CN112778303A - Preparation method of CDK4/6 kinase inhibitor SHR6390 - Google Patents
Preparation method of CDK4/6 kinase inhibitor SHR6390 Download PDFInfo
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- CN112778303A CN112778303A CN202011643688.7A CN202011643688A CN112778303A CN 112778303 A CN112778303 A CN 112778303A CN 202011643688 A CN202011643688 A CN 202011643688A CN 112778303 A CN112778303 A CN 112778303A
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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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Abstract
The invention relates to a preparation method of a CDK4/6 kinase inhibitor SHR 6390. The invention can rapidly and effectively prepare and obtain the SHR6390 through 6 steps of chemical reaction. The first step of the reaction of the invention fully utilizes the advantage of high 4-position reaction activity of pyrimidine, the target product compound 3 can be well obtained under mild conditions, the post-treatment of the synthesis reaction of the compound 8 obtained by the fourth step of the reaction is simple, a good white solid product can be obtained basically by filtration and washing, and the method does not need purification and is suitable for amplification and process production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of a CDK4/6 kinase inhibitor SHR 6390.
Background
SHR6390 is a high-efficiency and selective small molecule CDK4/6 kinase inhibitor developed by constant medicines, so that a complex consisting of CDK4/6 and Cyclin D cannot phosphorylate downstream Rb protein, and prevents cells from entering S phase from G1 phase, thereby playing the roles of inhibiting cell proliferation and resisting tumors and being used for treating malignant tumors. The drug is currently in phase 3 clinical research, and the clinical trial has the following indications: female patients with HR positive, HER2 negative locally advanced or advanced metastatic breast cancer.
SHR6390 has a structural formula shown in formula I:
the preparation method of SHR6390 still needs to be improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide a method for synthesizing and preparing the Rispertinib, which has the advantages of mild reaction conditions, simple process operation, high yield and easy industrial production.
In one aspect of the invention, the invention provides a preparation method of a compound SHR6390 shown as the formula I. According to an embodiment of the invention, the method 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 the compound represented by formula 5 with N-bromosuccinimide (NBS) to obtain a compound represented by formula 6;
(4) contacting a compound represented by formula 6 with LHMDS, and a compound represented by formula 7, to obtain a compound represented by formula 8;
(5) contacting a compound represented by formula 8 with a compound represented by formula 9 to obtain a compound represented by formula 10;
(6) contacting a compound of formula 10 with a hydrochloric acid solution to obtain a compound of formula I,
the inventors found that the compound SHR6390 shown in the formula I can be effectively prepared by using the synthetic preparation method disclosed by the invention.
The term "contacting" as used herein is to be understood broadly and can be any means that enables a chemical reaction of at least two reactants, such as mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and may be, for example, mechanical stirring, that is, stirring under the action of a mechanical force.
Herein, a "compound of formula N" is also sometimes referred to herein as "compound N", where N is any integer from 1 to 10, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to 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 6, the compound represented by formula 8, the compound represented by formula 10, and the compound represented by formula I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the raw materials for preparing the compound represented by formula 3, the compound represented by formula 5, the compound represented by formula 6, the compound represented by formula 8, the compound represented by formula 10, 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 step (1), the contacting manner of the compound represented by formula 1 and the compound represented by formula 2 is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 1 and the compound shown in the formula 2 can be improved, the reaction speed 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: dissolving the compound 1 into dioxane, adding the compound 2, stirring at room temperature for reaction, adding the reaction liquid into water after TLC detection reaction is completed, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound 3, wherein the obtained crude product is directly put into the next step without purification. Thus, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to the embodiment of the invention, in the step (1), the compound shown in the formula 1 is contacted with the compound shown in the formula 2 at room temperature, and the reaction is carried out for 5-8 hours under stirring; the compound represented by formula 1 is preferably contacted with the compound represented by formula 2 at room temperature, and the reaction is stirred for 6 hours.
According to the embodiment of the invention, in the step (1), the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is 1 (1.0-1.5).
According to the 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 preferably 1:1.2, so that the utilization rate of the reactants is high, the raw materials and the actual waste are not caused, and the yield of the target compound is high.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: dissolving the compound 1(1g,4.39mmol) into dioxane (20mL), adding the compound 2(448.41mg,5.27mmol), stirring the mixture at room temperature for reacting for 6h, after the TLC detection reaction is completed, adding the reaction liquid into water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound 3, wherein the obtained crude product is directly put into the next step without purification, and the calculated yield of the crude product is 100%. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (2), the contacting manner of the compound represented by formula 3 with the compound represented by formula 4 is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 3 with the compound shown in the formula 4 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 (2), the following steps are included: adding a compound 3 into N-methylpyrrolidone, adding a compound 4 and triethylamine into a stirring reaction system, adding palladium chloride under the protection of nitrogen, quickly heating the whole reaction system to 70-80 ℃ under the environment of nitrogen, stirring for reaction for 5-7.5 h, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, adding acetic anhydride into the reaction liquid, stirring for 0.5h, adding bromate of triethylamine, stirring for 1h, dissolving a filter cake obtained by filtering the suspension by ethyl acetate, drying by anhydrous magnesium sulfate, filtering, and spin-drying to obtain a crude product, and recrystallizing the crude product by N-hexane to obtain the compound shown in the formula 5. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound shown in the formula 3 to the compound shown in the formula 4 to triethylamine to palladium chloride is 1 (1.2-2): (3-6): (0.025 to 0.1).
According to an embodiment of the present invention, in the step (2), it is preferable that the compound represented by formula 3, the compound represented by formula 4, triethylamine, and palladium chloride are present in a molar ratio of 1: 1.5: 4: 0.03, therefore, the utilization rate of reactants is high, the waste of raw materials and actual materials is not caused, and the yield of the target compound is high.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: adding a compound 3(1g,3.62mmol) into N-methylpyrrolidone (5mL), adding a compound 4(470mg,5.46mmol) and triethylamine (1.47g,14.49mmol) into a stirring reaction system, adding palladium chloride (19.5mg,0.11mmol) under the protection of nitrogen, quickly heating the whole reaction system to 75 ℃ under the nitrogen environment, stirring for reacting for 6 hours, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, adding acetic anhydride into the reaction liquid, stirring for 0.5 hour, adding a bromate of triethylamine, stirring for 1 hour, dissolving a filter cake obtained by filtering the suspension by using ethyl acetate, drying by using anhydrous magnesium sulfate, filtering, and carrying out spin drying to obtain a crude product, and recrystallizing the crude product by using N-hexane to obtain a compound 5, wherein the yield is 94.8%. 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 (3), the contacting manner of the compound represented by formula 5 with N-bromosuccinimide (NBS) is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 5 with NBS can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 6 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the following steps are included: dissolving a compound 5 in DMF, dropwise adding NBS dissolved by the DMF under the protection of nitrogen, heating to 45-55 ℃ under the nitrogen environment, stirring for 5-9 h, detecting complete reaction by LCMS, then cooling a reaction system to 5 ℃, slowly adding a proper amount of 39% sodium bisulfite solution into the reaction solution, stirring overnight at room temperature, filtering after solid precipitation is seen, washing a filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain a compound 6. Thus, the efficiency of preparing the compound represented by formula 6 using this method can be further improved.
According to an embodiment of the present invention, in step (3), the molar ratio of the compound represented by formula 5 to NBS is 1: (2-4).
According to the embodiment of the present invention, in the step (3), the molar ratio of the compound represented by formula 5 to NBS is preferably 1:2.5, so that the utilization rate of the reactant is high, the raw material and the actual waste are not caused, and the yield of the target compound is high.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: dissolving compound 5(1g,3.79mmol) in DMF (8mL), adding NBS (1.69g,9.48mmol) dissolved in DMF (2mL) dropwise under nitrogen protection, heating to 50 ℃ under nitrogen atmosphere, stirring for 6.5h, LCMS detecting reaction completion, cooling the reaction system to 5 ℃, slowly adding an appropriate amount of 39% sodium bisulfite solution into the reaction solution, stirring overnight at room temperature, after solid precipitation, filtering, washing the filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain compound 6 with yield of 88.3%. 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 manner of contacting the compound represented by formula 6 with the compound represented by formula 7 is not particularly limited. Therefore, the efficiency of contacting the compound shown as the formula 6 with the compound shown as the formula 7 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown as the formula 8 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 a compound 6 into THF, cooling a reaction solution to 0-10 ℃, dropwise adding Lithium Hexamethyldisilazide (LHMDS) into the stirring reaction solution, after dropwise adding, adding a compound 7 into the reaction system, stirring for 1-2 h at room temperature, detecting complete reaction by TLC, quenching by saturated ammonium chloride, then adding acetic acid and water, stirring in an ice bath until a large amount of solids are separated out, then continuing stirring for 0.5h, filtering, washing a filter cake by acetone, adding a saturated ammonium chloride solution into the obtained filter cake, stirring for 2h, filtering again, washing the filter cake by water and acetone in sequence, and finally drying the obtained filter cake in vacuum to obtain a compound 8. Thus, the efficiency of preparing the compound represented by formula 8 by this method can be further improved.
According to an embodiment of the invention, in the step (4), the molar ratio of the compound shown in the formula 6 to the LHMDS to the compound shown in the formula 7 is 1 (1.2-2): (1-1.6).
According to an embodiment of the present invention, in step (4), it is preferable that the compound represented by formula 6, LHMDS, and the compound represented by formula 7 are present in a molar ratio of 1: 1.5: 1.27, therefore, the utilization rate of reactants is high, the waste of raw materials and actual materials is not caused, and the yield of the target compound is high.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: adding compound 6(1g,2.92mmol) into THF (10mL), cooling the reaction solution to 0-10 ℃, dropwise adding LHMDS (733.1mg,4.38mmol) into the stirring reaction solution, adding compound 7(1.27g,3.71mmol) into the reaction system after the dropwise addition is finished, stirring the reaction system at room temperature for 1.5h, detecting the reaction completion by TLC, quenching the reaction system by saturated ammonium chloride, adding 0.3g of acetic acid and water, stirring the mixture in an ice bath until a large amount of solid is separated out, continuing stirring the mixture for 0.5h, filtering, washing the filter cake by acetone, adding saturated ammonium chloride solution into the obtained filter cake, stirring the mixture for 2h, filtering the mixture, washing the filter cake by water and acetone in sequence, and finally drying the obtained filter cake in vacuum to obtain compound 8 with the yield of 57.8%. 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 (5), the manner of contacting the compound represented by formula 8 with the compound represented by formula 9 is not particularly limited. Therefore, the efficiency of contacting the compound shown as the formula 8 with the compound shown as the formula 9 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown as the formula 10 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 the compound 8, the compound 9 and palladium tetratriphenylphosphine into toluene, refluxing overnight at 130 ℃ under the protection of nitrogen, detecting by LCMS that the reaction is complete, cooling the reaction liquid to room temperature, concentrating under vacuum and reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound shown in the formula 10. Thus, the efficiency of preparing the compound represented by formula 10 using this method can be further improved.
According to an embodiment of the present invention, in the step (5), the molar ratio of the compound 8, the compound 9 and the palladium tetratriphenylphosphine is 1: (1.8-3): (0.05-0.2).
According to an embodiment of the present invention, in step (5), it is preferable that the molar ratio of compound 8, compound 9, and tetrakistriphenylphosphine palladium is 1: 2: 0.1, therefore, the utilization rate of reactants is high, the waste of raw materials and actual materials is not caused, and the yield of the target compound is high.
According to the embodiment of the invention, in the step (5), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (15-100): 1.
According to an embodiment of the present invention, in step (5), it is preferable that the column chromatography uses a mixed solvent of dichloromethane and methanol in a volume ratio of 50: 1.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: compound 8(1g,1.71mmol), compound 9(1.24g,3.43mmol) and tetratriphenylphosphine palladium (197mg,0.17mmol) were added together to toluene (120mL), refluxed overnight at 130 ℃ under nitrogen, LCMS checked for reaction completion, then the reaction was cooled to room temperature and concentrated under reduced pressure in vacuo to give a crude product, which was purified by column chromatography (dichloromethane: methanol ═ 50:1(v/v)) to give compound 10 in 51% yield. 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 (6), the contacting manner of the compound represented by formula 10 with hydrochloric acid is not particularly limited. Therefore, the contact efficiency of the compound shown in the formula 10 and hydrochloric acid can be improved, the reaction speed is increased, and the preparation efficiency of the compound shown in the formula I by using the method is further improved.
According to the embodiment of the invention, in the step (6), the following steps are included: dissolving the compound 10 in dichloromethane, adding 6M hydrochloric acid into the reaction solution, stirring at room temperature for 2 hours, detecting the reaction completion by LCMS and TLC, adjusting the pH to 8-9 by using saturated sodium bicarbonate solution, filtering, concentrating the obtained filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the compound SHR6390 shown in the formula I. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to an embodiment of the present invention, in step (6), the mass-to-volume ratio of the compound represented by formula 10 to 6M hydrochloric acid is 1: 25, therefore, the utilization rate of the reactants is high, the waste of raw materials and actual materials is not caused, and the yield of the target compound is high.
According to the embodiment of the invention, in the step (6), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (30-80): 1.
According to an embodiment of the present invention, in step (6), it is preferable that the column chromatography uses a mixed solvent of dichloromethane and methanol in a volume ratio of 60: 1.
According to a specific embodiment of the present invention, in the step (6), the following steps are included: compound 10(1g,1.74mmol) was dissolved in dichloromethane (500mL), then 6M hydrochloric acid (25mL) was added to the reaction solution and stirred at room temperature for 2h, LCMS and TLC checked for reaction completion, and saturated sodium bicarbonate solution was used to adjust pH 8-9, followed by filtration, and the resulting filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (dichloromethane: methanol 60:1(v/v)) to give compound SHR6390 of formula I in 62% yield with HPLC purity of 99.5%. 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 embodiments of the present invention, synthetic routes to compounds of formula I can be as follows:
according to the second aspect of the invention, the invention also relates to a new compound of a medical intermediate, wherein the compound is shown as a formula 8,
the compound shown as the formula 8 is used as a medical intermediate for preparing the compound SHR6390 shown as the formula I.
According to a third aspect of the present invention, the present invention also relates to a novel compound which is a pharmaceutical intermediate, the compound being represented by formula 10,
the compound shown as the formula 10 is used as a medical intermediate for preparing the compound SHR6390 shown as the formula I.
The invention has the beneficial effects that:
the synthesis preparation method can quickly and effectively prepare the compound SHR6390 shown in the formula I through 6 steps of chemical reaction, has the advantages of simple and cheap raw materials, convenient operation of post-treatment steps, mild reaction, high product yield, suitable industrial scale-up production and lower production cost and is more economic. Particularly, the first step of the reaction of the invention fully utilizes the advantage of high 4-position reaction activity of pyrimidine, the target product compound 3 can be well obtained under mild conditions, the post-treatment of the synthesis reaction of the compound 8 obtained by the fourth step of the reaction is simple, a good white solid product can be obtained basically by filtering and washing, purification is not required, and the method is suitable for amplification and process production.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 3
Dissolving the compound 1(1g,4.39mmol) in dioxane (20mL), adding the compound 2(448.41mg,5.27mmol), stirring the mixture at room temperature for reacting for 6h, after the TLC detection reaction is completed, adding the reaction liquid into water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound 3, wherein the obtained crude product is directly put into the next step without purification to obtain the yield of the crude product of 100%.
1HNMR:(500MHz,DMSO d6)δ8.23(s,1H),7.37(d,J＝7.3Hz,1H),4.31(m,1H),1.92(m,2H),1.71(m,2H),1.59-1.53(m,4H).
EXAMPLE 2 Synthesis of Compound represented by formula 3
Dissolving the compound 1(1g,4.39mmol) in dioxane (20mL), adding the compound 2(373.8mg,4.39mmol), stirring the mixture at room temperature for reaction for 5 hours, adding the reaction liquid into water after the TLC detection reaction is completed, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound 3, wherein the obtained crude product is directly put into the next step without purification to obtain the yield of the crude product of 92%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
Dissolving the compound 1(1g,4.39mmol) in dioxane (20mL), adding the compound 2(560.7mg,6.585mmol), stirring the mixture at room temperature to react for 8 hours, after the TLC detection reaction is completed, adding the reaction liquid into water, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound 3, wherein the obtained crude product is directly put into the next step without purification to obtain the yield of the crude product of 97%.
EXAMPLE 4 Synthesis of Compound represented by formula 5
Adding a compound 3(1g,3.62mmol) into N-methylpyrrolidone (5mL), adding a compound 4(470mg,5.46mmol) and triethylamine (1.47g,14.49mmol) into a stirring reaction system, adding palladium chloride (19.5mg,0.11mmol) under the protection of nitrogen, quickly heating the whole reaction system to 75 ℃ under the nitrogen environment, stirring for reacting for 6 hours, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, adding acetic anhydride into the reaction liquid, stirring for 0.5 hour, adding a bromate of triethylamine, stirring for 1 hour, dissolving a filter cake obtained by filtering the suspension by using ethyl acetate, drying by using anhydrous magnesium sulfate, filtering, and carrying out spin drying to obtain a crude product, and recrystallizing the crude product by using N-hexane to obtain a compound 5, wherein the yield is 94.8%.
1HNMR:(400MHz,CDCl3)δ8.74(s,1H),6.53(brs,1H),5.84(m,1H),2.44(s,3H),2.22(brs,2H),2.12(brs,2H),1.98-1.84(m,2H),1.68(brs,2H).
EXAMPLE 5 Synthesis of Compound represented by formula 5
Adding a compound 3(1g,3.62mmol) into N-methylpyrrolidone (5mL), adding a compound 4(374mg,4.344mmol) and triethylamine (1.10g,10.87mmol) into a stirring reaction system, adding palladium chloride (16.0mg,0.0902mmol) under the protection of nitrogen, quickly heating the whole reaction system to 70 ℃ under the nitrogen environment, stirring for reaction for 7.5h, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, adding acetic anhydride into the reaction liquid, stirring for 0.5h, adding a bromate of triethylamine, stirring for 1h, dissolving a filter cake obtained by filtering the suspension by using ethyl acetate, drying by using anhydrous magnesium sulfate, filtering, and carrying out spin drying to obtain a crude product, and recrystallizing the crude product by using N-hexane to obtain the compound 5 with the yield of 91.4%.
EXAMPLE 6 Synthesis of Compound represented by formula 5
Adding a compound 3(1g,3.62mmol) into N-methylpyrrolidone (5mL), adding a compound 4(623mg,7.24mmol) and triethylamine (2.20g,21.74mmol) into a stirring reaction system, adding palladium chloride (64.2mg,0.362mmol) under the protection of nitrogen, quickly heating the whole reaction system to 80 ℃ under the nitrogen environment, stirring for 5 hours, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, adding acetic anhydride into the reaction liquid, stirring for 0.5 hour, adding a bromate of triethylamine, stirring for 1 hour, dissolving a filter cake obtained by filtering the suspension by ethyl acetate, drying by anhydrous magnesium sulfate, filtering, and carrying out rotary drying to obtain a crude product, and recrystallizing the crude product by using normal hexane to obtain the compound 5 with the yield of 93.0%.
Example 7 Synthesis of Compound represented by formula 6
Dissolving compound 5(1g,3.79mmol) in DMF (8mL), adding NBS (1.69g,9.48mmol) dissolved in DMF (2mL) dropwise under nitrogen protection, heating to 50 ℃ under nitrogen atmosphere, stirring for 6.5h, LCMS detecting reaction completion, cooling the reaction system to 5 ℃, slowly adding an appropriate amount of 39% sodium bisulfite solution into the reaction solution, stirring overnight at room temperature, after solid precipitation, filtering, washing the filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain compound 6 with yield of 88.3%.
1HNMR:(500MHz,DMSO d6)δ9.02(s,1H),5.82(m,1H),2.65(s,3H),2.11(m,2H),2.04(m,2H),1.86(m,2H),1.64(m,2H).
LCMS:342.0[M+H]+.
EXAMPLE 8 Synthesis of Compound represented by formula 6
Dissolving compound 5(1g,3.79mmol) in DMF (8mL), adding NBS (1.35g,7.58mmol) dissolved in DMF (2mL) dropwise under nitrogen protection, heating to 55 ℃ under nitrogen atmosphere, stirring for 5h, detecting complete reaction by LCMS, cooling the reaction system to 5 ℃, slowly adding an appropriate amount of 39% sodium bisulfite solution into the reaction solution, stirring overnight at room temperature, after solid precipitation, filtering, washing the filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain compound 6 with yield of 84.5%.
Example 9 Synthesis of Compound represented by formula 6
Dissolving compound 5(1g,3.79mmol) in DMF (8mL), adding NBS (2.70g,15.16mmol) dissolved in DMF (2mL) dropwise under nitrogen protection, heating to 45 ℃ under nitrogen, stirring for 9h, detecting complete reaction by LCMS, cooling the reaction system to 5 ℃, slowly adding an appropriate amount of 39% sodium bisulfite solution into the reaction solution, stirring overnight at room temperature, after solid precipitation, filtering, washing the filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain compound 6 with yield of 87.0%.
EXAMPLE 10 Synthesis of Compound represented by formula 8
Adding compound 6(1g,2.92mmol) into THF (10mL), cooling the reaction solution to 0-10 ℃, dropwise adding LHMDS (733.1mg,4.38mmol) into the stirring reaction solution, adding compound 7(1.03g,3.71mmol) into the reaction system after the dropwise addition is finished, stirring the reaction system for 1.5h at room temperature, detecting the reaction completion by TLC, quenching the reaction system by saturated ammonium chloride, then adding 0.3g of acetic acid and water, stirring the mixture in an ice bath until a large amount of solid is separated out, then continuing stirring for 0.5h, filtering, washing the filter cake by acetone, adding saturated ammonium chloride solution into the obtained filter cake, stirring for 2h, filtering, washing the filter cake by water and acetone in sequence, and finally drying the obtained filter cake in vacuum to obtain compound 8 with the yield of 57.8%.
LCMS:583.0[M+H]+.
EXAMPLE 11 Synthesis of Compound represented by formula 8
Adding compound 6(1g,2.92mmol) into THF (10mL), cooling the reaction solution to 0-10 ℃, dropwise adding LHMDS (586.5mg,3.504mmol) into the stirring reaction solution, adding compound 7(810mg,2.92mmol) into the reaction system after the dropwise adding is finished, stirring the reaction system at room temperature for 1h, detecting the completion of the reaction by TLC, quenching the reaction system by saturated ammonium chloride, adding 0.3g of acetic acid and water, stirring the mixture in an ice bath until a large amount of solid is separated out, continuing to stir the mixture for 0.5h, filtering, washing a filter cake by acetone, adding a saturated ammonium chloride solution into the obtained filter cake, stirring the mixture for 2h, filtering again, washing the filter cake by water and acetone in turn, and finally drying the obtained filter cake in vacuum to obtain compound 8 with the yield of 53.0%.
EXAMPLE 12 Synthesis of Compound represented by formula 8
Adding compound 6(1g,2.92mmol) into THF (10mL), cooling the reaction solution to 0-10 ℃, dropwise adding LHMDS (977.4mg,5.84mmol) into the stirring reaction solution, adding compound 7(1.30g,4.69mmol) into the reaction system after the dropwise addition is finished, stirring the reaction system at room temperature for 2h, detecting the completion of the reaction by TLC, quenching the reaction system by saturated ammonium chloride, adding 0.3g of acetic acid and water, stirring the mixture in an ice bath until a large amount of solid is separated out, continuing stirring the mixture for 0.5h, filtering, washing the filter cake by acetone, adding a saturated ammonium chloride solution into the obtained filter cake, stirring the mixture for 2h, filtering the mixture, washing the filter cake by water and acetone in turn, and finally drying the obtained filter cake in vacuum to obtain compound 8 with the yield of 56.1%.
Example 13 Synthesis of Compound represented by formula 10
Compound 8(1g,1.71mmol), compound 9(1.24g,3.43mmol) and tetratriphenylphosphine palladium (197mg,0.17mmol) were added together to toluene (120mL), refluxed overnight at 130 ℃ under nitrogen, LCMS checked for reaction completion, then the reaction was cooled to room temperature and concentrated under reduced pressure in vacuo to give a crude product, which was purified by column chromatography (dichloromethane: methanol ═ 50:1(v/v)) to give compound 10 in 51% yield.
LCMS:575.0[M+H]+.
The molar ratio is 1: (1.8-3): (0.05-0.2);
the molar ratio is 1: 2: 0.1;
EXAMPLE 14 Synthesis of Compound represented by formula 10
Compound 8(1g,1.71mmol), compound 9(1.11g,3.07mmol) and tetratriphenylphosphine palladium (98.8mg,0.0855mmol) were added together to toluene (120mL), refluxed overnight at 130 ℃ under nitrogen protection, LCMS checked for reaction completion, then the reaction was cooled to room temperature, concentrated under reduced pressure in vacuo to give a crude product, which was purified by column chromatography (dichloromethane: methanol ═ 15:1(v/v)) to give compound 10 in 46% yield.
EXAMPLE 15 Synthesis of Compound represented by formula 10
Compound 8(1g,1.71mmol), compound 9(1.85g,5.12mmol) and tetratriphenylphosphine palladium (394mg,0.34mmol) were added together in toluene (120mL), refluxed overnight at 130 ℃ under nitrogen protection, reaction completion was detected by LCMS, then the reaction was cooled to room temperature and concentrated under reduced pressure in vacuo to give a crude product, which was purified by column chromatography (dichloromethane: methanol 100:1(v/v)) to give compound 10 in 49% yield.
EXAMPLE 16 Synthesis of Compound of formula I
Compound 10(1g,1.74mmol) was dissolved in dichloromethane (500mL), then 6M hydrochloric acid (25mL) was added to the reaction solution and stirred at room temperature for 2h, LCMS and TLC checked for reaction completion, and saturated sodium bicarbonate solution was used to adjust pH 8-9, followed by filtration, and the resulting filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (dichloromethane: methanol 60:1(v/v)) to give compound SHR6390 of formula I in 62% yield with HPLC purity of 99.5%.
1HNMR:(500MHz,DMSO d6)δ10.21(s,1H),8.99(s,1H),8.22(s,1H),7.98(d,J＝8.5Hz,1H),7.69(d,J＝8.6Hz,1H),5.84(m,1H),3.03(d,J＝11.9Hz,2H),2.60(dd,J＝23.9,11.9Hz,3H),2.43(s,3H),2.32(s,3H),2.26(s,3H),1.90(s,2H),1.79(s,2H),1.70(d,J＝12.0Hz,2H),1.55(ddd,J＝21.3,11.3,7.0Hz,4H).
LCMS:447.0[M+H]+.
EXAMPLE 17 Synthesis of Compound of formula I
Compound 10(1g,1.74mmol) was dissolved in dichloromethane (500mL), then 6M hydrochloric acid (25mL) was added to the reaction solution and stirred at room temperature for 2h, LCMS and TLC checked for reaction completion, and saturated sodium bicarbonate solution was used to adjust pH 8-9, followed by filtration, and the resulting filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (dichloromethane: methanol ═ 30:1(v/v)) to give compound SHR6390 of formula I in 59% yield with HPLC purity of 99.2%.
EXAMPLE 18 Synthesis of Compound of formula I
Compound 10(1g,1.74mmol) was dissolved in dichloromethane (500mL), then 6M hydrochloric acid (25mL) was added to the reaction solution and stirred at room temperature for 2h, LCMS and TLC checked for completion of the reaction, saturated sodium bicarbonate solution was used to adjust pH 8-9, then filtered, and the resulting filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (dichloromethane: methanol 80:1(v/v)) to give compound SHR6390 of formula I in 61% yield and 99.4% HPLC purity.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A method of making SHR6390, comprising:
(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 the compound represented by formula 5 with N-bromosuccinimide to obtain a compound represented by formula 6;
(4) contacting a compound represented by formula 6 with lithium hexamethyldisilazide and a compound represented by formula 7, so as to obtain a compound represented by formula 8;
(5) contacting a compound represented by formula 8 with a compound represented by formula 9 to obtain a compound represented by formula 10;
(6) contacting a compound of formula 10 with a hydrochloric acid solution to obtain a compound of formula I,
2. the method according to claim 1, wherein in step (1), the following steps are included: dissolving a compound 1 into dioxane, adding a compound 2, stirring at room temperature for reaction, adding a reaction solution into water after TLC detection reaction is completed, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound 3, wherein the obtained crude product is directly put into the next step without purification;
optionally, in the step (1), contacting the compound shown in the formula 1 with the compound shown in the formula 2 at room temperature, and stirring for reaction for 5-8 hours;
optionally, in the step (1), contacting the compound shown as the formula 1 with the compound shown as the formula 2 at room temperature, and stirring for reacting for 6 hours;
optionally, in the step (1), the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 is 1 (1.0-1.5);
optionally, in step (1), the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 is 1: 1.2.
3. The method of claim 1, wherein in step (2), the following steps are included: adding a compound 3 into N-methylpyrrolidone, then adding a compound 4 and triethylamine into a stirring reaction system, adding palladium chloride under the protection of nitrogen, rapidly heating the whole reaction system to 70-80 ℃ under the environment of nitrogen, stirring for reaction for 5-7.5 h, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, then adding acetic anhydride into the reaction liquid, stirring for 0.5h, then adding bromate of triethylamine, stirring for 1h, dissolving a filter cake obtained by filtering the suspension by ethyl acetate, drying by anhydrous magnesium sulfate, filtering, and spin-drying to obtain a crude product, and recrystallizing the crude product by N-hexane to obtain the compound shown in the formula 5;
optionally, in the step (2), the molar ratio of the compound shown in the formula 3 to the compound shown in the formula 4 to triethylamine to palladium chloride is 1 (1.2-2): (3-6): (0.025 to 0.1);
optionally, in the step (2), the molar ratio of the compound shown in the formula 3 to the compound shown in the formula 4 to the triethylamine to the palladium chloride is 1: 1.5: 4: 0.03.
4. the method of claim 1, wherein in step (3), the following steps are included: dissolving a compound 5 in DMF, dropwise adding NBS dissolved by the DMF under the protection of nitrogen, heating to 45-55 ℃ under the nitrogen environment, stirring for 5-9 h, detecting complete reaction by LCMS, then cooling a reaction system to 5 ℃, slowly adding a proper amount of 39% sodium bisulfite solution into a reaction solution, stirring overnight at room temperature, filtering after solid precipitation is seen, washing a filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain a compound 6;
optionally, in step (3), the molar ratio of the compound of formula 5 to NBS is 1: (2-4);
optionally, in step (3), the molar ratio of the compound of formula 5 to NBS is 1: 2.5.
5. The method according to claim 1, wherein in step (4), the following steps are included: adding a compound 6 into THF, cooling a reaction solution to 0-10 ℃, dropwise adding lithium hexamethyldisilazide into the stirring reaction solution, after dropwise adding, adding a compound 7 into a reaction system, stirring for 1-2 h at room temperature, detecting by TLC (thin layer chromatography), completely reacting, quenching by saturated ammonium chloride, adding acetic acid and water, stirring in an ice bath until a large amount of solids are separated out, continuing stirring for 0.5h, filtering, washing a filter cake by acetone, adding a saturated ammonium chloride solution into the obtained filter cake, stirring for 2h, filtering again, washing the filter cake by water and acetone in sequence, and finally vacuum-drying the obtained filter cake to obtain a compound 8;
optionally, in the step (4), the molar ratio of the compound shown in the formula 6, the lithium hexamethyldisilazide and the compound shown in the formula 7 is 1 (1.2-2): (1-1.6);
optionally, in the step (4), the molar ratio of the compound represented by the formula 6, the lithium hexamethyldisilazide and the compound represented by the formula 7 is 1: 1.5: 1.27.
6. the method according to claim 1, wherein in step (5), the following steps are included: adding the compound 8, the compound 9 and palladium tetratriphenylphosphine into toluene, refluxing overnight at 130 ℃ under the protection of nitrogen, detecting by LCMS to complete the reaction, cooling the reaction liquid to room temperature, concentrating under vacuum and reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound shown in a formula 10;
optionally, in the step (5), the molar ratio of the compound 8 to the compound 9 to the tetrakistriphenylphosphine palladium is 1: (1.8-3): (0.05-0.2);
optionally, in the step (5), the molar ratio of the compound 8 to the compound 9 to the tetrakistriphenylphosphine palladium is 1: 2: 0.1;
optionally, in the step (5), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (15-100): 1;
optionally, in the step (5), the column chromatography uses a mixed solvent of dichloromethane and methanol in a volume ratio of 50: 1.
7. The method according to claim 1, wherein in step (6), the following steps are included: dissolving the compound 10 in dichloromethane, adding 6M hydrochloric acid into the reaction solution, stirring at room temperature for 2 hours, detecting complete reaction by LCMS and TLC, adjusting pH to 8-9 with saturated sodium bicarbonate solution, filtering, concentrating the obtained filtrate under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain a compound SHR6390 shown in formula I;
optionally, in the step (6), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (30-80): 1;
optionally, in the step (6), the column chromatography uses a mixed solvent of dichloromethane and methanol in a volume ratio of 60: 1.
8. The method of claim 1, wherein the synthetic route is selected from the group consisting of:
optionally, it comprises the steps of:
(1) dissolving a compound 1(1g,4.39mmol) in dioxane (20mL), adding a compound 2(448.41mg,5.27mmol), stirring the mixture at room temperature to react for 6 hours, adding a reaction solution into water after the TLC detection reaction is completed, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a compound 3, wherein the obtained crude product is directly put into the next step without purification;
(2) adding a compound 3(1g,3.62mmol) into N-methylpyrrolidone (5mL), adding a compound 4(470mg,5.46mmol) and triethylamine (1.47g,14.49mmol) into a stirring reaction system, adding palladium chloride (19.5mg,0.11mmol) under the protection of nitrogen, quickly heating the whole reaction system to 75 ℃ under the nitrogen environment, stirring for reacting for 6 hours, detecting that the compound 3 is completely reacted by TLC (sampling and detecting by ethyl acetate extraction), cooling the reaction to room temperature, adding acetic anhydride into the reaction liquid, stirring for 0.5 hour, adding a bromate of triethylamine, stirring for 1 hour, dissolving a filter cake obtained by filtering the suspension by using ethyl acetate, drying by using anhydrous magnesium sulfate, filtering, and spin-drying to obtain a crude product, and recrystallizing the crude product by using N-hexane to obtain a compound 5;
(3) dissolving a compound 5(1g,3.79mmol) in DMF (8mL), dropwise adding NBS (1.69g,9.48mmol) dissolved in DMF (2mL) under the protection of nitrogen, heating to 50 ℃ under the nitrogen environment, stirring for 6.5h, detecting the reaction completion by LCMS, cooling the reaction system to 5 ℃, slowly adding an appropriate amount of 39% sodium bisulfite solution into the reaction solution, stirring overnight at room temperature, after a solid is separated out, filtering, washing a filter cake with water and isopropanol in sequence, and drying the obtained filter cake in vacuum for 24h to obtain a compound 6;
(4) adding compound 6(1g,2.92mmol) into THF (10mL), cooling the reaction solution to 0-10 ℃, dropwise adding LHMDS (733.1mg,4.38mmol) into the stirring reaction solution, after the dropwise addition is finished, adding compound 7(1.27g,3.71mmol) into the reaction system, stirring for 1.5h at room temperature, detecting that the reaction is complete by TLC, quenching with saturated ammonium chloride, then adding 0.3g of acetic acid and water, stirring in an ice bath until a large amount of solid is separated out, then continuing stirring for 0.5h, filtering, washing the filter cake with acetone, adding saturated ammonium chloride solution into the obtained filter cake, stirring for 2h, filtering, washing the filter cake with water and acetone in sequence, and finally vacuum-drying the obtained filter cake to obtain compound 8;
(5) adding the compound 8(1g,1.71mmol), the compound 9(1.24g,3.43mmol) and tetratriphenylphosphine palladium (197mg,0.17mmol) into toluene (120mL) together, refluxing overnight at 130 ℃ under nitrogen protection, detecting reaction completion by LCMS, cooling the reaction solution to room temperature, concentrating under reduced pressure in vacuum to obtain a crude product, and purifying the crude product by column chromatography (dichloromethane: methanol ═ 50:1(v/v)) to obtain the compound 10;
(6) compound 10(1g,1.74mmol) was dissolved in dichloromethane (500mL), then 6M hydrochloric acid (25mL) was added to the reaction solution and stirred at room temperature for 2h, LCMS and TLC checked for reaction completion, and saturated sodium bicarbonate solution was used to adjust pH 8-9, followed by filtration, and the resulting filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography (dichloromethane: methanol 60:1(v/v)) to give compound SHR6390 of formula I in 62% yield with HPLC purity of 99.5%.
9. Novel medical intermediate compound of compound shown as formula 8
The compound SHR6390 is characterized by being used as a medical intermediate for preparing the compound SHR6390 shown in the formula I.
10. A new pharmaceutical intermediate compound of a compound shown as a formula 10
The compound SHR6390 is characterized by being used as a medical intermediate for preparing the compound SHR6390 shown in the formula I.
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