CN115448925B - Preparation method and application of nonafluorokamtinib and salt thereof - Google Patents
Preparation method and application of nonafluorokamtinib and salt thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to the field of medicines, in particular to a preparation method and application of nine-fluorine-contained carbamazepine and salt thereof, wherein the structure of the nine-fluorine-contained carbamazepine is shown in a formula IV, and the structure of the salt is shown in a formula V. The nonafluorokamtinib and the salt thereof can be used for preparing tumor diagnosis products. The synthesis method of the nonafluorokatinib and the salt thereof is simple and easy to prepare, and the contrast agent prepared by the nonafluorokatinib and the salt thereof has targeting property and can target hepatocyte growth factor receptor, thereby improving the specificity of MRI.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and application of nonafluorokatinib and salt thereof.
Background
Magnetic Resonance Imaging (MRI) has played an important role as a non-invasive detection tool in early disease diagnosis and therapy monitoringIs used. MRI, which is commonly used in medicine, is 1 H MRI requires the assistance of contrast agents such as iron oxide nanoparticles, but existing contrast agents lack specificity and are less sensitive.
Carbamazepine is a hepatocyte growth factor receptor (c-Met) inhibitor that has been FDA approved for the treatment of non-small cell lung cancer and which is targeted.
Disclosure of Invention
In view of the above-described drawbacks of the prior art, an object of the present invention is to provide a method for preparing nonafluorokatinib and salts thereof and use thereof for solving the problems in the prior art.
To achieve the above and other related objects, the present invention provides a compound having a structure as shown in formula IV:
the invention also provides pharmaceutically acceptable salts of the compounds, and the structures of the pharmaceutically acceptable salts of the compounds are shown as formula V:
the invention also provides a preparation method of the compound, which comprises the following steps: the method comprises the steps of reacting a carbamazepine precursor carboxylic acid with a compound of formula III in the presence of a condensing agent to obtain the compound, wherein the reaction route is as follows:
the invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing tumor diagnosis products.
The invention also provides a contrast agent comprising the compound or a pharmaceutically acceptable salt thereof.
As described above, the preparation method and the application of the nonafluorokatinib and the salt thereof have the following beneficial effects: the synthesis method is simple and easy to prepare, and the contrast agent prepared by the method has targeting property and can target hepatocyte growth factor receptor, thereby improving the specificity of MRI.
Drawings
FIG. 1 shows a compound of formula I according to the invention 1 H NMR characterization data.
FIG. 2 shows a compound of formula II according to the invention 1 H NMR characterization data.
FIG. 3 shows a compound of formula III according to the invention 1 H NMR characterization data.
FIG. 4 shows a compound of formula IV according to the invention 1 H NMR characterization data.
Figure 5 shows mass spectrometry characterization data for compounds of formula IV of the present invention.
FIG. 6 shows a compound of formula V according to the invention 1 H NMR characterization data.
FIG. 7 shows a chemical shift spectrum (MRS) of fluorine element in the nonafluoro tert-butoxy group.
FIG. 8 shows that detection limit of nonafluorokatinib is at 10 mM.
Detailed Description
The invention provides a compound, the structure of which is shown in a formula IV:
the invention also provides pharmaceutically acceptable salts of the compounds, and the structures of the pharmaceutically acceptable salts of the compounds are shown as formula V:
in one embodiment, the fluorine element in the compound represented by formula IV or the nonafluoro tert-butoxy group in the compound represented by formula V is 19 F。 19 F has good magnetic propertiesIs absent in human tissue, thus 19 F can be used as a probe, and can be used for 1 The information provided by H MRI is supplemented. Will be 19 F is combined into the carbamazepine molecule or the salt thereof to obtain the targeting 19 F MRI contrast agent-a compound of formula IV or a compound of formula V.
The invention also provides derivatives of the compounds or pharmaceutically acceptable salts thereof, each of which may be substituted with nonafluoro tert-butyl, trifluoromethoxy or trifluoromethyl.
The invention also provides a preparation method of the compound, which comprises the following steps: the method comprises the steps of reacting a carbamazepine precursor carboxylic acid with a compound of formula III in the presence of a condensing agent to obtain the compound, wherein the reaction route is as follows:
in one embodiment, the carbamazepine precursor carboxylic acid is selected from the salts thereof. The carbamazepine precursor carboxylate is, for example, a carbamazepine precursor carboxylate.
The compound of formula III may be synthesized by prior art techniques. For example, reference may be made to the synthetic methods in the following documents: kasper J.J., hitro J.E., fitzgerald S.R., schniter J.M., rutowski J.J., heck J.A., steinbacher J.L.A. Library of Fluorinated Electrophiles for Chemical Tagging and Materials Synthesis [ J ]. J.org. chem.2016,81 (17), 8095-8103.
In one embodiment, the compound of formula III is synthesized as follows:
in certain embodiments of the invention, the condensing agent is selected from onium salt condensing agents. The onium salt condensing agent is selected from carbonium salt condensing agent or phosphonium salt condensing agent. The carbonium salt condensing agent is HATU, HBTU, HCTU, HAPyU, HBPyU, for example. The phosphonium salt condensing agent is selected from BOP, pyBOP, pyAOP. In a preferred embodiment, the condensing agent is selected from PyBOP, HOBt, EDC. PyBOP is relatively active in phosphonium salt condensing agents and does not produce toxic byproducts.
The reaction is carried out in a solvent, which may be generally an aprotic solvent, and a person skilled in the art may select an appropriate kind and amount of solvent according to the reaction raw materials so that the reaction raw materials have good solubility in the solvent. For example, the solvent may be DMF. In one embodiment, the solvent is an ultra-dry solvent. The super-dry solvent refers to the water content in the solvent being within 50 ppm.
The reaction is carried out in the presence of a base. The base may typically be an organic base, for example TEA or the like. The amount of base used is generally equal or in excess relative to the compound of formula III. For example, the molar ratio of the carbamazepine precursor carboxylic acid to base can be 1:3 to 7.
The compound of formula III is typically used in an amount equivalent or in excess to the amount of the carbotinib precursor carboxylic acid in the reaction. For example, the molar ratio of the compound of formula III to the carbamazepine precursor carboxylic acid is 1:1 to 1.5.
The temperature of the reaction may be from room temperature to the reflux temperature of the solvent. For example, the reaction may be carried out at 20 to 35 ℃.
The reaction may generally be carried out in the presence of a shielding gas. The shielding gas may be nitrogen, an inert gas, etc., and more specifically may be helium, neon, argon, krypton, xenon, etc.
The reaction time can be adjusted by the person skilled in the art according to the reaction progress, which can be monitored by methods such as TLC, HPLC, etc., and can be 0.1-24h. In one embodiment, the reaction time is from 6 to 18 hours.
After the reaction is completed, the reaction product can be separated and purified to obtain the compound of the formula IV. The person skilled in the art can choose a suitable method for purification, for example, the product can be extracted with a suitable solvent. The solvent that can be used may be a combination of one or more of water, ethyl acetate, methanol, and the like. For another example, separation with a silica gel column is also possible.
In one embodiment, the method of preparing the compound comprises the steps of:
1) Adding a carbotinib precursor carboxylic acid and a condensing agent into a dry reaction container, and filling the reaction container with a protective gas;
2) Adding a solvent into the reaction vessel;
3) Dissolving a compound of formula III in a solvent, and adding the dissolved compound into a reaction container;
4) Adding alkali into the reaction vessel for reaction for 6-18 h;
5) And after the reaction is finished, extracting, washing, drying, removing a solvent and separating to obtain the compound.
The process for the preparation of the compounds of formula V comprises reacting a compound of formula IV with a suitable acid.
In certain embodiments of the present invention, the compound of formula IV is reacted with hydrochloric acid, washed after a solid has occurred, and dried to obtain a solid, i.e., the compound of formula V.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing tumor diagnosis products.
In certain embodiments of the invention, the tumor diagnostic product is a contrast agent; preferably, the contrast agent is an MRI contrast agent.
The tumor is selected from tumors with high expression of c-Met. Such as non-small cell lung cancer, head and neck squamous cell carcinoma, gastric cancer, colon cancer, liver cancer, ovarian cancer, renal cell carcinoma, bladder cancer, breast cancer, etc.
The invention also provides a contrast agent comprising the compound or a pharmaceutically acceptable salt thereof.
The contrast agent can also comprise pharmaceutically acceptable carriers or auxiliary materials and the like.
In the present invention, "pharmaceutically acceptable" means that the drug does not produce adverse, allergic or other untoward reactions when properly administered to an animal or human.
The "pharmaceutically acceptable carrier or adjuvant" should be compatible with the active ingredient, i.e. it can be blended therewith without substantially reducing the efficacy of the drug in the usual manner. Specific examples of some substances which may be pharmaceutically acceptable carriers or excipients are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium methyl cellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifying agents, such as Tween; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting and stabilizing agent; an antioxidant; a preservative; non-thermal raw water; isotonic saline solution; and phosphate buffer, etc. These substances are used as needed to aid stability of the formulation or to aid in enhancing the activity or its bioavailability or to produce an acceptable mouthfeel or odor in the case of oral administration.
The contrast agent is capable of targeting c-Met.
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention.
Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention; in the description and claims of the invention, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, materials used in the embodiments, any methods, devices, and materials of the prior art similar or equivalent to those described in the embodiments of the present invention may be used to practice the present invention according to the knowledge of one skilled in the art and the description of the present invention.
EXAMPLE 1 Synthesis of Compound I
4.62mL of redistilled triethylamine, 1.7932g of di-tert-butyl dicarbonate (Boc 2 O), 10mL of redistilled Tetrahydrofuran (THF) were added to the round bottom flask and placed in an ice-water bath, 495.1mg of 3-hydroxypropionamine was slowly added to the round bottom flask with a syringe, the system was kept at 0 ℃, the reaction solution was stirred for 20 hours, and the temperature of the reaction solution was allowed to naturally rise to room temperature during the reaction. At the end of the reaction, the solvent was removed by rotary evaporation, and the residue was dissolved in ethyl acetate. Washing with deionized water, extracting the aqueous layer with ethyl acetate twice, combining the organic layers, and extracting with saturated NaHCO 3 Aqueous solution and saturated brine, then washed with anhydrous Na 2 SO4 is dried, the drying agent is removed by filtration, and the solvent is removed by rotary evaporation to obtain the compound I, which can be directly used in the next step without additional purification. 1 H NMR(400MHz,CDCl 3 ,ppm):δ4.77(br,1H),3.59(t,J＝6.0Hz,2H),3.21(t,J＝6.0Hz,2H),2.73(br,1H),1.60(m,2H),1.38(s,9H).
EXAMPLE 2 Synthesis of Compound II
625mg triphenylphosphine (PPh) 3 ) Adding into a Schlenk bottle dried in advance, and extracting N 2 Three times, 276.7mg of Compound I was dissolved in a small amount of ultra-dry THF and added to a syringe containing triphenylphosphine (PPh 3 ) In a Schlenk flask of (A), and 6mL of ultra-dry THF was again added and placed in an ice-water bath. 423mg of diethyl azodicarboxylate (DEAD) was slowly added by syringe, and after the addition was completed, the mixture was allowed to stand at room temperature and stirred for 20 minutes. Then rapidly add 600 via syringemg of perfluoro-tert-butanol was reacted at 55℃for 22 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (90:10=pe: etOAc to 80:20=pe: etOAc, gradient elution) gave compound II. 1 H NMR(400MHz,CDCl 3 ,ppm):δ4.67(br,1H),4.08(t,J＝6.0Hz,2H),3.23(d,J＝4.0Hz,2H),1.88(m,2H),1.43(s,9H).
EXAMPLE 3 Synthesis of Compound III
326mg of Compound II was added to a round-bottomed flask, 2.5mL of diethyl ether was added, followed by dropwise addition of 0.16mL of concentrated hydrochloric acid and stirring for 20h. After the reaction was completed, the solvent was removed by rotary evaporation, a small amount of methanol (about 0.5 mL) was added, and then about 5mL of diethyl ether was added to cause phase separation, and the lower layer was transferred to a clean round bottom flask, and the methanol was removed by rotary evaporation to give compound III. 1 H NMR(400MHz,DMSO-d 6 ,ppm):δ8.08(s,3H),4.19(t,J＝6.0Hz,2H),2.86(s,2H),1.98(m,2H).
EXAMPLE 4 Synthesis of Compound IV
8.2mg of the Carnitine precursor carboxylic acid and 15.1mg of PyBOP were added to a previously dried Schlenk flask, and N was exchanged 2 Three times, 3mL of ultra-dry DMF was added. Then, 15.3mg of Compound III was dissolved in 0.5mL of ultra-dry DMF, slowly added to a Schlenk flask at room temperature by syringe, the temperature was raised to 30℃during the addition, then 0.1mL of redistilled triethylamine was added, and the reaction solution was stirred at room temperature overnight. After the reaction, ethyl acetate is used for extraction, deionized water is used for washing, and anhydrous Na is used for 2 SO 4 Drying, rotary evaporating to remove solvent, and separating with silica gel column (eluting with ethyl acetate) to obtain compound IV. 1 H NMR(400MHz,CDCl 3 ,ppm):δ8.91(s,1H),8.88(s,1H),8.27(t,J＝8.0Hz,1H),8.14(t,J＝8.0Hz,2H),7.95(s,1H),7.86(dd,J＝8.4,1.6Hz,1H),7.79(s,1H),7.76-7.71(m,2H),7.45-7.42(m,1H),6.94-6.89(m,1H),4.62(s,2H),4.18(t,J＝4.0Hz,2H),3.68-3.63(m,2H),2.12-2.06(m,2H). 19 F NMR(376MHz,DMSO-d 6 ,ppm):δ-69.9(s),-113.5(s).MS(EI)m/z:calcd for C 29 H 20 F 10 N 6 O 2 [M + ]:674.15；found:674.1
EXAMPLE 5 Synthesis of Compound V
14.6mg of Compound IV was dissolved in a small amountTo the ethyl acetate solution was added 0.1mL of a 2.0M solution of HCl in ethyl acetate, and the mixture was centrifuged, washed with diethyl ether, centrifuged again, and repeated 3 to 4 times to obtain a solid, which was dried under vacuum at 55 ℃. 1 H NMR(400MHz,DMSO-d 6 ,ppm):δ9.29(s,1H),9.17(d,J＝4.0Hz,1H),8.95(d,J＝8.0Hz,1H),8.56(t,J＝4.0Hz,1H),8.28-8.25(m,2H),8.12(d,J＝8.0Hz,1H),8.07-8.04(m,3H),7.96-7.93(m,1H),7.77(t,J＝8.0Hz,1H),4.74(s,2H),4.18(t,J＝6.0Hz,2H),3.40-3.35(m,2H),1.98-1.93(m,2H).
Example 6
Detection spectra with 1H/19F surface coil on small animal magnetic resonance imaging device (9.4T MRI), fluorine element chemical shift acquisition parameters in nine-fluoro-T-butoxy: nucleos1= 19F,Repetition Time =1500 ms, acq.bandwidth= 4385.96Hz, chemical shift of-67.621 ppm. And (3) adjusting the Bopu detection point to the vicinity of-113.48 ppm of the chemical displacement value of F in the Kamattinib skeleton, and searching for a peak of the F, wherein the peak is not detected.
The imaging potential of the present compounds was verified in a 9.4T magnetic resonance imaging system (Biospec 94/20USR, bruker;19F coil). Each 500. Mu.L of the three (10 mM, 5mM, 1 mM) 9F-Capmatinib DMSO solutions was placed in an EP tube to avoid bubbles as much as possible. Binding the sample FIG. 8 to a 1H/19F surface coil, performing a spacer and 1 in H imaging, 1H coil mode is selected, in 19 F selection in imaging 19 F coil mode. And (5) performing FLASH sequence imaging. The results are shown in FIG. 8, with the detection limit of 9F-Capmatinib at 10 mM.
The above examples are provided to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. Further, various modifications of the methods set forth herein, as well as variations of the methods of the invention, will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the present invention.
Claims (11)
1. A compound is characterized in that the structure of the compound is shown as a formula IV, wherein fluorine in the nonafluoro tert-butoxy group is 19 F，
2. The pharmaceutically acceptable salt of the compound of claim 1, wherein the pharmaceutically acceptable salt has a structure as shown in formula V, and wherein the fluorine element in the nonafluoro tert-butoxy group is 19 F，
3. A process for the preparation of a compound according to claim 1, comprising the steps of: the method comprises the steps of reacting a carbotinib precursor carboxylic acid with a compound shown in a formula III in the presence of a condensing agent, wherein the condensing agent is an onium salt condensing agent, and the reaction is carried out in the presence of a base, wherein the reaction route is as follows:
4. a method of preparation according to claim 3, further comprising one or more of the following features:
1) The reaction is carried out in a solvent, which is an aprotic solvent;
2) The condensing agent is selected from BOP, pyBOP, pyAOP;
3) The alkali is an organic alkali;
4) The reaction temperature is 20-35 ℃;
5) The reaction is carried out in the presence of a shielding gas;
6) The reaction time is 6-18 h.
5. A process according to claim 3, wherein the reaction is carried out in DMF solvent; and/or the reaction is carried out in the presence of nitrogen or an inert gas.
6. A method of preparation according to claim 3, further comprising one or more of the following features:
1) The molar ratio of the carbamazepine precursor carboxylic acid to the compound of formula III is 1:1 to 1.5;
2) The molar ratio of the carbotinib precursor carboxylic acid to the base is 1:3 to 7;
3) The base is TEA.
7. A process for the preparation of a salt according to claim 2, characterized in that it comprises reacting a compound of formula IV with hydrochloric acid to obtain said salt.
8. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a diagnostic product for a tumor.
9. The use of claim 8, wherein the tumor diagnostic product is a contrast agent.
10. The use of claim 8, wherein the tumor diagnostic product is an MRI contrast agent.
11. A contrast agent comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
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| CN113896732A (en) * | 2021-10-13 | 2022-01-07 | 沈阳红旗制药有限公司 | Preparation method and application of anti-cancer drug carbamatinib |
| CN114425092A (en) * | 2021-12-23 | 2022-05-03 | 西安电子科技大学 | MRI/NIR II dual-mode imaging spray contrast agent and preparation method and application thereof |
| WO2022157629A1 (en) * | 2021-01-19 | 2022-07-28 | Lupin Limited | Pharmaceutical combinations of sos1 inhibitors for treating and/or preventing cancer |
| CN114853762A (en) * | 2021-02-03 | 2022-08-05 | 四川科伦药物研究院有限公司 | Solid form of imidazotriazine compound and preparation method and application thereof |
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| CN111825678A (en) * | 2020-06-05 | 2020-10-27 | 连庆泉 | Preparation method of carbamatinib |
| WO2022157629A1 (en) * | 2021-01-19 | 2022-07-28 | Lupin Limited | Pharmaceutical combinations of sos1 inhibitors for treating and/or preventing cancer |
| CN114853762A (en) * | 2021-02-03 | 2022-08-05 | 四川科伦药物研究院有限公司 | Solid form of imidazotriazine compound and preparation method and application thereof |
| CN113896732A (en) * | 2021-10-13 | 2022-01-07 | 沈阳红旗制药有限公司 | Preparation method and application of anti-cancer drug carbamatinib |
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