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CN110950872A - Method for preparing targeted anticancer drug avapritinib - Google Patents

Method for preparing targeted anticancer drug avapritinib Download PDF

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CN110950872A
CN110950872A CN201911357283.4A CN201911357283A CN110950872A CN 110950872 A CN110950872 A CN 110950872A CN 201911357283 A CN201911357283 A CN 201911357283A CN 110950872 A CN110950872 A CN 110950872A
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许勇
余艳平
范昭泽
陈龙
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Wuhan Jiuzhou Yumin Medical Technology Co ltd
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Wuhan Jiuzhou Yumin Medical Technology Co ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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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Abstract

The invention relates to a method for preparing a targeted anticancer drug avapritinib. The method adopts the intermediate which is easily obtained at present as the initial raw material, performs the Boc protection on the amino group and then performs the halogenation reaction, thereby effectively improving the yield of the halogenation reaction and avoiding generating the halogenated byproducts on the imine.

Description

Method for preparing targeted anticancer drug avapritinib
Technical Field
The invention relates to the technical field of medicines, in particular to a method for preparing a targeted anticancer drug avapritinib.
Background
Avapritinib (BLU-285) is a small molecule kinase inhibitor that effectively inhibits the activity of the PDGFR α D842V mutant, and is also an inhibitor of KIT mutation (KIT D816V). Avapritinib selectively and potently inhibits KIT and PDGFRA mutant kinases Avapritinib has been shown to have broad inhibitory effects on KIT and PDGFRA mutations associated with gastrointestinal stromal tumors (GIST), including strong activity against activating loop mutations associated with current approved therapy resistance.
The structural formula of Avapritinib is shown as formula I:
Figure BDA0002336274210000011
the current process for preparing Avapritinib remains to be 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. To this end, it is an object of the present invention to propose a process for preparing Avapritinib. The route greatly improves the selectivity and the total yield of the reaction and has good experimental operability.
In one aspect of the invention, the invention provides a process for preparing a compound of formula I, Avapritinib. According to an embodiment of the invention, the method comprises:
(1) reacting a compound represented by formula 1 with di-tert-butyl dicarbonate ((Boc)2O) to obtain a compound represented by formula 2;
(2) contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(3) contacting the compound of formula 4 with hydrochloric acid to obtain a compound of formula I, Avapritinib,
Figure BDA0002336274210000021
the inventor finds that the preparation method adopts the intermediate which is easily obtained in the prior art as the starting material, performs the Boc protection on the amino group and then performs the halogenation reaction, and can quickly and effectively prepare the compound shown in the formula I by using the method. The method effectively improves the yield of the halogenation reaction, avoids generating halogenated byproducts on imine, greatly improves the selectivity and the total yield of the reaction, and has good experimental operability.
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 2, the compound represented by formula 4, and 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 2, the compound represented by formula 4, and 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 the step (1), represented by formula 1Compound and (Boc)2The contact manner of O is not particularly limited. Thus, the compound represented by the formula 1 and (Boc) can be promoted2The efficiency of O contact accelerates the reaction speed, and further improves the efficiency of preparing the compound shown in the formula 2 by using the method.
According to an embodiment of the present invention, in the step (1), the following steps are included: adding compound 1 into DCM at 0 ℃, stirring, and adding saturated NaHCO3The solution was then slowly added dropwise (Boc)2And O, stirring for reaction, separating an organic layer, extracting an aqueous phase by using a DCM solution, combining the organic layers, drying by using anhydrous sodium sulfate, filtering, concentrating a filtrate, and purifying by using column chromatography to obtain the compound shown in the formula 2. Therefore, the contact efficiency of the compound 1 and the compound 2 can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 2 by using the method is further improved.
According to an embodiment of the present invention, in step (1), the compound 1 is reacted with (Boc)2The molar ratio of O is 1 (1.05-1.5), preferably the compound 1 and Boc2The molar ratio of O is 1: 1.1. Thus, the efficiency of preparing the compound represented by formula 2 by the method can be further improved.
According to an embodiment of the present invention, in step (1), the compound 1 is reacted with saturated NaHCO3The weight to volume ratio of the solution was 1: 4.
According to an embodiment of the present invention, in step (1), the compound 1 is reacted with (Boc)2And stirring and reacting the O at the temperature of between 20 and 30 ℃ for 2.5 to 4 hours.
According to the embodiment of the invention, in the step (1), the column chromatography is eluted by using a dichloromethane/methanol mixed solvent with a volume ratio of (30-60): 1, and preferably, the column chromatography is eluted by using a dichloromethane/methanol mixed solvent with a volume ratio of 50: 1. Thus, the efficiency of preparing the compound represented by formula 2 by the method can be further improved.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: to DCM (25mL) was added compound 1(30.1g,0.1mol) at 0 deg.C, stirred, and saturated NaHCO was added3The solution (120mL) was added slowly dropwise (Boc)2O (24.0g,0.11mol), stirred and reacted at 25 ℃ for 3 h. Is divided intoThe organic layer was separated, the aqueous layer was extracted with DCM solution (300mL) and the organic phases were combined. Drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 50: 1) to obtain the compound shown in formula 2.
According to an embodiment of the present invention, in the step (2), the contacting manner of the compound represented by formula 2, N-Diisopropylethylamine (DIPEA), and the compound represented by formula 3 is not particularly limited. Preferably, the solvent of the reaction is selected from THF. Therefore, the contact efficiency of the compound shown in the formula 2, DIPEA and the compound shown in the formula 3 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 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 2 and DIPEA were added to THF at room temperature, compound 3 was added with stirring, and the mixture was kept stirring at room temperature. Reaction solution is concentrated to half volume and saturated NaHCO is added3Washing the solution, extracting with EA, drying, concentrating the organic phase, and purifying by column chromatography to obtain the compound shown in formula 4. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in the step (2), the molar ratio of the compound represented by the formula 2, DIPEA and the compound represented by the formula 3 is 1 (1.0-1.5) to (1.0-1.5), preferably the molar ratio of the compound represented by the formula 2, DIPEA and the compound represented by the formula 3 is 1: 1.2: 1.1. 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 invention, in the step (2), the compound represented by the formula 2, DIPEA and the compound represented by the formula 3 are stirred at room temperature for 3.5-5 h.
According to the embodiment of the invention, in the step (2), the column chromatography is eluted by using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (5-20): 1, and preferably, the column chromatography is eluted by using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to a specific embodiment of the present invention, at step(2) The method comprises the following steps: compound 2(40.1g,0.1mol) and DIPEA (15.5g,0.12mol) were added to THF (400mL) at room temperature, and Compound 3(25.7g,0.11mol) was added with stirring and kept stirring at room temperature for 4 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (200mL) is washed, extracted with EA (400mL), dried and concentrated in an organic phase, and purified by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1) to obtain the compound represented by formula 4.
According to an embodiment of the present invention, in step (3), the contacting manner of the compound represented by formula 4 with hydrochloric acid is not particularly limited. Therefore, the contact efficiency of the compound shown in the formula 4 and hydrochloric acid can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula I by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the following steps are included: slowly adding 4M dioxane solution of hydrochloric acid into compound 4 at 0 deg.C, stirring at room temperature for reaction, concentrating the solution under reduced pressure, adding saturated NaHCO3Washing the solid with the solution, adding dichloromethane for extraction, combining organic layers, drying and concentrating to obtain the compound 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 present invention, in the step (3), the reaction may be stirred at room temperature for 45 minutes to 1.5 hours, whereby the efficiency of contacting the compound represented by formula 4 with hydrochloric acid may be improved, and the efficiency of preparing the compound represented by formula I using the method may be further improved.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: to compound 4(2.0g, 3.34mmol) was slowly added a solution of 4M hydrochloric acid in dioxane at 0 deg.C, stirred at room temperature for 1 hour, then the solution was concentrated under reduced pressure, and saturated NaHCO was added3The solid was washed with solution (10mL), extracted with dichloromethane (20mL), and the organic layers were combined, dried and concentrated to give the compound of formula I.
According to the examples of the present invention, the synthetic route of the compound avapritinib of formula I can be as follows:
Figure BDA0002336274210000061
compared with the prior art, the method for preparing the targeted anticancer drug avapritinib has at least the following beneficial effects: the method adopts the intermediate which is easily obtained at present as the initial raw material, performs the Boc protection on the amino group and then performs the halogenation reaction, thereby effectively improving the yield of the halogenation reaction and avoiding generating the halogenated byproducts on the imine. The route greatly improves the selectivity and the total yield of the reaction and has good experimental operability.
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 2
To DCM (25mL) was added compound 1(30.1g,0.1mol) at 0 deg.C, stirred, and saturated NaHCO was added3The solution (120mL) was added slowly dropwise (Boc)2O (24.0g,0.11mol), stirred and reacted at 25 ℃ for 3 h. The organic layer was separated, the aqueous phase was extracted with DCM solution (300mL), and the organic phases were combined. Drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 50: 1) to obtain the compound shown in formula 2, wherein the amount of the compound is 33.8g, and the yield is 84.2%.
LC-MS(APCI):m/z=402.4(M+1)+
Example 2 Synthesis of Compound represented by formula 2
To DCM (25mL) was added compound 1(30.1g,0.1mol) at 0 deg.C, stirred, and saturated NaHCO was added3The solution (120mL) was added slowly dropwise (Boc)2O (22.9g,0.105mol), stirred and reacted at 20 ℃ for 4 h. The organic layer was separated, the aqueous layer was extracted with DCM solution (300mL), and the organics were combinedAnd (4) phase(s). Drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 30: 1) to obtain the compound shown in formula 2, wherein the amount of the compound is 32.5g, and the yield is 81.0%.
EXAMPLE 3 Synthesis of Compound represented by formula 2
To DCM (25mL) was added compound 1(30.1g,0.1mol) at 0 deg.C, stirred, and saturated NaHCO was added3The solution (120mL) was added slowly dropwise (Boc)2O (32.7g,0.15mol), stirred at 30 ℃ for 2.5 h. The organic layer was separated, the aqueous phase was extracted with DCM solution (300mL), and the organic phases were combined. Drying with anhydrous sodium sulfate, filtering, concentrating the filtrate, and purifying by column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 60: 1) to obtain the compound shown in formula 2, wherein the amount of the compound is 31.6g, and the yield is 78.8%.
Example 4 Synthesis of Compound represented by formula 4
Compound 2(40.1g,0.1mol) and DIPEA (15.5g,0.12mol) were added to THF (400mL) at room temperature, and Compound 3(25.7g,0.11mol) was added with stirring and kept stirring at room temperature for 4 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (200mL) was washed, extracted with EA (400mL), dried and concentrated in the organic phase, and purified by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 10: 1) to give the compound of formula 4 in an amount of 48.1g with a yield of 80.3%.
LC-MS(APCI):m/z=599.4(M+1)+
EXAMPLE 5 Synthesis of Compound represented by formula 4
Compound 2(40.1g,0.1mol) and DIPEA (12.9g,0.1mol) were added to THF (400mL) at room temperature, and Compound 3(23.4g,0.1mol) was added with stirring and kept stirring at room temperature for 3.5 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (200mL) was washed, extracted with EA (400mL), dried and the organic phase concentrated and purified by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 5: 1) to give the compound of formula 4 in an amount of 43.5g with a yield of 72.7%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
Compound 2(40.1g,0.1mol) and DIPEA (19.4) were added to THF (400mL) at room temperatureg,0.15mol), compound 3(35.1g,0.15mol) was added with stirring, and stirred at room temperature for 5 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (200mL) was washed, extracted with EA (400mL), dried and concentrated in the organic phase, and purified by column chromatography (using a 20:1 by volume petroleum ether/ethyl acetate solvent mixture) to give the compound of formula 4 in 44.3g, 74.0% yield.
Example 7 Synthesis of Avapritinib Compound of formula I
To compound 4(2.0g, 3.34mmol) was slowly added a solution of 4M hydrochloric acid in dioxane at 0 deg.C, stirred at room temperature for 1 hour, then the solution was concentrated under reduced pressure, and saturated NaHCO was added3The solid was washed with solution (10mL), extracted with dichloromethane (20mL), and the organic layers were combined, dried and concentrated to give the compound of formula I in 1.6g yield 90.1% with HPLC purity 99.6%.
LC-MS(APCI):m/z=499.4(M+1)+
EXAMPLE 8 Synthesis of Avapritinib Compound of formula I
To compound 4(2.0g, 3.34mmol) was slowly added a solution of 4M hydrochloric acid in dioxane at 0 deg.C, the reaction was stirred at room temperature for 45 minutes, then the solution was concentrated under reduced pressure, and saturated NaHCO was added3The solid was washed with solution (10mL), extracted with dichloromethane (20mL), and the organic layers were combined, dried and concentrated to give the compound of formula I in an amount of 1.5g, yield 83.6%, and HPLC purity 99.3%.
Example 9 Synthesis of Avapritinib Compound of formula I
To compound 4(2.0g, 3.34mmol) was slowly added a solution of 4M hydrochloric acid in dioxane at 0 deg.C, stirred at room temperature for 1.5h, then the solution was concentrated under reduced pressure and saturated NaHCO was added3The solid was washed with solution (10mL), extracted with dichloromethane (20mL), the organic layers combined, dried and concentrated to give the compound of formula I in an amount of 1.5g, yield 83.6%, and HPLC purity 99.1%.
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 (10)

1. A method of preparing Avapritinib, comprising:
(1) contacting a compound represented by formula 1 with di-tert-butyl dicarbonate to obtain a compound represented by formula 2;
(2) contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(3) contacting the compound of formula 4 with hydrochloric acid to obtain a compound of formula I, Avapritinib,
Figure FDA0002336274200000011
2. the method according to claim 1, wherein in step (1), the following steps are included: adding compound 1 into DCM at 0 ℃, stirring, and adding saturated NaHCO3The solution was then slowly added dropwise (Boc)2And O, stirring for reaction, separating an organic layer, extracting an aqueous phase by using a DCM solution, combining the organic layers, drying by using anhydrous sodium sulfate, filtering, concentrating a filtrate, and purifying by using column chromatography to obtain the compound shown in the formula 2.
3. The method of claim 2, wherein in step (1), compound 1 is reacted with (Boc)2The molar ratio of O is 1 (1.05-1.5), preferably the compound 1 and Boc2The molar ratio of O is 1: 1.1.
Optionally, in step (1), the compound 1 is reacted with saturated NaHCO3The weight to volume ratio of the solution was 1: 4.
Optionally, in step (1), said compound 1 is reacted with (Boc)2And stirring and reacting the O at the temperature of between 20 and 30 ℃ for 2.5 to 4 hours.
4. The method according to claim 2, wherein in the step (1), the column chromatography is eluted by using a dichloromethane/methanol mixed solvent with a volume ratio of (30-60): 1, preferably the column chromatography is eluted by using a dichloromethane/methanol mixed solvent with a volume ratio of 50: 1.
5. The method of claim 1, wherein in step (2), the following steps are included: compound 2 and DIPEA were added to THF at room temperature, compound 3 was added with stirring, and the mixture was kept stirring at room temperature. Reaction solution is concentrated to half volume and saturated NaHCO is added3Washing the solution, extracting with EA, drying, concentrating the organic phase, and purifying by column chromatography to obtain the compound shown in formula 4.
6. The method according to claim 5, wherein in step (2), the molar ratio of the compound represented by formula 2 to the DIPEA to the compound represented by formula 3 is 1 (1.0-1.5) to (1.0-1.5), preferably the molar ratio of the compound represented by formula 2 to the DIPEA to the compound represented by formula 3 is 1: 1.2: 1.1;
optionally, the compound shown in the formula 2, DIPEA and the compound shown in the formula 3 are stirred at room temperature for 3.5-5 h.
7. The method as claimed in claim 5, wherein in the step (2), the column chromatography is eluted by using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (5-20): 1, preferably the column chromatography is eluted by using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1.
8. The method of claim 1, wherein in step (3), the following steps are included: slowly adding 4M dioxane solution of hydrochloric acid into compound 4 at 0 deg.C, stirring at room temperature for reaction, concentrating the solution under reduced pressure, adding saturated NaHCO3Washing the solid with the solution, adding dichloromethane for extraction, combining organic layers, drying and concentrating to obtain the compound shown in the formula I.
9. The method according to claim 8, wherein in the step (3), the reaction can be stirred at room temperature for 45 minutes to 1.5 hours.
10. The method according to claims 1-9, wherein in step (1), the following steps are included: to DCM (25mL) was added compound 1(30.1g,0.1mol) at 0 deg.C, stirred, and saturated NaHCO was added3The solution (120mL) was added slowly dropwise (Boc)2O (24.0g,0.11mol), stirring and reacting at 25 ℃ for 3h, separating an organic layer, extracting an aqueous phase with a DCM solution (300mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating a filtrate, and purifying by column chromatography (eluting by a dichloromethane/methanol mixed solvent with a volume ratio of 50: 1) to obtain a compound shown in formula 2;
the step (2) comprises the following steps: compound 2(40.1g,0.1mol) and DIPEA (15.5g,0.12mol) were added to THF (400mL) at room temperature, compound 3(25.7g,0.11mol) was added with stirring, the mixture was kept at room temperature for 4h with stirring, and the reaction was concentrated to half volume and saturated NaHCO was added3Washing the solution (200mL), extracting with EA (400mL), drying, concentrating the organic phase, and purifying by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate at a volume ratio of 10: 1) to obtain a compound shown in formula 4;
in the step (3), the method comprises the following steps: to compound 4(2.0g, 3.34mmol) was slowly added a solution of 4M hydrochloric acid in dioxane at 0 deg.C, stirred at room temperature for 1 hour, then the solution was concentrated under reduced pressure, and saturated NaHCO was added3The solid was washed with solution (10mL), extracted with dichloromethane (20mL), and the organic layers were combined, dried and concentrated to give the compound of formula I.
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WO2022180416A1 (en) * 2021-02-26 2022-09-01 Egis Gyógyszergyár Zrt Process for obtaining avapritinib and its intermediates
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