CN112625038A - Method for preparing Ripoctinib - Google Patents
Method for preparing Ripoctinib Download PDFInfo
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- CN112625038A CN112625038A CN202011644308.1A CN202011644308A CN112625038A CN 112625038 A CN112625038 A CN 112625038A CN 202011644308 A CN202011644308 A CN 202011644308A CN 112625038 A CN112625038 A CN 112625038A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to a method for synthesizing and preparing a new medicine, namely Rispertinib. By utilizing the synthetic preparation method provided by the invention, the compound Ripoctinib shown in the formula I can be quickly and effectively prepared through 6 steps of chemical reaction. The synthetic reaction of the invention greatly simplifies the reaction steps and the post-treatment steps, and has mild reaction conditions, easy realization of industrial industrialization, lower production cost and more economy.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a method for preparing Rispertinib.
Background
Ripeptib was developed by Deciphera Pharmaceuticals and is an innovative anti-tumor drug. In 11 months 2017, EMA awards orphan drug qualification to rapentinib for the treatment of gastrointestinal stromal tumors. In 11 months 2019, the U.S. FDA approved breakthrough therapy identification of rapatinib for the treatment of advanced gastrointestinal stromal tumor patients who previously received imatinib, sunitinib, and regorafenib treatment. In 5 months of 2020, the FDA in the united states approved the drug for the treatment of gastrointestinal stromal tumors. In addition, many indications such as germ cell and embryo cancer, brain glioma, melanoma, non-small cell lung cancer, penile tumor, soft tissue sarcoma, solid tumor, systemic mastocytosis are under clinical study.
The structure of the Riptotinib is shown as the formula I:
the existing method for synthesizing and preparing the Rispertinib 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 shown as a formula I, namely the rapatinib. According to an embodiment of the invention, the method comprises:
(1) contacting a compound represented by formula 1 with nitric acid to obtain a compound represented by formula 2;
(2) contacting the compound shown in the formula 2 with concentrated sulfuric acid and ethanol to obtain a compound shown in a formula 3;
(3) contacting the compound shown in the formula 3 with iron powder and ammonium chloride so as to obtain a compound shown in a formula 4;
(4) contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula 6;
(5) contacting a compound represented by formula 6 with methylamine to obtain a compound represented by formula 7;
(6) contacting the compound shown as the formula 7 with the compound shown as the formula 8 so as to obtain the compound shown as the formula I, namely the Ripidinib.
The inventor finds that the synthetic preparation method can be used for quickly and effectively preparing the compound Rispertinib shown in the formula I, saves 3 steps of reaction in the synthetic reaction operation, greatly simplifies reaction steps and post-treatment steps, is mild in reaction conditions, is easy to realize industrial industrialization, and is lower in production cost and more economical compared with the prior art.
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 8, 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 2, the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 6, 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 raw materials for preparing the compound represented by formula 2, the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 6, 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 step (1), the contacting manner of the compound represented by formula 1 with nitric acid is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 1 with nitric acid 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: slowly adding the compound shown in the formula 1 into nitric acid at about-5 ℃, continuously stirring at the temperature of about-5 ℃ after the addition is finished, slowly dropwise adding the reaction liquid into the stirred ice water until solid is separated out after TLC detection reaction is completed, then filtering, washing a filter cake with proper amount of water, and drying to obtain the compound shown in the formula 2. Thus, the efficiency of preparing the compound represented by formula 2 by the method can be further improved.
According to the embodiment of the invention, in the step (1), the mass-to-volume ratio of the compound shown in the formula 1 to the nitric acid is 1 (1.3-1.6) (g/v).
According to the embodiment of the present invention, in the step (1), the mass volume ratio of the compound represented by formula 1 to nitric acid is preferably 1:1.5(g/v), 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 (1), the following steps are included: slowly adding the compound shown in the formula 1 (1.0g and 4.29mmol) into nitric acid (1.5mL) at about-5 ℃, keeping the temperature at about-5 ℃ and continuing stirring after the addition is finished, slowly dripping the reaction liquid into ice water (20mL) in stirring after the TLC detection reaction is completed until solid is separated out, then filtering, washing a filter cake with proper amount of water, and drying to obtain the compound shown in the formula 2, wherein the amount of the compound is 1.1g, the yield is 92.2%, and the HPLC purity is 98.1%. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (2), the contacting manner of the compound represented by formula 2 with concentrated sulfuric acid, ethanol is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 2 with concentrated sulfuric acid and ethanol 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 (2), the following steps are included: dissolving the compound 2 in ethanol, dropwise adding concentrated sulfuric acid at 0 ℃, heating, refluxing and stirring overnight, after TLC detection reaction is completed, adding ethyl acetate, extracting with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating the organic layer, and purifying with silica gel column to obtain the compound shown in the formula 3. 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 (2), the mass-to-volume ratio of the compound shown in the formula 2 to concentrated sulfuric acid and ethanol is 1 (0.18-0.25): (18-25) (g/v/v).
According to the embodiment of the invention, in the step (2), the mass-to-volume ratio of the compound represented by the formula 1 to concentrated sulfuric acid and ethanol is preferably 1:0.2:20(g/v/v), so that 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 (2), the mixed solvent of dichloromethane and methanol with a volume ratio of (30-60): 1 is adopted for column purification, and the mixed solvent of dichloromethane and methanol with a volume ratio of 50:1 is preferably adopted for column purification.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: compound 2(1.0g,3.60mmol) was dissolved in ethanol (20mL), concentrated sulfuric acid (0.2mL) was added dropwise at 0 ℃, the mixture was heated under reflux and stirred overnight, after completion of the TLC detection reaction, ethyl acetate (20mL) was added, and extraction was performed with water (20mL), followed by washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration of the organic layer, and purification through a silica gel column (DCM/MeOH ═ 50/1(v/v)) gave the compound represented by formula 3 in an amount of 0.97g, a yield of 88.0%, and a HPLC purity of 98.5%. 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 an embodiment of the present invention, in the step (3), the contacting manner of the compound represented by formula 3 with iron powder and ammonium chloride is not particularly limited. Therefore, the contact efficiency of the compound shown in the formula 3 with iron powder and ammonium chloride 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 (3), the following steps are included: dissolving the compound 3 in ethanol, sequentially adding iron powder and saturated ammonium chloride, then reacting, heating, stirring, detecting by TLC (thin layer chromatography) to complete reaction, cooling the reaction solution to room temperature, filtering with diatomite to obtain a filtrate, spin-drying the filtrate, dissolving with ethyl acetate, adding water for extraction, washing with saturated sodium bicarbonate, drying an organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound shown in the formula 4. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to the embodiment of the invention, in the step (3), the compound shown in the formula 3 is contacted with iron powder and ammonium chloride at 55-65 ℃, and is stirred and reacted for 45 minutes-1.5 hours; the compound represented by formula 3 is contacted with iron powder and ammonium chloride, preferably at 60 c, and stirred to react for 1 hour.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound shown in the formula 3 to the iron powder and the ammonium chloride is 1 (10-13): (10-13).
According to an embodiment of the present invention, in step (3), it is preferable that the molar ratio of the compound represented by formula 3 to the iron powder and the ammonium chloride is 1: 11: 11, therefore, the utilization rate of the reactant 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 (3), the following steps are included: dissolving compound 3(1g,3.27mmol) in ethanol (30mL), adding iron powder (2g,35.9mmol) and saturated ammonium chloride (7mL,35.9mmol) in sequence, heating the reaction to 60 ℃, stirring for 1h, detecting complete reaction by TLC, cooling the reaction solution to room temperature, filtering with celite to obtain a filtrate, spinning the filtrate, dissolving with ethyl acetate (20mL), extracting with water (20mL), washing with saturated sodium bicarbonate (10mL), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound represented by formula 4, wherein the amount is 0.75g, the yield is 83.1%, and the HPLC purity is 97.9%. 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 4 with the compound represented by formula 5 is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 4 with the compound shown in the formula 5 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 (4), the following steps are included: mixing compound 4, compound 5 and KF
(40% alumina) was dissolved in Dimethylacetamide (DMA), the reaction was stirred at room temperature, the reaction was completed by TLC detection, the reaction solution was filtered, the cake was washed with ethyl acetate, the filtrate was extracted with saturated sodium bicarbonate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a compound represented by formula 6. Thus, the efficiency of preparing the compound represented by formula 6 using this method can be further improved.
According to the embodiment of the invention, in the step (4), the contact stirring reaction time of the compound shown in the formula 4, the compound shown in the formula 5 and 40% of alumina is 1.5-2.5 hours; preferably, the reaction time of the compound represented by the formula 4, the compound represented by the formula 5, and 40% alumina by contact stirring is 2 hours.
According to the embodiment of the invention, in the step (4), the molar ratio of the compound shown in the formula 4 to the compound shown in the formula 5 and 40% of alumina is 1 (0.98-1.3): (1.8-2.3).
According to an embodiment of the present invention, in step (4), it is preferable that the molar ratio of the compound represented by formula 4 to the compound represented by formula 5, and 40% alumina is 1: 2, the utilization rate of reactants is high, raw materials and 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 (4), the following steps are included: compound 4(1g,3.6mmol), compound 5(668.6mg,3.6mmol), KF (40% alumina) (420.8mg,7.2mmol) were dissolved in DMA (15mL), the reaction was stirred at room temperature for 2h, TLC checked for completion of the reaction, the reaction solution was filtered, the cake was washed with ethyl acetate, the filtrate was extracted with saturated sodium bicarbonate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula 6 in an amount of 1128mg, a yield of 78.6%, and an HPLC purity of 98.5%. 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 an embodiment of the present invention, in step (5), the contacting manner of the compound represented by formula 6 with methylamine is not particularly limited. Therefore, the contact efficiency of the compound shown as the formula 6 and methylamine can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown as the formula 7 by using the method is further improved.
According to an embodiment of the present invention, in the step (5), the following steps are included: dissolving the compound 6 in dioxane, adding methylamine, stirring overnight in a closed kettle, detecting by TLC to completely react, then cooling to room temperature, extracting with ethyl acetate, washing the obtained organic phase with saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and pulping and washing with an appropriate amount of acetonitrile and water to obtain the compound shown in the formula 7. This can further improve the efficiency of producing the compound represented by formula 7 by this method.
According to the embodiment of the invention, in the step (5), the compound shown as the formula 6 is contacted with methylamine and stirred to react at the temperature of 95-100 ℃; preferably, the compound represented by formula 6 is contacted with methylamine at 100 ℃ and stirred for reaction.
According to an embodiment of the present invention, in the step (5), the molar ratio of the compound represented by formula 6 to methylamine is 1: (8-12).
According to the embodiment of the present invention, in the step (5), the molar ratio of the compound represented by formula 6 to methylamine is preferably 1:10, so that the utilization rate of the reactants is high, no waste of raw materials and actual materials is caused, and the yield of the target compound is high.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: compound 6(1.5g,3.76mmol) was dissolved in dioxane (15mL), methylamine (1.17g,37.6mmol) was added, the mixture was stirred overnight in a closed kettle at 100 ℃, the reaction was detected by TLC, then cooled to room temperature, extracted with ethyl acetate (10mL), the resulting organic phase was washed with saturated sodium bicarbonate solution (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed with an appropriate amount of acetonitrile and water by beating to give the compound of formula 7 in an amount of 1.36g, yield 92.0%, and HPLC purity of 98.9%. 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 manner of contacting the compound represented by formula 7 with the compound represented by formula 8 is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 7 with the compound shown in the formula 8 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 the embodiment of the invention, in the step (6), the following steps are included: dissolving a compound 7 and triethylamine in THF, dropwise adding a compound 8 under the protection of nitrogen, stirring overnight at room temperature for reaction, filtering reaction liquid after TLC detection reaction is complete, pulping and washing obtained filter cakes with an appropriate amount of acetonitrile and water, and drying to obtain the compound 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 the step (6), the molar ratio of the compound represented by formula 7 to the compound represented by formula 8 is 1: (1.5-2).
According to the embodiment of the present invention, in the step (6), the molar ratio of the compound represented by formula 7 to the compound represented by formula 8 is preferably 1:1.8, 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 (6), the following steps are included: dissolving compound 7(1.50g,3.81mmol) and triethylamine (0.5mL) in THF (25mL), adding compound 8(832.2mg,6.87mmol) dropwise under the protection of nitrogen, stirring overnight at room temperature, after TLC detection reaction is complete, filtering the reaction solution, pulping and washing the obtained filter cake with an appropriate amount of acetonitrile and water, and drying to obtain the compound shown in formula I with the yield of 1.673g and the 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:
by utilizing the synthetic preparation method, the compound Ripoctinib shown in the formula I can be quickly and effectively prepared through 6 steps of chemical reaction, the synthetic reaction greatly simplifies the reaction steps and the post-treatment steps, the reaction condition is mild, the industrial industrialization is easy to realize, and the production cost is lower and more economic.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 2
Slowly adding the compound shown in the formula 1 (1.0g and 4.29mmol) into nitric acid (1.5mL) at about-5 ℃, keeping the temperature at about-5 ℃ and continuing stirring after the addition is finished, slowly dripping the reaction liquid into ice water (20mL) in stirring after the TLC detection reaction is completed until solid is separated out, then filtering, washing a filter cake with proper amount of water, and drying to obtain the compound shown in the formula 2, wherein the amount of the compound is 1.1g, the yield is 92.2%, and the HPLC purity is 98.1%.
Example 2 Synthesis of Compound represented by formula 2
Slowly adding the compound shown in the formula 1 (1.0g and 4.29mmol) into nitric acid (1.6mL) at about-5 ℃, keeping the temperature at about-5 ℃ and continuing stirring after the addition is finished, slowly dripping the reaction liquid into ice water (20mL) in stirring after the TLC detection reaction is completed until solid is separated out, then filtering, washing a filter cake by using proper amount of water, and drying to obtain the compound shown in the formula 2, wherein the amount of the compound is 1.0g, the yield is 83.8%, and the HPLC purity is 97.7%.
EXAMPLE 3 Synthesis of Compound represented by formula 2
Slowly adding the compound shown in the formula 1 (1.0g and 4.29mmol) into nitric acid (1.3mL) at about-5 ℃, keeping the temperature at about-5 ℃ and continuing stirring after the addition is finished, slowly dripping the reaction liquid into ice water (20mL) in stirring after the TLC detection reaction is completed until solid is separated out, then filtering, washing a filter cake with proper amount of water, and drying to obtain the compound shown in the formula 2, wherein the amount of the compound is 0.98g, the yield is 82.2%, and the HPLC purity is 97.3%.
Example 4 Synthesis of Compound represented by formula 3
Compound 2(1.0g,3.60mmol) was dissolved in ethanol (20mL), concentrated sulfuric acid (0.2mL) was added dropwise at 0 ℃, the mixture was heated under reflux and stirred overnight, after completion of the TLC detection reaction, ethyl acetate (20mL) was added, and extraction was performed with water (20mL), followed by washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration of the organic layer, and purification through a silica gel column (DCM/MeOH ═ 50/1(v/v)) gave the compound represented by formula 3 in an amount of 0.97g, a yield of 88.0%, and a HPLC purity of 98.5%.
EXAMPLE 5 Synthesis of Compound represented by formula 3
Compound 2(1.0g,3.60mmol) was dissolved in ethanol (18mL), concentrated sulfuric acid (0.18mL) was added dropwise at 0 ℃, the mixture was heated under reflux and stirred overnight, after completion of the TLC detection reaction, ethyl acetate (20mL) was added, and extraction was performed with water (20mL), and the mixture was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and the organic layer was concentrated and purified by silica gel column (DCM/MeOH-30/1 (v/v)) to give the compound represented by formula 3 in an amount of 0.95g, a yield of 86.2% and an HPLC purity of 98.2%.
EXAMPLE 6 Synthesis of Compound represented by formula 3
Compound 2(1.0g,3.60mmol) was dissolved in ethanol (25mL), concentrated sulfuric acid (0.25mL) was added dropwise at 0 ℃, the mixture was heated under reflux and stirred overnight, after completion of the TLC detection reaction, ethyl acetate (20mL) was added, and extraction was performed with water (20mL), followed by washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration of the organic layer, and purification through a silica gel column (DCM/MeOH ═ 60/1(v/v)) gave the compound represented by formula 3 in an amount of 0.92g, a yield of 83.5%, and a HPLC purity of 98.0%.
Example 7 Synthesis of Compound represented by formula 4
Dissolving compound 3(1g,3.27mmol) in ethanol (30mL), adding iron powder (2g,35.9mmol) and saturated ammonium chloride (7mL,35.9mmol) in sequence, heating the reaction to 60 ℃, stirring for 1h, detecting complete reaction by TLC, cooling the reaction solution to room temperature, filtering with celite to obtain a filtrate, spinning the filtrate, dissolving with ethyl acetate (20mL), extracting with water (20mL), washing with saturated sodium bicarbonate (10mL), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound represented by formula 4, wherein the amount is 0.75g, the yield is 83.1%, and the HPLC purity is 97.9%.
EXAMPLE 8 Synthesis of Compound represented by formula 4
Dissolving compound 3(1g,3.27mmol) in ethanol (30mL), adding iron powder (1.82g,32.7mmol) and saturated ammonium chloride (6.4mL,32.7mmol) in sequence, heating the reaction to 55 deg.C, stirring for 45 min, detecting by TLC that the reaction is complete, cooling the reaction solution to room temperature, filtering with celite to obtain a filtrate, spin-drying the filtrate, dissolving with ethyl acetate (20mL), extracting with water (20mL), washing with saturated sodium bicarbonate (10mL), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound of formula 4 with an amount of 0.73g, yield 80.9%, and HPLC purity of 97.9%.
Example 9 Synthesis of Compound represented by formula 4
Dissolving compound 3(1g,3.27mmol) in ethanol (30mL), adding iron powder (2.6g,42.5mmol) and saturated ammonium chloride (9.1mL,42.5mmol) in sequence, heating the reaction to 65 ℃, stirring for 1.5h, detecting the reaction completion by TLC, cooling the reaction solution to room temperature, filtering with celite to obtain a filtrate, spin-drying the filtrate, dissolving with ethyl acetate (20mL), extracting with water (20mL), washing with saturated sodium bicarbonate (10mL), drying the organic phase with anhydrous sodium sulfate, filtering, concentrating to obtain the compound of formula 4, the yield is 0.72g, the yield is 80.0%, and the HPLC purity is 97.9%.
EXAMPLE 10 Synthesis of Compound represented by formula 6
Compound 4(1g,3.6mmol), compound 5(668.6mg,3.6mmol), KF (40% alumina) (420.8mg,7.2mmol) were dissolved in DMA (15mL), the reaction was stirred at room temperature for 2h, TLC checked for completion of the reaction, the reaction solution was filtered, the cake was washed with ethyl acetate, the filtrate was extracted with saturated sodium bicarbonate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula 6 in an amount of 1128mg, a yield of 78.6%, and an HPLC purity of 98.5%.
EXAMPLE 11 Synthesis of Compound represented by formula 6
Compound 4(1g,3.6mmol), compound 5(655.2mg,3.528mmol), KF (40% alumina) (378.7mg,6.48mmol) were dissolved in DMA (15mL), the reaction was stirred at room temperature for 2h, TLC detected complete reaction, the reaction solution was filtered, the cake was washed with ethyl acetate, the filtrate was extracted with saturated sodium bicarbonate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula 6 in an amount of 1096mg, yield 76.4%, and HPLC purity 98.0%.
EXAMPLE 12 Synthesis of Compound represented by formula 6
Compound 4(1g,3.6mmol), compound 5(869.18mg,4.68mmol), KF (40% alumina) (483.9mg,8.28mmol) were dissolved in DMA (15mL), the reaction was stirred at room temperature for 2h, TLC detected complete reaction, then the reaction solution was filtered, the cake was washed with ethyl acetate, the filtrate was extracted with saturated sodium bicarbonate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula 6 in an amount of 1089mg, yield 75.8%, and HPLC purity 98.4%.
Example 13 Synthesis of Compound represented by formula 7
Compound 6(1.5g,3.76mmol) was dissolved in dioxane (15mL), methylamine (1.17g,37.6mmol) was added, the mixture was stirred overnight in a closed kettle at 100 ℃, the reaction was detected by TLC, then cooled to room temperature, extracted with ethyl acetate (10mL), the resulting organic phase was washed with saturated sodium bicarbonate solution (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed with an appropriate amount of acetonitrile and water by beating to give the compound of formula 7 in an amount of 1.36g, yield 92.0%, and HPLC purity of 98.9%.
EXAMPLE 14 Synthesis of Compound represented by formula 7
Compound 6(1.5g,3.76mmol) was dissolved in dioxane (15mL), methylamine (0.936g,30.08mmol) was added, the mixture was stirred overnight in a closed vessel at 100 ℃, the reaction was detected by TLC, then cooled to room temperature, extracted with ethyl acetate (10mL), the resulting organic phase was washed with saturated sodium bicarbonate solution (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed with an appropriate amount of acetonitrile and water by beating to give the compound of formula 7 in an amount of 1.31g, yield 88.6%, and HPLC purity of 98.5%.
EXAMPLE 15 Synthesis of Compound represented by formula 7
Compound 6(1.5g,3.76mmol) was dissolved in dioxane (15mL), methylamine (1.404g,45.12mmol) was added, the mixture was stirred overnight in a closed kettle at 100 ℃, the reaction was detected by TLC, then cooled to room temperature, extracted with ethyl acetate (10mL), the resulting organic phase was washed with saturated sodium bicarbonate solution (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and washed with an appropriate amount of acetonitrile and water by beating to give the compound of formula 7 in an amount of 1.33g, a yield of 89.9%, and an HPLC purity of 98.2%.
EXAMPLE 16 Synthesis of Compound of formula I
Dissolving compound 7(1.50g,3.81mmol) and triethylamine (0.5mL) in THF (25mL), adding compound 8(832.2mg,6.87mmol) dropwise under the protection of nitrogen, stirring overnight at room temperature, after TLC detection reaction is complete, filtering the reaction solution, pulping and washing the obtained filter cake with an appropriate amount of acetonitrile and water, and drying to obtain the compound shown in formula I with the yield of 1.673g and the HPLC purity of 99.5%.
EXAMPLE 17 Synthesis of Compound of formula I
Dissolving a compound 7(1.50g,3.81mmol) and triethylamine (0.5mL) in THF (25mL), dropwise adding a compound 8(693.5mg,5.725mmol) under the protection of nitrogen, stirring overnight at room temperature, after TLC detection of complete reaction, filtering the reaction solution, pulping and washing the obtained filter cake with an appropriate amount of acetonitrile and water, and drying to obtain the compound shown in the formula I, wherein the yield is 83.0%, and the HPLC purity is 99.5%.
EXAMPLE 18 Synthesis of Compound of formula I
Dissolving a compound 7(1.50g,3.81mmol) and triethylamine (0.5mL) in THF (25mL), dropwise adding a compound 8(924.6mg,7.63mmol) under the protection of nitrogen, stirring overnight at room temperature, after TLC detection of complete reaction, filtering the reaction solution, pulping and washing the obtained filter cake with an appropriate amount of acetonitrile and water, and drying to obtain the compound shown in the formula I, wherein the yield is 1.585g, and the HPLC purity is 99.7%.
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 (9)
1. A process for preparing remotinib, comprising:
(1) contacting a compound represented by formula 1 with nitric acid to obtain a compound represented by formula 2;
(2) contacting the compound shown in the formula 2 with concentrated sulfuric acid and ethanol to obtain a compound shown in a formula 3;
(3) contacting the compound shown in the formula 3 with iron powder and ammonium chloride so as to obtain a compound shown in a formula 4;
(4) contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula 6;
(5) contacting a compound represented by formula 6 with methylamine to obtain a compound represented by formula 7;
(6) contacting a compound represented by formula 7 with a compound represented by formula 8 to obtain a compound represented by formula I, namely Rispertinib,
2. the method according to claim 1, wherein in step (1), the following steps are included: slowly adding the compound shown in the formula 1 into nitric acid at about-5 ℃, continuously stirring at the temperature of about-5 ℃ after the addition is finished, slowly dropwise adding the reaction liquid into the stirred ice water until solids are separated out after TLC detection reaction is completed, then filtering, washing a filter cake with proper amount of water, and drying to obtain the compound shown in the formula 2;
optionally, the mass volume ratio of the compound shown in the formula 1 to the nitric acid is 1 (1.3-1.6) (g/v);
optionally, the mass to volume ratio of the compound of formula 1 to nitric acid is 1:1.5 (g/v).
3. The method of claim 1, wherein in step (2), the following steps are included: dissolving the compound 2 in ethanol, dropwise adding concentrated sulfuric acid at 0 ℃, heating, refluxing and stirring overnight, after TLC detection reaction is completed, adding ethyl acetate, extracting with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating an organic layer, and purifying with a silica gel column to obtain a compound shown in a formula 3;
optionally, the mass-to-volume ratio of the compound shown in the formula 2 to concentrated sulfuric acid and ethanol is 1 (0.18-0.25): (18-25) (g/v/v);
optionally, the mass-to-volume ratio of the compound shown in the formula 1 to concentrated sulfuric acid and ethanol is 1:0.2:20 (g/v/v);
optionally, the column purification adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (30-60): 1;
optionally, the column purification uses a mixed solvent of dichloromethane and methanol in a volume ratio of 50: 1.
4. The method of claim 1, wherein in step (3), the following steps are included: dissolving the compound 3 in ethanol, sequentially adding iron powder and saturated ammonium chloride, then reacting, heating, stirring, detecting by TLC (thin layer chromatography) to complete reaction, cooling the reaction solution to room temperature, filtering with diatomite to obtain a filtrate, spin-drying the filtrate, dissolving with ethyl acetate, adding water for extraction, washing with saturated sodium bicarbonate, drying an organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain a compound shown in a formula 4;
optionally, at the temperature of 55-65 ℃, the compound shown in the formula 3 is contacted with iron powder and ammonium chloride, and the mixture is stirred and reacts for 45 minutes to 1.5 hours;
optionally, contacting the compound shown in the formula 3 with iron powder and ammonium chloride at 60 ℃, and stirring for reaction for 1 hour;
optionally, the molar ratio of the compound shown in the formula 3 to the iron powder and the ammonium chloride is 1 (10-13): (10-13);
optionally, the molar ratio of the compound shown in formula 3 to the iron powder and the ammonium chloride is 1: 11: 11.
5. the method according to claim 1, wherein in step (4), the following steps are included: dissolving compound 4, compound 5 and 40% alumina in dimethylacetamide, stirring at room temperature for reaction, detecting by TLC to complete the reaction, then filtering the reaction solution, washing the filter cake with ethyl acetate, extracting the filtrate with saturated sodium bicarbonate, washing with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound shown in formula 6;
optionally, the contact stirring reaction time of the compound shown in the formula 4, the compound shown in the formula 5 and 40% of alumina is 1.5-2.5 hours;
optionally, the contact stirring reaction time of the compound shown in the formula 4, the compound shown in the formula 5 and 40% of alumina is 2 hours;
optionally, the molar ratio of the compound shown in the formula 4 to the compound shown in the formula 5 to 40% of alumina is 1 (0.98-1.3): (1.8-2.3);
optionally, the molar ratio of the compound of formula 4 to the compound of formula 5, and 40% alumina is 1: 2.
6. the method according to claim 1, wherein in step (5), the following steps are included: dissolving a compound 6 in dioxane, adding methylamine, stirring overnight in a closed kettle, detecting by TLC to completely react, then cooling to room temperature, extracting by using ethyl acetate, washing an obtained organic phase by using a saturated sodium bicarbonate solution, drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure, pulping and washing by using an appropriate amount of acetonitrile and water to obtain a compound shown in a formula 7;
optionally, at the temperature of 95-100 ℃, the compound shown in the formula 6 is contacted with methylamine to be stirred and reacted;
optionally, contacting the compound shown as the formula 6 with methylamine at 100 ℃ and stirring for reaction;
optionally, the molar ratio of the compound of formula 6 to methylamine is 1: (8-12);
optionally, the molar ratio of the compound of formula 6 to methylamine is 1: 10.
7. The method according to claim 1, wherein in step (6), the following steps are included: dissolving a compound 7 and triethylamine in THF, dropwise adding a compound 8 under the protection of nitrogen, stirring overnight at room temperature for reaction, filtering reaction liquid after TLC detection reaction is complete, pulping and washing obtained filter cakes with an appropriate amount of acetonitrile and water, and drying to obtain a compound shown in a formula I;
optionally, the molar ratio of the compound of formula 7 to the compound of formula 8 is 1: (1.5-2);
optionally, the molar ratio of the compound of formula 7 to the compound of formula 8 is 1: 1.8.
8. The method of claim 1, wherein the synthetic route is selected from the group consisting of:
9. method according to claims 1-8, characterized in that it comprises the following steps:
(1) slowly adding the compound shown in the formula 1 (1.0g and 4.29mmol) into nitric acid (1.5mL) at about-5 ℃, keeping the temperature at about-5 ℃ and continuing stirring after the addition is finished, slowly dripping the reaction liquid into ice water (20mL) in stirring after TLC detection reaction is completed until solid is separated out, then filtering, washing a filter cake with proper amount of water, and drying to obtain the compound shown in the formula 2, wherein the amount of the compound is 1.1g, the yield is 92.2%, and the HPLC purity is 98.1%;
(2) compound 2(1.0g,3.60mmol) was dissolved in ethanol (20mL), concentrated sulfuric acid (0.2mL) was added dropwise at 0 ℃, the mixture was heated under reflux and stirred overnight, after completion of the TLC detection reaction, ethyl acetate (20mL) was added, followed by extraction with water (20mL), washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration of the organic layer, and purification through a silica gel column (DCM/MeOH ═ 50/1(v/v)) gave the compound represented by formula 3 in an amount of 0.97g, a yield of 88.0%, and an HPLC purity of 98.5%;
(3) dissolving compound 3(1g,3.27mmol) in ethanol (30mL), sequentially adding iron powder (2g,35.9mmol) and saturated ammonium chloride (7mL,35.9mmol), heating the reaction to 60 ℃, stirring for 1h, detecting complete reaction by TLC, cooling the reaction solution to room temperature, filtering with diatomite to obtain a filtrate, dissolving the filtrate with ethyl acetate (20mL) after spin-drying, adding water (20mL) for extraction, washing with saturated sodium bicarbonate (10mL), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating to obtain the compound shown in formula 4, wherein the yield is 0.75g, the yield is 83.1%, and the HPLC purity is 97.9%;
(4) dissolving compound 4(1g,3.6mmol), compound 5(668.6mg,3.6mmol) and KF (40% alumina) (420.8mg,7.2mmol) in DMA (15mL), stirring at room temperature for 2h, detecting by TLC that the reaction is complete, filtering the reaction solution, washing the filter cake with ethyl acetate, extracting the filtrate with saturated sodium bicarbonate, washing with saturated saline, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the compound shown in formula 6 with the yield of 1128mg, yield of 78.6% and HPLC purity of 98.5%;
(5) dissolving a compound 6(1.5g,3.76mmol) in dioxane (15mL), adding methylamine (1.17g,37.6mmol), stirring overnight in a closed kettle at 100 ℃, detecting complete reaction by TLC, cooling to room temperature, extracting with ethyl acetate (10mL), washing the obtained organic phase with a saturated sodium bicarbonate solution (10mL), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, pulping with an appropriate amount of acetonitrile and water, and washing to obtain a compound shown in a formula 7, wherein the yield is 1.36g, the yield is 92.0%, and the HPLC purity is 98.9%;
(6) dissolving compound 7(1.50g,3.81mmol) and triethylamine (0.5mL) in THF (25mL), adding compound 8(832.2mg,6.87mmol) dropwise under the protection of nitrogen, stirring overnight at room temperature, after TLC detection reaction is complete, filtering the reaction solution, pulping and washing the obtained filter cake with an appropriate amount of acetonitrile and water, and drying to obtain the compound shown in formula I with the yield of 1.673g and the HPLC purity of 99.5%.
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| CN114213411A (en) * | 2022-01-24 | 2022-03-22 | 成都伊诺达博医药科技有限公司 | Synthetic method of Rispertinib |
| WO2023122322A1 (en) * | 2021-12-24 | 2023-06-29 | Teva Pharmaceuticals International Gmbh | Improved processes for the preparation of ripretinib |
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| US8461179B1 (en) * | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
| CN104902895A (en) * | 2012-06-07 | 2015-09-09 | 德西费拉制药有限责任公司 | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
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| US8461179B1 (en) * | 2012-06-07 | 2013-06-11 | Deciphera Pharmaceuticals, Llc | Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases |
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| WO2023122322A1 (en) * | 2021-12-24 | 2023-06-29 | Teva Pharmaceuticals International Gmbh | Improved processes for the preparation of ripretinib |
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