky R., Pastorekova S, Zelnik V, et al.Human MN/CA9gene, a
novel member of the carbonic anhydrase family:Structure and exon to protein
domain relationships[J].Genomics,1996,(3),480-487.Supuran C T,Scozzafava
A.Carbonic anhydrase inhibitors and their therapeutic potential[J].Expert
Opinion on Therapeutic Patents,2000,10(5),575-600.).CA Ⅸ major function is to participate in regulation
The ion and gas transfer of cross-film, while may also participate in regulation cell propagation and convert, and it is close with the generation development of tumour
Correlation (Zhu Y, Zhou X Y, Yao X D, et al.Prognostic value of carbonic anhydrase IX
expression in penile squamous cell carcinoma:A pilot study[J].Urologic
Oncology-Seminars and Original Investigations,2013,31(5),706-711.Dungwa J V,
Hunt L P,Ramani P.Carbonic anhydrase IX up-regulation is associated with
adverse clinicopathologic and biologic factors in neuroblastomas[J].Human
Pathology,2012,43(10),1651-1660.).The albumen of CA Ⅸ is removed has expression in normal person's alimentary canal and its related organ
Outside, hardly expressed in most of health adult tissues.And the overexpressions in corresponding tumor tissues of CA Ⅸ, research discovery,
CA Ⅸ is in clear-cell carcinoma, colorectal cancer, cervical carcinoma, carcinoma of urinary bladder, non-small cell lung cancer, liver cancer, cancer of pancreas, oophoroma, breast cancer
Increase (Takacova M, Bartosova M, Skvarkova L, et al.Carbonic anhydrase IX is Deng expression
a clinically significant tissue and serum biomarker associated with renal
cell carcinoma[J].Oncology Letters,2013,5(1),191-197.Pirincci N,Gecit I,Gunes
M,et al.Serum adenosine deaminase,catalase and carbonic anhydrase activities
in patients with bladder cancer[J].Clinics,2012,67(12),1443-1446.Yu S J,Yoon
J H,Lee J H,et al.Inhibition of hypoxia-inducible carbonic anhydrase-IX
enhances hexokinase II inhibitor-induced hepatocellular carcinoma cell
apoptosis[J].Acta Pharmacologica Sinica,2011,32(7),912-920.Schutze D,Milde-
Langosch K,Witzel I,et al.Relevance of cellular and serum carbonic anhydrase
IX in primary breast cancer [J].Journal of Cancer Research and Clinical
Oncology,2013,139(5),747-754.).CA Ⅸ is the GAP-associated protein GAP of tumour-specific, thus it is great potential
The target diagnosed as neoplasm targeted therapy and molecular image.
Positron emission tomography (Positron Emission Tomography, PET) technology have quantitative analysis,
The features such as high sensitivity, high spatial resolution, whole body 3-dimensional image, in grinding for tumour, cerebral nervous system disease, heart disease etc.
Study carefully and clinical practice in play more and more important effect.And in the conventional nucleic that PET is imaged, F-18 half-life period is relative
It is longer, there are relatively low dose of radiation and shorter range to tissue, be the most frequently used positron radionuclide, suitable for complicated PET medicines
The synthesis and clinical practice of thing.
At present, sulfonamides compound is the mostly important inhibitor of a kind of CA Ⅸ clinically used.By to sulfamido
The inhibitor of CA Ⅸ carry out F-18, develop a species specific PET probes, the early stage for the tumour to the overexpressions of CA Ⅸ
Diagnosis and prognosis evaluation, with highly important application prospect.But, the sulfamido on targetting CA Ⅸ18F marks PET is visited
The correlative study of pin is rarely reported both at home and abroad so that this invention has innovative and better application value well.
The content of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide one kind targets carbonic anhydrase
Ⅸ sulfonamides compound, intermediate and preparation and application.
The purpose of the present invention can be achieved through the following technical solutions：
First aspect present invention provides a kind of sulfonamides compound for targetting carbonic anhydrase Ⅸ, and targeting carbonic anhydrase Ⅸ
Sulfonamides compound reference compound.Target the sulfonamides compound of carbonic anhydrase Ⅸ and the structural formula of reference compound
Respectively shown in following formula A and A '
Wherein, n=0~6, preferably 0,1 and 2, R1For H, C1~C4Straight chained alkyl, C3~C4Branched alkyl, C3~
C6Cycloalkyl or phenyl-C1~C4Alkyl.
Wherein, described C1~C4Straight chained alkyl be following any group：
Wherein n=1~4, preferably 1 and 2；
Described C3~C4Branched alkyl is following any group：
Described C3~C6Cycloalkyl is following any group：
Wherein n=1~4；
Described phenyl-C1~C4Alkyl is following any group：
Wherein n=1~4.
In the present invention, when F is18During F, described sulfonamides compound is18F marks sulfonamides compound, i.e. compound A.
When F is common fluorine element, described sulfonamides compound is reference compound A '.
Second aspect of the present invention provides a kind of sulfonamides compound intermediate for targetting carbonic anhydrase Ⅸ, and its structural formula is such as
Under：
Wherein, n=0~6, R1For H, C1~C4Straight chained alkyl, C3~C4Branched alkyl, C3~C6Cycloalkyl or phenyl-C1
~C4Alkyl, R1Specifically chosen same compound A, R2For leaving group common in nucleophilic substitution, selected from following group：
NO2、I-、Br-
Or Cl-。
Third aspect present invention provides sulfonamides compound (compound A), its reference compound of targeting carbonic anhydrase Ⅸ
The preparation method of the sulfonamides compound intermediate of A ' and targeting carbonic anhydrase Ⅸ.
By compound B with18F-Nucleophilic substitution is carried out, that is, the sulfonamides compound that targeting carbonic anhydrase Ⅸ is made (is changed
Compound A).
Wherein, n and R1The definition in sulfonamides compound with targetting carbonic anhydrase Ⅸ is identical, R2With targeting carbonic anhydrase
It is identical defined in Ⅸ sulfonamides compound intermediate.
In the present invention, the method and condition of described nucleophilic substitution can be used in the such reaction of organic synthesis field
Method and condition, when carrying out nucleophilic substitution, phase transfer catalyst is that cyclic crown ether class catalyst or quaternary ammonium salt are catalyzed
Agent, described cyclic crown ether class catalyst is selected from 18 6 or 4,7,13,16,21,24- six oxygen -1,10- diaza-bicyclos [8.8.8] of hat
Hexacosane (is abbreviated as K222), and described quaternary ammonium salt catalyst is selected from bicarbonate tetrabutylammonium or tetrabutylammonium.
Also need to add conventional sylvite, predominantly potassium carbonate, bicarbonate when using cyclic crown ether class phase transfer catalyst, in reaction
Potassium, potassium oxalate etc..
The present invention passes through many experiments, particularly preferably goes out following methods and condition：In organic solvent, inert gas shielding
Under, K222, sylvite and18F-Mixture and compound B carry out nucleophilic substitution, you can.
Wherein, described sylvite is preferably potassium oxalate and saleratus, preferably potassium oxalate.It is described preferred solvents
One kind in anhydrous acetonitrile, anhydrous tetrahydro furan, dry DMF (N,N-dimethylformamide) and anhydrous DMSO (dimethyl sulfoxide (DMSO))
Or a variety of, preferred dry DMF.Concentration of the compound B in reaction solution is preferably 10~500mmol/L, more preferably 50~
100mmol/L.Described K222 and the mol ratio of potassium oxalate are preferably 1:5~10:1, more preferably 1:2~3:1.18F-'s
Activity is preferably 50 μ Ci~5Ci, more preferably 10mCi~1Ci.K222 and compound B mass ratio are preferably 1:4~
10:1, more preferably 2:1-5:1.Described inert gas is preferably nitrogen and/or argon gas and/or helium.Described nucleophilic
The temperature of substitution reaction is preferably 60~200 DEG C, more preferably 90~160 DEG C.Described nucleophilic substitution can be very
Completed in the short time, such as 1~80 minute, more preferably 5~30 minutes.
It is described containing K222, potassium oxalate and18F-Mixture can by following methods be made：With K222 (i.e.
Kryptofix 222) solution elution enrichment18F-QMA posts, solvent evaporated, you can.
Wherein, K222 solution can be made by following methods：By K222, potassium oxalate, acetonitrile and water wiring solution-forming, you can.
Wherein, each component content scope is as follows：Per in 1mL acetonitriles, there are 30~120 μ L water, 1~10mg potassium oxalates, 5~25mg K222.
The method of configuration can be that 30~140 μ L water, 1~10mg potassium oxalates, 5~25mg K222 are added into 1mL acetonitriles, you can.Most
Conventional one kind, which is matched, is：In every 960 μ L acetonitriles, there are 15mg K222,4.0mg potassium oxalates, 40 μ L water, wiring solution-forming.
After the completion of above-mentioned nucleophilic substitution, it can be purified with the conventional post processing in this area and method of purification.This hair
It is bright preferably to isolate and purify marked product with radioactivity HPLC, before being isolated and purified with radioactivity HPLC, it also can first use Sep-Pak
C18 posts are purified to product.
HPLC is isolated and purified to obtained solution decompression concentration, the mixed solution (ethanol of ethanol and physiological saline is re-dissolved in
Content<10%), filter, obtain through sterilised membrane filter18F marks preparation.
In the present invention, work as R2For NO2When, described labelled precursor compound B can be made by following method, work as R2For other
During leaving group, preparation method is similar.
Wherein, n and R1It is as defined above described.
Wherein, the method and condition of described reaction can be the conventional method and condition of the such reaction in this area, the present invention
Particularly preferred following methods and condition：
In acetonitrile, 1- ethyls -3- (3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl), triethylamine
(TEA) in mixture, compound C and D is reacted, you can.Wherein, the temperature of described reaction is preferably 5~50
℃.Described compound C：D：EDC.HCl：TEA=1：(1~3)：(1~5)：(1~8).After the completion of the reaction, ability can be used
The conventional post processing in domain and method of purification are purified.Preferably following methods of purification and condition of the invention：Reaction solution is concentrated under reduced pressure
Most of solvent is removed, after addition silica gel concentration is dry, column chromatography purifying (solvent：Petroleum ether, ethyl acetate).
Wherein, as n=0, compound Cn (i.e. C0) can be made by following method：
Wherein, the method and condition of described reaction can be the conventional method and condition of the such reaction in this area, the present invention
Particularly preferred following methods and condition：
In E concentrated sulfuric acid solution, the mixed acid solution of concentrated nitric acid and the concentrated sulfuric acid, completion of dropping reaction is slowly added dropwise.
Wherein, the temperature of the mixed acid solution of described dropwise addition concentrated nitric acid and the concentrated sulfuric acid is preferably -25~5 DEG C, described completion of dropping
Reaction temperature is preferably 5~50 DEG C afterwards.Described compound E：HNO3=1：(1~10), described nitration mixture volume ratio HNO3：
H2SO4=1：(0.5~10).After the completion of the reaction, it can be purified with the conventional post processing in this area and method of purification.This hair
Bright preferably following methods of purification and condition：Column chromatography is purified, and solvent is petroleum ether and ethyl acetate.
As n=1~6, compound Cn can be made by following method：
Wherein, the method and condition of described reaction can be the conventional method and condition of the such reaction in this area, the present invention
Particularly preferred following methods and condition：
C0 preparation is the same as those described above.
F preparation method is as described below：
By C0 in thionyl chloride (SO2Cl2) middle reaction.Wherein, the temperature of described reaction is preferably 25~100
℃.After the completion of the reaction, it can be purified with the conventional post processing in this area and method of purification.Preferably following purification sides of the invention
Method and condition：It is concentrated under reduced pressure after reaction solution cooling.
G preparation method is as described below：
In ether, calcium oxide (CaO), compound F mixture, CH is slowly added dropwise2N2Diethyl ether solution reacted,
.Wherein, described reaction temperature is preferably -20~5 DEG C.Described compound F：CH2N2：CaO=1：(1~10)：(1
~10).After the completion of the reaction, it can be purified with the conventional post processing in this area and method of purification.The present invention is preferably following to be carried
Pure method and condition：Reactant mixture is concentrated under reduced pressure after solvent, silica gel column chromatography purifying (solvent：N-hexane/acetic acid second
Ester).
C1 preparation method is as described below：
In compound G dioxane solution, the catalytic solution for adding silver oxide is reacted, you can.Wherein, it is described
The temperature of reaction be preferably 25~100 DEG C, described compound G：Silver oxide=1：(1~5).Described silver oxide is urged
Changing solution can be prepared by following methods：The aqueous solution that silver nitrate and sodium hydroxide are dissolved in sodium thiosulfate can (silver nitrate：Hydrogen-oxygen
Change sodium：Sodium thiosulfate：Water=1:1:2:250).After the completion of the reaction, the conventional post processing in this area and method of purification can be used
Purified.Preferably following methods of purification and condition of the invention：Concentration is removed after solvent, silica gel column chromatography purifying (solvent：Stone
Oily ether/ethyl acetate).
Compound C (n=2~6) preparation only need to repeat C0 → F → G → C1 preparation process.
In the present invention, described reference compound A ' can be made by following method：
In acetonitrile, 1- ethyls -3- (3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl), triethylamine
(TEA) in mixture, compound C ' and D is reacted, you can.Wherein, the temperature of described reaction is preferably 5~50
℃.Described compound C：D：EDC.HCl：TEA=1：(1~3)：(1~5)：(1~8).After the completion of the reaction, ability can be used
The conventional post processing in domain and method of purification are purified.Preferably following methods of purification and condition of the invention：Reaction solution is concentrated under reduced pressure
Except rear silica gel column chromatography purifies (solvent：Petroleum ether, ethyl acetate).
As n=1~6, compound C ' can be made by following method：
F ' preparation method is as described below：
By C0 ' in thionyl chloride (SO2Cl2) middle reaction.Wherein, the temperature of described reaction is preferably 25~100
℃.After the completion of the reaction, it can be purified with the conventional post processing in this area and method of purification.Preferably following purification sides of the invention
Method and condition：It is concentrated under reduced pressure after reaction solution cooling.
G ' preparation method is as described below：
In ether, calcium oxide (CaO), compound F ' mixture, CH is slowly added dropwise2N2Diethyl ether solution reacted,
.Wherein, described reaction temperature is preferably -20~5 DEG C.Described compound F：CH2N2：CaO=1：(1~10)：(1
~10).After the completion of the reaction, it can be purified with the conventional post processing in this area and method of purification.The present invention is preferably following to be carried
Pure method and condition：Reactant mixture is concentrated under reduced pressure after solvent, silica gel column chromatography purifying (solvent：N-hexane/acetic acid second
Ester).
C1 ' preparation method is as described below：
In compound G ' dioxane solution, the catalytic solution for adding silver oxide is reacted, you can.Wherein, institute
The temperature for the reaction stated is preferably 25~100 DEG C, described compound G：Silver oxide=1：(1~5).Described silver oxide
Catalytic solution can be prepared by following methods：The aqueous solution that silver nitrate and sodium hydroxide are dissolved in sodium thiosulfate can (silver nitrate：Hydrogen
Sodium oxide molybdena：Sodium thiosulfate：Water=1:1:2:250).After the completion of the reaction, the conventional post processing in this area and purification side can be used
Method is purified.Preferably following methods of purification and condition of the invention：Concentration is removed after solvent, silica gel column chromatography purifying (solvent：
Petrol ether/ethyl acetate).
Compound C ' (n=2~6) preparation need to only repeat C0 ' → F ' → G ' → C1 ' preparation process.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and produce the present invention each preferably
Example.
The fourth aspect of the present invention provides a kind of application for the sulfonamides compound for targetting carbonic anhydrase Ⅸ, target of the invention
It is used as the inhibitor of carbonic anhydrase Ⅸ to the sulfonamides compound of carbonic anhydrase Ⅸ, as a species specificity PET Imaging probes, uses
Early diagnosis and prognosis evaluation in the tumour to the overexpressions of CA Ⅸ.
Compared with prior art, the present invention has advantages below and beneficial effect：
1st, it is used for radiolabeled precursor synthesis step in the present invention simple, yield height, it is easy to a large amount of to prepare.
2nd, the sulfonamides compound preparation method of targeting carbonic anhydrase Ⅸ of the invention is simple, and the reaction time is short, more fits
Radiopharmaceuticals clinical practice is closed, is prepared18F labeled compounds radiochemical purity is more than 99%.
3rd, reagent used in the present invention is commercial reagents, and raw material is conveniently easy to get.
Brief description of the drawings
Fig. 1 is the common sample introduction of marked product A0 and its reference compound A0 ' (embodiment 5) of the example one of embodiment 6
HPLC detects spectrogram.
Fig. 2 sample introductions together with the labelled precursor compound B0 of embodiment 3 for the reference compound A0 ' in embodiment 5
HPLC spectrograms.
Embodiment
The present invention is described in detail with specific embodiment below in conjunction with the accompanying drawings.
Embodiment 1
The synthesis of the trifluoro-benzoic acid of 5- nitros -2,3,6 (C0)
Under ice bath, 2,3,6 trifluoro-benzoic acids (E) 4.0g is dissolved in the 30mL concentrated sulfuric acid, and less than 0 DEG C is slowly added dropwise concentrated nitric acid
5h is reacted at room temperature after (5.1mL) and the concentrated sulfuric acid (5.1mL) mixed acid solution, completion of dropping.Ice bath cools down above-mentioned reaction solution, under stirring
Frozen water 60mL is slowly added dropwise.Ethyl acetate is extracted twice for 100mL/ times, and combined ethyl acetate layer, saturated nacl aqueous solution washes two
It is secondary, after organic layer anhydrous sodium sulfate drying, it is concentrated under reduced pressure, obtains faint yellow solid 4.4g.Yield is 87.6%, purity>98%
(HPLC)。
C0 appraising datum is as follows：TOF-ESI-MS:M (C7H2F3NO4)=221.09 (m/z), 244.0 [M+Na]+,
276[M+Na+CH3OH]+.
1H-NMR(300MHz,CDCl3)δ8.18(m,1H,H)
Embodiment 2
The synthesis of the trifluoro benzene acetic acid of 5- nitros -2,3,6 (C1)
1. at room temperature, 235.7mg (1.07mmol) C0 is dissolved in 5mL SOCl2,80 DEG C of back flow reaction 5h, reaction solution
Weak yellow liquid F is concentrated under reduced pressure to give, next step reaction is directly used in.
2. obtained F is dissolved in 5mL ether in above-mentioned 1, adds and slowly dripped under CaO 120mg (2.14mmol), ice bath
Plus CH2N2 (2.14mmol) diethyl ether solution is reacted.After reaction terminates, product purifies (solvent with silica gel column chromatography：Just
Hexane, ethyl acetate).Product G 233.7mg is obtained, yield is 89.1%, purity 99% (HPLC).
3. compound G 123.0mg (501.8umol) are dissolved in 5mL dioxane solutions, add and pass through silver nitrate 170mg
(1mmol) and sodium hydroxide 40mg (1mmol) are dissolved in sodium thiosulfate 316mg (2mmol) aqueous solution 9mL (500mmol) systems
The catalytic solution of the silver oxide obtained, 50 DEG C of heating are reacted.After reaction terminates, product purifies (solvent with silica gel column chromatography：
N-hexane, ethyl acetate).Products C 1102.1mg is obtained, yield is 86.5%, purity 99% (HPLC).
C1 appraising datum is as follows：TOF-ESI-MS:M (C8H4F3NO4)=235.01 (m/z), 258.0 [M+Na]+
1H-NMR(300MHz,CDCl3):8.75(s,1H,H),8.15(m,1H,CH),3.74(s,2H,CH2).
Embodiment 3
Labelled precursor compound B0 preparation
Metanilyl amine 68.9mg (0.4mmol), C0 88.5mg (0.4mmol) are dissolved in 6mL acetonitriles, are added
Reaction is stirred at room temperature in EDC.HCl 76.7mg (0.4mmol), triethylamine 56uL (0.4mmol).After reaction terminates, product silicon
Gel column chromatography eluting (solvent：N-hexane, ethyl acetate).Product B0125.2mg is obtained, yield is 83.4%, purity 99%
(HPLC)。
B0 appraising datum is as follows：TOF-ESI-MS:M (C13H8F3N3O5S)=375.28 (m/z), 398.0 [M+Na]
+,430.0[M+Na+CH3OH]+.
1H-NMR(300MHz,CDCl3):δ11.36(s,1H,NH),8.67(m,1H,CH),8.23(s,1H,CH),7.75
(m,1H,CH),7.59(m,2H,CH),7.43(s,2H,NH2).
Embodiment 4
The synthesis of 2,3,5,6- tetrafluoros phenylacetic acid (C1)
1. at room temperature, 194.1mg (1.0mmol) C0 ' is dissolved in 5mL SOCl2,80 DEG C of back flow reaction 5h, reaction solution
Weak yellow liquid F ' is concentrated under reduced pressure to give, next step reaction is directly used in.
2. obtained F ' is dissolved in 5mL ether in above-mentioned 1, adds and slowly dripped under CaO 112mg (2.0mmol), ice bath
Plus CH2N2 (2.0mmol) diethyl ether solution is reacted.After reaction terminates, product purifies (solvent with silica gel column chromatography：Just
Hexane, ethyl acetate).Obtain product G ' 193.9mg, yield is 88.9%, purity 99% (HPLC).
3. compound G ' 109.1mg (0.5mmol) are dissolved in 5mL dioxane solutions, add and pass through silver nitrate 170mg
(1mmol) and sodium hydroxide 40mg (1mmol) are dissolved in sodium thiosulfate 316mg (2mmol) aqueous solution 9mL (500mmol) systems
The catalytic solution of the silver oxide obtained, 50 DEG C of heating are reacted.After reaction terminates, product purifies (solvent with silica gel column chromatography：
N-hexane, ethyl acetate).The 96.0mg of products C 1 ' is obtained, yield is 92.3%, purity 99% (HPLC).
C1 ' appraising datum is as follows：TOF-ESI-MS:M (C8H4F4O2)=208.11 (m/z), 231.1 [M+Na]+,
263.1[M+Na+CH3OH]+.
1H-NMR(300MHz,CDCl3):δ10.1(s,1H,H),6.72(m,1H,CH),3.71(s,2H,CH2).
Embodiment 5
Reference compound A0 ' preparation
Metanilyl amine 34.5mg (0.2mmol), C0 ' 38.8mg (0.2mmol) are dissolved in 6mL acetonitriles, are added
Reaction is stirred at room temperature in EDC.HCl 57.5mg (0.3mmol), triethylamine 42uL (0.3mmol).After reaction terminates, product silicon
Gel column chromatography eluting (solvent：Petroleum ether, ethyl acetate).Product B0 ' 57.6mg are obtained, yield is 82.7%, purity 99%
(HPLC)。
A0 ' appraising datum is as follows：TOF-ESI-MS:M (C13H8F4N2O3S)=348.27 (m/z), 371.0 [M+Na]
+,403.0[M+Na+CH3OH]+.
1H-NMR(300MHz,CDCl3):δ11.27(s,1H,NH),8.24(s,1H,CH),8.09(m,1H,CH),7.75
(m,1H,CH),7.58(m,2H,CH),7.41(s,2H,NH2).
Embodiment 6
18The fluoro- 5- of F mark PET probes N- (a sulfophenyl phenyl) -2,3,6- three [18F] fluoro- benzamide A0 preparation
【Example 1】20mCi18F-After being captured by quaternary ammonium type anion post QMA (Waters, US's product), 1.0mL is taken
(the oxalic acid hydrate potassium of 15.0mg K222,5.1mg bis-, 1000 μ L acetonitriles, 40 μ L water are made into K222 (i.e. Kryptofix 222) solution
Solution) will18F-It is flushed in reaction bulb, reaction bulb immerses 100 DEG C of oil bath, then nitrogen drying adds 500 μ L anhydrous
Acetonitrile is dried up, and repeats aforesaid operations twice；By labelled precursor compound B0 (5mg) 500 μ L anhydrous DMF solutions, nitrogen protection
Under be rapidly added confined reaction 10min at reaction bulb, 100 DEG C, stop reaction, ice-water bath cooling, mark rate is 35%.
HPLC detection spectrograms such as Fig. 1 of the common sample introductions of the marked product A0 and its reference compound A0 ' (embodiment 5) of example one
It is shown, HPLC conditions：Analytical column Agilent C18column (5 μm, 4.6mm × 250mm).Mobile phase is water containing 0.05%TFA
Solution (X) and the acetonitrile (Y) containing 0.05%TFA, gradient separations condition is：0 → 10 → 15 → 30min, 5% → 5% → 50%
→ 50%Y.Flow velocity is 1.0mL/min.By UV (254nm) detections and radiological measuring.
Marked product detects and separated with HPLC, radiochemicsl purity after separation>99%.It is concentrated under reduced pressure and removes solvent, with containing 8%
The 0.9% medical saline dissolving of ethanol, injectable PET probes are obtained after sterilised membrane filter filtering.
【Example 2】50mCi18F-After being captured by quaternary ammonium type anion post QMA (Waters, US's product), 1.0mL is taken
K222 (i.e. Kryptofix 222) solution (match somebody with somebody by the oxalic acid hydrate potassium of 20.0mg K222,13.5mg bis-, 1000 μ L acetonitriles, 50 μ L water
Into solution) will18F-Be flushed in reaction bulb, reaction bulb immerses 150 DEG C of oil bath, nitrogen drying, then add 500 μ L without
Water-acetonitrile is dried up, and repeats aforesaid operations twice；By labelled precursor compound B0 (10mg) 800 μ L anhydrous DMF solutions, nitrogen is protected
Confined reaction 5min at reaction bulb, 150 DEG C is rapidly added under shield, stops reaction, ice-water bath is cooled down, and mark rate is 38%.
The HPLC spectrograms of reference compound A0 ' sample introductions together with the labelled precursor compound B0 of embodiment 3 in embodiment 5
As shown in Fig. 2 marked product is detected with HPLC and separates that (U.S.'s Agilent 1100HPLC systems, semi-preparative column is Agilent
C18column(9.3mm×250mm).Mobile phase is the aqueous solution containing 0.05%TFA (X) and the acetonitrile (Y) containing 0.05%TFA, ladder
Spending separation condition is：0-5-30-30.01-37-37.01-40min, 30% → 30% → 40% → 100% → 100% → 30%
→ 30%Y.Flow velocity is 4.0mL/min.By UV (254nm) detections and radiological measuring.) collect product peak (tR=
17.3min), radiochemicsl purity after separation>99%.It is concentrated under reduced pressure and removes solvent, with the medical physiology salt of 0.9% containing 8% ethanol
Water is dissolved, and injectable PET probes are obtained after sterilised membrane filter filtering.
The above-mentioned description to embodiment is understood that for ease of those skilled in the art and using invention.
Person skilled in the art obviously can easily make various modifications to these embodiments, and described herein general
Principle is applied in other embodiment without passing through performing creative labour.Therefore, the invention is not restricted to above-described embodiment, ability
Field technique personnel are according to the announcement of the present invention, and not departing from improvement and modification that scope made all should be the present invention's
Within protection domain.
Claims (3)
1. it is a kind of target carbonic anhydrase Ⅸ sulfonamides compound preparation method, it is characterised in that by compound B with18F-Enter
Row nucleophilic substitution, the sulfonamides compound structural formula for targetting carbonic anhydrase Ⅸ is as follows：
Wherein, n=0~6, R1For H, C1~C4Straight chained alkyl, C3~C4Branched alkyl, C3~C6Cycloalkyl or phenyl-C1~C4
Alkyl；
Described compound B structural formula is as follows：
Wherein, n=0~6, R1For H, C1~C4Straight chained alkyl, C3~C4Branched alkyl, C3~C6Cycloalkyl or phenyl-C1~C4
Alkyl, R2For NO2；
Compound B is made by following method：
Wherein, n=0~6, R1For H, C1~C4Straight chained alkyl, C3~C4Branched alkyl, C3~C6Cycloalkyl or phenyl-C1~C4
Alkyl.
2. a kind of preparation method of sulfonamides compound for targetting carbonic anhydrase Ⅸ according to claim 1, its feature exists
In as n=0, compound Cn is made by following method：
3. a kind of preparation method of sulfonamides compound for targetting carbonic anhydrase Ⅸ according to claim 1, its feature exists
In as n=1~6, compound C is made by following method：
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585816A (en) * | 2008-05-20 | 2009-11-25 | 中国科学院上海应用物理研究所 | A kind of benzene sulfonamide hydroxyl derivative and intermediate thereof and preparation method and application |
| WO2009140743A2 (en) * | 2008-05-23 | 2009-11-26 | Katholieke Universiteit Leuven | Blood imaging |
| CN102757296A (en) * | 2012-04-10 | 2012-10-31 | 中国科学院上海应用物理研究所 | Method for marking compound with [18F] |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585816A (en) * | 2008-05-20 | 2009-11-25 | 中国科学院上海应用物理研究所 | A kind of benzene sulfonamide hydroxyl derivative and intermediate thereof and preparation method and application |
| WO2009140743A2 (en) * | 2008-05-23 | 2009-11-26 | Katholieke Universiteit Leuven | Blood imaging |
| CN102757296A (en) * | 2012-04-10 | 2012-10-31 | 中国科学院上海应用物理研究所 | Method for marking compound with [18F] |
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| Title |
|---|
| "Carbonic anhydrase inhibitors: inhibition of the tumor-associated isozyme IX with fluorine-containing sulfonamides. The first subnanomolar CA IX inhibitor discovered";Daniela Vullo等;《Bioorganic & Medicinal Chemistry Letters》;20140503;第14卷;第2353-2354页 * |
| "Synthesis and evaluation of 18F-labeled tertiary benzenesulfonamides for imaging carbonic anhydrase IX expression in tumours with positron emission tomography";Joseph Lau等;《Bioorganic & Medicinal Chemistry Letters》;20140517;第24卷;第3064-3068页 * |
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