CN102115474A - New type18F-labeled pyrazolo [1,5-a] pyrimidines and their preparation and application - Google Patents

New type18F-labeled pyrazolo [1,5-a] pyrimidines and their preparation and application Download PDF

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CN102115474A
CN102115474A CN2009102157425A CN200910215742A CN102115474A CN 102115474 A CN102115474 A CN 102115474A CN 2009102157425 A CN2009102157425 A CN 2009102157425A CN 200910215742 A CN200910215742 A CN 200910215742A CN 102115474 A CN102115474 A CN 102115474A
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compound
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pyrazolo
methyl
pyrimidine
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齐传民
刘航
许荆立
贺勇
李桂霞
丁瑞
王潇
冯曼
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Beijing Normal University
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Beijing Normal University
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Abstract

The invention discloses a novel <18>F-marked pyrazolo[1,5-a]pyrimidine compound. The compound is characterized by having a parent structure 3-cyan pyrazolo[1,5-a]pyrimidine, wherein the fifth bit of the compound has substituents R, namely methyl, chloromethyl, (N,N-dimethylamino)methyl, acetoxymethyl, hydroxymethyl and carboxyl; amido on the seventh bit of the compound is connected with fluorine-18 through a carbon chain with n carbon atoms; and the structure of the compound is shown as a formula A. The compound is simple to synthesize and mark with operation easiness. The compound can maintain higher concentration for a longer time in a tumor tissue, and has low absorption rate or high clearing rate in normal tissues and blood. In particular, the compound has very high ratios of tumor to blood ratio and tumor to muscle tissues. The invention also relates to application of the compound serving as a PET (Polyethylene Terephthalate) brain tumor developer. In a formula A of the compound, R=CH3, CH2Cl, CH2N(CH3)2, CH2OCOCH3 and CH2OH; and COOHn=2,3.

Description

Novel＜sup〉18＜/sup〉pyrazolo [1,5-a] pyrimidines and the preparation and the application of F mark
Technical field:
The present invention relates to a class novel is that leavings group carries out with tolysulfonyl oxygen base 18The pyrazolo of F mark [1,5-a] pyrimidines and chemical preparation process thereof and as the application of tumour (especially cerebral tumor) developer of positron emission tomography (PET).
Background technology:
The early diagnosis of tumour is a big focus of current medical science, and positron emission tomography (PET) is subjected to very big attention as a kind of means of more and more popularizing, thereby the breakthrough of the early diagnosis of tumour depends on the exploitation of PET tumor developer.
Radionuclide 18F is suitable as the video picture nucleic of PET because of its good nucleic character very much.
The generation of tumour is directly related with the cell cycle.Cyclin E and cell cycle deopendent protein kinase 2 (CyclinE-CDK 2) mixture is at cell cycle G 1The transformation point of/S phase is directly related, is the downstream target spot gene of multiple oncogene, plays a crucial role in many tumours take place.CDK is found in clinical study 2Overexpression is arranged in tumour cell, and its content in tumour cell and the content in normal tissue cell have notable difference.
Pyrazolo [1,5-a] pyrimidines is the novel CDK of a class 2Inhibitor is one of research focus of antitumor drug in recent years.Because CDK 2The mensuration of single crystal structure, pyrazolo [1,5-a] pyrimidines acts on CDK 2Structure activity relationship comparatively clear and definite, to this CDK 2The stage of comparative maturity has been arrived in the research of micromolecular inhibitor.Though 18Pyrimidines does not appear in the newspapers as the research of PET tumor developer the pyrazolo of F mark [1,5-a] as yet, but CDK 2Overexpression is arranged, as CDK in tumour cell 2The pyrazolo of inhibitor [1,5-a] pyrimidines carries out 18Behind the F mark, there is it to become the potential possibility of specificity and target PET tumor developer.
Summary of the invention:
The first, the invention provides tumor uptake height, radioactivity that specificity is good 18The pyrazolo of F mark [1,5-a] pyrimidines.
It is characterized in that: have precursor structure 3-cyano pyrazole also [1; 5-a] pyrimidine; its 5 substd R; methyl, chloromethyl, (N; the N dimethylamine base) methyl, acetyl-o-methyl, methylol, methoxy acyl group, carboxyl; the carbochain that its 7 amidos are n by carbonatoms links to each other with fluoro-18, and its structure is suc as formula A:
Figure G2009102157425D00011
R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，CH 2OH，COOCH 3，COOH
n＝2，3
Formula A
Its preparation mainly is divided into the synthetic and precursor compound of labelled precursor compound 18Two parts of F mark and aftertreatment.Concrete steps are as follows:
One. synthesizing of labelled precursor compound (formula B)
Figure G2009102157425D00021
R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，COOCH 3
n＝2，3
Formula B
1.1 pyrazolo [1,5-a] pyrimidine parent nucleus (label 4 among the formula C) is synthetic, synthetic route is suc as formula C:
Figure G2009102157425D00022
a：HC(OC 2H 5) 3，Ac 2O；b：H 2NNH 2H 2O；c：RCOCH 2COOCH 2CH 3，AcOH；d：POCl 3，Py
R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，COOCH 3
Formula C
1.1.1 ethoxy methylene the third two eyeballs (label 1 among the formula C) is synthetic:
The third two eyeball 9.9g (150mmol), triethyl orthoformate 33.3g (225mmol) and acetic anhydride 38.4g (376.5mmol) are joined in the 250ml single port flask.Behind the back flow reaction 6h, cooling adds gac post-heating backflow 30min, heat filtering, and behind the hot ethanol washing leaching cake, filtrate places refrigerator overnight, and suction filtration gets faint yellow tabular crystal, productive rate 84%.
1.1.23-amino-4-cyano pyrazole (label 2 among the formula C) is synthetic:
Ethoxy methylene the third two eyeball (label 1 among the formula C) 15g (123mmol) at room temperature slowly join among the 85% hydrazine hydrate 12ml (248mmol), and heating in water bath for reaction one hour adds 10ml water in reaction system.Place in the refrigerator and spend the night, suction filtration, the washing filter cake, dry faint yellow solid, productive rate 81%.
1.1.33-cyano group-5-(chlorine) methyl-7-hydroxypyrazoles is synthesizing of [1,5-a] pyrimidine (label 3 among the formula C) also:
3-amino-4-cyano pyrazole (label 2 among the formula C) 4g (37mmol) and (chlorine) methyl aceto acetate 38mmol are added in the 33ml glacial acetic acid back flow reaction 4h.Reaction finishes postcooling to room temperature, filters, and uses Glacial acetic acid and water wash filter cake successively each 3 times, gets yellow solid.Obtain pure product with re-crystallizing in ethyl acetate.
1.1.43-cyano group-5-(chlorine) methyl-7-chlorine pyrazolo [1,5-a] pyrimidine (label 4 among the formula C) is synthetic:
In the four-necked bottle of 250ml, add 3-cyano group-5-(chlorine) methyl-7-hydroxypyrazoles also [1,5-a] behind pyrimidine (label 3 among the C) 9.95mmol, after adding pyridine 0.82ml (10.55mmol), slowly drip phosphorus oxychloride 4.05ml (43.2mmol), finish and begin after slowly being heated to 85 ℃ to stir, in 120 ℃ of reaction 1h.Be cooled to the adding of back below 60 ℃ chloroform 150ml.Back flow reaction 1h.Be cooled to 0-5h and add cold water 90ml, suction filtration is removed insolubles, tells organic phase, washing twice, each water 90ml.Outstanding steaming gets solid 3-cyano group-5-(chlorine) methyl-7-chlorine pyrazolo [1,5-a] pyrimidine (label 4 among the formula C) after removing chloroform.
1.2 the side chain to parent nucleus is modified, complex sign precursor compound (formula B), and synthetic route is suc as formula D:
Figure G2009102157425D00031
e：HO(CH 2) nNH 2，CH 3CH 2OH；f：TsCl，TEA，DMAP，DMF
R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，COOCH 3
n＝2，3
Formula D
1.2.1 compound 5 is synthetic among the formula D:
With 3-cyano group-5-(chlorine) methyl-7-chlorine pyrazolo [1,5-a] pyrimidine (5) 2mmol joins in the 12ml ethanolic soln of hydramine 4mmol that carbon chain lengths is n, heating reflux reaction 4h, after TLC shows that reaction finishes, revolve to steam to remove and desolvate, get cotton-shaped solid,, get the product crystal with the mixed solvent recrystallization of methyl alcohol and ether.
1.2.2 compound 6 among the formula D (labelled precursor compound) is synthetic:
3-cyano group-5-(chlorine) methyl-7-(2-hydroxyethyl amino) pyrazolo [1,5-a] pyrimidine (7) 1mmol is joined 20ml heavily steam CH 2Cl 2In, ice bath adds down TEA 0.21ml (1.5mmol), and be cooled to below 0 ℃ after, add the TsCl 0.29g (1.5mmol) that DMAP 0.03g (0.2mmol) and purification process are crossed, rise to room temperature reaction behind the continuation low-temp reaction 30min and spend the night.After the TLC demonstration reacted completely, suction filtration got the product solid, uses the acetonitrile recrystallization.
Two. 18The radiological chemistry of F target compound (formula A) is synthesized (formula E)
Figure G2009102157425D00032
R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，COOCH 3
R′＝CH 2OH，COOH
n＝2，3
Formula E
2.1 precursor compound 18The F mark:
18After F is caught by anion column QMA, with containing 10mg K2.2.2 and 3mg K 2CO 3The 1mL acetonitrile and the mixed solution of 0.5mL water it is flushed in the reaction flask, the anhydrous acetonitrile that in reaction flask, adds 0.5mL, be heated to 100 ℃, constantly feed nitrogen, utilize acetonitrile and water azeotropic water removing, after treating solvent dried up, the anhydrous acetonitrile that adds 0.5mL more respectively, repeat twice of this operation, 5mg precursor compound (formula B) is dissolved in the 1.5mL anhydrous acetonitrile and adds in the reaction flask, suitably reduce temperature (remaining on more than the acetonitrile boiling point), closed reaction vessel is kept about this thermotonus 30min, stopped reaction, add about 10mL water reaction system is diluted, by Sep-Pak C18 post, filtrate collection (is not mainly participated in reacting in headpin again 18F-), and then with 10ml water washing pillar, will (guarantee and not participate in reaction in filtrate collection to 2 bottle 18F -Thoroughly drip washing is clean), with nitrogen Sep-Pak C18 post is dried up, with 2ml acetonitrile washing C18 post, in filtrate collection to 3 bottle, obtain 18F marked product (label 8 among the formula E), behind the HPLC purifying, radiochemical purity＞99%.
2.2 the hydrolysis of part marker:
18F marked product (label 8 among the formula E, and the R base is respectively acetoxyl group, methoxy acylated compound) removes dry acetonitrile, adds and contains 10mgLiOH3H 2The water 1mL of O, 80 ℃ of reaction 5min transfer PH to 5-6 with 1mol/L HCl, 18F marked product (label 9 among the formula E)
The second, the present invention is above-mentioned 18F mark p-nitrophenyl benzoyl amino acid derivative thing is as the application of PET tumor developer.
The present invention has following good characteristic:
1) is used among the present invention carry out 18F labelled precursor compound is synthetic easy, and raw material is cheap and easy to get.Mark total time is short, and effectively the radioactivity loss is few.
2) of the present invention 18The compound of F mark has suitable tumor imaging, particularly the good biological property of cerebral tumor video picture.Mainly contain following some:
2.1 compound of the present invention clearance rate in blood, muscle tissue and brain is very fast, higher initial picked-up is arranged in tumour and remove relatively slow, initial picked-up is low or remove very fast in other internal organs, thereby can be after injection the short period reach period of the high ratio of tumour/background, especially between half an hour and one hour, the ratio of tumour and related tissue is bigger, has experiment to be card:
Make by embodiment 18The acetonitrile solution of F tagged compound dries up acetonitrile with nitrogen, is that 8-10 μ Ci/0.1mL is as injection liquid with physiological saline with the product dilution again.Take out the injection liquid of three parts of 0.1mL, add 9.9mL physiological saline respectively, behind the mixing, from every part, take out 0.1mL respectively again, as standardized solution, measure its radiocounting in the time of the radiocounting of each tissue of mouse to be determined and internal organs, averaging is that 1%ID uses.
Kunming mouse is divided into five groups at random, 3 every group.From tail vein injection 18The injection liquid 0.1mL of F marked product (8-10 μ Ci), respectively at 5min, 15min after the injection, 30min, 60min, 120min each is organized the mouse sacrificed by decapitation, with its rapid dissection, get tissue and internal organs such as brain, the heart, liver, lung, kidney, back bone, muscle, small intestine, large intestine, spleen, blood, tumour, weigh after drying, and measure its radiocounting separately, and calculating the radioactive uptake %ID/g of its each tissue and internal organs, three groups of panel datas are got in each experiment.
Among the embodiment 18F marked product (R=CH among the formula A 3, n=2) experimental result is as shown in table 1:
Table 1 18F marked product (R=CH among the formula A 3, n=2) the body of lotus S180 knurl mouse in the bio distribution data (%ID/g ± SD, n=3)
What obtain after the arrangement should 18The F marked product each the time item tumour and healthy tissues ratio such as table 2:
Table 2 18F marked product (R=CH among the formula A 3, n=2) the intravital tumour of lotus S180 knurl mouse/healthy tissues ratio
Figure G2009102157425D00042
Above data presentation should 18The F marked product all has bigger absorption at each tissue and organ.But the intake in the non-target tissue As time goes on, and less gradually trend is all arranged.Wherein, it is 6.99%ID/g and 7.93%ID/g that liver and kidney have all demonstrated the highest radioactive activity intake at 5min, have only the absolute intake of 2.45%ID/g and 2.58ID%/g when 60min, promptly 34% and 32% radioactive activity is residual, has shown metabolic rate preferably.Initial intake in the tumour is less, but passes in time and become big, reaches peak value 5.51ID%/g when 30min, slowly diminishes subsequently again, has shown in the tumour retention effect preferably.In non-target tissues such as the heart that the initial picked-up of radioactivity is comparatively concentrated, lung and organ, this compound all has good clearance rate and effect in addition.But clearance rate is slower in the blood, and the intake in the large and small intestines is bigger than normal unusually, and metabolic rate is slower, and this may be because the ester water partition coefficient of this radioactively labelled substance determines.The ester water partition coefficient of this compound is 0.68, and the ester water partition coefficient of intestinal absorption the best that document shows is 0.5-2.However, should 18Radioactive activity intake peak value 5.51ID%/g has not only appearred in the F marked product when 30min, and when being this mutually down except that small intestine (radioactive activity intake peak value 6.86ID%/g), radioactive activity is definitely absorbed the tissue (definitely picked-up value of each organ or tissue's radioactive activity to such as shown in the Figure 31) of maximum in all organs.This is described 18The F marked product might become PET whole body PET tumor developer, and 30min can be used as this 18The first-selected time of F marked product PET tumor imaging.
2.2 compare with present technology, of the present invention 18The F tagged compound has novelty, is embodied in the remarkable advantages of some aspects of biological property, is exemplified below:
2.2.1 with the PET tumor imaging is most widely used clinically at present 18F-FDG compares, and is of the present invention 18The F tagged compound has the advantage of some aspects in the differentiation of tumour and brain healthy tissues.Have experiment to be card:
Undertaken by 2.1 identical implementation methods 18Distribute in the tumor-bearing mice body of F-FDG and test, obtain behind the disposal data 18The tumour of F-FDG/brain ratio and tumour/meat ratio is as shown in table 3:
Table 3 18F-FDG is at the intravital tumour/brain of lotus S180 knurl mouse and tumour/meat ratio
Figure G2009102157425D00051
Contrast table 2, table 3 be as can be seen: of the present invention 18F tagged compound ratio 18The tumour of F-FDG/normal cerebral tissue's discrimination is good; Of the present invention 18F tagged compound ratio 18The tumour of F-FDG/normal muscle tissue division degree is good, and certain potentiality may also be arranged on the periphery tumor imaging.
2.2.2 with the PET tumor developer that has very big application potential at present 18F-FET compares, and is of the present invention 18The F tagged compound also has a clear superiority in the differentiation of tumour and healthy tissues.Have experiment to be card:
Undertaken by 2.1 identical implementation methods 18Distribute in the tumor-bearing mice body of F-FET and test, obtain behind the disposal data 18Tumour/healthy tissues of F-FDG (choosing the most tangible brain of imaging results influence, blood and muscle tissue) ratio is as shown in table 4:
Table 4 18F-FET is at the intravital tumour of lotus S180 knurl mouse/healthy tissues ratio
Figure G2009102157425D00052
Contrast table 2, table 4 are as can be seen, and be of the present invention 18The F tagged compound 30-60min section tumour/brain, tumour/blood ratio apparently higher than 18The F-FET analog value, but tumour/brain ratio is not so good as 18The F-FET analog value.This makes of the present invention 18The F tagged compound carries out the periphery tumor imaging may obtain ratio especially 18The higher-quality image of F-FDG, but do not possess special advantage for the cerebral tumor video picture.
In sum, provided by the present invention 18F mark pyrazolo [1,5-a] pyrimidines compared with prior art in the contrast of tumour and some healthy tissues, has certain advantage, has the potentiality as the periphery tumor developer, has again that preparation is simple, markers step short, few characteristics consuming time.
Embodiment:
Below by embodiment the present invention is more clearly described, but the present invention is not limited to following examples.
Embodiment
According to the following steps preparation is R among the formula A 1=H, R 2The compound of=2-fluorine 18-4-nitro, n=1 comprises labelled precursor (R among the formula B 1=H, R 2The compound of=2-fluorine 18-4-nitro, n=1) synthetic and precursor compound 18Two parts of F mark.
1) labelled precursor (R among the formula B 1=H, R 2=2-fluorine 18-4-nitro, n=1 compound) synthetic
1.1 ethoxy methylene the third two eyeballs is synthetic, sees formula F:
Figure G2009102157425D00061
Formula F
The third two eyeball 9.9g (150mmol), triethyl orthoformate 33.3g (225mmol) and acetic anhydride 38.4g (376.5mmol) are joined in the 250ml single port flask.Behind the back flow reaction 6h, cooling adds gac post-heating backflow 30min, heat filtering, and behind the hot ethanol washing leaching cake, filtrate places refrigerator overnight, and suction filtration gets faint yellow tabular crystal, productive rate 84%.
1.23-amino-4-cyano pyrazole is synthetic, sees formula G:
Figure G2009102157425D00062
Formula G
Ethoxy methylene the third two eyeball 15g (123mmol) at room temperature slowly join among the 85% hydrazine hydrate 12ml (248mmol), and heating in water bath for reaction one hour adds 10ml water in reaction system.Place in the refrigerator and spend the night, suction filtration, the washing filter cake, dry faint yellow solid, productive rate 81%.
1.33-cyano group-5-methyl-7-hydroxypyrazoles is [1,5-a] pyrimidine synthetic also, formula H:
Figure G2009102157425D00063
Formula H
(4.2ml 38mmol) adds in the 33ml glacial acetic acid back flow reaction 4h with 3-amino-4-cyano pyrazole 4g (37mmol) and methyl aceto acetate 5g.Reaction finishes postcooling to room temperature, filters, and uses Glacial acetic acid and water wash filter cake successively each 3 times, gets yellow solid.Obtain pure product with re-crystallizing in ethyl acetate, productive rate 78%.
1.43-cyano group-5-methyl-7-chlorine pyrazolo [1,5-a] pyrimidine is synthetic, sees formula I:
Figure G2009102157425D00064
Formula I
In the four-necked bottle of 250ml, add 3-cyano group-5-methyl-7-hydroxypyrazoles also [1,5-a] behind the pyrimidine 1.67g (9.95mmol), after adding pyridine 0.82ml (10.55mmol), slowly drip phosphorus oxychloride 4.05ml (43.2mmol), finish and begin after slowly being heated to 85 ℃ to stir, in 120 ℃ of reaction 1h.Be cooled to the adding of back below 60 ℃ chloroform 150ml.Back flow reaction 1h.Be cooled to 0-5h and add cold water 90ml, suction filtration is removed insolubles, tells organic phase, washing twice, each water 90ml.Outstanding steaming gets orange/yellow solid 3-cyano group-5-methyl-7-chlorine pyrazolo [1,5-a] pyrimidine (label 4 among the formula C), productive rate 87% after removing chloroform.
1.53-cyano group-5-methyl-7-(2-hydroxyl-ethylamino) pyrazolo [1,5-a] pyrimidine is synthetic, sees formula J:
Formula J
With 3-cyano group-5 methyl-7-chlorine pyrazolo [1,5-a] pyrimidine (5) 0.38mg (2mmol) joins in the 12ml ethanolic soln of thanomin 0.24ml (4mmol), heating reflux reaction 4h, after TLC shows that reaction finishes, revolve to steam to remove and desolvate, get yellow cotton-shaped solid, with the mixed solvent recrystallization of methyl alcohol and ether, get purple crystals, productive rate 54%.mp：192-194℃；IR(KBr)υ(cm -1)：3267.9，3093.1，2928.2，2222.0，1627.5，1588.6，1533.6，1452.0，1314.7，1193.9，1070.4； 1H-NMR(DMSO，400MHz)δ(ppm)：8.55(s，1H，Pyrazole-H)，8.19-8.16(m，1H，-NHCH 2-)，6.41(s，1H，Pyrimidine-H)，4.89-4.86(m，1H，OHCH 2-)，3.63-3.60(m，2H，OHCH 2CH 2-)，3.46-3.42(m，2H，OHCH 2CH 2-)，2.43(s，3H，-CH 3)； 13C-NMR(DMSO，100MHz)δ(ppm)：162.51，150.46，147.34，146.09，114.41，88.60，77.70，59.19，44.05，24.36；MS(EI)m/z：217.10，found：217.16[M] +；Anal.calcd?for?C 10H 11N 5O：C?55.29，H?5.10，N?32.24，found：C?55.33，H?5.29，N32.12.
1.62-(3-cyano group-5-methyl-pyrazolo [1,5-a] pyrimidine 7-amino) ethyl p-toluenesulfonic esters is synthetic, sees formula K:
Figure G2009102157425D00072
Formula K
3-cyano group-5-methyl-7-(2-hydroxyethyl amino) pyrazolo [1,5-a] pyrimidine (7) 0.22mg (1mmol) is joined 20ml heavily steam CH 2Cl 2In, ice bath adds down TEA 0.21ml (1.5mmol), and be cooled to below 0 ℃ after, add the TsCl 0.29g (1.5mmol) that DMAP 0.03g (0.2mmol) and purification process are crossed, rise to room temperature reaction behind the continuation low-temp reaction 30min and spend the night.After the TLC demonstration reacted completely, suction filtration got faint yellow solid, uses the acetonitrile recrystallization, productive rate 45%.Mp: decompose blackening greater than 250 ℃; IR (KBr) υ (cm -1): 3444.4,3320.3,3110.3,2948.1,2223.2,1615.8,1581.1,1531.3,1448.4,1351.1,1313.6,1174.6,1006.6; 1H-NMR (DMSO, 400MHz) δ (ppm): 8.54 (s, 1H, Pyrazole-H), 8.31-8.28 (m, 1H ,-NHCH 2-), 7.49 (d, 2H, J=8.2Hz, Ar-H), 6.98 (d, 2H, J=8.1Hz, Ar-H), 6.21 (s, 1H, Pyrimidine-H), 4.26 (t, 2H, J=4.8Hz ,-OCH 2CH 2-), 3.63-3.59 (m, 2H ,-NHCH 2CH 2-), 2.36 (s, 3H ,-CH 3), 2.36 (s, 3H ,-CH 3); 13C-NMR (DMSO, 100MHz) δ (ppm): 162.42,150.25,146.31,145.95,144.50,131.58,129.24,127.18,114.34,88.40,77.91,67.76,59.70,24.33,20.87; MS (EI) m/z:371.1, found:372.1[M+H] +Anal.calcd for C 17H 17N 5O 3S:C 54.97, and H 4.61, and N 18.86, and found:C 55.03, H4.78, N 18.55.
2) mark of precursor 2-(3-cyano group-5-methyl-pyrazolo [1,5-a] pyrimidine 7-amino) ethyl p-toluenesulfonic esters 18The F mark, see formula L:
Figure G2009102157425D00073
Formula L
18After F-is caught by anion column QMA, with containing 10mg K2.2.2 and 3mg K 2CO 3The 1mL acetonitrile and the mixed solution of 0.5mL water it is flushed in the reaction flask, the anhydrous acetonitrile that in reaction flask, adds 0.5mL, be heated to 100 ℃, constantly feed nitrogen, utilize acetonitrile and water azeotropic water removing, after treating solvent dried up, the anhydrous acetonitrile that adds 0.5mL more respectively, repeat twice of this operation, (2-(3-cyano group-5-methylpyrazole is [1,5-a] pyrimidine-7-amino also) ethyl-2,4-dinitrobenzamide are dissolved in the 1.5mL anhydrous acetonitrile and add the suitable temperature (remaining on more than the acetonitrile boiling point) that reduces in the reaction flask with 5mgN-, closed reaction vessel, keep about this thermotonus 30min, stopped reaction adds about 10mL water reaction system is diluted, by Sep-Pak C18 post, filtrate collection (is not mainly participated in reacting in headpin again 18F -), and then with 10mL water washing pillar, will (guarantee and will not participate in reaction in filtrate collection to 2 bottle 18F -Thoroughly drip washing is clean), with nitrogen Sep-Pak C18 post is dried up, with 2mL acetonitrile washing C18 post, in filtrate collection to 3 bottle, obtain 18F marked product 3-cyano group-5-methyl-7-(2-fluoro-18-ethylamino) pyrazolo [1,5-a] pyrimidine, through HPLC (band radioactivity probe) separation and purification (HPLC condition: flow velocity 5mL/min, moving phase is acetonitrile: water=70%: 30%, retention time are 3.1min).
Lipid is an important physical and chemical parameter of bioactive compounds, and it is as follows that 2-(2-fluorine 18-4-dinitrobenzene) benzoylamino-3 Methylbutanoic acid lipid is measured enforcement:
In centrifuge tube, add 2ml n-Octanol and 1.9mL pH successively and be 7.4 phosphate buffer soln, and radioactive activity is about 3-cyano group-5-methyl-7-(2-fluoro-18-ethylamino) pyrazolo [1 of 8-10 μ Ci, 5-a] the 0.1mL aqueous solution of pyrimidine, the centrifugal layering 5min in back fully vibrates, get each 0.1mL of organic phase and water respectively in clean tube, measure its radiocounting N respectively, calculation of distribution coefficient P=N Have/ N Water, repeat to average after this operation 3 times, P is taken the logarithm, logP is this 18The lipid of F marked product.The lipid that records 3-cyano group-5-methyl-7-(2-fluoro-18-ethylamino) pyrazolo [1,5-a] pyrimidine is 0.68.
Undue toxicity is checked:
Undertaken by Pharmacopoeia of People's Republic of China described method of version in 2005.10 normal kunming mices (18-20g) tail vein is injected 0.5mL (37MBq) 3-cyano group-5-methyl-7-(2-fluoro-18-ethylamino) pyrazolo [1,5-a] pyrimidine injection liquid (being equivalent to hundreds of times to adult's consumption), observed 48 hours.The mouse growth is normal, and no death and untoward reaction phenomenon take place.Dissect the back and observe, do not see any organ damage.The undue toxicity inspection meets requirements of radiopharmaceuticals..
Thank you:
Research of the present invention has obtained the support of key lab of the radiopharmaceutical chemistry the Ministry of Education of Beijing Normal University and state natural sciences fund, and (fund number: fund 20371009 and 20671014) is subsidized, and expresses thanks at this.

Claims (3)

  1. One kind novel 18F mark pyrazolo [1; 5-a] pyrimidines; it is characterized in that: have precursor structure 3-cyano pyrazole also [1; 5-a] pyrimidine; its 5 substd R is respectively methyl, chloromethyl, (N, N dimethylamine base) methyl, acetyl-o-methyl, methylol, methoxy acyl group, carboxyl; the carbochain that its 7 amidos are n by carbonatoms links to each other with fluoro-18, and its structure is suc as formula A:
    Figure F2009102157425C00011
    R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，CH 2OH，COOCH 3，COOH
    n＝2，3
    Formula A
  2. 2. claim 1 is described 18F mark pyrazolo [1; 5-a] precursor compound of pyrimidines; it is characterized in that: have precursor structure 3-cyano pyrazole also [1; 5-a] pyrimidine; its 5 substd R is respectively methyl, chloromethyl, (N, N dimethylamine base) methyl, acetyl-o-methyl, methoxy acyl group; the carbochain that its 7 amidos are n by carbonatoms links to each other with tolysulfonyl oxygen base, and its structure is suc as formula B:
    Figure F2009102157425C00012
    R＝CH 3，CH 2Cl，CH 2N(CH 3) 2，CH 2OCOCH 3，COOCH 3
    n＝2，3
    Formula B
  3. 3. claim 1 is described 18F mark pyrazolo [1,5-a] pyrimidines is as the application of positron emission tomography (PET) tumor developer.
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CN103254139A (en) * 2012-02-17 2013-08-21 北京师范大学 Novel <18>F marked 4-aminoquinazoline derivatives, and preparation methods and tumor PET development application thereof
CN108997372A (en) * 2018-07-31 2018-12-14 华中科技大学同济医学院附属协和医院 Positron imaging compound, wherein mesosome, preparation method and imaging agent
CN111138439A (en) * 2020-01-17 2020-05-12 厦门大学 Fluoro pyrrolopyrimidine compound and preparation method and application thereof
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WO2004087707A1 (en) * 2003-03-31 2004-10-14 Vernalis (Cambridge) Limited Pyrazolopyrimidine compounds and their use in medicine
CN101967148A (en) * 2009-07-28 2011-02-09 北京师范大学 New18F substituted p-toluenesulfonyloxy labeled pyrazolo [1,5-a] pyrimidines and their preparation and application

Cited By (8)

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Publication number Priority date Publication date Assignee Title
CN102584626A (en) * 2011-12-21 2012-07-18 蚌埠丰原医药科技发展有限公司 Synthetic method of (ethoxymethylene)-malononitrile
CN102584626B (en) * 2011-12-21 2014-04-16 蚌埠丰原医药科技发展有限公司 Synthetic method of (ethoxymethylene)-malononitrile
CN103254139A (en) * 2012-02-17 2013-08-21 北京师范大学 Novel <18>F marked 4-aminoquinazoline derivatives, and preparation methods and tumor PET development application thereof
CN103254139B (en) * 2012-02-17 2016-04-20 北京师范大学 Novel 18f marks 4-amino quinazoline derivative and preparation method thereof and applies with PET tumor imaging
CN108997372A (en) * 2018-07-31 2018-12-14 华中科技大学同济医学院附属协和医院 Positron imaging compound, wherein mesosome, preparation method and imaging agent
WO2021036022A1 (en) * 2019-08-30 2021-03-04 四川大学华西医院 Pet/ct tracer having selectivity for different lung cancer cells, preparation method therefor and use thereof
CN111138439A (en) * 2020-01-17 2020-05-12 厦门大学 Fluoro pyrrolopyrimidine compound and preparation method and application thereof
CN111138439B (en) * 2020-01-17 2021-06-25 厦门大学 Fluoro pyrrolopyrimidine compound and preparation method and application thereof

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