CN114736205A - Preparation method of compound Tomivosertib - Google Patents
Preparation method of compound Tomivosertib Download PDFInfo
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- CN114736205A CN114736205A CN202210346083.4A CN202210346083A CN114736205A CN 114736205 A CN114736205 A CN 114736205A CN 202210346083 A CN202210346083 A CN 202210346083A CN 114736205 A CN114736205 A CN 114736205A
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- C07—ORGANIC CHEMISTRY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to a preparation method of a kinase inhibitor compound Tomivosertib. Compared with the prior art, the preparation method has the advantages that the cyclohexanone is creatively added in the step (2), and then intramolecular dehydration condensation cyclization is carried out to obtain the target product, and compared with the problem of low selectivity when halogenated reaction is adopted to generate the product in other documents, the method not only simplifies the reaction steps, but also improves the reaction yield and is beneficial to reaction and purification. The preparation method of the compound Tomivosertib adopts commercial raw materials, is prepared by 5 steps of reaction, has higher overall yield of the route, mild reaction conditions, simple operation and simple purification process, and is suitable for the requirement of industrial mass production of the raw material medicines.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a preparation method of a kinase inhibitor compound Tomivosertib.
Background
The eFFECTATOR treatment company is developing Tomivosertib (EFT-508), a potent MNK1 and MNK2 kinase selective inhibitor, for oral treatment of cancer. At present, the clinical trial indications cover: diffuse large B-cell lymphoma, head and neck tumors, hepatocellular carcinoma, hormone refractory prostate cancer, lymphoma, metastatic breast cancer, metastatic colorectal cancer, non-small cell lung cancer, transitional cell carcinoma, solid tumors, all of which are currently in phase 2 clinical research, with the exception of metastatic breast cancer in phase 2 clinical research in canada, the remaining indications in phase 2 clinical research in the united states.
The chemical structure of Tomivosertib is specifically shown as formula I:
however, the current new preparation method of the compound Tomivosertib 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, an object of the present invention is to provide a novel method for preparing Tomivosertib. Compared with the prior art, the preparation method provided by the invention adopts commercially available raw materials, is prepared by 5 steps of reaction, has the advantages of higher overall yield of the route, mild reaction conditions, simplicity in operation and simple purification process, and is suitable for the requirement of industrial mass production of the raw material medicines. In the step (1), the carboxylic acid protecting group is removed by ammonia water, and then the amidation reaction is carried out simultaneously, so that the reaction steps are reduced, the yield is high, and the reaction time can be effectively shortened and the reaction efficiency is improved by adopting a sealed tube as a reaction container. Compared with the problem of low selectivity when products are generated by adopting a halogenation reaction in other documents, the method not only simplifies the reaction steps, but also can improve the reaction yield and is beneficial to reaction and purification. And (4) a catalyst and a ligand are added to carry out a specific halogenation reaction, so that the selectivity of the reaction is effectively improved, and side reactions are reduced.
In one aspect of the present invention, the present invention provides a process for the preparation of the compound Tomivosertib of formula I. According to an embodiment of the invention, the method comprises:
(1) contacting the compound represented by formula 1 with ammonia water to obtain a compound represented by formula 2;
(2) contacting the compound represented by formula 2 with cyclohexanone (the compound represented by formula 3) to obtain a compound represented by formula 4;
(3) contacting the compound represented by the formula 4 with Pd/C to obtain a compound represented by the formula 5;
(4) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(5) contacting the compound of formula 7 with Pd/C to obtain the compound of formula I,
the synthetic route of the invention adopts commercial raw materials (wherein the cas number of the compound shown in the formula 1 is 1509897-31-7, the cas number of the compound shown in the formula 3 is 108-94-1, and the cas number of the compound shown in the formula 6 is 126827-19-8), and the compound Tomivosertib shown in the formula I is prepared through 5 steps of reaction. The inventor finds that the preparation method has the advantages of high overall yield of the route, mild reaction conditions, simple operation and simple purification process, and is suitable for the requirement of industrial mass production of the bulk drugs.
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 an embodiment of the present invention, the above method for preparing the compound represented by formula 2, the compound represented by formula 4, 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 materials for preparing the compound represented by formula 2, the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, and the compound represented by formula I is not particularly limited, and it may be prepared by any known method or commercially available.
According to an embodiment of the present invention, in the step (1), the manner of contacting the compound represented by formula 1 with aqueous ammonia is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 and ammonia water can be improved, the reaction speed is increased, 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: adding a compound shown as a formula 1 into methanol at room temperature, adding ammonia water into a sealed tube, stirring the mixture, heating the mixture at 60-68 ℃ for 2-45-3-30 min for reaction, wherein TLC shows that the raw materials are completely consumed, cooling the reaction liquid to room temperature, extracting the mixed liquid for three times by using ethyl acetate, combining organic phases, washing by using brine, concentrating, and using the volume ratio of a concentrate to be (8-12): purifying the product by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 2. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 and ammonia water 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 the embodiment of the invention, in the step (1), the mass volume ratio of the compound shown in the formula 1 to the ammonia water is 1 (30-40) (g/v), and the mass volume ratio of the compound shown in the formula 1 to the ammonia water is preferably 1: 36. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (1), it is preferable that the reaction temperature of the compound represented by formula 1 and aqueous ammonia is 65 ℃ and the reaction time is 3 hours. 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 (1), it is preferable that the solvent for silica gel column chromatography is a solvent having a volume ratio of 10:1, a mixed solvent of petroleum ether and ethyl acetate.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: adding the compound shown in the formula 1 (5.0g,0.0221mol) into methanol (15mL) at room temperature, adding ammonia water (180mL) into a 500mL sealed tube, stirring the mixture, heating at 65 ℃ for reaction for 3 hours, completely consuming raw materials by TLC, cooling the reaction liquid to room temperature, extracting the mixed liquid with ethyl acetate (3X 90mL) for three times, combining organic phases, washing with brine (90mL), concentrating, and concentrating the concentrate by using a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 2 in an amount of 4.0g with a yield of 91.8%.
According to an embodiment of the present invention, in the step (2), the contact manner of the compound represented by formula 2 with the compound represented by formula 3, and the dioxane hydrochloride solution is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and the dioxane hydrochloride solution 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 a 4M dioxane hydrochloride solution into anhydrous dioxane solutions of a compound shown as a formula 2 and a compound shown as a formula 3 at room temperature in a sealed tube, heating to 100 ℃, reacting for 10 hours in the sealed tube, wherein TLC shows that raw materials are completely consumed, and after the reaction solution is subjected to reduced pressure concentration, concentrating a concentrate according to a volume ratio of (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 4. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and the dioxane hydrochloride solution 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 4M dioxane hydrochloride solution is prepared by: weighing a certain amount of dioxane, introducing dry HCl gas, weighing to a calculated amount, and stopping introducing gas to obtain the dioxane.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound represented by the formula 2 to the compound represented by the formula 3 is 1 (1.0-1.2), and preferably the molar ratio of the compound represented by the formula 2 to the compound represented by the formula 3 is 1: 1.0. 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 mass-to-volume ratio of the compound represented by formula 2 to the anhydrous dioxane solution and the dioxane hydrochloride solution is 1:10: 10. 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), it is preferable that the solvent for silica gel column chromatography is a solvent having a volume ratio of 10:1, a mixed solvent of petroleum ether and ethyl acetate.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: to an anhydrous dioxane solution (200mL) of a compound represented by formula 2 (19.7g,0.1mol) and a compound represented by formula 3 (9.8g,0.1mol) was added a dioxane solution (200mL) of 4M hydrochloric acid at room temperature in a sealed tube, and then heated to 100 ℃ to react in the sealed tube for 10 hours, TLC showed complete consumption of the starting material, and after the reaction solution was concentrated under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 4 in an amount of 23.7g with a yield of 85.5%.
According to an embodiment of the present invention, the contacting manner of the compound represented by formula 4 with Pd/C in step (3) is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 and Pd/C can be improved, 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 the step (3), the following steps are included: adding Pd/C into a methanol solution containing the compound shown in the formula 4 under the protection of nitrogen, replacing for 2-5 times by using hydrogen under vacuum, keeping the reaction liquid at 2.0-3.0 atmospheric pressure, keeping the temperature of 20-25 ℃, stirring for reaction, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to be dry to obtain a crude solid of the compound shown in the formula 5. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 and Pd/C can be improved, 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 the step (3), the Pd/C is 5% to 20% Pd/C, preferably the Pd/C is 5% Pd/C, 10% Pd/C, or 20% Pd/C. 5% to 20% Pd/C is used as a catalyst for the catalytic hydrogenation, for example, 5% Pd/C means that the content of metallic Pd in the Pd/C mixture is 5%, and 10% Pd/C means that the content of metallic Pd in the Pd/C mixture is 10%.
According to an embodiment of the present invention, in step (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 10% Pd/C is 1: 0.1. 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 (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 5% Pd/C is 1: 0.2. 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 the step (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 20% Pd/C is 1: 0.05. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: adding 10% Pd/C (380mg) into a methanol (150ml) solution containing a compound (3.8g,0.0137mol) shown in formula 4 under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, keeping the reaction solution at 2.5 atmospheric pressure, keeping the temperature of between 20 and 25 ℃ and stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in formula 5, wherein the crude solid is 3.25g, the yield is 95.9%, and the crude product can be directly used for the next reaction.
According to an embodiment of the present invention, in the step (4), the compound represented by the formula 5 is reacted with the compound represented by the formula 6 and Pd (OAc)2、Xantphos、Cs2CO3The contact manner of (3) is not particularly limited. Thus, the compounds represented by the formula 5, the compounds represented by the formula 6, and Pd (OAc) can be increased2、Xantphos、Cs2CO3The efficiency of the contact reaction is improved, the reaction speed is accelerated, 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 (4), the following steps are included: adding the compound shown as the formula 5 and the compound shown as the formula 6 into 1, 4-dioxane at room temperature, stirring uniformly, and adding Pd (OAc)2Xantphos and Cs2CO3Heating the reaction solution under the protection of nitrogen, keeping the temperature at 96-100 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of a concentrate is (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 7. Thus, the compounds represented by the formula 5, the compounds represented by the formula 6, and Pd (OAc) can be increased2、Xantphos、Cs2CO3The efficiency of the contact reaction is improved, the reaction speed is accelerated, 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 (4), the compound represented by the formula 5 is reacted with the compound represented by the formula 6 and Pd (OAc)2、Xantphos、Cs2CO3The molar ratio of the reaction is 1 (1.0-1.2): (0.12-0.2): 2.5-5, preferably 5 or 6, and Pd (OAc)2、Xantphos、Cs2CO3The molar ratio of the reaction was 1:1.05:0.15:0.15: 3.6. 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 (4), it is preferable that the solvent for silica gel column chromatography is 10:1, a mixed solvent of petroleum ether and ethyl acetate.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: the compound represented by the formula 5 (24.7g,0.1mol) and the compound represented by the formula 6 (16.7g,0.105mol) were added to 1, 4-dioxygen at room temperatureTo hexacyclic ring (500mL), stir well, add Pd (OAc)2(3.4g,0.015mol), Xantphos (14.4g,0.015mol) and Cs2CO3(117.3g,0.36mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, concentrating under reduced pressure, and concentrating the concentrate by using a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 7 in an amount of 34.6g with a yield of 93.4%.
According to an embodiment of the present invention, in step (5), the manner of contacting the compound represented by formula 7 with Pd/C is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 7 and Pd/C 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 (5), the following steps are included: adding Pd/C into a methanol solution containing the compound shown in the formula 7 under the protection of nitrogen, replacing for 2-5 times by using hydrogen under vacuum, keeping the reaction solution at 2.0-3.0 atmospheric pressure, keeping the temperature of 20-25 ℃, stirring for reaction, filtering the reaction solution to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude product solid of the compound shown in the formula I, and recrystallizing the crude product to obtain a refined product solid of the compound shown in the formula I. Therefore, the efficiency of the contact reaction of the compound shown in the formula 7 and Pd/C 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 (5), the Pd/C is 5% -20% Pd/C, preferably the Pd/C is 5% Pd/C, 10% Pd/C, or 20% Pd/C. In the present invention, 5% to 20% Pd/C is used as a catalyst for catalytic hydrogenation, for example, 5% Pd/C means that the content of metallic Pd in the Pd/C mixture is 5%, and 10% Pd/C means that the content of metallic Pd in the Pd/C mixture is 10%.
According to an embodiment of the present invention, in step (5), it is preferable that the mass ratio of the compound represented by formula 7 to be reacted with the 10% Pd/C is 1: 0.1. 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 (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 5% Pd/C is 1: 0.2. 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 (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 20% Pd/C is 1: 0.05. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: adding 10% Pd/C (300mg) into a methanol (30mL) solution containing a compound shown as a formula 7 (3.0g,0.0081mol) under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, keeping the reaction solution at 2.5 atmospheric pressure, keeping the temperature to 25 ℃, stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown as the formula I, and recrystallizing the crude product (the solvent for recrystallization is petroleum ether/ethyl acetate 5/1, the crude product is about 2.8g, and the using amount ratio of the solvent is 1g/10mL (28 mL used for crystallization solvent)) to obtain a refined solid of the compound shown as the formula I, wherein the refined solid of the compound shown as the formula I is obtained, and the yield is 2.50g, the yield is 90.7%, and the purity is 99.8% by HPLC.
According to embodiments of the present invention, the synthetic route for the compounds of formula I may be as follows:
compared with the prior art, the preparation method disclosed by the invention at least has the following beneficial effects: according to the method, the compound Tomivosertib shown in the formula I is prepared by using commercially available raw materials through 5 reaction steps. In the step 1, the amidation reaction is carried out simultaneously after the carboxylic acid protecting group is removed by using ammonia water, so that the reaction steps are reduced, and the yield is high. The reaction vessel is a sealed tube, so that the reaction time can be effectively shortened, and the reaction efficiency can be improved. Compared with the problem of low selectivity when halogenated reaction is adopted to generate products in other documents, the method not only simplifies the reaction steps, but also can improve the reaction yield and is beneficial to reaction and purification. Step 3 is a nitro reduction reaction. And 4, a catalyst and a ligand are added to carry out a specific halogenation reaction, so that the selectivity of the reaction is effectively improved, and side reactions are reduced. Step 3 is a nitro reduction reaction without purification. According to the preparation method, 2 steps (step 3 and step 5) in the 5-step reaction belong to a nitro reduction reaction, the nitro compound is selected as a raw material, so that the sites in the reaction can be reduced, the cyclization and halogenation reactions can be selectively carried out, and the reaction yield of each step can be effectively improved; the method has the advantages of high overall yield of the route, mild reaction conditions, simple operation and simple purification process, and is suitable for the requirement of industrial mass production of the raw material medicines.
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 conventional products which are commercially available, and are not indicated by manufacturers.
EXAMPLE 1 Synthesis of Compound represented by formula 2
Adding the compound shown in the formula 1 (5.0g,0.0221mol) into methanol (15mL) at room temperature, adding ammonia water (180mL) into a 500mL sealed tube, stirring the mixture, heating at 65 ℃ for reaction for 3 hours, completely consuming raw materials by TLC, cooling the reaction liquid to room temperature, extracting the mixed liquid with ethyl acetate (3X 90mL) for three times, combining organic phases, washing with brine (90mL), concentrating, and concentrating the concentrate by using a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 2 in an amount of 4.0g with a yield of 91.8%.
LC-MS(APCI):m/z＝198.2(M+1)+。
Example 2 Synthesis of Compound represented by formula 2
Adding the compound shown in the formula 1 (5.0g,0.0221mol) into methanol (15mL) at room temperature, adding ammonia water (150mL) into a 500mL sealed tube, stirring the mixture, heating at 60 ℃ for reaction for 3 hours and 30 minutes, wherein TLC shows that the raw materials are completely consumed, cooling the reaction liquid to room temperature, extracting the mixed liquid with ethyl acetate (3X 90mL) for three times, combining organic phases, washing with brine (90mL), concentrating, and using the volume ratio of the concentrate to be 8: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 2 in an amount of 3.8g with a yield of 87.2%.
EXAMPLE 3 Synthesis of Compound represented by formula 2
Adding the compound shown in the formula 1 (5.0g,0.0221mol) into methanol (15mL) at room temperature, adding ammonia water (200mL) into a 500mL sealed tube, stirring the mixture, heating at 68 ℃ for reacting for 2 hours and 45 minutes, wherein TLC shows that the raw materials are completely consumed, cooling the reaction liquid to room temperature, extracting the mixed liquid with ethyl acetate (3X 90mL) for three times, combining organic phases, washing with brine (90mL), concentrating, and using the volume ratio of the concentrate to 12: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 2 in an amount of 3.9g with a yield of 89.5%.
Example 4 Synthesis of Compound represented by formula 4
To an anhydrous dioxane solution (200mL) of a compound represented by formula 2 (19.7g,0.1mol) and a compound represented by formula 3 (9.8g,0.1mol) was added a dioxane solution (200mL) of 4M hydrochloric acid at room temperature in a sealed tube, and then heated to 100 ℃ to react in the sealed tube for 10 hours, TLC showed complete consumption of the starting material, and after the reaction solution was concentrated under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 4 in an amount of 23.7g with a yield of 85.5%.
LC-MS(APCI):m/z＝278.3(M+1)+。
EXAMPLE 5 Synthesis of Compound represented by formula 4
To an anhydrous dioxane solution (200mL) of a compound represented by formula 2 (19.7g,0.1mol) and a compound represented by formula 3 (10.3g,0.105mol) was added a dioxane solution (200mL) of 4M hydrochloric acid, and the mixture was heated to 100 ℃ at room temperature in a sealed tube, followed by reaction for 10 hours in the sealed tube, TLC showed complete consumption of the starting material, and after the reaction solution was concentrated under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 4 in an amount of 23.6g with a yield of 85.1%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
To an anhydrous dioxane solution (200mL) of the compound of formula 2 (19.7g,0.1mol) and the compound of formula 3 (11.8g,0.12mol) was added a 4M dioxane hydrochloride solution (200mL) at room temperature in a sealed tube, and then heated to 100 ℃ to react in the sealed tube for 10 hours, TLC showed complete consumption of the starting material, and after the reaction solution was concentrated under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 4 in an amount of 22.7g with a yield of 81.9%.
Example 7 Synthesis of Compound represented by formula 5
Adding 10% Pd/C (380mg) into a methanol (150ml) solution containing a compound (3.8g,0.0137mol) shown in formula 4 under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, keeping the reaction solution at 2.5 atmospheric pressure, keeping the temperature of between 20 and 25 ℃ and stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in formula 5, wherein the crude solid is 3.25g, the yield is 95.9%, and the crude product can be directly used for the next reaction.
LC-MS(APCI):m/z＝248.3(M+1)+。
EXAMPLE 8 Synthesis of Compound represented by formula 5
Adding 5% Pd/C (760mg) into a methanol (150ml) solution containing a compound (3.8g,0.0137mol) shown in formula 4 under the protection of nitrogen, replacing the solution with hydrogen for 2 times under vacuum, keeping the reaction solution at 2.0 atmospheric pressure, keeping the temperature of between 20 and 25 ℃ and stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in formula 5, wherein the crude solid is 3.21g, the yield is 94.8%, and the crude product can be directly used for the next reaction.
Example 9 Synthesis of Compound represented by formula 5
Adding 20% Pd/C (190mg) into a methanol (150ml) solution containing a compound (3.8g,0.0137mol) shown in formula 4 under the protection of nitrogen, replacing the solution with hydrogen for 5 times under vacuum, keeping the reaction solution at 3.0 atmospheric pressure, keeping the temperature of between 20 and 25 ℃ and stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in formula 5, wherein the crude solid is 3.22g, the yield is 95.1%, and the crude product can be directly used for the next reaction.
EXAMPLE 10 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (24.7g,0.1mol) and the compound represented by the formula 6 (16.7g,0.105mol) were added to 1, 4-dioxane (500mL) at room temperature, stirred well, and Pd (OAc) was added2(3.4g,0.015mol), Xantphos (14.4g,0.015mol) and Cs2CO3(117.3g,0.36mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, concentrating under reduced pressure, and concentrating the concentrate by using a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 7 in an amount of 34.6g with a yield of 93.4%.
LC-MS(APCI):m/z＝371.3(M+1)+。
EXAMPLE 11 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (24.7g,0.1mol) and the compound represented by the formula 6 (15.9g,0.10mol) were added to 1, 4-dioxane (500mL) at room temperature, stirred well, and Pd (OAc) was added2(2.7g,0.012mol), Xantphos (11.5g,0.012mol) and Cs2CO3(81.5g,0.25mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 96 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, concentrating under reduced pressure, and concentrating the concentrate by using a volume ratio of 8: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 7 in an amount of 34.1g with a yield of 92.1%.
EXAMPLE 12 Synthesis of Compound represented by formula 7
The compound represented by the formula 5 (24.7g,0.1mol) and the compound represented by the formula 6 (19.1g,0.12mol) were added to 1, 4-dioxane (650mL) at room temperature, stirred well, and added with Pd (OAc)2(4.5g,0.02mol), Xantphos (19.2g,0.02mol) and Cs2CO3(163.0g,0.5mol), the reaction solution was purged with nitrogen,heating and keeping the temperature at 98 ℃ for reacting for 4h, filtering the reaction liquid after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of a concentrate is 12: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 7 in an amount of 33.6g with a yield of 90.7%.
EXAMPLE 13 Synthesis of Compound of formula I
Adding 10% Pd/C (300mg) into a methanol (30mL) solution containing a compound shown as a formula 7 (3.0g,0.0081mol) under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, keeping the reaction solution at 2.5 atmospheric pressure, keeping the temperature to 25 ℃, stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown as the formula I, and recrystallizing the crude product (the solvent for recrystallization is petroleum ether/ethyl acetate (5/1 (v/v), about 2.8g of the crude product, and the using amount of the solvent is 1g/10mL (28 mL of the used crystallization solvent)) to obtain a refined solid of the compound shown as the formula I, wherein the yield is 2.53g, 91.8% and the HPLC purity is 99.8%.
LC-MS(APCI):m/z＝341.2(M+1)+。
EXAMPLE 14 Synthesis of Compound of formula I
Adding 20% Pd/C (150mg) into a methanol (30ml) solution containing a compound (3.0g,0.0081mol) shown in formula 7 under the protection of nitrogen, replacing the solution with hydrogen for 5 times under vacuum, keeping the reaction solution at 3.0 atmospheric pressure, keeping the temperature of between 20 and 25 ℃ and stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in formula I, and recrystallizing the crude product (the recrystallization method is the same as in example 13) to obtain a refined solid of the compound shown in formula I, wherein the yield is 2.50g, the yield is 90.7 percent, and the HPLC purity is 99.5 percent.
EXAMPLE 15 Synthesis of Compound of formula I
Adding 5% Pd/C (600mg) into a methanol (30ml) solution containing a compound (3.0g,0.0081mol) shown in formula 7 under the protection of nitrogen, replacing the solution with hydrogen for 2 times under vacuum, keeping the reaction solution at 2.0 atmospheric pressure, keeping the temperature of between 20 and 25 ℃, stirring and reacting, filtering the reaction solution to remove the Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude solid of the compound shown in formula I, and recrystallizing the crude product (the recrystallization method is the same as in example 13) to obtain a refined solid of the compound shown in formula I, wherein the yield is 2.44g, the yield is 88.7 percent, and the HPLC purity is 99.4 percent.
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 preparing a compound of formula I, Tomivosertib, comprising:
(1) contacting the compound represented by formula 1 with ammonia water to obtain a compound represented by formula 2;
(2) contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(3) contacting the compound represented by the formula 4 with Pd/C to obtain a compound represented by the formula 5;
(4) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(5) contacting the compound of formula 7 with Pd/C to obtain the compound of formula I,
2. the method according to claim 1, wherein in step (1), the following steps are included: adding a compound shown as a formula 1 into methanol at room temperature, adding ammonia water into a sealed tube, stirring the mixture, heating the mixture at 60-68 ℃ for 2-45-3-30 min for reaction, wherein TLC shows that the raw materials are completely consumed, cooling the reaction liquid to room temperature, extracting the mixed liquid for three times by using ethyl acetate, combining organic phases, washing by using brine, concentrating, and using the volume ratio of a concentrate to be (8-12): purifying the product by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 2.
3. The method according to claim 2, wherein in the step (1), the mass-to-volume ratio of the compound shown in the formula 1 to the ammonia water is 1 (30-40) (g/v), preferably the mass-to-volume ratio of the compound shown in the formula 1 to the ammonia water is 1: 36;
optionally, in the step (1), it is preferable that the temperature for the reaction of the compound represented by formula 1 and aqueous ammonia is 65 ℃ and the reaction time is 3 hours;
optionally, in step (1), the solvent for silica gel column chromatography is preferably 10:1, a mixed solvent of petroleum ether and ethyl acetate.
4. The method of claim 1, wherein in step (2), the following steps are included: adding a 4M dioxane hydrochloride solution into anhydrous dioxane solutions of a compound shown as a formula 2 and a compound shown as a formula 3 at room temperature in a sealed tube, heating to 100 ℃, reacting for 10 hours in the sealed tube, wherein TLC shows that raw materials are completely consumed, and after the reaction solution is subjected to reduced pressure concentration, concentrating a concentrate according to a volume ratio of (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 4.
5. The method according to claim 4, wherein in the step (2), the molar ratio of the compound represented by the formula 2 to the compound represented by the formula 3 is 1 (1.0-1.2), preferably the molar ratio of the compound represented by the formula 2 to the compound represented by the formula 3 is 1: 1.0;
optionally, in the step (2), the mass-to-volume ratio of the compound shown in the formula 2 to the anhydrous dioxane solution and the dioxane hydrochloride solution is 1:10: 10;
optionally, in step (2), the solvent for silica gel column chromatography is preferably 10:1, a mixed solvent of petroleum ether and ethyl acetate.
6. The method of claim 1, wherein in step (3), the following steps are included: adding Pd/C into a methanol solution containing the compound shown in the formula 4 under the protection of nitrogen, replacing for 2-5 times by using hydrogen under vacuum, keeping the reaction liquid at 2.0-3.0 atmospheric pressure, keeping the temperature of 20-25 ℃, stirring and reacting, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to be dry to obtain a crude solid of the compound shown in the formula 5;
optionally, in step (3), the Pd/C is 5% -20% Pd/C, preferably the Pd/C is 5% Pd/C, 10% Pd/C, or 20% Pd/C;
optionally, in the step (3), it is preferable that the mass ratio of the compound represented by the formula 4 to the 10% Pd/C is 1:0.1
Optionally, in the step (3), it is preferable that the mass ratio of the compound represented by the formula 4 to the 5% Pd/C is 1: 0.2;
optionally, in the step (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 20% Pd/C is 1: 0.05.
7. The method according to claim 1, wherein in step (4), the following steps are included: adding the compound shown as the formula 5 and the compound shown as the formula 6 into 1, 4-dioxane at room temperature, stirring uniformly, and adding Pd (OAc)2Xantphos and Cs2CO3Heating the reaction solution under the protection of nitrogen and keeping the temperature at 96-100 ℃ for 4 hours, and after the reaction is finished, reactingFiltering the solution, concentrating under reduced pressure, and concentrating the concentrate according to the volume ratio of (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 7.
8. The method according to claim 7, wherein in the step (4), the compound represented by the formula 5 is reacted with the compound represented by the formula 6 and Pd (OAc)2、Xantphos、Cs2CO3The molar ratio of the reaction is 1 (1.0-1.2): (0.12-0.2): 2.5-5, preferably 5 or 6, and Pd (OAc)2、Xantphos、Cs2CO3The molar ratio of the reaction is 1:1.05:0.15:0.15: 3.6;
optionally, in step (4), the solvent for silica gel column chromatography is preferably 10:1, a mixed solvent of petroleum ether and ethyl acetate.
9. The method of claim 1, wherein the step (5) comprises the steps of: adding Pd/C into a methanol solution containing the compound shown in the formula 7 under the protection of nitrogen, replacing for 2-5 times by using hydrogen under vacuum, keeping the reaction liquid at 2.0-3.0 atmospheric pressure, keeping the temperature of 20-25 ℃, stirring for reaction, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude product solid of the compound shown in the formula I, and recrystallizing the crude product to obtain a refined product solid of the compound shown in the formula I;
optionally, in step (5), the Pd/C is 5% -20% Pd/C, preferably the Pd/C is 5% Pd/C, 10% Pd/C, or 20% Pd/C;
optionally, in the step (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 10% Pd/C is 1: 0.1;
optionally, in the step (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 5% Pd/C is 1: 0.2;
optionally, in the step (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 20% Pd/C is 1: 0.05.
10. The method according to claim 1, wherein in step (1), the following steps are included: adding the compound shown in the formula 1 (5.0g,0.0221mol) into methanol (15mL) at room temperature, adding ammonia water (180mL) into a 500mL sealed tube, stirring the mixture, heating at 65 ℃ for reaction for 3 hours, completely consuming raw materials by TLC, cooling the reaction liquid to room temperature, extracting the mixed liquid with ethyl acetate (3X 90mL) for three times, combining organic phases, washing with brine (90mL), concentrating, and concentrating the concentrate by using a volume ratio of 10: purifying the product of the petroleum ether/ethyl acetate mixed solvent of 1 on silica gel column chromatography to obtain a compound shown as a formula 2, wherein the yield is 4.0g and 91.8%;
in the step (2), the method comprises the following steps: to an anhydrous dioxane solution (200mL) of a compound represented by formula 2 (19.7g,0.1mol) and a compound represented by formula 3 (9.8g,0.1mol) was added a dioxane solution (200mL) of 4M hydrochloric acid at room temperature in a sealed tube, and then heated to 100 ℃ to react in the sealed tube for 10 hours, TLC showed complete consumption of the starting material, and after the reaction solution was concentrated under reduced pressure, the concentrate was concentrated with a volume ratio of 10: purifying the product by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 4, wherein the yield is 23.7g and 85.5%;
in the step (3), the method comprises the following steps: adding 10% Pd/C (380mg) into a methanol (150ml) solution containing a compound (3.8g,0.0137mol) shown in a formula 4 under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, keeping the reaction solution at 2.5 atmospheric pressure, keeping the temperature of between 20 and 25 ℃, stirring and reacting, filtering the reaction solution to remove the Pd/C after TLC shows that raw materials are completely consumed, concentrating the filtrate to be dry to obtain 3.25g of a crude solid of the compound shown in the formula 5, wherein the yield is 95.9%, and the crude product can be directly used for the next reaction;
in the step (4), the method comprises the following steps: the compound represented by the formula 5 (24.7g,0.1mol) and the compound represented by the formula 6 (16.7g,0.105mol) were added to 1, 4-dioxane (500mL) at room temperature, stirred well, and Pd (OAc) was added2(3.4g,0.015mol), Xantphos (14.4g,0.015mol) and Cs2CO3(117.3g,0.36mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, concentrating under reduced pressure, and concentrating the concentrate by using a volume ratio of 10:1 stonePurifying the product by column chromatography on silica gel with the mixed solvent of the oil ether and the ethyl acetate to obtain a compound shown in the formula 7, wherein the yield is 34.6g and 93.4%;
in the step (5), the method comprises the following steps: adding 10% Pd/C (300mg) into a methanol (30mL) solution containing a compound (3.0g,0.0081mol) shown in formula 7 under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, maintaining the reaction solution at 2.5 atmospheric pressures, keeping the temperature between 20 and 25 ℃, stirring for reaction, filtering the reaction solution to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude solid of the compound shown in formula I, and recrystallizing the crude product (the solvent for recrystallization is petroleum ether/ethyl acetate 5/1, about 2.8g of the crude product, and the dosage ratio of the solvent is 1g/10mL (28 mL of the used crystallization solvent)) to obtain a refined solid of the compound shown in formula I, wherein the yield is 2.50g, the yield is 90.7%, and the purity HPLC is 99.8%.
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| WO2015200481A1 (en) * | 2014-06-25 | 2015-12-30 | Effector Therapeutics, Inc. | Mnk inhibitors and methods related thereto |
| US20180228803A1 (en) * | 2017-02-14 | 2018-08-16 | Effector Therapeutics, Inc. | Piperidine-Substituted Mnk Inhibitors and Methods Related Thereto |
| WO2020086713A1 (en) * | 2018-10-24 | 2020-04-30 | Effector Therapeutics, Inc. | Crystalline forms of mnk inhibitors |
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Denomination of invention: Preparation method of compound Tomivosertib Effective date of registration: 20230704 Granted publication date: 20230303 Pledgee: Agricultural Bank of China Co.,Ltd. Wuhan Branch Business Department Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2023420000290 |