阅读说明：本技术 Wee1抑制剂adavosertib的制备工艺 (Preparation process of Wee1 inhibitor avaposertib ) 是由 余艳平 柳少群 范昭泽 于 2021-09-29 设计创作，主要内容包括：本发明涉及一种Wee1抑制剂adavosertib的制备工艺。本发明所述的方法,采用已有的中间体,经过微波反应、卤代反应、氨基脱保护后,再经卤代反应合成目标化合物adavosertib,有效提高了反应的总收率和工业化操作性。(The invention relates to a preparation process of Wee1 inhibitor avacostertib. The method adopts the existing intermediate, and the target compound adavosertib is synthesized through microwave reaction, halogenation reaction and amino deprotection, so that the total yield and the industrial operability of the reaction are effectively improved.)

1. A preparation process of avasertib is characterized by comprising the following steps:

(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 represented by formula 3 with a compound represented by formula 4 to obtain a compound represented by formula 5;

(3) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;

(4) contacting a compound of formula 7 with a compound of formula 8 to obtain a compound of formula I,

2. the method according to claim 1, wherein in step (1), the following steps are included: mixing the compound shown in the formula 1 and the compound shown in the formula 2, reacting by using a microwave tube under the condition of no solvent, adding water into the reaction mixture after the reaction is finished, filtering and collecting a solid product, and pulping and purifying the solid by using straight chain or branched chain alcohol containing C1-C5 to obtain the compound shown in the formula 3.

3. The method according to claim 2, wherein in the step (1), the molar ratio of the compound represented by the formula 1 to the compound represented by the formula 2 is 1 (1.05-1.2), preferably the molar ratio of the compound represented by the formula 1 to the compound represented by the formula 2 is 1: 1.1;

optionally, in the step (1), reacting the compound shown in the formula 1 with hydrazine at room temperature and power of 400W for 5-6 minutes;

optionally, in step (1), the C1-C5 containing straight or branched chain alcohol is selected from methanol, ethanol, isopropanol, butanol, pentanol.

4. The method of claim 1,in the step (2), the method comprises the following steps: reacting a compound represented by the formula 3 with K at room temperature₂CO₃Adding the mixture into stirred DMF, mixing, adding the compound shown in the formula 4, heating, stirring, reacting, performing post-treatment and pulping purification after the reaction is finished, filtering the solid, and drying to obtain the compound shown in the formula 5.

5. The method according to claim 4, wherein in the step (2), the compound represented by the formula 3, K₂CO₃The molar ratio of the compound represented by the formula 4 is 1 (1.0-1.2) to 1.0-1.2, preferably the compound represented by the formula 3, K₂CO₃The molar ratio of the compound shown in the formula 4 is 1:1.1: 1.05;

optionally, in step (2), a compound of formula 3, K₂CO₃The reaction time of the compound shown as the formula 4 in contact stirring is 1.5-2.5 h, and the compound shown as the formula 3 and K are preferably selected₂CO₃The reaction time of the contact stirring of the compound shown in the formula 4 is 2 hours;

optionally, in step (2), a compound of formula 3, K₂CO₃The reaction temperature for the contact stirring and temperature rise of the compound represented by the formula 4 is 55 to 65 ℃, and the compound represented by the formula 3 and K are preferably selected₂CO₃Heating the compound shown in the formula 4 to 60 ℃, and stirring for reaction;

optionally, in the step (2), the pulping purification adopts a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1.

6. The method of claim 1, wherein in step (3), the following steps are included: adding a compound shown as a formula 5 and a compound shown as a formula 6 into dichloromethane at room temperature, stirring reaction liquid, heating up, carrying out reflux reaction, cooling the reaction liquid to room temperature after the reaction is finished, adding ice water, stirring, and adding saturated NaHCO₃After the solution is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred and pulped by using a mixed solvent for purification, and the solid is filtered and dried to obtain the compound shown in the formula 7.

7. The method according to claim 6, wherein in the step (3), the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6 is 1 (8-12), preferably the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6 is 1: 10;

optionally, in the step (3), the contact and stirring reaction time of the compound shown in the formula 5 and the compound shown in the formula 6 is 3.5 hours to 5 hours, and preferably the contact and stirring reaction time of the compound shown in the formula 5 and the compound shown in the formula 6 is 4 hours;

optionally, in the step (3), the pulping purification adopts a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1.

8. The method according to claim 1, wherein in step (4), the following steps are included: reacting a compound represented by the formula 7 with K at room temperature₂CO₃Adding the mixture into stirred DMF, adding a compound shown as a formula 8, heating the mixture, stirring, reacting, cooling the reaction liquid to room temperature, pouring the reaction liquid into water, extracting the mixture by using ethyl acetate, combining organic phases, washing by using saturated saline solution, drying by using sodium sulfate, filtering, concentrating the filtrate, and purifying by using silica gel column chromatography to obtain the compound Adavosertib shown as the formula I.

9. The method according to claim 8, wherein in step (4), the compound represented by formula 7, K₂CO₃The molar ratio of the compound represented by the formula 8 is 1 (1.0-1.3) to 1.0-1.2, preferably 7, and K₂CO₃The molar ratio of the compound shown in the formula 8 is 1:1.15: 1.05;

optionally, in step (4), a compound of formula 7, K₂CO₃The reaction time of the compound represented by the formula 8 under contact stirring is 45 minutes to 1.5 hours, and the compound represented by the formula 7 and K are preferable₂CO₃The reaction time of the contact stirring of the compound shown in the formula 8 is 1 hour;

optionally, in step (4), a compound of formula 7, K₂CO₃The reaction temperature for the contact stirring and temperature increase of the compound represented by the formula 8 is 55 to 65 ℃, and the compound represented by the formula 7,K₂CO₃Heating the compound shown in the formula 8 to 60 ℃, and stirring for reaction;

optionally, in the step (4), the silica gel column chromatography adopts a mixed solvent of dichloromethane and methanol in a volume ratio of (10-30): 1, and preferably, the column chromatography adopts a mixed solvent of dichloromethane and methanol in a volume ratio of 20: 1.

10. The method according to claims 1-9, characterized in that in step (1) it comprises the steps of: mixing 27.0g of the compound shown in the formula 1 and 7.92g of the compound shown in the formula 2 at 20 ℃, reacting by using a microwave tube under the condition of no solvent, reacting for 5 minutes at room temperature under the power of 400W, adding 30mL of water into a reaction mixture after the reaction is finished, filtering and collecting a solid product, pulping and purifying the solid by 120mL of methanol, filtering, and drying the solid to obtain the compound shown in the formula 3, wherein the yield is 24.9g and 96.0%;

in the step (2), the method comprises the following steps: mixing 5.19g of the compound represented by the formula 3 and 3.04g K at room temperature₂CO₃Adding the mixture into stirred 40mL of mixed solution of DMMF (lithium-magnesium-manganese mixed) for mixing, adding 4.54g of a compound shown as a formula 4, heating to 60 ℃, stirring for reaction for 2 hours, pouring the reaction solution into 40mL of water after the reaction is finished, filtering and collecting precipitated solids, stirring and pulping for 30 minutes by using 50mL of mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 1:1, purifying, filtering the solids, and drying to obtain a compound shown as a formula 5, wherein the yield is 7.22g and 91.5%;

in the step (3), the method comprises the following steps: adding 3.94g of the compound shown in the formula 5 and 15.3g of the compound shown in the formula 6 into 60mL of dichloromethane at room temperature, stirring the reaction liquid, heating, refluxing for reaction for 4 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding 30mL of ice water, stirring, adding 30mL of saturated NaHCO₃After the solution is washed, concentrating the organic layer under reduced pressure until the organic layer is dried, stirring and pulping the crude product for 30min by using 30mL of mixed solvent consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1, filtering the solid, and drying to obtain the compound shown in the formula 7, wherein the yield is 2.58g and 79.1%;

in the step (4), the method comprises the following steps: 32.6g of the compound represented by the formula 7 and 15.9g of a solvent were added at room temperature K₂CO₃Adding the mixture into 200mL of stirred LDMF, adding 22.1g of the compound shown in the formula 8, heating the mixture to 60 ℃, stirring and reacting for 1h, after the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into 40mL of water, extracting the mixture by using 3 x 40mL of ethyl acetate, combining organic phases, washing the organic phases by using 30mL of saturated saline solution, drying the organic phases by using sodium sulfate, filtering the mixture, concentrating the filtrate, and purifying the filtrate by using a mixed solvent of dichloromethane and methanol with a volume ratio of 20:1 through silica gel column chromatography to obtain the compound Adavosertib shown in the formula I, wherein the solid content is 44.0g, the yield is 87.9 percent, and the HPLC purity is 99.5 percent.

Technical Field

The invention relates to the technical field of biological medicines, in particular to a preparation process of Wee1 inhibitor avacostertib.

Background

Aslicon, licensed by Merck, is developing the Wee-1 protein kinase inhibitor, adavosertib (development code AZD-1775; MK-1775), which is used for oral treatment of solid tumors. The Adavosertib is a small molecular inhibitor, and the dosage form is a capsule. In month 4 2012, european EMA awards avaposertib an orphan drug title for treating ovarian cancer. Adavosertib is currently in phase 2 clinical trials in the united states, canada, europe, the netherlands, korea at the highest. The clinical indications in stage 2 are: breast cancer, fallopian tube cancer, head and neck tumor, ovarian cancer, pancreatic cancer, peritoneal tumor, small cell lung cancer, uterine tumor; it has been in phase 1 clinical studies in the united states, australia, canada, france, japan, korea, spain, uk, with phase 1 clinical indications: advanced solid tumor, metastatic bladder cancer, small cell lung cancer, and solid tumor.

The chemical structure of Adavosertib is disclosed in WO2011034743, which has a specific structural formula as shown in formula I:

however, the chemical synthesis preparation process of Adavosertib still 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. Therefore, the invention aims to provide a preparation process of a novel Wee1 inhibitor Adavosertib. Compared with the prior art, the preparation process effectively improves the total yield of the reaction and the industrial operability.

In one aspect of the invention, the invention provides a preparation process of a compound Adavosertib shown in formula I. According to an embodiment of the invention, the preparation process 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 represented by formula 3 with a compound represented by formula 4 to obtain a compound represented by formula 5;

(3) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;

(4) contacting a compound of formula 7 with a compound of formula 8 to obtain a compound of formula I,

the inventor finds that the compound adavosertib shown in the formula I can be quickly and effectively prepared by the preparation process of the invention through microwave reaction, halogenation reaction, amino deprotection and halogenation reaction by using the existing intermediate.

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.

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 embodiments of the present invention, the above-described method for preparing the compound represented by formula 3, the compound represented by formula 5, the compound represented by formula 7, 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 starting material for preparing the compound represented by formula 3, the compound represented by formula 5, the compound represented by formula 7, 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 contacting manner of the compound represented by formula 1 with the compound represented by formula 2 is not particularly limited. Therefore, the efficiency of the contact reaction between the compound shown in the formula 1 and the compound shown in the formula 1 can be improved, the speed of the microwave reaction 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: mixing the compound shown in the formula 1 and the compound shown in the formula 2, reacting by using a microwave tube under the condition of no solvent, adding water into the reaction mixture after the reaction is finished, filtering and collecting a solid product, and pulping and purifying the solid by using straight chain or branched chain alcohol containing C1-C5 to obtain the compound shown in the formula 3. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 and the compound shown in the formula 2 can be improved, the speed of the microwave reaction 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 molar ratio of the compound represented by formula 1 to the compound represented by formula 2 is 1 (1.05-1.2), and preferably the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 is 1: 1.1. Therefore, the utilization rate of the reactant is high, the waste of raw materials and reality is avoided, the yield of the target compound is high, and the efficiency of preparing the compound shown in the formula 3 by using the method can be further improved.

According to the embodiment of the invention, in the step (1), the compound shown in the formula 1 and hydrazine are subjected to microwave reaction, and the reaction is carried out for 5-6 minutes at the room temperature power of 400W, so that the efficiency of the microwave reaction of the compound shown in the formula 1 and hydrazine can be improved, and the efficiency of preparing the compound shown in the formula 3 by using the method can be further improved.

According to an embodiment of the present invention, in step (1), the C1-C5 containing linear or branched alcohol is selected from methanol, ethanol, isopropanol, butanol, pentanol.

According to a specific embodiment of the present invention, in the step (1), the following steps are included: 27.0g of the compound represented by the formula 1 and 7.92g of the compound represented by the formula 2 were mixed at 20 ℃, and the mixture was reacted at room temperature for 5 minutes under a power of 400W using a microwave tube without a solvent, 30mL of water was added to the reaction mixture after the completion of the reaction, the solid product was collected by filtration, and the solid was purified by beating with 120mL of methanol, filtered, and dried to obtain the compound represented by the formula 3 in an amount of 24.9g with a yield of 96.0%.

According to an embodiment of the present invention, in step (2), the compound represented by formula 3, K₂CO₃The contact mode with the compound represented by formula 4 is not particularly limited. Thus, the compound represented by the formula 3, K, can be promoted₂CO₃The efficiency of the contact reaction with the compound shown in the formula 4 is improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.

According to an embodiment of the present invention, in the step (2), the following steps are included: reacting a compound represented by the formula 3 with K at room temperature₂CO₃Adding the mixture into stirred DMF, mixing, adding the compound shown in the formula 4, heating, stirring, reacting, performing post-treatment and pulping purification after the reaction is finished, filtering the solid, and drying to obtain the compound shown in the formula 5. Thus, the compound represented by the formula 3, K, can be promoted₂CO₃And the efficiency of the contact reaction with the compound shown in the formula 4, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.

According to an embodiment of the present invention, in step (2), the compound represented by formula 3, K₂CO₃The molar ratio of the compound represented by the formula 4 is 1 (1.0-1.2) to 1.0-1.2, preferably the compound represented by the formula 3, K₂CO₃The molar ratio of the compound represented by formula 4 is 1:1.1: 1.05. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.

According to an embodiment of the present invention, in step (2), the compound represented by formula 3, K₂CO₃The reaction time of the compound shown as the formula 4 in contact stirring is 1.5-2.5 h, and the compound shown as the formula 3 and K are preferably selected₂CO₃And the reaction time of the compound represented by the formula 4 with contact stirring was 2 hours. Thus, the compound represented by the formula 3, K, can be promoted₂CO₃And the efficiency of the contact reaction of the compound shown in the formula 4, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.

According to an embodiment of the present invention, in step (2), the compound represented by formula 3, K₂CO₃The reaction temperature for the contact stirring and temperature rise of the compound represented by the formula 4 is 55 to 65 ℃, and the compound represented by the formula 3 and K are preferably selected₂CO₃And heating the compound shown in the formula 4 to 60 ℃, and stirring for reaction. Thus, the compound represented by the formula 3, K, can be promoted₂CO₃And the efficiency of the contact reaction of the compound shown in the formula 4, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.

According to an embodiment of the invention, in the step (2), the pulping purification adopts a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1.

According to a specific embodiment of the present invention, in the step (2), the following steps are included: mixing 5.19g of the compound represented by the formula 3 and 3.04g K at room temperature₂CO₃Adding the mixture into stirred 40mL of DMMF, mixing, adding 4.54g of the compound shown in the formula 4, heating to 60 ℃, stirring and reacting for 2h, pouring the reaction liquid into 40mL of water after the reaction is finished, filtering and collecting precipitated solids, stirring and pulping for 30min by using 50mL of mixed solvent consisting of petroleum ether and ethyl acetate in a volume ratio of 1:1, filtering the solids, and drying to obtain the compound shown in the formula 5, wherein the yield is 7.22g and 91.5%.

According to an embodiment of the present invention, in step (3), the contacting manner of the compound represented by formula 5 with the compound represented by formula 6 is not particularly limited. Therefore, the efficiency of the contact reaction between the compound shown in the formula 5 and the compound shown in the formula 6 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.

According to an embodiment of the present invention, in the step (3), the following steps are included: adding a compound shown as a formula 5 and a compound shown as a formula 6 into dichloromethane at room temperature, stirring reaction liquid, heating up, carrying out reflux reaction, cooling the reaction liquid to room temperature after the reaction is finished, adding ice water, stirring, and adding saturated NaHCO₃After the solution is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred, pulped and purified by using a mixed solvent, and the solid is filtered and dried to obtain the compound shown in the formula 7. Therefore, the efficiency of the contact reaction between the compound shown in the formula 5 and the compound shown in the formula 6 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.

According to the embodiment of the invention, in the step (3), the molar ratio of the compound represented by the formula 5 to the compound represented by the formula 6 is 1 (8-12), and preferably the molar ratio of the compound represented by the formula 5 to the compound represented by the formula 6 is 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 (3), the reaction time of contacting the compound represented by formula 5 with the compound represented by formula 6 with stirring is 3.5 hours to 5 hours, and preferably the reaction time of contacting the compound represented by formula 5 with the compound represented by formula 6 with stirring is 4 hours. Therefore, the efficiency of the contact reaction between the compound shown in the formula 5 and the compound shown in the formula 6 can be improved, and the efficiency of preparing the compound shown in the formula 7 by using the method can be further improved.

According to an embodiment of the invention, in the step (3), the pulping purification adopts a mixed solvent of petroleum ether/ethyl acetate with a volume ratio of 1:1.

According to a specific embodiment of the present invention, in the step (3), the following steps are included: adding 3.94g of the compound shown in the formula 5 and 15.3g of the compound shown in the formula 6 into 60mL of dichloromethane at room temperature, stirring the reaction liquid, heating, refluxing for reaction for 4 hours, cooling the reaction liquid to room temperature after the reaction is finished, adding 30mL of ice water, stirring, adding 30mL of saturated NaHCO₃After the solution is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred and pulped for purification for 30min by using 30mL of mixed solvent consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, the solid is filtered, and the compound shown in the formula 7 is obtained after drying, the yield is 2.58g, and the yield is 79.1%.

According to an embodiment of the present invention, in step (4), the compound represented by formula 7, K₂CO₃The contact manner of the compound represented by formula 8 is not particularly limited. Thus, the compound represented by the formula 7, K, can be promoted₂CO₃And the efficiency of the contact reaction of the compound shown as the formula 8 is improved, the reaction speed is accelerated, and the efficiency of preparing 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 (4), the following steps are included: reacting a compound represented by the formula 7 with K at room temperature₂CO₃Adding the mixture into stirred DMF, adding a compound shown as a formula 8, heating the mixture, stirring for reaction, after the reaction is finished, cooling the reaction liquid to room temperature, pouring the reaction liquid into water, extracting the mixture by using ethyl acetate, combining organic phases, washing the organic phases by using saturated saline, drying the organic phases by using sodium sulfate, filtering the mixture, concentrating the filtrate, and purifying the filtrate by using silica gel column chromatography to obtain the compound Adavosertib shown as the formula I. Therefore, the efficiency of preparing the compound Adavosertib shown in the formula I by using the method can be further improved.

According to an embodiment of the present invention, in step (4), the compound represented by formula 7, K₂CO₃The molar ratio of the compound represented by the formula 8 is 1 (1.0-1.3) to 1.0-1.2, preferably 7, and K₂CO₃The molar ratio of the compound represented by formula 8 is 1:1.15: 1.05. 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 step (4), the compound represented by formula 7, K₂CO₃The reaction time of the compound represented by the formula 8 under contact stirring is 45 minutes to 1.5 hours, and the compound represented by the formula 7 and K are preferable₂CO₃The reaction time for the contact stirring of the compound represented by the formula 8 was 1 hour. Thus, the compound represented by the formula 7, K, can be promoted₂CO₃And the efficiency of the contact reaction of the compound shown as the formula 8 further improves the efficiency of preparing the compound shown as the formula I by using the method.

According to an embodiment of the present invention, in step (4), the compound represented by formula 7, K₂CO₃The reaction temperature for the contact stirring and temperature rise of the compound represented by the formula 8 is 55 to 65 ℃, and preferably the compound represented by the formula 7 and K₂CO₃And heating the compound shown in the formula 8 to 60 ℃, and stirring for reaction. Thus, the compound represented by the formula 7, K, can be promoted₂CO₃And the efficiency of the contact reaction of the compound shown as the formula 8 further improves the efficiency of preparing the compound shown as the formula I by using the method.

According to the embodiment of the invention, in the step (4), the mixed solvent of dichloromethane/methanol with a volume ratio of (10-30): 1 is adopted for silica gel column chromatography, and preferably, the mixed solvent of dichloromethane/methanol with a volume ratio of 20:1 is adopted for column chromatography.

According to a specific embodiment of the present invention, in the step (4), the following steps are included: mixing 32.6g of the compound represented by the formula 7 with 15.9g K at room temperature₂CO₃Adding into 200mL of stirring LDMF, adding 22.1g of compound shown in formula 8, heating the mixture to 60 deg.C, stirring for 1h, cooling to room temperature, pouring into 40mL of water, adding 3 × 40mL of acetic acidThe mixture was extracted with ethyl ester, the organic phases were combined and washed with 30mL of saturated brine, dried with sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography using a mixed solvent of dichloromethane/methanol at a volume ratio of 20:1 to obtain the compound Adavosertib of formula I, with a solid content of 44.0g, a yield of 87.9%, and an HPLC purity of 99.5%.

According to the embodiment of the present invention, the synthetic route of the preparation process of the compound adavosertib shown in the formula I can be shown as follows:

compared with the prior art, the preparation process of the Wee1 inhibitor avaposertib has at least the following beneficial effects: the method adopts the existing intermediate, and synthesizes the target compound adavosertib through microwave reaction, halogenation reaction and amino deprotection. More specifically, in the step (1), the compound shown in the formula 1 with protected amino is selected as a raw material, and the reaction time can be greatly reduced and the reaction yield can be improved by utilizing microwave reaction to close the loop; selecting low-cost K for halogenation in step (2)₂CO₃The catalyst is used as an alkaline reagent to participate in the reaction, so that the use of expensive NaH is avoided, and the reaction cost is reduced; removing the amino protecting group in the compound shown in the formula 5 by using the compound shown in the formula 6 (bromomethyl phenyl propane); step (4) adopts K₂CO₃The alkaline reagent participates in the reaction, so that the halogenation reaction of the amino group in the compound shown in the formula 7 can be specifically carried out, and the generation of-OH halogenated byproducts in the compound shown in the formula 7 can be reduced. The preparation process has the advantages of few reaction steps, small reaction difficulty of each step and simple treatment operation after reaction. In addition, the method utilizes the characteristic of poor product solubility, adopts a pulping purification mode mostly for purification of the reaction, and has simple and rapid purification process and higher overall reaction yield. The preparation process of Wee1 inhibitor avaposertib effectively improves the total yield of the reaction and the industrial 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 specific techniques or conditions are not indicated in the examples, and are performed according to the techniques or conditions described in the literature in the field or according to the product specification. 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

A compound represented by the formula 1 (27.0g,0.1mol) and a compound represented by the formula 2 (7.92g,0.11mol) were mixed at 20 ℃ and reacted using a microwave tube without a solvent at a room temperature power of 400W for 5 minutes, water (30mL) was added to the reaction mixture after the reaction was completed, the solid product was collected by filtration, the solid was purified by slurrying with methanol (120mL), and the solid was dried to obtain a compound represented by the formula 3 in an amount of 24.9g with a yield of 96.0%.

LC-MS(APCI):m/z＝260.3(M+1)⁺。

EXAMPLE 2 Synthesis of Compound represented by formula 3

A compound represented by formula 1 (27.0g,0.1mol) and a compound represented by formula 2 (7.57g,0.105mol) were mixed at 20 ℃ and reacted at room temperature for 5.5 minutes using a microwave tube without a solvent, and the power at room temperature was 400W, after the reaction was completed, water (5 mL) was added to the reaction mixture, and a solid product was collected by filtration, and the solid was purified by slurrying with methanol (20mL), filtered, and dried to obtain a compound represented by formula 3 in an amount of 24.3g with a yield of 93.7%.

EXAMPLE 3 Synthesis of Compound represented by formula 3

A compound represented by the formula 1 (27.0g,0.1mol) and a compound represented by the formula 2 (8.65g,0.12mol) were mixed at 20 ℃ and reacted at room temperature for 6 minutes using a microwave tube without a solvent, the power at room temperature was 400W, water (5 mL) was added to the reaction mixture after the reaction was completed, the solid product was collected by filtration, the solid was purified by slurrying with methanol (20mL), and the solid was dried to obtain a compound represented by the formula 3, the amount of which was 24.4g, and the yield was 94.1%.

EXAMPLE 4 Synthesis of Compound represented by formula 5

A compound represented by the formula 3 (5.19g,20mmol) and K were reacted at room temperature₂CO₃(3.04g,22mmol) is added into DMF (40mL) which is stirred for mixing, then the compound shown in formula 4 (4.54g,21mmol) is added, the temperature is raised to 60 ℃, the stirring reaction is carried out for 2h, after the reaction is finished, the reaction liquid is poured into water (40mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring, pulping and purifying for 30min, the solid is filtered and dried, and then the compound shown in formula 5 is obtained, the yield is 7.22g, the yield is 91.5%, and the HPLC purity of the product is 97.22%.

LC-MS(APCI):m/z＝395.3(M+1)⁺。

EXAMPLE 5 Synthesis of Compound represented by formula 5

A compound represented by the formula 3 (5.19g,20mmol) and K were reacted at room temperature₂CO₃(2.76g,20mmol) is added into DMF (40mL) which is stirred for mixing, then the compound shown in formula 4 (4.32g,20mmol) is added, the temperature is raised to 55 ℃, stirring reaction is carried out for 2.5h, after the reaction is finished, the reaction liquid is poured into water (40mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring and pulping for purification for 30min, the solid is filtered and dried, and then the compound shown in formula 5 is obtained, the yield is 7.18g, the yield is 91.0%, and the HPLC purity is 96.93%.

EXAMPLE 6 Synthesis of Compound represented by formula 5

A compound represented by the formula 3 (3.50g,20mmol) and K are reacted at room temperature₂CO₃(3.32g,24mmol) is added into DMF (40mL) which is stirred for mixing, then the compound shown in formula 4 (5.19g,24mmol) is added, the temperature is raised to 65 ℃, the stirring reaction is carried out for 1.5h, after the reaction is finished, the reaction liquid is poured into water (40mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring and pulping for purification for 30min, the solid is filtered and dried, and then the compound shown in formula 5 is obtained, the yield is 7.08g, and the yield is 89.7%.

Example 7 Synthesis of Compound represented by formula 5

Example 7 is a comparative example, in this example 7, the inventors preparedCompound represented by the general formula 3, K₂CO₃The reaction molar ratio of the compound shown in the formula 4 to the compound shown in the formula 4 is 1:1.5:1.3, and the technical effect is that the yield of the obtained product is lower than that of the compound shown in the formula 3 and K₂CO₃The yield of the product when the molar ratio of the compound represented by the formula 4 is 1 (1.0-1.2) to 1.0-1.2.

A compound represented by the formula 3 (5.19g,20mmol) and K were reacted at room temperature₂CO₃(4.15g,30mmol) is added into DMF (50mL) which is stirred for mixing, then the compound shown in formula 4 (5.62g,26mmol) is added, the temperature is raised to 60 ℃, the stirring reaction is carried out for 2h, after the reaction is finished, the reaction liquid is poured into water (50mL), the precipitated solid is filtered and collected, then the mixed solvent (60mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring, pulping and purifying for 30min, the solid is filtered and dried, and then the compound shown in formula 5 is obtained, the yield is 6.38g, the yield is 80.9%, and the HPLC purity is 91.60%.

EXAMPLE 8 Synthesis of Compound represented by formula 5

Example 8 is a comparative example, and in this example 8, the inventors adjusted the compound represented by formula 3, K₂CO₃The reaction molar ratio of the compound shown in the formula 4 to the compound shown in the formula 4 is 1:0.95:0.98, and the technical effect is that the yield of the obtained product is lower than that of the compound shown in the formula 3 and K₂CO₃And when the molar ratio of the compound shown in the formula 4 is 1 (1.0-1.2) to 1.0-1.2, the yield of the product is high, and the purity of the intermediate product is obviously reduced.

A compound represented by the formula 3 (5.19g,20mmol) and K were reacted at room temperature₂CO₃(2.63g,19mmol) is added into DMF (40mL) which is stirred for mixing, then the compound shown in formula 4 (4.24g,19.6mmol) is added, the temperature is raised to 60 ℃, the stirring reaction is carried out for 2h, after the reaction is finished, the reaction liquid is poured into water (40mL), the precipitated solid is filtered and collected, then the mixed solvent (50mL) consisting of petroleum ether and ethyl acetate with the volume ratio of 1:1 is used for stirring and pulping for purification for 30min, the solid is filtered and dried, and then the compound shown in formula 5 is obtained, the yield is 5.62g, the yield is 71.3%, and the HPLC purity is 85.54%.

Example 9 Synthesis of Compound represented by formula 6

A compound represented by the formula 5 (3.94g,10mmol) and a compound represented by the formula 6 (15.3) were reacted at room temperatureg,100mmol) was added to methylene chloride (60mL), and the reaction mixture was stirred, heated, and refluxed for 4 hours. After the reaction, the reaction mixture was cooled to room temperature, ice water (30mL) was added and stirred, and then saturated NaHCO was added₃After the solution (30mL) is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred, pulped and purified for 30min by using a mixed solvent (30mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, the solid is filtered, and the compound shown in the formula 7 is obtained after drying, the yield is 2.58g, and the yield is 79.1%.

LC-MS(APCI):m/z＝327.2(M+1)⁺。

EXAMPLE 10 Synthesis of Compound represented by formula 6

The compound represented by the formula 5 (3.94g,10mmol) and the compound represented by the formula 6 (12.2g,80mmol) were added to dichloromethane (60mL) at room temperature, and the reaction mixture was stirred and heated under reflux for 3.5 hours. After the reaction, the reaction mixture was cooled to room temperature, ice water (30mL) was added and stirred, and then saturated NaHCO was added₃After the solution (30mL) is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred, pulped and purified for 30min by using a mixed solvent (30mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, the solid is filtered, and the compound shown in the formula 7 is obtained after drying, the yield is 2.51g, and the yield is 76.9%.

EXAMPLE 11 Synthesis of Compound represented by formula 6

The compound represented by the formula 5 (3.94g,10mmol) and the compound represented by the formula 6 (18.4g,120mmol) were added to dichloromethane (65mL) at room temperature, and the reaction mixture was stirred and refluxed for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, ice water (30mL) was added and stirred, and then saturated NaHCO was added₃After the solution (30mL) is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred, pulped and purified for 30min by using a mixed solvent (30mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, the solid is filtered, and the compound shown in the formula 7 is obtained after drying, the yield is 2.55g, and the yield is 78.1%.

EXAMPLE 12 Synthesis of Compound represented by formula 6

Example 12 is a comparative example in which the inventors adjusted the molar ratio of the compound represented by formula 5 to the compound represented by formula 6 to 1:6, and reacted for 3.5 hours. In the technical effect of the comparative example, the yield of the obtained product is lower than that of the product obtained when the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6 is 1 (8-12).

The compound represented by the formula 5 (3.94g,10mmol) and the compound represented by the formula 6 (9.2g,60mmol) were added to dichloromethane (60mL) at room temperature, and the reaction mixture was stirred and heated under reflux for 3.5 hours. After the reaction, the reaction mixture was cooled to room temperature, ice water (30mL) was added and stirred, and then saturated NaHCO was added₃After the solution (30mL) is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred, pulped and purified for 30min by using a mixed solvent (30mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, the solid is filtered, and the compound shown in the formula 7 is obtained after drying, the yield is 2.07g, and the yield is 63.5%.

Example 13 Synthesis of Compound represented by formula 6

Example 13 is a comparative example in which the inventors adjusted the molar ratio of the compound represented by formula 5 to the compound represented by formula 6 to 1:15, and reacted for 5 hours. In the technical effect of the comparative example, the yield of the obtained product is lower than that of the product obtained when the molar ratio of the compound shown in the formula 5 to the compound shown in the formula 6 is 1 (8-12).

The compound represented by the formula 5 (3.94g,10mmol) and the compound represented by the formula 6 (23.0g,150mmol) were added to dichloromethane (80mL) at room temperature, and the reaction mixture was stirred and refluxed for 5 hours. After the reaction, the reaction mixture was cooled to room temperature, ice water (40mL) was added thereto and stirred, and then saturated NaHCO was added thereto₃After the solution (40mL) is washed, the organic layer is decompressed and concentrated to be dry, the crude product is stirred, pulped and purified for 30min by using a mixed solvent (40mL) consisting of petroleum ether/ethyl acetate with the volume ratio of 1:1, the solid is filtered, and the compound shown in the formula 7 is obtained after drying, the yield is 2.24g, and the yield is 68.7%.

Example 14 Synthesis of Adavosertib, a Compound of formula I

A compound represented by the formula 7 (32.6g,0.1mol) and K were reacted at room temperature₂CO₃(15.9g,0.115mol) was added to DMF (200mL) while stirring, the compound represented by formula 8 (22.1g,0.105mol) was added thereto, the mixture was heated to 60 ℃ and stirred for 1 hour, after completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (40mL), and ethyl acetate (3 mL) was usedX 40mL), combining the organic phases, washing with saturated brine (30mL), drying with sodium sulfate, filtering, concentrating the filtrate, and purifying by silica gel column chromatography with a dichloromethane/methanol mixed solvent with a volume ratio of 20:1 to obtain the compound Adavosertib shown in the formula I, wherein the solid content is 44.0g, the yield is 87.9%, and the HPLC purity is 99.5%.

LC-MS(APCI):m/z＝501.4(M+1)⁺。

Example 15 Synthesis of Adavosertib, a Compound of formula I

A compound represented by the formula 7 (32.6g,0.1mol) and K were reacted at room temperature₂CO₃(13.8g,0.1mol) was added to stirred DMF (200mL), then the compound of formula 8 (21.1g,0.1mol) was added, the mixture was heated to 65 ℃ and stirred for reaction for 45 minutes, after the reaction was completed, the reaction solution was cooled to room temperature and poured into water (40mL), the mixture was extracted with ethyl acetate (3 × 40mL), the organic phases were combined and washed with saturated brine (30mL), dried over sodium sulfate, filtered, the filtrate was concentrated and purified by chromatography using a mixed solvent of dichloromethane and methanol at a volume ratio of 10:1 to obtain the compound adavosibb of formula I, the amount of solid was 42.4g, the yield was 84.7%, and the HPLC purity was 99.2%.

Example 16 Synthesis of Adavosertib, a Compound of formula I

A compound represented by the formula 7 (32.6g,0.1mol) and K were reacted at room temperature₂CO₃(18.0g,0.13mol) is added into DMF (200mL) which is stirred, then the compound shown in the formula 8 (25.3g,0.12mol) is added, the mixture is heated to 55 ℃ and stirred for reaction for 1.5h, after the reaction is finished, the reaction liquid is cooled to room temperature and poured into water (40mL), the mixture is extracted by ethyl acetate (3X 40mL), the organic phases are combined and washed by saturated saline (30mL), dried by sodium sulfate, filtered, the filtrate is concentrated and purified by silica gel column chromatography by using a mixed solvent of dichloromethane and methanol with the volume ratio of 30:1 to obtain the compound Adavosertib shown in the formula I, the solid content is 43.2g, the yield is 86.3%, and the HPLC purity is 99.3%.

Example 17 Synthesis of Adavosertib, a Compound of formula I

Example 17 is a comparative example in which the inventors have adjusted the compound shown as formula 7, K₂CO₃The molar ratio of the compound shown in the formula 8 is 1:1.5:1.5, and the technical effect is that the yield of the obtained product is lower than that of the compound shown in the formula 7 and K₂CO₃And (3) the yield of the compound represented by the formula 8 is 1 (1.0-1.3) to (1.0-1.2), and the purity of the final product of the obtained Adavosertib compound is reduced and the amount of impurities is increased.

A compound represented by the formula 7 (32.6g,0.1mol) and K were reacted at room temperature₂CO₃(20.7g,0.15mol) is added into DMF (250mL) which is stirred, then the compound shown in formula 8 (31.6g,0.15mol) is added, the mixture is heated to 60 ℃ and stirred for reaction for 1.5h, after the reaction is finished, the reaction liquid is cooled to room temperature and poured into water (40mL), the mixture is extracted by ethyl acetate (3X 40mL), the organic phases are combined and washed by saturated saline (30mL), dried by sodium sulfate, filtered, the filtrate is concentrated and purified by silica gel column chromatography by using a mixed solvent of dichloromethane and methanol with the volume ratio of 30:1 to obtain the compound Adavosertib shown in formula I, the solid content is 40.4g, the yield is 80.8%, and the HPLC purity is 97.2%.

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. Moreover, various embodiments or examples and features of various 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.