CN113354707A - Synthetic method of three-function diagnosis and treatment integrated prodrug for prostate cancer and product thereof - Google Patents
Synthetic method of three-function diagnosis and treatment integrated prodrug for prostate cancer and product thereof Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a three-function diagnosis and treatment integrated prodrug for prostatic cancer and a product thereof, wherein a compound 1 is used as a raw material, and the compound 1 and three different amino acids are used for gradually synthesizing the three-function diagnosis and treatment integrated prodrug to obtain a markable precursor18F、68Ga and177capacity of three radionuclides of Lu. The invention realizes the pair18F marking rate reaches 40%, and the pair is realized68Ga and177the Lu labeling rate reaches more than 90 percent, more bifunctional or trifunctional diagnosis and treatment medicines can be designed by combining with other targeting molecules except PSMA (prostate cancer), the adaptability is very wide, different structures or different synthetic routes do not need to be purchased, the cost is reduced, the structure can greatly open the PSMA structural medicine market, more flexible and more comprehensive-function radionuclide labeling selection is provided for the medicines, and the diagnosis and treatment of the prostate cancer are realizedThe huge promotion effect is suitable for industrialized popularization and use.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, marking, imaging, drug therapy and treatment of prostate cancer, and particularly relates to a synthesis method and a product of a three-function diagnosis and treatment integrated prodrug for prostate cancer.
Background
Prostate Cancer (PCa) refers to epithelial malignant tumor which occurs in Prostate gland, and is one of the most common malignant tumors in men, and it is expected that the number of Prostate Cancer patients will exceed 1100 in 2022 years worldwide, see Siegel RL, Miller KD, Jemal A. Cancer standards, 2020. CACACACAcancer J Clin 2020; 70: 7-30. In recent years, the incidence rate of prostate cancer in China also shows a remarkable rising trend, and as far as 2020, the number of newly-increased prostate cancer patients in China reaches 15.3 thousands, 23.7 thousands are predicted to be reached in 2030, and the annual composite growth rate of the number of newly-increased prostate cancer patients is 5%. PCa has obvious heterogeneity, has latent onset, has no obvious specific symptoms at the early stage, and seriously threatens the global male health. Statistical results show that 5-year survival rate after early low-risk prostate cancer treatment can reach 82%; in the case of middle and advanced stages of PCa, antiandrogen combination endocrine therapy is the first line treatment regimen, but resistance rapidly progresses to Castration-resistant Prostate Cancer (CRPC). Therefore, early diagnosis and treatment are important for the prognosis of prostate cancer.
At present, image technologies such as transrectal ultrasound, Magnetic Resonance Imaging (MRI), bone scanning, Positron Emission Tomography/computed Tomography (PET/CT) are conventional means for diagnosing and staging prostate cancer.
Prostate Specific Membrane Antigen (PSMA), a type II transmembrane glycoprotein, also known as glutamate carboxypeptidase, is expressed only in small amounts in normal Prostate and other tissues (kidney, small intestine, brain, etc.) and in Prostate cancerThe expression in the cells is increased by 100-1000 times, particularly in late PCa and CRPC, and the molecular marker is a prostate cancer specific molecular marker. In recent 20 years, the PSMA related research is developed rapidly, and the PSMA related research, which is taken as an ideal target of the prostate cancer, lays a foundation for the targeted therapy of the prostate cancer in the imaging diagnosis and becomes a development hotspot of nuclear medicine in recent years. PSMA-11 is a small molecule inhibitor of PSMA, can specifically bind to PSMA, and can chelate trivalent gallium ion: (PSMA)68Ga) has a very good prostate-specific diagnostic effect, but cannot be labeled as such177Lu、90Y and other therapeutic nuclides of actinides, and do not have the ability to use nuclide therapy. Martina Weineisen et al 68Ga-and 177Lu-Labeled PSMA I&T: the Optimization of a PSMA-Targeted therapeutic Concept and First Proof-of-Concept Human students discloses PSMA I&T-polypeptide structures which can simultaneously label diagnostic nuclides (e.g.68Ga) and therapeutic nuclides (e.g. Ga)177Lu，90Y). At present, a large number of preliminary experiments are carried out on the medicine, and a large number of clinical trials are carried out in Europe, and clinical results show that the effect of the medicine is similar to the result of similar substances (PSMA-617) purchased by Nowa, and the two substances are two medicines which are clinically proved to be the most effective at present and can treat metastatic diseases.
For PSMAI&T polypeptide structure has the advantage of being capable of simultaneously marking diagnostic nuclide68Ga and therapeutic nuclides177Lu is a relatively excellent diagnostic and therapeutic integration molecule. Wherein68Ga is mainly used for contrast diagnosis, but due to its high production cost and low yield (from68Ge/68Ga generator production), most hospitals do not currently have autonomous production68Capability of Ga-based contrast agents, and68the half-life of Ga is short, only 68min is needed, the Ga can only be prepared and used on site, if the Ga is produced and distributed professionally by a third party organization, only 1/4 of the original yield is left when the Ga is delivered to a client in consideration of the path factor (the general path time is 2h), therefore, the commercial production can not be realized basically, and the PSMA I is severely limited&The production and sale of the T medicament. But also as a diagnostic nuclear species,18f fromThe rotary accelerator is used for generating, and can be synthesized stably in large quantity; and the half-life period is 110min, which is beneficial to the distribution of the product to other areas. Therefore, if it can be applied to PSMA I&T is modified to a certain extent without affecting the targeting and marking thereof68Ga/177In the case of Lu capability, it is marked18F, the novel structure is used as a prodrug, the PSMA structural medicine market is greatly opened, more flexible and more comprehensive-function radionuclide marker selection is provided for the medicines, the diagnosis and treatment of the prostate cancer are greatly promoted, and the development of diagnosis and treatment integrated medicines is further promoted. In fact, the dual-labeled nuclide is basically rare at the present stage, and may be generally used in the research of special needs in laboratories, and the nuclide dual-label is also relatively strict on the selected nuclide, and the selected labeled atoms are preferably nuclides with different energies or emitting different types of rays, thereby greatly improving the design and synthesis difficulty.
Disclosure of Invention
In order to solve the problems in the prior art, the invention aims to provide a synthetic method of a three-function diagnosis and treatment integrated prodrug for prostate cancer and a product thereof.
In order to achieve the purpose and achieve the technical effect, the invention adopts the technical scheme that:
a synthetic method of a three-function diagnosis and treatment integrated prodrug for prostate cancer comprises the following steps:
(1) dripping the compound 1 into an active ester solution, stirring for reaction, and then performing suction filtration, washing and drying to obtain a compound 2;
(2) mixing the compound 2 obtained in the step (1), amino acid 1 and an aprotic polar solvent, then dropwise adding an organic base, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 3;
(3) adding a piperidine solution into the compound 3, and performing suction filtration, washing and drying after reaction to obtain a compound 4;
(4) mixing the compound 4, the amino acid 2 and the aprotic polar solvent, then dropwise adding an organic base, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 5;
(5) adding a piperidine solution into the compound 5, and performing suction filtration, washing and drying after reaction to obtain a compound 6;
(6) mixing the compound 6, the amino acid 3 and the aprotic polar solvent, dripping organic base, stirring for reaction, and performing suction filtration, washing and drying to obtain a compound 7;
(7) adding a piperidine solution into the compound 7, and reacting to obtain resin;
(8) mixing the resin obtained in the step (7), DOTA-GA anhydride and an aprotic polar solvent, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 8;
(9) adding cutting fluid into the compound 8 for low-temperature reaction, then adding ether, performing centrifugal separation to obtain a crude product, and performing preparative chromatographic separation to obtain the required three-function diagnosis and treatment integrated prodrug, wherein the structural formula of the three-function diagnosis and treatment integrated prodrug is as follows:
wherein the linker is any one of alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, ether, epoxy and mercapto; AA1And AA2Each is any one amino acid; r2Is any one of N, N-trimethyl salt, nitryl and halogen, and the structural formula of the N, N-trimethyl salt is as follows:
further, in the step (1), the molar ratio of the compound 1 to the active ester solution is 1: 1.10-2.00, the reaction temperature is room temperature, and the amino reaction is judged to be complete through color reaction.
Further, in the steps (1) to (6) and (8), washing and drying operations are respectively carried out using dimethylformamide; the aprotic polar solvent comprises or an analog thereof, and the organic base comprises N, N-diisopropylethylamine or an analog thereof.
Further, in the above-mentioned case,in the step (2), the structural formula of the amino acid 1 is as follows:
1.00eq compound 1 is used as a raw material, 1 equivalent of amino acid is 2-4 eq, and 2-4 eq of N, N-diisopropylethylamine is equivalent.
Further, in the step (4), the structural formula of the amino acid 2 is as follows:
1.00eq compound 1 is used as a raw material, 2 eq of amino acid is 2-4 eq, and 2-4 eq of N, N-diisopropylethylamine is equivalent.
Further, in the step (6), the structural formula of the amino acid 3 is as follows:
1.00eq compound 1 is used as a raw material, 3 equivalents of amino acid is 2-4 eq, and 2-4 eq of N, N-diisopropylethylamine is equivalent.
Further, in the step (3), the step (5) and the step (7), the piperidine solution is a dimethylformamide solution containing 10% -30% piperidine, the amount is 4-8 mL/g, the reaction temperature is room temperature, and the reaction time is 10-60 min.
Further, in the step (8), 1.00eq of the compound 1 is used as a raw material, the DOTA-GA acid anhydride equivalent is 1.3-1.8 eq, the reaction temperature is 20-60 ℃, and the reaction time is 24-72 hours.
Further, in the step (9), the cutting fluid is trifluoroacetic acid with a mass fraction of 95%, the using amount is 20-60 mL/g, and the volume ratio of the ether to the cutting fluid is 8-10: 1, the low-temperature reaction conditions are as follows: and (3) keeping the temperature of-10-0 ℃ for reaction for 10-30 min, then heating to room temperature, and stirring for reaction for 3-8 h.
The invention discloses a three-function diagnosis and treatment integrated prodrug for prostate cancer, which is synthesized by adopting a synthesis method of the three-function diagnosis and treatment integrated prodrug for the prostate cancer, wherein the structural formula of the three-function diagnosis and treatment integrated prodrug is as follows:
wherein the linker is any one of alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, ether, epoxy and mercapto; AA1And AA2Each is any one amino acid; r2Is any one of N, N-trimethyl salt, nitryl and halogen, and the structural formula of the N, N-trimethyl salt is as follows:
compared with the prior art, the invention has the beneficial effects that:
the invention discloses a method for synthesizing a three-function diagnosis and treatment integrated prodrug for prostatic cancer and a product thereof, wherein a compound 1 is taken as a raw material, the compound 1 and three different amino acids are utilized to gradually synthesize a brand-new three-function diagnosis and treatment integrated prodrug structure which can simultaneously contain an N, N-trimethyl structure and a DOTA structure so as to obtain a markable prodrug18F、68Ga and177the capacity and the marking site of three radionuclides Lu are different, and the markers can be selected according to actual requirements18F、68Ga and/or177Lu. The three-function diagnosis and treatment integrated prodrug obtained by the invention can fully exert on a molecular structure18F、68Ga、177The respective advantages and functions of the three nuclides Lu realize the pairing18The F marking rate reaches 40 percent, and the pair is realized68Ga and177the Lu labeling rate reaches more than 90 percent, more difunctional or trifunctional diagnosis and treatment medicines can be designed by combining other targeting molecules except PSMA, the structure can greatly open the PSMA structural medicine market, more flexible and more comprehensive-function radionuclide label selection is provided for the medicines, and the diagnosis and treatment of the prostate cancer are greatly promoted; for having autonomous production68Ga contrast agent-capable hospitals, selectable markers68Ga is directly used, otherwise, the Ga can be selected to be marked by a third-party professional institution18F post delivery, for administration to a treatment, selectable markers177Lu; for onlyThe unit which needs to mark and operate to produce the contrast agent, such as a hospital, the synthesized prodrug of the invention is closer to the actual technical capability of the unit due to higher nuclide marking selectivity, and the adaptability is very wide; for other enterprises producing contrast agents, multiple nuclide markers can be marked on the prodrug structure of the invention, different structures or different synthetic routes do not need to be purchased, the cost is reduced, and the invention is suitable for industrial popularization and use.
Drawings
FIG. 1 is a structural formula of a three-functional diagnosis and treatment integrated prodrug of the present invention;
FIG. 2 is a scheme showing the synthesis of example 1 of the present invention;
FIG. 3 shows the results of example 4 of the present invention18A labeling scheme for F radionuclides;
FIG. 4 shows a schematic view of a display device according to example 5 of the present invention68Labeling flowsheet of Ga radionuclide;
FIG. 5 shows a schematic view of a display device according to example 6 of the present invention177Labeling scheme of Lu radionuclide.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. The components of embodiments of the present invention generally described and illustrated in the figures herein may be arranged and designed in a wide variety of different configurations.
The following detailed description of the embodiments of the present invention, presented in the figures, is not intended to limit the scope of the invention, as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
As shown in fig. 1 to 5, a method for synthesizing a three-functional diagnosis and treatment integrated prodrug for prostate cancer includes the following steps:
(1) taking 1.00eq of the compound 1 as a raw material, dripping the compound 1 into an active ester solution, stirring for reaction completely, and then carrying out suction filtration, washing and drying to obtain a compound 2; the solvent of the active ester solution is preferably dimethylformamide; the molar ratio of the compound 1 to the active ester solution is 1: 1.10-2.00, the reaction temperature is room temperature, and the amino reaction is judged to be complete through color reaction;
(2) putting the compound 2 obtained in the step (1), the amino acid 1 and the aprotic polar solvent into a reaction bottle for mixing, then dropwise adding the organic base, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 3;
(3) adding a piperidine solution into the compound 3, and performing suction filtration, washing and drying after reaction to obtain a compound 4;
(4) putting the compound 4, the amino acid 2 and the aprotic polar solvent into a reaction bottle for mixing, then dropwise adding an organic base, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 5;
(5) adding a piperidine solution into the compound 5, and performing suction filtration, washing and drying after reaction to obtain a compound 6;
(6) adding the compound 6, the amino acid 3 and the aprotic polar solvent into a reaction bottle, mixing, dropwise adding organic base, stirring for reaction, and performing suction filtration, washing and drying to obtain a compound 7;
(7) adding a piperidine solution into the compound 7, performing suction filtration after reaction to obtain resin, and washing and drying the resin;
(8) adding the resin obtained in the step (7), DOTA-GA anhydride and the aprotic polar solvent into a reaction bottle, mixing, stirring for reaction, and performing suction filtration, washing and drying to obtain a compound 8;
(9) adding cold cutting fluid into the compound 8 to perform low-temperature reaction, adding diethyl ether after stirring reaction, performing centrifugal separation to obtain a crude product, and performing preparative chromatographic separation to obtain the required three-function diagnosis and treatment integrated prodrug, wherein the structural formula of the three-function diagnosis and treatment integrated prodrug is as follows:
wherein the linker is any one of alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, ether, epoxy and mercapto; AA1And AA2Each is any one amino acid; r2Is any one of N, N-trimethyl salt, nitryl and halogen, and the structural formula of the N, N-trimethyl salt is as follows:
in the steps (1) to (6) and (8), washing and drying operations are respectively carried out by using dimethylformamide; the aprotic polar solvent includes or an analog thereof, and the organic base includes N, N-diisopropylethylamine or an analog thereof.
The equivalent weight of amino acid 1, amino acid 2 and amino acid 3 is 2-4 eq, and the equivalent weight of N, N-diisopropylethylamine is 2-4 eq.
In the step (3), the step (5) and the step (7), the piperidine solution is a dimethylformamide solution containing 10-30% piperidine, the dosage is 4-8 mL/g, the reaction temperature is room temperature, and the reaction time is 10-60 min.
In the step (8), the equivalent weight of the DOTA-GA acid anhydride is 1.3-1.8 eq, the reaction temperature is 20-60 ℃, and the reaction time is 24-72 hours.
In the step (9), the cutting fluid is trifluoroacetic acid with a mass fraction of 95%, the dosage is 20-60 mL/g, and the volume ratio of the ether to the cutting fluid is 8-10: 1, the low-temperature reaction conditions are as follows: and (3) keeping the temperature of-10-0 ℃ for reaction for 10-30 min, then heating to room temperature, and stirring for reaction for 3-8 h.
Example 1
As shown in fig. 1-2, a method for synthesizing a three-functional diagnosis and treatment integrated prodrug for prostate cancer comprises the following steps:
(1) taking a compound 1(1.00eq) as a raw material, dripping the compound 1(5.08g, 2.69mmol) into 10mL of dimethylformamide solution (containing active ester 1.77g, 4.02mmol), stirring and reacting at room temperature for 3 hours, performing suction filtration after a color reaction shows that amino groups have basically reacted completely, and washing and drying by using the dimethylformamide solution to obtain a compound 2;
(2) mixing the above compound 2 and amino acid 1
(3.45g, 8.14mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (1.02g, 7.89mmol) is added dropwise at room temperature, the mixture is stirred and reacted for 3 hours at room temperature, and the reaction product is filtered, washed by dimethylformamide and dried to obtain a compound 3;
(3) adding a solution (20mL) containing 20% N, N-dimethylformamide into the compound 3, reacting at room temperature for 20min, performing suction filtration, washing with dimethylformamide, and drying to obtain a compound 4;
(4) mixing the above compound 4 and amino acid 2
(3.51g, 7.86mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (1.01g, 7.83mmol) is added dropwise at room temperature, the mixture is stirred and reacted for 2-8 hours at room temperature, and the reaction product is filtered, washed by dimethylformamide and dried to obtain a compound 5;
(5) adding a solution (20mL) containing 20% N, N-dimethylformamide into the compound 5, reacting at room temperature for 20min, performing suction filtration, washing with dimethylformamide, and drying to obtain a compound 6;
(6) mixing the above compound 6 and amino acid 3
(3.85g, 7.28mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (0.99g, 7.68mmol) is added dropwise at room temperature, the mixture is stirred and reacted for 4 hours at room temperature, and the reaction product is filtered, washed by dimethylformamide and dried to obtain a compound 7;
(7) adding a 20% N, N-dimethylformamide solution (20mL) into the compound 7, reacting at room temperature for 30min, performing suction filtration to obtain resin, and washing and drying the resin with dimethylformamide;
(8) adding the resin, DOTA-GA acid anhydride (2.10g, 3.88mmol) and dimethylformamide (10mL) into a reaction bottle, stirring at 20-60 ℃ for reaction for 48h, performing suction filtration, washing with dimethylformamide and drying to obtain a compound 8;
(9) adding cold cutting fluid (95% trifluoroacetic acid, 60mL) into the compound 8, keeping the temperature at-10-0 ℃ for reaction for 20min, heating to room temperature, stirring for reaction for 3h, adding diethyl ether (600mL), centrifuging 6000g for 5min, and separating out a crude product; the crude product is separated by preparative chromatography, the eluent used for the preparative chromatography is trifluoroacetic acid aqueous solution with the concentration of 0.1 percent and trifluoroacetic acid acetonitrile solution with the concentration of 0.1 percent, and the three-function diagnosis and treatment integrated prodrug, namely the compound 9, is finally obtained after gradient elution.
All reagents used in washing, drying and the like operations referred to in this example were dimethylformamide.
Example 2
As shown in fig. 1-2, a method for synthesizing a three-functional diagnosis and treatment integrated prodrug for prostate cancer comprises the following steps:
(1) taking a compound 1(1.00eq) as a raw material, dripping the compound 1(4.74g, 2.51mmol) into 10mL of dimethylformamide solution (containing active ester 1.22g, 2.77mmol), stirring and reacting for 4 hours at room temperature, performing suction filtration after a color reaction shows that amino groups have basically reacted completely, and washing and drying by using the dimethylformamide solution to obtain a compound 2;
(2) mixing the above compound 2 and amino acid 1
(2.13g, 5.03mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (0.65g, 5.04mmol) is added dropwise at room temperature, the mixture is stirred at room temperature for reaction for 2-8 h, and the reaction product is subjected to suction filtration, washed by dimethylformamide and dried to obtain a compound 3;
(3) adding an N, N-dimethylformamide solution (20mL) containing 20% piperidine into the compound 3, reacting at room temperature for 10-60 min, performing suction filtration, and washing and drying by using dimethylformamide to obtain a compound 4;
(4) mixing the above compound 4 and amino acid 2
(2.25g, 5.04mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (0.65g, 5.04mmol) is added dropwise at room temperature, the mixture is stirred at room temperature for reaction for 2-8 h, and the reaction product is subjected to suction filtration, washed by dimethylformamide and dried to obtain a compound 5;
(5) adding an N, N-dimethylformamide solution (20mL) containing 20% piperidine into the compound 5, reacting at room temperature for 10-60 min, performing suction filtration, and washing and drying by using dimethylformamide to obtain a compound 6;
(6) mixing the above compound 6 and amino acid 3
(2.65g, 5.02mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (0.65g, 5.04mmol) is added dropwise at room temperature, the mixture is stirred at room temperature for reaction for 2-8 h, and the reaction product is subjected to suction filtration, washed with dimethylformamide and dried to obtain a compound 7;
(7) adding an N, N-dimethylformamide solution (20mL) containing 20% piperidine into the compound 7, reacting at room temperature for 10-60 min, performing suction filtration to obtain resin, and washing and drying the resin by using dimethylformamide;
(8) adding the resin, DOTA-GA acid anhydride (1.77g, 3.27mmol) and dimethylformamide (10mL) into a reaction bottle, stirring and reacting at 20-60 ℃ for 24-72 h, performing suction filtration, washing with dimethylformamide and drying to obtain a compound 8;
(9) adding cold cutting fluid (95% trifluoroacetic acid, 60mL) into the compound 8, keeping the temperature at-10-0 ℃ for reaction for 10-30 min, heating to room temperature, stirring for reaction for 3-8h, adding ether (600mL), and centrifuging at 6000g for 5min to separate a crude product; the crude product is separated by preparative chromatography, the eluent used for the preparative chromatography is trifluoroacetic acid aqueous solution with the concentration of 0.1 percent and trifluoroacetic acid acetonitrile solution with the concentration of 0.1 percent, and the three-function diagnosis and treatment integrated prodrug, namely the compound 9, is finally obtained after gradient elution.
The same as in example 1.
Example 3
As shown in fig. 1-2, a method for synthesizing a three-functional diagnosis and treatment integrated prodrug for prostate cancer comprises the following steps:
(1) taking a compound 1(1.00eq) as a raw material, dripping the compound 1(5.17g, 2.74mmol) into 10mL of dimethylformamide solution (containing active ester 2.41g, 5.48mmol), stirring and reacting at room temperature for 3-4h, wherein the color reaction shows that amino has basically reacted completely, then carrying out suction filtration, and washing and drying by using the dimethylformamide solution to obtain a compound 2;
(2) mixing the above compound 2 and amino acid 1
(4.63g, 10.92mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (1.41g, 10.91mmol) is added dropwise at room temperature, the mixture is stirred and reacted for 2-8 hours at room temperature, and the reaction product is subjected to suction filtration, washed by dimethylformamide and dried to obtain a compound 3;
(3) adding an N, N-dimethylformamide solution (20mL) containing 20% piperidine into the compound 3, reacting at room temperature for 10-60 min, performing suction filtration, and washing and drying by using dimethylformamide to obtain a compound 4;
(4) mixing the above compound 4 and amino acid 2
(4.87g, 10.90mmol) and dimethylformamide (10mL) are added into a reaction bottle, N-diisopropylethylamine (1.41g, 10.91mmol) is added dropwise at room temperature, the mixture is stirred and reacted for 2-8 hours at room temperature, and the reaction product is subjected to suction filtration, washed by dimethylformamide and dried to obtain a compound 5;
(5) adding an N, N-dimethylformamide solution (20mL) containing 20% piperidine into the compound 5, reacting at room temperature for 10-60 min, performing suction filtration, and washing and drying by using dimethylformamide to obtain a compound 6;
(6) mixing the above compound 6 and amino acid 3
(5.76g, 10.89mmol) and dimethylformamide (10mL) were added to the reaction flask and N, N-diisopropylethylamine (1.41g, 10.9 g) was added dropwise at room temperature1mmol), stirring and reacting for 2-8 h at room temperature, performing suction filtration, washing with dimethylformamide and drying to obtain a compound 7;
(7) adding an N, N-dimethylformamide solution (20mL) containing 20% piperidine into the compound 7, reacting at room temperature for 10-60 min, performing suction filtration to obtain resin, and washing and drying the resin by using dimethylformamide;
(8) adding the resin, DOTA-GA acid anhydride (2.67g, 4.93mmol) and dimethylformamide (10mL) into a reaction bottle, stirring and reacting at 20-60 ℃ for 24-72 h, performing suction filtration, washing with dimethylformamide and drying to obtain a compound 8;
(9) adding cold cutting fluid (95% trifluoroacetic acid, 80mL) into the compound 8, keeping the temperature at-10-0 ℃ for reaction for 10-30 min, heating to room temperature, stirring for reaction for 3-8h, adding diethyl ether (800mL), centrifuging for 5min at 6000g, and separating out a crude product; the crude product is separated by preparative chromatography, the eluent used for the preparative chromatography is trifluoroacetic acid aqueous solution with the concentration of 0.1 percent and trifluoroacetic acid acetonitrile solution with the concentration of 0.1 percent, and the three-function diagnosis and treatment integrated prodrug, namely the compound 9, is finally obtained after gradient elution.
The same as in example 1.
Example 4
The compound 9 obtained in example 1 was subjected to the conventional method18Labeled F as shown in fig. 3.18The structure of N, N-trimethyl is used as the label of F, and the substitution of F18 is carried out to make the structure of compound 9 labeled18F。
Example 5
The compound 9 obtained in example 1 was subjected to the conventional method68Ga-marked as shown in FIG. 4.68Ga label uses DOTA structure, which is labeled with drug structure after chelating metal ion68Ga。
Example 6
The compound 9 obtained in example 1 was subjected to the conventional method177Lu, as shown in FIG. 5.177The Lu label uses DOTA structure, and the drug structure is labeled after chelating metal ions177Lu。
The parts of the invention not specifically described can be realized by adopting the prior art, and the details are not described herein.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
1. A synthetic method of a three-function diagnosis and treatment integrated prodrug for prostatic cancer is characterized by comprising the following steps:
(1) dripping the compound 1 into an active ester solution, stirring for reaction, and then performing suction filtration, washing and drying to obtain a compound 2;
(2) mixing the compound 2 obtained in the step (1), amino acid 1 and an aprotic polar solvent, then dropwise adding an organic base, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 3;
(3) adding a piperidine solution into the compound 3, and performing suction filtration, washing and drying after reaction to obtain a compound 4;
(4) mixing the compound 4, the amino acid 2 and the aprotic polar solvent, then dropwise adding an organic base, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 5;
(5) adding a piperidine solution into the compound 5, and performing suction filtration, washing and drying after reaction to obtain a compound 6;
(6) mixing the compound 6, the amino acid 3 and the aprotic polar solvent, dripping organic base, stirring for reaction, and performing suction filtration, washing and drying to obtain a compound 7;
(7) adding a piperidine solution into the compound 7, and reacting to obtain resin;
(8) mixing the resin obtained in the step (7), DOTA-GA anhydride and an aprotic polar solvent, stirring for reaction, and then carrying out suction filtration, washing and drying to obtain a compound 8;
(9) adding cutting fluid into the compound 8 for low-temperature reaction, then adding ether, performing centrifugal separation to obtain a crude product, and performing preparative chromatographic separation to obtain the required three-function diagnosis and treatment integrated prodrug, wherein the structural formula of the three-function diagnosis and treatment integrated prodrug is as follows:
wherein the linker is any one of alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, ether, epoxy and mercapto; AA1And AA2Each is any one amino acid; r2Is any one of N, N-trimethyl salt, nitryl and halogen, and the structural formula of the N, N-trimethyl salt is as follows:
2. the method for synthesizing the trifunctional medical-diagnostic integrated prodrug for the prostate cancer according to claim 1, wherein in the step (1), the molar ratio of the compound 1 to the active ester solution is 1: 1.10-2.00, the reaction temperature is room temperature, and the amino reaction is judged to be complete through color reaction.
3. The method for synthesizing a trifunctional diagnosis and treatment integrated prodrug for prostate cancer according to claim 1, wherein the washing and drying operations in steps (1) to (6) and (8) are performed with dimethylformamide, respectively.
4. The method for synthesizing the triple-functional diagnosis and treatment integrated prodrug for prostate cancer according to claim 1, wherein in the step (2), the structural formula of the amino acid 1 is as follows:
1.00eq compound 1 is used as a raw material, 1 equivalent of amino acid is 2-4 eq, and 2-4 eq of N, N-diisopropylethylamine is equivalent.
5. According to the rightThe method for synthesizing the triple-functional diagnosis and treatment integrated prodrug for prostate cancer according to claim 1, wherein in the step (4), the structural formula of the amino acid 2 is as follows:
1.00eq compound 1 is used as a raw material, 2 eq of amino acid is 2-4 eq, and 2-4 eq of N, N-diisopropylethylamine is equivalent.
6. The method for synthesizing the triple-functional diagnosis and treatment integrated prodrug for prostate cancer according to claim 1, wherein in the step (6), the structural formula of the amino acid 3 is as follows:
1.00eq compound 1 is used as a raw material, 3 equivalents of amino acid is 2-4 eq, and 2-4 eq of N, N-diisopropylethylamine is equivalent.
7. The method for synthesizing a trifunctional diagnosis and treatment integrated prodrug for prostate cancer according to claim 1, wherein in the step (3), the step (5) and the step (7), the piperidine solution is a dimethylformamide solution containing 10% -30% piperidine, the reaction temperature is room temperature, and the reaction time is 10-60 min.
8. The method for synthesizing the triple-function diagnosis and treatment integrated prodrug for the prostate cancer according to claim 1, wherein in the step (8), 1.00eq of the compound 1 is used as a raw material, the DOTA-GA acid anhydride equivalent is 1.3-1.8 eq, the reaction temperature is 20-60 ℃, and the reaction time is 24-72 hours.
9. The method for synthesizing the triple-function diagnosis and treatment integrated prodrug for the prostate cancer according to claim 1, wherein in the step (9), the cutting fluid is trifluoroacetic acid with a mass fraction of 95%, the dosage of the trifluoroacetic acid is 20-60 mL/g, and the volume ratio of the diethyl ether to the cutting fluid is 8-10: 1, the low-temperature reaction conditions are as follows: and (3) keeping the temperature of-10-0 ℃ for reaction for 10-30 min, then heating to room temperature, and stirring for reaction for 3-8 h.
10. A three-functional diagnosis and treatment integrated prodrug for prostate cancer, which is synthesized by the method for synthesizing the three-functional diagnosis and treatment integrated prodrug for prostate cancer according to any one of claims 1 to 9, wherein the structural formula of the three-functional diagnosis and treatment integrated prodrug is as follows:
wherein the linker is any one of alkyl, alkenyl, alkynyl, phenyl, phenylalkyl, ether, epoxy and mercapto; AA1And AA2Each is any one amino acid; r2Is any one of N, N-trimethyl salt, nitryl and halogen, and the structural formula of the N, N-trimethyl salt is as follows:
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