CN115448925A - Preparation method and application of nonafluoro carbamatinib and salt thereof - Google Patents
Preparation method and application of nonafluoro carbamatinib and salt thereof Download PDFInfo
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- CN115448925A CN115448925A CN202211129548.7A CN202211129548A CN115448925A CN 115448925 A CN115448925 A CN 115448925A CN 202211129548 A CN202211129548 A CN 202211129548A CN 115448925 A CN115448925 A CN 115448925A
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- 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
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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, and particularly relates to a preparation method and application of nonafluoro carbamatinib and salt thereof, wherein the structure of the nonafluoro carbamatinib is shown in a formula IV, and the structure of the salt is shown in a formula V. The nonafluoro carbamatinib and the salt thereof can be used for preparing tumor diagnosis products. The synthetic method of the nonafluoro carbamatinib and the salt thereof is simple and easy to prepare, and the contrast agent prepared by using the nonafluoro carbamatinib has targeting property and can target hepatocyte growth factor receptors, so that the specificity of MRI can be improved.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method and application of nonafluoro carbamatinib and salt thereof.
Background
Magnetic Resonance Imaging (MRI) as a non-invasive detection tool plays an important role in early disease diagnosis and therapy monitoring. The MRI commonly used in medicine is 1 H MRI requires the assistance of contrast agents such as iron oxide nanoparticles, but the existing contrast agents lack specificity and have lower sensitivity.
Carbamatinib is a hepatocyte growth factor receptor (c-Met) inhibitor that has been approved by the FDA for the treatment of non-small cell lung cancer and is targeted.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, it is an object of the present invention to provide a method for preparing and use of nonafluorocamatinib and salts thereof, which solves the problems of the prior art.
To achieve the above and other related objects, the present invention provides a compound having a structure represented by formula IV:
the invention also provides a pharmaceutically acceptable salt of the compound, and the structure of the pharmaceutically acceptable salt of the compound is shown as the formula V:
the invention also provides a preparation method of the compound, which comprises the following steps: reacting a carbamatinib 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 the pharmaceutically acceptable salt thereof in preparing tumor diagnosis products.
The invention also provides a contrast agent, which comprises the compound or the pharmaceutically acceptable salt thereof.
As described above, the preparation method and the use of the nonafluorocamatinib and the salt thereof of the present invention have the following beneficial effects: the synthetic method is simple and easy to prepare, and the contrast agent prepared by the method has targeting property and can target a hepatocyte growth factor receptor, so that the specificity of MRI can be improved.
Drawings
FIG. 1 shows compounds of formula I according to the invention 1 H NMR characterization data.
FIG. 2 shows compounds of formula II of the present invention 1 H NMR characterization data.
FIG. 3 shows compounds of formula III according to the invention 1 H NMR characterization data.
FIG. 4 shows compounds of formula IV of the present invention 1 H NMR characterization data.
Figure 5 shows mass spectrometry characterization data for a compound of formula IV of the present invention.
FIG. 6 shows compounds of formula V of the present invention 1 H NMR characterization data.
FIG. 7 shows the fluorine element chemical shift spectrum (MRS) in nonafluoro-tert-butoxy.
FIG. 8 shows the limit of detection for nonafluorocamatinib at 10 mM.
Detailed Description
The invention provides a compound, which has a structure shown in a formula IV:
the invention also provides a pharmaceutically acceptable salt of the compound, and the structure of the pharmaceutically acceptable salt of the compound is shown as the formula V:
in one embodiment, the fluorine element in the nonafluoro-tert-butoxy group in the compound of formula IV or the compound of formula V is 19 F。 19 F has good magnetism and is absent in human tissues, and 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 provided with 19 F combined with carbaminib molecules or salts thereof to obtain targeting 19 F MRI contrast agent-compound of formula IV or compound of formula V.
The present invention also provides a derivative of the compound or a pharmaceutically acceptable salt thereof, each of which may be a derivative obtained by substituting a nonafluoro-tert-butoxy group in the compound or salt with a nonafluoro-tert-butyl group, a trifluoromethoxy group or a trifluoromethyl group.
The invention also provides a preparation method of the compound, which comprises the following steps: the compound is obtained by reacting carbaminib precursor carboxylic acid with a compound shown in a formula III in the presence of a condensing agent, wherein the reaction route is as follows:
in one embodiment, the carbamatinib precursor carboxylic acid is selected from salts thereof. The carbamatinib precursor carboxylate is, for example, carbamatinib precursor carboxylic acid hydrochloride.
The compound of formula III may be synthesized by prior art techniques. For example, reference may be made to the following synthetic methods: kasper J.J., hitro J.E., fitzgerald S.R., schnitter J.M., rutowski J.J., heck J.A., steinbacher J.L.A. Library of Fluorinated electronics for Chemical labeling and Materials Synthesis [ J.Org.Chem.2016, (17), 8095-8103.
In one embodiment, the compound of formula III is synthesized as follows:
in certain embodiments of the present invention, the condensing agent is selected from onium salt type condensing agents. The onium salt condensing agent is selected from a carbonium salt condensing agent or a phosphonium salt condensing agent. Examples of the carbonium salt condensing agent include HATU, HBTU, HCTU, HAPyU, and HBPyU. The phosphonium salt condensing agent is selected from BOP, pyBOP and PyAOP. In a preferred embodiment, the condensing agent is selected from PyBOP, HOBt, EDC. PyBOP has better activity in the phosphonium salt condensing agent, and toxic byproducts are not generated.
The reaction is carried out in a solvent, which may be generally an aprotic solvent, and one skilled in the art can select a suitable kind of solvent and an amount to be used according to the reaction raw material, so that the reaction raw material has good solubility in the solvent. For example, the solvent may be DMF. In one embodiment, the solvent is an ultra-dry solvent. The ultra-dry solvent means that the water content in the solvent is within 50 ppm.
The reaction is carried out in the presence of a base. The base may typically be an organic base, which may be, for example, TEA, and the like. The base is generally used in an equal amount or in excess relative to the compound of formula III. For example, the molar ratio of the carbamatinib precursor carboxylic acid to base may be 1:3 to 7.
The compound of formula III is generally used in an equivalent or excess amount relative to the carbamatinib precursor carboxylic acid in the reaction. For example, the molar ratio of the compound of formula III to the carbamatinib 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 can generally be carried out in the presence of a protective gas. The shielding gas may be nitrogen, an inert gas, and the like, and the inert gas may be more specifically helium, neon, argon, krypton, xenon, and the like.
The reaction time can be adjusted by the skilled person according to the progress of the reaction, which can be monitored by methods such as TLC, HPLC, etc., and the reaction time can be 0.1-24h. In one embodiment, the reaction time is 6 to 18 hours.
After the reaction is finished, the reaction product can be separated and purified to obtain the compound shown in the formula IV. The skilled person can select a suitable method for purification, for example, a suitable solvent can be selected for extraction of the product. The solvent that can be used may be one or a combination of more of water, ethyl acetate, methanol, and the like. For another example, the separation can be performed by a silica gel column.
In one embodiment, the method of making the compound comprises the steps of:
1) Adding carbaminib precursor carboxylic acid and a condensing agent into a dry reaction vessel, and filling the reaction vessel with a protective gas;
2) Adding a solvent into the reaction vessel;
3) Dissolving the compound shown in the formula III by using a solvent, and adding the solution 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 the solvent and separating to obtain the compound.
The process for the preparation of the compound of formula V comprises reacting a compound of formula IV with a suitable acid.
In some embodiments of the invention, the compound of formula IV is reacted with hydrochloric acid, and the solid is washed and dried after the solid appears, to obtain the solid which is the compound of formula V.
The invention also provides application of the compound or the 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 c-Met high-expression tumor. 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, and the like.
The invention also provides a contrast agent, which comprises the compound or the pharmaceutically acceptable salt thereof.
The contrast agent can also comprise a pharmaceutically acceptable carrier or auxiliary material and the like.
In the present invention, "pharmaceutically acceptable" means that they do not produce adverse, allergic or other untoward effects when the medicament is properly administered to an animal or human.
The "pharmaceutically acceptable carrier or adjuvant" should be compatible with the active ingredient, i.e., capable of being blended therewith without substantially diminishing the effectiveness of the drug under ordinary circumstances. Specific examples of some substances that can serve as pharmaceutically acceptable carriers or adjuvants are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose and methylcellulose; powdered tragacanth; 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; polyhydric alcohols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as Tween; wetting agents, such as sodium lauryl sulfate; a colorant; a flavoring agent; tabletting agents, stabilizers; an antioxidant; a preservative; pyrogen-free water; isotonic saline solution; and phosphate buffer, and the like. These materials are used as needed to aid in the stability of the formulation or to aid in the enhancement of the activity or its bioavailability or to produce an acceptable mouth feel or odor in the case of oral administration.
The contrast agent is capable of targeting c-Met.
The following embodiments of the present invention are provided by way of specific examples, and other advantages and effects of the present invention will be readily apparent to those skilled in the art from the disclosure herein. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments, and is not intended to limit the scope of the present invention; in the description and claims of the present application, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any number between the two endpoints are optional unless otherwise specified in the invention. 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, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the 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) was added to the round-bottom flask and placed in an ice-water bath, 495.1mg of 3-hydroxypropylamine was slowly added to the round-bottom flask by syringe, the system was maintained at 0 ℃ and 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. After the reaction was completed, 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 purifying with saturated NaHCO 3 The aqueous solution was washed with saturated brine and then with anhydrous Na 2 Drying with SO4, filtering to remove the residueSolvent was removed by rotary evaporation to give compound I, which was used directly 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 of triphenylphosphine (PPh) 3 ) Adding into a Schlenk bottle dried in advance, and replacing N 2 Three times, 276.7mg of Compound I are dissolved in a small amount of ultra-dry THF and added by syringe to the solution containing triphenylphosphine (PPh) 3 ) Into a Schlenk flask, and 6mL of ultra-dry THF was added again 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. 600mg of perfluoro-tert-butanol was then added rapidly via syringe and reacted at 55 ℃ for 22 hours. After the reaction was completed, the solvent was removed by rotary evaporation and column chromatography (90. 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-bottom flask, 2.5mL of diethyl ether was added, then 0.16mL of concentrated HCl was added dropwise, and stirred for 20h. After the reaction is complete, the solvent is removed by rotary evaporation, a small amount of methanol (about 0.5 mL) is added followed by about 5mL of diethyl ether resulting in phase separation, the lower layer is transferred to a clean round bottom flask and the methanol is 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 carbamatinib precursor carboxylic acid and 15.1mg of PyBOP were added to a Schlenk flask dried in advance, and N was replaced 2 Three times, 3mL of ultra dry DMF was added. 15.3mg of compound III are then dissolved in 0.5mL of ultra-dry DMF and slowly added to a Schlenk flask at room temperature using a syringe, the temperature is raised to 30 ℃ during the addition, then 0.1mL of redistilled triethylamine is added and the reaction is stirred at room temperature overnight. After the reaction is finished, acetic acid ethyl is usedEster extraction, deionized water washing, anhydrous Na 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 amount of ethyl acetate, 0.1mL of 2.0M HCl ethyl acetate solution was added, a solid appeared, centrifuged, washed with ether, centrifuged again, repeated 3 to 4 times, the solid was taken out, and vacuum-dried 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
Spectra were detected on a small animal magnetic resonance imaging device (9.4T MRI) with a 1H/19F surface coil, and the fluorine element chemical shift in the nonafluoro-tert-butoxy group was used to obtain the parameters: nucleus 1=19F, repetition time =1500ms, acq.Bandwidth =4385.96Hz, and chemical shift-67.621 ppm. And (3) adjusting the Bopu detection point to be near the chemical shift value-113.48 ppm of F in the Caratinib framework, searching the peak of the F, and not detecting.
The imaging possibilities of the present compounds were verified in a 9.4T magnetic resonance imaging system (BioSpec 94/20USR, bruker, 19F coil. Each 500. Mu.L of 9F-Capmatic nib in DMSO solutions at three concentrations (10 mM, 5mM, 1 mM) was loaded into an EP tube to avoid air bubbles as much as possible. The sample pattern 8 was bound to a 1H/19F surface coil, and the spacer and 1 in H imaging, the 1H coil mode is selected 19 F imaging time selection 19 F coil mode. And carrying out FLASH sequence imaging. As shown in FIG. 8, the detection limit of 9F-Capmatic was 10 mM.
The above examples are intended to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, various modifications of the invention set forth herein, as well as variations of the methods of the invention, will be apparent to persons 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 above-described embodiments which are obvious to those skilled in the art to which the invention pertains are intended to be covered by the scope of the present invention.
Claims (10)
1. The compound is characterized by having a structure shown in a formula IV, wherein fluorine element in nonafluoro-tert-butoxy is 19 F，
2. A pharmaceutically acceptable salt of the compound of claim 1, wherein the pharmaceutically acceptable salt has the structure of formula V, and 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: reacting a carbamatinib 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:
4. the production method according to claim 3, wherein the condensing agent is an onium salt-based condensing agent.
5. The method of 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; preferably, the solvent is DMF;
2) The condensing agent is selected from BOP, pyBOP and PyAOP;
3) The reaction is carried out in the presence of a base; preferably, the base is an organic base;
4) The reaction temperature is 20-35 ℃;
5) The reaction is carried out in the presence of a protective gas; preferably, the protective gas is nitrogen or inert gas;
6) The reaction time is 6-18 h.
6. The method of claim 3, further comprising one or more of the following features:
1) The molar ratio of the carbamatinib precursor carboxylic acid to the compound of formula III is 1:1 to 1.5;
2) The molar ratio of the carbamatinib precursor carboxylic acid to the base is 1:3 to 7;
3) The base is TEA.
7. A process for preparing a salt according to claim 2, which comprises reacting a compound of formula IV with an acid to obtain said salt.
8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a tumor diagnostic product.
9. Use according to claim 8, wherein the tumour diagnostic product is a contrast agent; preferably, the contrast agent is an MRI contrast agent.
10. A contrast agent comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111825678A (en) * | 2020-06-05 | 2020-10-27 | 连庆泉 | Preparation method of carbamatinib |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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