CN111057075B - RET inhibitor and preparation method thereof - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a RET inhibitor and a preparation method thereof. The preparation method has the advantages of fewer reaction steps and mild reaction conditions, greatly improves the total yield of reaction products, ensures that the purity of the products reaches more than 99.5 percent, and has good economic advantages.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a RET inhibitor and a preparation method thereof.
Background
RET is a protooncogene (The transfected REarranged gene). RET receptor tyrosine kinase is an oncogene that appears in various cancers including non-small cell lung cancer (NSCLC), Medullary Thyroid Cancer (MTC), etc., abnormal activation of which is a key driver leading to growth and proliferation of various solid tumors, and it has been found that various diseases occur in close relation to RET gene mutation, such as NSCLC, MTC, multiple endocrine adenomatosis type 2 (multiple endocrine neoplasma ii, MEN2), Papillary Thyroid Cancer (PTC), megacolon congenital, lung adenocarcinoma, etc.
RET gene variation includes gene fusion and activating point mutations, which can lead to excessive activation of the RET signaling pathway and uncontrolled cell growth. RET gene fusions occur in 2% of non-small cell lung cancers (NSCLC), 10-20% of thyroid cancers and a few other cancer types. Whereas activating RET point mutations occur in 60% of patients with Medullary Thyroid Carcinoma (MTC). Cancers carrying the variation of the RET gene are largely dependent on abnormal activation of this protein kinase to promote their proliferation and growth, and thus these cancers are very sensitive to RET inhibitors.
At present, selective and specific medicines and therapies aiming at RET are not approved by regulatory agencies such as FDA, and no selective RET inhibitor is on the market all over the world. A total of 17 selective RET inhibitor drugs are currently under investigation, with 2 in phase 2, 3 in phase 1, 6 in Discovery stage, and 6 reported without progression. The selective Ret inhibitor drugs associated with tumor indications entered 3 out of 3 in the clinic, with stage 2 clinic 1 (selpercatinib/LOXO-292), and stage 1 clinic 2 (pralseatinib/BLU-667, BOS-172738). Another 2 drugs, BOS-589 (phase 2 clinical), GSK-3179106 (phase 1 clinical), are used in intestinal diseases such as irritable bowel syndrome, gastrointestinal pain, inflammatory bowel disease.
Selpercatinib is a highly specific, potent oral RET inhibitor obtained when LOXO Oncology is purchased from gifts. It can inhibit not only the natural RET signaling pathway but also the acquired resistance mechanisms that may occur. It has been identified by FDA-granted breakthrough therapy to treat NSCLC patients carrying RET gene fusions and MTC patients carrying RET activating mutations, as well as patients with advanced thyroid cancer carrying RET gene fusions. From the current clinical test, the treatment effect is very good and more accurate, and the biochemical index remission rate obtains a good result. In addition, the compound is effective not only for patients with RET gene mutation, but also for patients with RET gene fusion. Finally, of particular interest is the very low side effects. The structural formula of the high-selectivity RET gene mutation inhibitor Selpercatinib is a compound shown as a formula I:
research on the RET inhibitor Selpercatinib is still in depth, and the preparation method of the Selpercatinib is still improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a high-selectivity RET gene inhibitor Selpercatinib and a preparation method thereof.
In one aspect of the invention, the invention provides a method for preparing a compound Selpercatinib shown in formula I. According to an embodiment of the invention, the method comprises:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting a compound of formula 3 with a compound of formula 4 to obtain a compound of formula I,
the inventor finds that the compound shown in the formula I can be quickly and effectively prepared by using the method, and compared with the preparation method of Selpercatinib reported in the prior art, the preparation method has the advantages of less reaction steps, mild reaction conditions, greatly improved total yield of reaction products, high product purity of over 99.5 percent, good economic advantages and easiness in industrial industrialization.
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and may be, for example, mechanical stirring, that is, stirring under the action of a mechanical force.
Herein, a "compound of formula N" is also sometimes referred to herein as "compound N", where N is any integer from 1 to 4, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to an embodiment of the present invention, the above method for preparing the compound represented by formula 3, the compound represented by formula I, may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the raw materials for preparing the compound represented by formula 3, the compound represented by formula I is not particularly limited, and it may be prepared by any known method or may be commercially available.
According to an embodiment of the present invention, in step (1), the contact manner of the compound represented by formula 1, NaH, and the compound represented by formula 2 is not particularly limited. Preferably, the solvent of the reaction is selected from DMF. Therefore, the efficiency of contacting the compound shown in the formula 1, NaH and the compound shown in the formula 2 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: adding NaH into DMF solution of compound 1 at 0 deg.C in batches, and stirring to react at 0 deg.C for 15 min. Then, the reaction mixture was kept at 25 ℃ and the compound 2 was added to the reaction mixture, and after the addition, the reaction mixture was stirred while heating. After the reaction is finished, the reaction liquid is cooled to room temperature, and H is added2O, solid citric acid was added to adjust the pH to 5 and stirred at room temperature for 0.5 h. And adding EA into the reaction solution for extraction, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain the compound shown in the formula 3. Thus, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to an embodiment of the invention, in the step (1), the molar ratio of the compound represented by the formula 1, NaH and the compound represented by the formula 2 is 1 (1.0-1.5) to (9-12), and preferably the molar ratio of the compound represented by the formula 1, NaH and the compound represented by the formula 2 is 1:1.1: 10. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (1), the compound represented by formula 1, NaH, and the compound represented by formula 2 may be contacted and reacted at 75 to 85 ℃ for 22 to 28 hours.
According to an embodiment of the present invention, in the step (1), the compound represented by formula 1, NaH, and the compound represented by formula 2 may be contacted and reacted at 80 ℃ for 24 hours.
According to the embodiment of the invention, in the step (1), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (10-30): 1, and preferably, the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of 20: 1.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: NaH (2.64g, 0.11mol) was added portionwise to a DMF solution (240mL) of Compound 1(25.4g, 0.1mol) at 0 deg.C, and after the addition was complete, the reaction was stirred at 0 deg.C for 15 min. Then, compound 2(72g, 1mol) was added to the reaction mixture while maintaining at 25 ℃ and, after the addition was completed, the temperature was raised to 80 ℃ to react for 24 hours. After the reaction solution was cooled to room temperature, H was added2O (600mL), adjust to pH 5 by addition of solid citric acid and stir at room temperature for 0.5 h. The reaction mixture was extracted with EA (300mL × 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (DCM/MeOH ═ 20/1) to give the compound represented by formula 3.
According to the embodiment of the present invention, in the step (2), the contact manner of the compound represented by formula 3 with the compound represented by formula 4, KOAc, is not particularly limited. Preferably, the solvent of the reaction is selected from DMSO. Therefore, the contact efficiency of the compound shown as the formula 3, the compound shown as the formula 4 and KOAc can be improved, the reaction speed is increased, and the preparation efficiency of the compound shown as the formula I by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the following steps are included: compound 3, Compound 4 and KOAc were added to DMSO at room temperature, and the reaction was stirred at elevated temperature. After the reaction solution was cooled to room temperature, H was added2O suspended solids appeared after stirring. Filtering the solid, pulping and purifying the solid by using 30% DMSO aqueous solution, filtering the solid, and drying the solid in vacuum to obtain the compound Selpercatinib shown in the formula I. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound represented by the formula 3 to the compound represented by the formula 4 to KOAc is 1 (1.0-1.3) to (1.8-3), and the molar ratio of the compound represented by the formula 3 to the compound represented by the formula 4 to KOAc is preferably 1:1.1: 2. Therefore, the utilization rate of reactants is high, the waste of raw materials and reality can not be caused, and the yield and the purity of the target compound are high.
According to the embodiment of the invention, in the step (2), the compound shown in the formula 3, the compound shown in the formula 4 and KOAc are stirred and reacted for 22-28 h at 70-80 ℃. Therefore, the contact efficiency of the compound 3 and the compound 4 can be improved, and the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to an embodiment of the present invention, in the step (2), the compound represented by formula 3, the compound represented by formula 4, and KOAc may be contact-reacted at 75 ℃ for 24 hours. Therefore, the contact efficiency of the compound 3 and the compound 4 can be improved, and the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: compound 3(32.6g, 0.1mol), Compound 4(24.1g, 0.11mol) and KOAc (19.6g, 0.2mol) were added to DMSO (330mL) at room temperature, and the reaction was stirred at 75 ℃ for 24 h. After the reaction solution was cooled to room temperature, H was added2O (20mL) appeared as a suspended solid upon stirring. Filtering the solid, pulping and purifying by using 30% DMSO aqueous solution (300mL), filtering the solid, and drying in vacuum to obtain the compound Selpercatinib shown in the formula I.
According to the examples of the present invention, the synthetic route of the compound Selpercatinib of formula I can be as follows:
in the preparation method of Selpercatinib reported in the prior art, the compound 3 needs to undergo 3 steps of halogenation, debo protection and reductive amination to obtain a target molecule, so that the synthesis steps are increased, the total yield is low, and the synthesis route is as follows:
the preparation method of Selpercatinib adopts the existing easily obtained compound 4 as an intermediate, and the compound 3 and the compound 4 are subjected to one-step halogenation reaction to prepare the compound Selpercatinib, so that the total reaction steps are reduced, and the total reaction yield is improved. The synthetic route and the preparation method have the advantages of fewer reaction steps and mild reaction conditions, greatly improve the total yield of reaction products, and have good economic advantages when the purity of the products reaches more than 99.5 percent.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 3
NaH (2.64g, 0.11mol) was added portionwise to a DMF solution (240mL) of Compound 1(25.4g, 0.1mol) at 0 deg.C, and after the addition was complete, the reaction was stirred at 0 deg.C for 15 min. Then, compound 2(72g, 1mol) was added to the reaction mixture while maintaining at 25 ℃ and, after the addition was completed, the temperature was raised to 80 ℃ to react for 24 hours. After the reaction solution was cooled to room temperature, H was added2O (600mL), adjust to pH 5 by addition of solid citric acid and stir at room temperature for 0.5 h. EA (300mL × 2) was added to the reaction solution for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (DCM/MeOH ═ 20/1) to give the compound represented by formula 3 as an off-white solid in an amount of 24.4g, yield 74.9%.
LC-MS(APCI):m/z=327.4(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
NaH (2.4g, 0.1mol) was added portionwise to a DMF solution (240mL) of Compound 1(25.4g, 0.1mol) at 0 deg.C, and after the addition was complete, the reaction was stirred at 0 deg.C for 15 min. Then, compound 2(64.9g, 0.9mol) was added to the reaction mixture while maintaining at 25 ℃ and, after the addition was completed, the temperature was raised to 75 ℃ to react for 28 hours. Cooling the reaction solution to the chamberAfter warming, H is added2O (600mL), adjust to pH 5 by addition of solid citric acid and stir at room temperature for 0.5 h. EA (300mL × 2) was added to the reaction solution for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (DCM/MeOH ═ 10/1) to give the compound represented by formula 3 as an off-white solid in an amount of 22.0g, yield 67.5%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
NaH (3.6g, 0.15mol) was added portionwise to a DMF solution (240mL) of Compound 1(25.4g, 0.1mol) at 0 deg.C, and after the addition was complete, the reaction was stirred at 0 deg.C for 15 min. Then, compound 2(86.4g, 1.2mol) was added to the reaction mixture while maintaining at 25 ℃ and, after the addition was completed, the temperature was raised to 85 ℃ to react for 22 hours. After the reaction solution was cooled to room temperature, H was added2O (600mL), adjust to pH 5 by addition of solid citric acid and stir at room temperature for 0.5 h. EA (300mL × 2) was added to the reaction solution for extraction, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (DCM/MeOH ═ 30/1) to give the compound represented by formula 3 as an off-white solid in an amount of 23.2g with a yield of 71.2%.
Example 4 Synthesis of Selpercatinib Compound of formula I
Compound 3(32.6g, 0.1mol), Compound 4(24.1g, 0.11mol) and KOAc (19.6g, 0.2mol) were added to DMSO (330mL) at room temperature, and the reaction was stirred at 75 ℃ for 24 h. After the reaction solution was cooled to room temperature, H was added2O (20mL) appeared as a suspended solid upon stirring. The solid was filtered, slurried with 30% aqueous DMSO (300mL) and purified, and after filtration, the solid was dried under vacuum to give the compound Selpercatinib of formula I in an amount of 45.3g, in 86.2% yield and 99.8% HPLC purity.
LC-MS(APCI):m/z=526.4(M+1)+。
Example 5 Synthesis of Selpercatinib Compound of formula I
Compound 3(32.6g, 0.1mol), Compound 4(21.9g, 0.1mol) and KOAc (17.7g, 0.18mol) were added to DMSO (330mL) at room temperature, and the reaction was stirred at 70 ℃ for 28 h. After the reaction solution was cooled to room temperature, H was added2O (20mL) appeared as a suspended solid upon stirring. Filtering the solid, pulping with 30% DMSO aqueous solution (300mL), purifying, and solidifyingAfter filtration, the product was dried in vacuo to give the compound Selpercatinib of formula I in an amount of 43.5g, a yield of 82.8% and a HPLC purity of 99.6%.
Example 6 Synthesis of Selpercatinib Compound of formula I
Compound 3(32.6g, 0.1mol), Compound 4(28.5g, 0.13mol) and KOAc (19.6g, 0.3mol) were added to DMSO (330mL) at room temperature, and the reaction was stirred at 80 ℃ for 22 h. After the reaction solution was cooled to room temperature, H was added2O (20mL) appeared as a suspended solid upon stirring. The solid was filtered, slurried with 30% aqueous DMSO (300mL), filtered, and dried under vacuum to give Selpercatinib, a compound of formula I, 44.2g, 84.1% yield, 99.5% HPLC purity.
Example 7 Synthesis of Selpercatinib Compound of formula I
Compound 3(32.6g, 0.1mol), Compound 4(21.5g, 0.098mol) and KOAc (14.7g, 0.15mol) were added to DMSO (330mL) at room temperature, and the reaction was stirred at 75 ℃ for 24 h. After the reaction solution was cooled to room temperature, H was added2O (20mL) appeared as a suspended solid upon stirring. The solid was filtered, slurried with 30% aqueous DMSO (300mL), filtered, and dried under vacuum to give the compound Selpercatinib of formula I in 28.9g, 55.0% yield, and 99.0% HPLC purity.
Example 8 Synthesis of Selpercatinib Compound of formula I
Compound 3(32.6g, 0.1mol), Compound 4(24.1g, 0.11mol) and KOAc (31.4g, 0.32mol) were added to DMSO (330mL) at room temperature, and the reaction was stirred at 75 ℃ for 24 hours. After the reaction solution was cooled to room temperature, H was added2O (20mL) appeared as a suspended solid upon stirring. The solid was filtered, slurried with 30% aqueous DMSO (300mL), filtered, and dried under vacuum to give the compound Selpercatinib of formula I in an amount of 38.2g, yield 72.7%, and HPLC purity 98.1%.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (8)
1. A method for preparing a compound Selpercatinib shown as a formula I, which is characterized by comprising the following steps:
(1) reacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) reacting a compound represented by formula 3 with a compound represented by formula 4 to obtain a compound represented by formula I,
in the step (1), the method comprises the following steps: adding NaH in batches into a DMF solution of a compound shown in a formula 1 at 0 ℃, keeping the temperature of 0 ℃ for stirring and reacting for 15 minutes after adding, then keeping the temperature of 25 ℃, adding the compound shown in the formula 2 into a reaction solution, heating to 75-85 ℃, stirring and reacting for 22-28 hours after adding, cooling the reaction solution to room temperature after reacting, adding H2Adding solid citric acid to adjust the pH value to 5, stirring at room temperature for 0.5 hour, adding EA into the reaction liquid for extraction, combining organic phases, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain a compound shown in a formula 3;
in the step (1), the molar ratio of the compound shown in the formula 1, NaH and the compound shown in the formula 2 is 1 (1.0-1.5) to (9-12);
in the step (2), the method comprises the following steps: adding a compound shown as a formula 3, a compound shown as a formula 4 and KOAc into DMSO at room temperature, heating to 70-80 ℃, stirring for reaction for 22-28 hours, cooling the reaction liquid to room temperature, and adding H2O, suspended solid appears after stirring, the solid is filtered, the mixture is pulped and purified by 30 percent DMSO aqueous solution, and after the solid is filtered, the mixture is dried in vacuum to obtain a compound Selpercatinib shown in the formula I;
in the step (2), the molar ratio of the compound represented by the formula 3 to the compound represented by the formula 4 to KOAc is 1 (1.0-1.3) to 1.8-3.
2. The method of claim 1, wherein the molar ratio of the compound of formula 1, NaH, and the compound of formula 2 is 1:1.1: 10.
3. The method according to claim 1, wherein the compound represented by formula 1, NaH, and the compound represented by formula 2 are reacted at 80 ℃ for 24 hours.
4. The method as claimed in claim 1, wherein in the step (1), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (10-30): 1.
5. The method of claim 4, wherein the column chromatography uses a mixed solvent of dichloromethane and methanol in a volume ratio of 20: 1.
6. The method according to claim 1, wherein the molar ratio of the compound represented by formula 3 to the compound represented by formula 4 to KOAc is 1:1.1: 2.
7. The method according to claim 1, wherein in the step (2), the compound represented by the formula 3, the compound represented by the formula 4, and KOAc are reacted at 75 ℃ for 24 hours.
8. The method according to claim 1, wherein in step (1), the following steps are included: adding 2.64g NaH in 240mL DMF solution containing 25.4g of the compound shown in the formula 1 at 0 ℃, keeping the temperature at 0 ℃ after the addition, stirring and reacting for 15 minutes, then adding 72g of the compound shown in the formula 2 into the reaction solution at 25 ℃, heating to 80 ℃ after the addition, reacting for 24 hours, cooling the reaction solution to room temperature, and adding 600mL H2Adding solid citric acid to adjust the pH value to 5, stirring at room temperature for 0.5 hour, adding 300mL of EA into the reaction liquid for extraction for 2 times, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography with a mixed solvent of dichloromethane and methanol in a volume ratio of 20:1 to obtain a compound shown in formula 3;
in the step (2), the method comprises the following steps: 32.6g of the compound represented by the formula 3, 24.1g of the compound represented by the formula 4 and 19.6g of KOAc were added to 330mL of DMSO at room temperature, the mixture was stirred and reacted at 75 ℃ for 24 hours, the reaction mixture was cooled to room temperature, and 20mL of H was added2O, stirring to generate suspended solid, filtering the solid, pulping and purifying by using 300mL of 30% DMSO aqueous solution, filtering the solid, and drying in vacuum to obtain the compound Selpercatinib shown in the formula I.
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Denomination of invention: RET inhibitors and their preparation methods Granted publication date: 20210427 Pledgee: Wuhan Optics Valley Small and Medium Duty Venture Capital Co.,Ltd. Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2024110000096 |