CN110938077A - Method for synthesizing Avapritinib - Google Patents
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Abstract
The invention relates to a method for synthesizing avapritinib. Compared with the existing synthetic route, the method has the advantages of multiple reaction steps, low yield and good experimental operability, and chiral compounds are resolved by using a chiral column.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for synthesizing 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:
the current method for synthesizing 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 method for synthesizing Avapritinib. The method does not need to use a chiral column to split chiral compounds, reduces the reaction steps, improves the total yield of the reaction, and effectively reduces the cost of final products.
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) contacting a compound represented by formula 1 with L-dibenzoyltartaric acid (L-DBTA) 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 a compound of formula 4 with said base to obtain a compound of formula I, Avapritinib,
the inventor finds that the compound shown in the formula I can be quickly and effectively prepared by adopting the intermediate compound 1 which is easily obtained at present as a starting material, carrying out chemical resolution on the intermediate compound 1 by using L-DBTA, carrying out halogenation reaction, and then removing the L-DBTA. Compared with the existing synthetic route, the synthetic method has the advantages of multiple reaction steps and low yield, and chiral compounds are resolved by using a chiral column, so that the synthetic method greatly reduces the reaction steps, improves the total yield of the reaction, effectively reduces the cost of final products, 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, the contacting manner of the compound represented by formula 1 with L-DBTA in step (1) is not particularly limited. Therefore, the contact efficiency of the compound shown in the formula 1 and L-DBTA can be improved, the resolution reaction efficiency can be improved, and the preparation efficiency of the compound shown in the formula 2 by using the method can be further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: adding the compound 1 into an ethanol/water/acetic acid mixed solution, heating to 50-70 ℃, then keeping the temperature at 50-70 ℃, dropwise adding the mixed solution of L-DBTA and ethanol/water/acetic acid, stirring the obtained solution at 50-70 ℃ so as to carry out chiral resolution, then cooling to room temperature, collecting solids by centrifugation, and washing with ethanol. And stirring the filter cake in a mixed solvent of ethanol/water/acetic acid at 55 ℃ for 4 hours, cooling to room temperature, collecting the solid by centrifugation, washing with ethanol, and drying the filter cake in vacuum to obtain the compound shown in the formula 2, wherein the compound is a chiral compound. Therefore, the contact efficiency of the compound 1 and L-DBTA can be improved, the resolution reaction efficiency is improved, 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 invention, in the step (1), the molar ratio of the compound 1 to the L-DBTA is 1 (1.05-1.5), and preferably the molar ratio of the compound 1 to the L-DBTA is 1: 1.2. Thus, the efficiency of preparing the compound represented by formula 2 by the method can be further improved.
According to the embodiment of the invention, in the step (1), the compound 1 is contacted with L-DBTA at 50-70 ℃ and stirred for chiral resolution for 15-20 h. Therefore, the contact efficiency of the compound 1 and L-DBTA can be improved, the resolution reaction efficiency is improved, and the efficiency of preparing the compound shown in the formula 2 by using the method is further improved.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: compound 1(30.0g, 0.1mol) was added to an ethanol/water/acetic acid mixture (600mL, formulation: obtained by mixing ethanol, water, acetic acid in a volume ratio of 7:3: 1), heated to 70 ℃, and then kept at 70 ℃ a mixture of L-DBTA (43.0g, 0.12mol) and ethanol/water/acetic acid (volume ratio of 7:3:1, 20mL) was added dropwise, the resulting solution was stirred at 70 ℃ for 16 hours, then cooled to room temperature, and the solid was collected by centrifugation and washed with ethanol (20 mL). After the filter cake was stirred in a mixed solvent of ethanol/water/acetic acid (7:3:1, 20mL) at 55 ℃ for 4 hours, it was cooled to room temperature, the solid was collected by centrifugation and washed with ethanol (20mL), and the filter cake was dried under vacuum to give the compound represented by 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: adding the compound 2, DIPEA and the compound 3 into THF at room temperature, and stirring at room temperature for 3.5-5 h. 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 (1.1-1.5) to (1.0-1.2), 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. 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 an embodiment of the present invention, in the step (2), the column chromatography is eluted using a petroleum ether/ethyl acetate mixed solvent 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, in the step (2), the following steps are included: compound 2(20.0g, 30.3mmol), DIPEA (4.7g, 36.4mmol) and compound 3(7.1g, 30.3mmol) were added to THF (200mL) at room temperature and stirred at room temperature for 4 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (50mL) is washed, extracted with EA (50mL), 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 the base is not particularly limited. Therefore, the contact efficiency of the compound shown in the formula 4 and the alkali 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: to a mixture of dichloromethane and the aqueous base solution was added compound 4 portionwise at room temperature and stirred at room temperature for 2 h. After completion of the reaction, the organic layer was collected and the aqueous layer was extracted with dichloromethane, the organic layers were combined, dried and concentrated to give a brown solid. The collected solids were slurried with methyl tert-butyl ether. The solid was collected by centrifugation and washed with methyl tert-butyl ether and then dried under vacuum to give the compound of formula I. Therefore, 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 step (3), the base is an organic base or an inorganic base, preferably the base is an inorganic base.
According to an embodiment of the present invention, in the step (3), the inorganic base is at least one selected from potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, and preferably the inorganic base is selected from potassium hydroxide or sodium hydroxide.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: to a mixture of dichloromethane (200mL) and 20% by mass aqueous KOH (40mL) was added compound 4(15.0g, 17.6mmol) portionwise at room temperature, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the organic layers were collected and the aqueous layer was extracted with dichloromethane (40mL), the organic layers were combined, dried and concentrated to give a brown solid. The collected solid was slurried with methyl tert-butyl ether (100 mL). The solid was collected by centrifugation and washed with methyl tert-butyl ether (50mL) and then dried in vacuo to give the compound of formula I in an amount of 8.3g, yield 94.6% and ee value 98.6%.
According to the examples of the present invention, the synthetic route of the compound avapritinib of formula I can be as follows:
compared with the prior art, the method for preparing avapritinib synthetically has at least the following beneficial effects: the method adopts the intermediate compound 1 which is easily obtained at present as a starting material, utilizes L-DBTA to carry out chemical resolution on the intermediate compound 1, then carries out halogenation reaction, and removes the L-DBTA to obtain the target compound molecule avapritinib. Compared with the existing synthetic route, the synthetic method has the advantages of multiple reaction steps and low yield, and chiral compounds are resolved by using a chiral column, so that the synthetic method greatly reduces the reaction steps, improves the total yield of the reaction, effectively reduces the cost of final products, 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
Compound 1(30.0g, 0.1mol) was added to an ethanol/water/acetic acid mixture (600mL, formulation: obtained by mixing ethanol, water, acetic acid in a volume ratio of 7:3: 1), heated to 70 ℃, and then kept at 70 ℃ a mixture of L-DBTA (43.0g, 0.12mol) and ethanol/water/acetic acid (volume ratio of 7:3:1, 20mL) was added dropwise, the resulting solution was stirred at 70 ℃ for 15 hours, then cooled to room temperature, and the solid was collected by centrifugation and washed with ethanol (20 mL). The filter cake was stirred in a mixed solvent of ethanol/water/acetic acid (7:3:1, 20mL) at 55 ℃ for 4 hours, then cooled to room temperature, the solid was collected by centrifugation and washed with ethanol (20mL), and the filter cake was vacuum-dried to give the compound represented by formula 2 in an amount of 27.4g with a yield of 41.5%.
Example 2 Synthesis of Compound represented by formula 2
Compound 1(30.0g, 0.1mol) was added to an ethanol/water/acetic acid mixture (600mL, preparation method: mixing ethanol, water, acetic acid in a volume ratio of 7:3: 1), heated to 50 deg.C, and then a mixture of L-DBTA (37.6g, 0.105mol) and ethanol/water/acetic acid (volume ratio of 7:3:1, 20mL) was added dropwise while maintaining at 50 deg.C, the resulting solution was stirred at 50 deg.C for 20 hours, then cooled to room temperature, the solid was collected by centrifugation and washed with ethanol (20 mL). The filter cake was stirred in a mixed solvent of ethanol/water/acetic acid (7:3:1, 20mL) at 55 ℃ for 4 hours, then cooled to room temperature, the solid was collected by centrifugation and washed with ethanol (20mL), and the filter cake was vacuum-dried to give the compound represented by formula 2 in an amount of 19.4g with a yield of 29.4%.
EXAMPLE 3 Synthesis of Compound represented by formula 2
Compound 1(30.0g, 0.1mol) was added to an ethanol/water/acetic acid mixture (600mL, formulation: obtained by mixing ethanol, water, acetic acid in a volume ratio of 7:3: 1), heated to 65 deg.C, and then kept at 65 deg.C, a mixture of L-DBTA (53.7g, 0.15mol) and ethanol/water/acetic acid (volume ratio of 7:3:1, 20mL) was added dropwise, the resulting solution was stirred at 65 deg.C for 18 hours, then cooled to room temperature, the solid was collected by centrifugation and washed with ethanol (20 mL). The filter cake was stirred in a mixed solvent of ethanol/water/acetic acid (7:3:1, 20mL) at 55 ℃ for 4 hours, then cooled to room temperature, the solid was collected by centrifugation and washed with ethanol (20mL), and the filter cake was vacuum-dried to give the compound represented by formula 2 in an amount of 24.9g with a yield of 37.7%.
Example 4 Synthesis of Compound represented by formula 4
Compound 2(20.0g, 30.3mmol), DIPEA (4.7g, 36.4mmol) and compound 3(7.1g, 30.3mmol) were added to THF (200mL) at room temperature and stirred at room temperature for 4 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (50mL) was washed, extracted with EA (50mL), dried and the organic phase concentrated and purified by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1) to give the compound of formula 4 in an amount of 21.0g with a yield of 81.2%.
EXAMPLE 5 Synthesis of Compound represented by formula 4
Compound 2(20.0g, 30.3mmol), DIPEA (4.3g, 33.3mmol) and compound 3(7.8g, 33.3mmol) were added to THF (200mL) at room temperature and stirred at room temperature for 3.5 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (50mL) was washed, extracted with EA (50mL), dried and the organic phase concentrated and purified by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1) to give the compound of formula 4 in an amount of 19.2g with a yield of 74.3%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
Compound 2(20.0g, 30.3mmol), DIPEA (5.9g, 45.45mmol) and compound 3(8.5g, 36.4mmol) were added to THF (200mL) at room temperature and stirred at room temperature for 5 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3The solution (50mL) was washed, extracted with EA (50mL), dried and the organic phase concentrated and purified by column chromatography (using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1) to give the compound of formula 4 in an amount of 19.9g and a yield of 77.0%.
Example 7 Synthesis of Avapritinib Compound of formula I
To a mixture of dichloromethane (200mL) and 20% by mass aqueous KOH (40mL) was added compound 4(15.0g, 17.6mmol) portionwise at room temperature, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the organic layers were collected and the aqueous layer was extracted with dichloromethane (40mL), the organic layers were combined, dried and concentrated to give a brown solid. The collected solid was slurried with methyl tert-butyl ether (100 mL). The solid was collected by centrifugation and washed with methyl tert-butyl ether (50mL) and then dried in vacuo to give the compound of formula I in an amount of 8.3g, yield 94.6% and ee value 98.6%.
LC-MS(APCI):m/z＝499.4(M+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 synthesizing Avapritinib, comprising:
(1) contacting a compound represented by formula 1 with L-dibenzoyltartaric acid 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 a compound of formula 4 with said base to obtain a compound of formula I, Avapritinib,
2. the method according to claim 1, wherein in step (1), the following steps are included: adding the compound 1 into an ethanol/water/acetic acid mixed solution, heating to 50-70 ℃, then keeping the temperature at 50-70 ℃, dropwise adding the mixed solution of L-DBTA and ethanol/water/acetic acid, stirring the obtained solution at 50-70 ℃ so as to carry out chiral resolution, then cooling to room temperature, collecting solids by centrifugation, and washing with ethanol. And stirring the filter cake in a mixed solvent of ethanol/water/acetic acid at 55 ℃ for 4 hours, cooling to room temperature, collecting the solid by centrifugation, washing with ethanol, and drying the filter cake in vacuum to obtain the compound shown in the formula 2.
3. The method according to claim 2, wherein in the step (1), the molar ratio of the compound 1 to the L-DBTA is 1 (1.05-1.5), preferably the molar ratio of the compound 1 to the L-DBTA is 1: 1.2.
4. The method according to claim 2, wherein in the step (1), the compound 1 is contacted with L-DBTA at 50-70 ℃ and stirred for chiral resolution for 15-20 h.
5. The method of claim 1, wherein in step (2), the following steps are included: adding the compound 2, DIPEA and the compound 3 into THF at room temperature, and stirring at room temperature for 3.5-5 h. 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 (1.1-1.5) to (1.0-1.2), 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.
7. the method according to claim 5, wherein 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.
8. The method as claimed in claim 5, wherein, in the step (2), the column chromatography is eluted with a mixed solvent of petroleum ether/ethyl acetate in a volume ratio of 10: 1.
9. The method of claim 1, wherein in step (3), the following steps are included: to a mixture of dichloromethane and the aqueous base solution was added compound 4 portionwise at room temperature and stirred at room temperature for 2 h. After completion of the reaction, the organic layer was collected and the aqueous layer was extracted with dichloromethane, the organic layers were combined, dried and concentrated to give a brown solid. The collected solids were slurried with methyl tert-butyl ether. The solid was collected by centrifugation and washed with methyl tert-butyl ether and then dried under vacuum to give the compound of formula I.
Optionally, the base is an organic base or an inorganic base,
optionally, the base is an inorganic base;
optionally, the inorganic base is at least one selected from potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate;
optionally, the inorganic base is selected from potassium hydroxide, or sodium hydroxide.
10. The method according to claim 1, wherein in step (1), the following steps are included: adding the compound 1(30.0g, 0.1mol) into an ethanol/water/acetic acid mixed solution (600mL, preparation method: obtained by mixing ethanol, water and acetic acid according to a volume ratio of 7:3: 1), heating to 70 ℃, then maintaining at 70 ℃, dropwise adding a mixed solution of L-DBTA (43.0g, 0.12mol) and ethanol/water/acetic acid (volume ratio of 7:3:1, 20mL), stirring the obtained solution at 70 ℃ for 16 hours, then cooling to room temperature, collecting a solid through centrifugation, washing with ethanol (20mL), stirring a filter cake in a mixed solvent of ethanol/water/acetic acid (7:3:1, 20mL) at 55 ℃ for 4 hours, cooling to room temperature, collecting the solid through centrifugation, washing with ethanol (20mL), and drying the filter cake in vacuum to obtain the compound shown in formula 2;
the step (2) comprises the following steps: compound 2(20.0g, 30.3mmol), DIPEA (4.7g, 36.4mmol) and compound 3(7.1g, 30.3mmol) were added to THF (200mL) at room temperature and stirred at room temperature for 4 h. Reaction solution is concentrated to half volume and saturated NaHCO is added3Washing the solution (50mL), extracting with EA (50mL), 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 a mixture of dichloromethane (200mL) and 20% by mass aqueous KOH (40mL) was added compound 4(15.0g, 17.6mmol) portionwise at room temperature, and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the organic layers were collected and the aqueous layer was extracted with dichloromethane (40mL), the organic layers were combined, dried and concentrated to give a brown solid. The collected solid was slurried with methyl tert-butyl ether (100mL), the solid was collected by centrifugation and washed with methyl tert-butyl ether (50mL), followed by vacuum drying to give the compound of formula I in an amount of 8.3g, yield 94.6%, ee value 98.6%.
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