CN110845504A - Novel method for synthesizing pratinib - Google Patents
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Abstract
The invention relates to a novel method for synthesizing zambutinib. The synthetic route of the invention has the characteristics of few reaction steps, high yield, good operability, simple process and the like, does not relate to low-temperature reaction, and can effectively realize industrialized large-scale production.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a novel method for synthesizing zambutinib.
Background
Zanbutib (Zanburtinib) is a potent BTK inhibitor that has been used as a single agent or in combination with other therapies to develop clinical trials in the treatment of a variety of lymphomas. In 2018, 8 and 10 months, the application of zebritinib to NMPA for the new drug marketing in the treatment of relapsed or refractory Mantle Cell Lymphoma (MCL) and relapsed refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) was filed in baiji state, and both were incorporated into the priority channel. On 15/11/2019, the U.S. FDA approved zebritinib developed in baiji state, a chinese company, as "breakthrough therapy" for its "priority rating" to be marketed under the trade designation BRUKINSA, which is a capsule with a dosage form of 80 mg.
The chemical structure of the pratinib is shown as formula I:
the preparation method of the currently pratinib still needs 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. Therefore, the invention aims to provide a novel method for synthesizing the zambutinib, which has the advantages of few steps, simple process and high total yield.
In one aspect of the invention, the invention provides a novel method for synthesizing the compound of formula I, zambutinib. According to an embodiment of the invention, the method comprises:
(1) contacting the compound shown in the formula 1 with hydrogen peroxide and sodium hydroxide to obtain a compound shown in a formula 2;
(4) contacting the compound shown as the formula 2 with the compound shown as the formula 3 so as to obtain the compound shown as the formula I, namely the brimonidine,
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 prior art, the method has the advantages of simple synthetic route and reaction steps, no need of extremely low temperature reaction, mild reaction conditions 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 3, 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 or 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 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), the contact manner of the compound represented by formula 1 with hydrogen peroxide and sodium hydroxide is not particularly limited. Therefore, the contact efficiency of the compound shown in the formula 1 with hydrogen peroxide and sodium hydroxide 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 the step (1), the following steps are included: dissolving Compound 1 in EtOH and DMF, adding aqueous NaOH solution and H2O2And heating and stirring the mixture for reaction until the reaction is finished. And (3) carrying out post-treatment on the reaction solution, concentrating the organic layer, and purifying by a silica gel column to obtain the compound shown in the formula 2. Thereby, the operation can be further performedThe efficiency of preparing the compound shown in the formula 2 by using the method is improved.
According to an embodiment of the present invention, in the step (1), the NaOH aqueous solution is selected from 4% to 15% by mass of NaOH aqueous solution, preferably 5% by mass of NaOH aqueous solution.
According to an embodiment of the invention, in step (1), said H2O2Is selected from 30% H2O2And (3) solution.
According to the embodiment of the invention, in the step (1), the compound shown in the formula 1 is contacted with hydrogen peroxide and sodium hydroxide at the temperature of 50-65 ℃, and the mixture is stirred and reacts for 1.5-2.5 hours; preferably, the compound shown in the formula 1 is contacted with hydrogen peroxide and sodium hydroxide at 60 ℃, and stirred and reacted for 2 hours.
According to the embodiment of the invention, in the step (1), the mass volume of the compound shown in the formula 1 and the 30% hydrogen peroxide solution is 2:5(g/v), so that the utilization rate of reactants is high, the raw materials and the actual waste are not caused, and the yield of the target compound is high.
According to the embodiment of the invention, in the step (1), the mixed solvent of dichloromethane and methanol with a volume ratio of (30-60): 1 is adopted for column purification, and the mixed solvent of dichloromethane and methanol with a volume ratio of 50:1 is preferably adopted for column purification.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: n is a radical of2Compound 1(4.0g,0.01mol) was dissolved in EtOH (40mL) and DMF (20mL) with the protection, and 5% aqueous NaOH (10mL) and 30% H by mass were added2O2(10mL), the reaction was stirred at 60 ℃ for 2 h. The reaction mixture was concentrated to remove EtOH, and then washed with water (20mL), extracted with ethyl acetate (20mL), and the organic layer was concentrated and purified with silica gel column (DCM/MeOH ═ 50/1(v/v)) to give the compound represented by formula 2 in an amount of 3.3 g. 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 (2), the contacting manner of the compound represented by formula 2 and the compound represented by formula 3 is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 2 with 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 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: n is a radical of2Under protection, the compound 2 is dissolved in DCM, and a 5% NaOH aqueous solution is added, and the mixture is stirred for 1h at 30 ℃. The organic layers were collected, the aqueous layer was extracted with DCM, the organic layers were combined and washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved with compound 3 in DCM, HATU was added, stirring, and Et was added dropwise3N in DCM, and the mixture was heated to 35-40 ℃ and stirred for 2 h. And (3) carrying out post-treatment on the reaction liquid, concentrating the obtained organic layer, and purifying by a silica gel column to obtain the compound shown in the formula I. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to the embodiment of the present invention, in the step (2), the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 1 (0.95-1.2), and preferably the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 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 the embodiment of the invention, in the step (2), the mixed solvent of dichloromethane and methanol with a volume ratio of (50-120): 1 is adopted for column purification, and the mixed solvent of dichloromethane and methanol with a volume ratio of 100:1 is preferably adopted for column purification.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: n is a radical of2Compound 2(41.8g,0.1mol) was dissolved in DCM (300mL) under protection, and 5% aqueous NaOH solution (80mL) was added and stirred at 30 ℃ for 1 h. The organic layers were collected, the aqueous layer was extracted with DCM (300mL), the organic layers were combined and washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved with Compound 3(7.2g,0.1mol) in DCM (300mL), HATU (41.8g,0.11mol) was added, stirring was performed, Et was added dropwise3N (30.4g,0.3mol) in DCM (50 mL). The mixed solution is heated to 35-40 ℃ and stirred for reaction for 2 h.The reaction was concentrated in vacuo and dissolved in DMF (100 mL). Water (300mL) was gradually added dropwise to precipitate a solid. Centrifuging and collecting a filter cake. The filter cake was dissolved in DCM (300mL) and washed with 8% NaHCO3And 15% brine to remove DMF residue. The organic layer was concentrated and purified by silica gel column (DCM/MeOH ═ 100/1) to give the compound of formula I in 37.6g, 79.7% yield and 99.5% HPLC purity. Therefore, the efficiency of contacting the compound shown in the formula 2 with 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 I by using the method is further improved.
According to embodiments of the present invention, a novel route to the synthesis of the compound zambutinib of formula I can be shown as follows:
compared with the prior art, the novel method for synthesizing pratinib has the following advantages: according to the preparation process route, the target molecule zambutinib is obtained by reducing the initial raw material with cyano and then condensing with carboxylic acid. Compared with the existing synthetic route, the synthetic route has the advantages of long reaction steps, few reaction steps and high yield. First step of using H2O2Reducing cyano group, having good experimental operability and safety, avoiding the use of strong reducing agents, such as NaBH4、LiAlH4And the like. In the second step of condensation, NaOH aqueous solution is used as alkali, and reacts with imino on the six-membered ring specifically, thereby simplifying the experimental steps. The novel method for synthesizing the Zanbutini has the characteristics of good operability, simple process, high yield and the like in the whole route, does not involve low-temperature reaction, and can effectively realize industrial scale-up production.
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
N2Compound 1(4.0g,0.01mol) was dissolved in EtOH (40mL) and DMF (20mL) with the protection, and 4% aqueous NaOH (13mL) and 30% H by mass were added2O2(10mL), the reaction was stirred at 60 ℃ for 2 h. The reaction mixture was concentrated to remove EtOH, and then washed with water (20mL), extracted with ethyl acetate (20mL), the organic layer was concentrated, and purified with silica gel column (DCM/MeOH ═ 50/1(v/v)) to give the compound represented by formula 2, which was 3.1g in 74.3% yield.
LC-MS(APCI):m/z＝418.4(M+1)+。
Example 2 Synthesis of Compound represented by formula 2
N2Under protection, compound 1(4.0g,0.01mol) was dissolved in EtOH (40mL) and DMF (20mL), and 15% by weight aqueous NaOH (4mL) and 30% by weight H were added2O2(10mL), the reaction was stirred at 50 ℃ for 2.5 h. The reaction mixture was concentrated to remove EtOH, and then washed with water (20mL), followed by extraction with ethyl acetate (20mL), and the organic layer was concentrated and purified with silica gel column (DCM/MeOH ═ 60/1(v/v)) to give the compound represented by formula 2 in an amount of 3.0g, yield 71.9%.
EXAMPLE 3 Synthesis of Compound represented by formula 2
N2Compound 1(4.0g,0.01mol) was dissolved in EtOH (40mL) and DMF (20mL) with the protection, and 5% aqueous NaOH (10mL) and 30% H by mass were added2O2(10mL), the reaction was stirred at 65 ℃ for 1.5 h. The reaction mixture was concentrated to remove EtOH, and then washed with water (20mL), followed by extraction with ethyl acetate (20mL), and the organic layer was concentrated and purified with silica gel column (DCM/MeOH ═ 30/1(v/v)) to give the compound represented by formula 2, which was 2.9g in 69.5% yield.
EXAMPLE 4 Synthesis of Compound Zanbrutinib of formula I
N2Compound 2(41.8g,0.1mol) was dissolved in DCM (300mL) under protection, and 5% aqueous NaOH solution (80mL) was added and stirred at 30 ℃ for 1 h. The organic layers were collected, the aqueous layer was extracted with DCM (300mL), and combinedThe organic layer was washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved in DCM (300mL) with Compound 3(7.2g,0.1mol), HATU (41.8g,0.11mol) was added, stirring was added, and Et was added dropwise3N (30.4g,0.3mol) in DCM (50 mL). The mixed solution is heated to 35-40 ℃ and stirred for reaction for 2 h. The reaction was concentrated in vacuo and dissolved in DMF (100 mL). Water (300mL) was gradually added dropwise to precipitate a solid. Centrifuging and collecting a filter cake. The filter cake was dissolved in DCM (300mL) and washed with 8% NaHCO3And 15% brine to remove DMF residue. The organic layer was concentrated and purified by silica gel column (DCM/MeOH ═ 100/1) to give the compound of formula I in 37.6g, 79.7% yield and 99.5% HPLC purity.
LC-MS(APCI):m/z＝472.4(M+1)+。
EXAMPLE 5 Synthesis of Compound Zanbrutinib of formula I
N2Compound 2(41.8g,0.1mol) was dissolved in DCM (300mL) under protection, and 5% aqueous NaOH solution (80mL) was added and stirred at 30 ℃ for 1 h. The organic layers were collected, the aqueous layer was extracted with DCM (300mL), the organic layers were combined and washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved with Compound 3(6.9g,0.095mol) in DCM (300mL), HATU (41.8g,0.11mol) was added, stirring was performed, Et was added dropwise3N (30.4g,0.3mol) in DCM (50 mL). The mixed solution is heated to 35-40 ℃ and stirred for reaction for 2 h. The reaction was concentrated in vacuo and dissolved in DMF (100 mL). Water (300mL) was gradually added dropwise to precipitate a solid. Centrifuging and collecting a filter cake. The filter cake was dissolved in DCM (300mL) and washed with 8% NaHCO3And 15% brine to remove DMF residue. The organic layer was concentrated and purified by silica gel column (DCM/MeOH ═ 100/1) to give the compound of formula I in 36.0g, 76.4% yield and 99.4% HPLC purity.
EXAMPLE 6 Synthesis of Compound Zanbrutinib of formula I
N2Compound 2(41.8g,0.1mol) was dissolved in DCM (300mL) under protection, and 5% aqueous NaOH solution (80mL) was added and stirred at 30 ℃ for 1 h. The organic layers were collected, the aqueous layer was extracted with DCM (300mL), the organic layers were combined and washed with15% brine twice, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved in DCM (300mL) with Compound 3(8.7g,0.12mol), added to HATU (41.8g,0.11mol), stirred, and Et was added dropwise3N (30.4g,0.3mol) in DCM (50 mL). The mixed solution is heated to 35-40 ℃ and stirred for reaction for 2 h. The reaction was concentrated in vacuo and dissolved in DMF (100 mL). Water (300mL) was gradually added dropwise to precipitate a solid. Centrifuging and collecting a filter cake. The filter cake was dissolved in DCM (300mL) and washed with 8% NaHCO3And 15% brine to remove DMF residue. The organic layer was concentrated and purified by silica gel column (DCM/MeOH ═ 100/1) to give the compound of formula I in 36.6g, 77.6% yield and 99.7% HPLC purity.
EXAMPLE 7 Synthesis of Compound Zanbrutinib of formula I
N2Compound 2(41.8g,0.1mol) was dissolved in DCM (300mL) under protection, and 5% aqueous NaOH solution (80mL) was added and stirred at 30 ℃ for 1 h. The organic layers were collected, the aqueous layer was extracted with DCM (300mL), the organic layers were combined and washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved with Compound 3(6.5g,0.09mol) in DCM (300mL), HATU (41.8g,0.11mol) was added, stirring was performed, and Et was added dropwise3N (30.4g,0.3mol) in DCM (50 mL). The mixed solution is heated to 35-40 ℃ and stirred for reaction for 2 h. The reaction was concentrated in vacuo and dissolved in DMF (100 mL). Water (300mL) was gradually added dropwise to precipitate a solid. Centrifuging and collecting a filter cake. The filter cake was dissolved in DCM (300mL) and washed with 8% NaHCO3And 15% brine to remove DMF residue. The organic layer was concentrated and purified by silica gel column (DCM/MeOH-100/1) to give 22.0g of the compound of formula I, 46.6% yield, 97.0% HPLC purity.
EXAMPLE 8 Synthesis of Compound Zanbrutinib of formula I
N2Compound 2(41.8g,0.1mol) was dissolved in DCM (300mL) under protection, and 5% aqueous NaOH solution (80mL) was added and stirred at 30 ℃ for 1 h. The organic layers were collected, the aqueous layer was extracted with DCM (300mL), the organic layers were combined and washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue which was washed withThe solid residue and Compound 3(10.8g,0.15mol) were dissolved in DCM (300mL), HATU (41.8g,0.11mol) was added, stirring was performed, and Et was added dropwise3N (30.4g,0.3mol) in DCM (50 mL). The mixed solution is heated to 35-40 ℃ and stirred for reaction for 2 h. The reaction was concentrated in vacuo and dissolved in DMF (100 mL). Water (300mL) was gradually added dropwise to precipitate a solid. Centrifuging and collecting a filter cake. The filter cake was dissolved in DCM (300mL) and washed with 8% NaHCO3And 15% brine to remove DMF residue. The organic layer was concentrated and purified by silica gel column (DCM/MeOH ═ 100/1) to give the compound of formula I in 33.1g, 70.2% yield and 98.5% HPLC purity.
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 for synthesizing zambutinib, comprising:
(1) contacting the compound shown in the formula 1 with hydrogen peroxide and sodium hydroxide to obtain a compound shown in a formula 2;
(4) contacting the compound shown as the formula 2 with the compound shown as the formula 3 so as to obtain the compound shown as the formula I, namely the brimonidine,
2. the method according to claim 1, wherein in step (1), the following steps are included: dissolving Compound 1 in EtOH and DMF, adding aqueous NaOH solution and H2O2And heating and stirring the mixture for reaction until the reaction is finished. And (3) carrying out post-treatment on the reaction solution, concentrating the organic layer, and purifying by a silica gel column to obtain the compound shown in the formula 2.
3. The method according to claim 2, wherein in step (1), the aqueous NaOH solution is selected from 4-15% by weight of aqueous NaOH solution, preferably 5% by weight of aqueous NaOH solution.
4. The method of claim 2, wherein in step (1), the H2O2Is selected from H with a concentration of 30%2O2And (3) solution.
5. The method according to claim 2, wherein in the step (1), the compound shown in the formula 1 is contacted with hydrogen peroxide and sodium hydroxide at 50-65 ℃, and the mixture is stirred and reacted for 1.5-2.5 hours; preferably, the compound shown in the formula 1 is contacted with hydrogen peroxide and sodium hydroxide at 60 ℃, and stirred and reacted for 2 hours.
6. The method according to claim 2, wherein in step (1), the mass volume of the compound represented by formula 1 to the 30% hydrogen peroxide solution is 2: 5.
7. The method according to claim 2, wherein in the step (1), the column purification adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (30-60): 1, preferably, the column purification adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1.
8. The method of claim 1, wherein in step (2), the following steps are included: n is a radical of2Under protection, the compound 2 is dissolved in DCM, and a 5% NaOH aqueous solution is added, and the mixture is stirred for 1h at 30 ℃. The organic layers were collected, the aqueous layer was extracted with DCM, the organic layers were combined and washed twice with 15% brine, the organic layer was concentrated in vacuo to give a yellow solid residue, which was dissolved with compound 3 in DCM, HATU was added, stirring, and Et was added dropwise3N in DCM, and the mixture was heated to 35-40 ℃ and stirred for 2 h. And (3) carrying out post-treatment on the reaction liquid, concentrating the obtained organic layer, and purifying by a silica gel column to obtain the compound shown in the formula I.
9. The method according to claim 8, wherein in the step (2), the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 1 (0.95-1.2), preferably the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 1: 1.
10. The method according to claim 8, wherein in the step (2), the column purification adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (50-120): 1, preferably, the column purification adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 100: 1.
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Cited By (1)
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| WO2022125862A1 (en) | 2020-12-11 | 2022-06-16 | Teva Pharmaceuticals International Gmbh | Processes for the preparation of zanubrutinib and intermediates thereof |
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