CN111100076A - Preparation method of JAK inhibitor mometalonib - Google Patents
Preparation method of JAK inhibitor mometalonib Download PDFInfo
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- CN111100076A CN111100076A CN201911397632.5A CN201911397632A CN111100076A CN 111100076 A CN111100076 A CN 111100076A CN 201911397632 A CN201911397632 A CN 201911397632A CN 111100076 A CN111100076 A CN 111100076A
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Abstract
The invention relates to a preparation method of a JAK inhibitor mometalonib. The preparation method has the advantages of simple and mild preparation route and conditions, cheap and easily-obtained raw materials and low synthesis cost.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a preparation method of a JAK inhibitor mometalonib.
Background
Mometalonib (Momelotinib, or CYT387) is a JAK inhibitor, in particular to an oral ATP competitive JAK1/2 small molecule kinase inhibitor, which is used for treating IC of JAK1 and JAK250The values are respectively 11nM and 18nM, the selectivity of the compound on JAK1/2 is about 10 times of that of JAK3, and the compound has potential antitumor activity. The JAK-STAT signaling pathway is a major mediator of cytokine activity, and is often dysregulated in various types of tumor cells. Momerotinib competes for ATP binding with JAK1/2, so that activation of JAK1/2 is inhibited, a JAK-STAT signal channel is inhibited, apoptosis of tumor cells expressing JAK1/2 is induced, and proliferation of the tumor cells is reduced. JAK2 is the most common mutant gene in BCR-ABL negative myeloproliferative diseases; the functional gain mutation of JAK2V617F relates to position 617Modification of valine to phenylalanine. Mometalonib has been used in research to treat polycythemia vera, primary myelofibrosis, primary thrombocythemia, Primary Myelofibrosis (PMF), and the like.
The structural formula of mometalonib is shown in formula I:
currently, the preparation method of the mometalonib 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 preparation method of the JAK inhibitor mometalonib. The preparation method has the advantages of simple and mild preparation route and conditions, cheap and easily-obtained raw materials and low synthesis cost.
In one aspect of the invention, the invention provides a preparation method of the compound mometalonib shown in 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 a compound represented by formula 5 with the base to obtain a compound represented by formula 6;
(4) contacting a compound of formula 6 with a compound of formula 7 to obtain a compound of formula I, mometalonib,
the inventors have found that, by the method of the present invention, the chlorine at the 4-position of pyrimidine is more reactive in step (1), and the coupling reaction is likely to occur preferentially. In the step (2), when the 2-position chlorine is subjected to substitution reaction, a product with relatively high yield can be obtained. The alkylamine in the last step has higher activity than arylamine, and a product with higher yield can be obtained by condensation.
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 7, 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 I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the starting materials for preparing the compound represented by formula 3, the compound represented by formula 5, the compound represented by formula 6, and the compound represented by formula I is not particularly limited, and it may be prepared by any known method or may be commercially available.
According to the embodiment of the present invention, in the step (1), the contacting manner of the compound 1, the compound 2, and the tetrakistriphenylphosphine palladium is not particularly limited. Therefore, the contact efficiency of the compound 1, the compound 2 and the palladium tetratriphenylphosphine can be improved, the reaction speed is accelerated, 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 a compound 1 and a compound 2 in toluene and n-propanol, sequentially adding 2M sodium carbonate and tetratriphenylphosphine palladium into a reaction solution at room temperature, refluxing and stirring the reaction system under the protection of nitrogen overnight, detecting that the compound 1 has completely reacted by TLC, cooling the reaction solution to room temperature, adding water and ethyl acetate, filtering a mixture suspension by using kieselguhr, washing by using ethyl acetate to obtain a filtrate, separating out a water phase, extracting for three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, spin-drying to obtain a crude product, and purifying the crude product by using column chromatography to obtain a compound 3. Therefore, the contact efficiency of the compound 1, the compound 2 and the palladium tetratriphenylphosphine can be improved, the reaction speed is accelerated, 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 invention, in the step (1), the molar ratio of the compound 1, the compound 2 and the tetratriphenylphosphine palladium is 1 (1.6-3) to (0.05-0.2), and the molar ratio of the compound 1, the compound 2 and the tetratriphenylphosphine palladium is preferably 1:2: 0.1. 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), a mixed solvent of dichloromethane/methanol with a volume ratio of (10-30): 1 is adopted for column chromatography, and preferably, a mixed solvent of dichloromethane/methanol with a volume ratio of 10:1 is adopted for column chromatography.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: dissolving the compound 1(1g,5.55mmol) and the compound 2(1.65g,11.11mmol) in toluene (20mL) and n-propanol (6.5mL), adding 2M sodium carbonate (5mL) and tetrakistriphenylphosphine palladium (0.65g,0.56mmol) to the reaction solution at room temperature, refluxing and stirring the reaction system overnight under nitrogen protection, detecting that the compound 1 has reacted completely by TLC, cooling the reaction solution to room temperature, adding water and ethyl acetate, filtering the mixture suspension by a Buchner funnel filled with kieselguhr, washing with ethyl acetate to obtain a filtrate, separating out an aqueous phase, extracting three times with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, filtering, spin-drying to obtain a crude product, and purifying the crude product by column chromatography (using a dichloromethane/methanol mixed solvent with a volume ratio of 10: 1) to obtain the compound 3.
According to an embodiment of the present invention, in the step (2), the contacting manner of the compound 3, the compound 4, and the p-toluenesulfonic acid is not particularly limited. Therefore, the contact efficiency of the compound 3, the compound 4 and the p-toluenesulfonic acid 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: dissolving a compound 3 and a compound 4 in dioxane, adding p-toluenesulfonic acid under the stirring condition, heating and refluxing the reaction after the addition is finished, detecting the reaction is finished by HPLC (high performance liquid chromatography), cooling the reaction to room temperature, concentrating the mixture in vacuum, adding ethyl acetate and a 5% sodium carbonate solution into the mixture, stirring for 30 minutes to find that yellow solid is separated out, filtering to obtain a filter cake, pulping and purifying by using methanol, filtering, and drying in vacuum to obtain a product compound 5. Therefore, the contact efficiency of the compound 3, the compound 4 and the p-toluenesulfonic acid 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 invention, in the step (2), the molar ratio of the compound 3 to the compound 4 to the p-toluenesulfonic acid is 1 (1.0-1.3) to 1.0-1.5, and the molar ratio of the compound 3 to the compound 4 to the p-toluenesulfonic acid is preferably 1:1.1: 1.1. 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 reaction time of the compound 3, the compound 4 and the p-toluenesulfonic acid in contact heating reflux is 19-22 h. Therefore, the contact efficiency of the compound 3, the compound 4 and the p-toluenesulfonic acid can be improved, and the efficiency of preparing the compound shown in the formula 5 by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: compound 3(1g,4.02mmol), compound 4(788.44mg,4.42mmol) were dissolved in dioxane (20mL), p-toluenesulfonic acid (761.74mg,4.42mmol) was added with stirring, after the addition, the reaction was heated under reflux for 20h, the reaction was complete as detected by HPLC, the reaction was cooled to room temperature, the mixture was concentrated in vacuo, then ethyl acetate (5mL) and 5% sodium carbonate solution (5mL) were added thereto, after stirring for 30 minutes, yellow solid was found to precipitate, a filter cake was obtained by filtration, and the product compound 5 was purified by methanol (8mL) slurrying, filtered, and dried in vacuo to give 1.32g, yield 84.1%.
According to an embodiment of the present invention, in step (3), the manner of contacting compound 5 with the base is not particularly limited. Therefore, the contact efficiency of the compound 5 and the alkali can be improved, the reaction speed is accelerated, 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 a mixed solution of methanol and tetrahydrofuran, adding sodium hydroxide and water, heating to 65 ℃, stirring for 2 hours, detecting by TLC to complete reaction, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water, adjusting the pH value to 3 by using 10% hydrochloric acid under stirring, separating out a large amount of solids, filtering, drying the obtained filter cake to obtain a crude product, and pulping and purifying by using methanol 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 the embodiment of the invention, in the step (3), the molar ratio of the compound 5 to the base is 1 (1.5-3), and the molar ratio of the compound 5 to the base is preferably 1: 2. 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 base is an inorganic base, preferably the base is at least one selected from sodium hydroxide, or potassium hydroxide.
According to the embodiment of the invention, in the step (3), the volume ratio of methanol to tetrahydrofuran in the mixed solution of methanol and tetrahydrofuran is 3: 1.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: dissolving the compound 5(1g,2.56mmol) in a mixed solution of methanol and tetrahydrofuran (16 mL in total, the volume ratio of methanol to tetrahydrofuran is 3:1), adding sodium hydroxide (204.88mg,5.12mmol) and water (4mL), heating to 65 ℃, stirring for 2h, detecting by TLC that the reaction is complete, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water (20mL), adjusting the pH value to 3 with 10% hydrochloric acid under stirring, precipitating a large amount of solid, filtering, drying the obtained filter cake to obtain a crude product, and pulping and purifying with methanol to obtain the compound 6.
According to the embodiment of the present invention, in the step (4), the contact manner of the compound 6, triethylamine, the compound 7, HOBt and EDCI is not particularly limited. 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 (4), the following steps are included: dissolving the compound 6 in DMF, adding triethylamine into the reaction solution, adding the compound 7 while stirring, sequentially adding HOBt and EDCI, stirring the reaction system at room temperature overnight, detecting the complete reaction by TLC, and concentrating the reaction mixture under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography to obtain the compound mometalonib 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 invention, in the step (4), the molar ratio of the compound 6, the triethylamine, the compound 7, the HOBt and the EDCI is 1:6 (1.6-3) to 1.2:1.2, and preferably the molar ratio of the compound 6, the triethylamine, the compound 7, the HOBt and the EDCI is 1:6:2:1.2: 1.2. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to the embodiment of the invention, in the step (4), the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (20-50): 1, and preferably adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 10: 1.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(298mg,5.32mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion of the reaction, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1) to obtain the compound mometalonib shown in the formula I, wherein the yield is 1.01g, and the purity of HPCL is 99.4%.
According to an embodiment of the present invention, the synthetic route of the compound mometalonib of formula I can be as follows:
compared with the prior art, the preparation method of mometalonib has the following beneficial effects: according to the method, the intermediate compound which is easily obtained commercially is used as the starting raw material, the raw material is cheap and easily available, and by using the method, the activity of 4-site chlorine of pyrimidine is higher in the step (1), and the coupling reaction is easily and preferentially generated; in the step (2), a product with higher yield can be obtained when the 2-site chlorine is subjected to substitution reaction; the alkylamine activity in the last step is higher than that of arylamine, and the target compound momerlotinib with higher yield can be prepared by the condensation reaction of the compound 6 and the compound 7. The preparation method has the advantages of simple and mild preparation route and conditions, cheap and easily-obtained raw materials and low synthesis cost.
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
Compound 1(1g,5.55mmol), compound 2(1.65g,11.11mmol) were dissolved in toluene (20mL) and n-propanol (6.5mL), then 2M sodium carbonate (5mL) and tetrakistriphenylphosphine palladium (0.65g,0.56mmol) were added to the reaction solution in order at room temperature, the reaction system was stirred under reflux overnight under nitrogen protection, TLC detected that compound 1 had reacted completely, the reaction was cooled to room temperature, then water and ethyl acetate were added, the mixture suspension was filtered with a buchner funnel packed with celite, ethyl acetate was washed to give a filtrate, the aqueous phase was separated, extracted three times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried to give crude product, which was purified by column chromatography (using dichloromethane/methanol mixed solvent at volume ratio 10: 1) to give compound 3 in an amount of 0.955g with a yield of 69.2%.
1HNMR:(400MHz,CDCl3)δ8.71-8.70(d,1H),8.19-8.14(m,4H),7.71-7.70(d,1H),3.97(s,3H).
LCMS:249[M+H]+,271[M+Na]+.
EXAMPLE 2 Synthesis of Compound represented by formula 3
Compound 1(1g,5.55mmol), compound 2(1.323g,8.88mmol) were dissolved in toluene (20mL) and n-propanol (6.5mL), then 2M sodium carbonate (5mL) and tetrakistriphenylphosphine palladium (0.325g,0.28mmol) were added to the reaction solution in order at room temperature, the reaction system was stirred under reflux overnight under nitrogen protection, TLC detected that compound 1 had reacted completely, the reaction was cooled to room temperature, then water and ethyl acetate were added, the mixture suspension was filtered with a buchner funnel packed with celite, ethyl acetate was washed to give a filtrate, the aqueous phase was separated, extracted three times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and spin-dried to give a crude product, which was purified by column chromatography (using dichloromethane/methanol mixed solvent at a volume ratio of 30: 1) to give compound 3 in an amount of 0.872g, yield of 63.2%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
Compound 1(1g,5.55mmol), compound 2(2.48g,16.65mmol) were dissolved in toluene (20mL) and n-propanol (6.5mL), then 2M sodium carbonate (5mL) and tetrakistriphenylphosphine palladium (1.3g,1.12mmol) were added to the reaction solution in order at room temperature, the reaction system was stirred under reflux overnight under nitrogen protection, TLC detected that compound 1 had reacted completely, the reaction was cooled to room temperature, then water and ethyl acetate were added, the mixture suspension was filtered with a buchner funnel padded with celite, ethyl acetate was washed to give a filtrate, the aqueous phase was separated, extracted three times with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, spun-dried to give a crude product, which was purified by column chromatography (using dichloromethane/methanol mixed solvent at volume ratio 20: 1) to give compound 3 in an amount of 0.922g, yield of 66.8%.
EXAMPLE 4 Synthesis of Compound represented by formula 5
Compound 3(1g,4.02mmol), compound 4(788.44mg,4.42mmol) were dissolved in dioxane (20mL), p-toluenesulfonic acid (761.74mg,4.42mmol) was added with stirring, after the addition, the reaction was heated under reflux for 20h, the reaction was complete as detected by HPLC, the reaction was cooled to room temperature, the mixture was concentrated in vacuo, then ethyl acetate (5mL) and 5% sodium carbonate solution (5mL) were added thereto, after stirring for 30 minutes, yellow solid was found to precipitate, a filter cake was obtained by filtration, and the product compound 5 was purified by methanol (8mL) slurrying, filtered, and dried in vacuo to give 1.32g, yield 84.1%.
1HNMR:(400MHz,CDCl3)δ8.50-8.49(d,1H),8.17-8.13(m,4H),7.60-7.58(d,1H),7.17-7.16(d,1H),6.99-6.97(d,1H),3.98(s,3H),3.92-3.89(t,4H),3.18-3.15(t,4H).
LCMS:249[M+H]+,271[M+Na]+.
EXAMPLE 5 Synthesis of Compound represented by formula 5
Compound 3(1g,4.02mmol), compound 4(717.1mg,4.02mmol) were dissolved in dioxane (20mL), p-toluenesulfonic acid (692.8mg,4.02mmol) was added with stirring, after the addition, the reaction was heated under reflux for 19h, the reaction was complete as detected by HPLC, the reaction was cooled to room temperature, the mixture was concentrated in vacuo, then ethyl acetate (5mL) and 5% sodium carbonate solution (5mL) were added thereto, after stirring for 30 minutes, yellow solid was found to precipitate, a filter cake was obtained by filtration, and the product compound 5 was purified by methanol (8mL) slurrying, filtered, and dried in vacuo to give 1.29g, yield 82.2%.
EXAMPLE 6 Synthesis of Compound represented by formula 5
Compound 3(1g,4.02mmol), compound 4(932mg,5.23mmol) were dissolved in dioxane (20mL), p-toluenesulfonic acid (1142.6mg,6.03mmol) was added with stirring, after the addition, the reaction was heated under reflux for 22h, the reaction was complete as detected by HPLC, the reaction was cooled to room temperature, the mixture was concentrated in vacuo, then ethyl acetate (5mL) and 5% sodium carbonate solution (5mL) were added thereto, after stirring for 30 minutes, precipitation of a yellow solid was observed, the cake was obtained by filtration, purified by slurrying with methanol (8mL), filtered, and dried in vacuo to give compound 5 in an amount of 1.28g, yield 81.6%.
Example 7 Synthesis of Compound represented by formula 6
Dissolving a compound 5(1g,2.56mmol) in a mixed solution of methanol and tetrahydrofuran (16 mL in total, the volume ratio of methanol to tetrahydrofuran is 3:1), adding sodium hydroxide (204.9mg,5.12mmol) and water (4mL), heating to 65 ℃, stirring for 2h, detecting by TLC that the reaction is complete, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water (20mL), adjusting the pH value to 3 by using 10% hydrochloric acid under stirring, precipitating a large amount of solid, filtering, drying the obtained filter cake to obtain a crude product, pulping and purifying by using methanol to obtain a compound 6, wherein the amount of the compound 6 is 857mg, and the yield is 88.9%.
1HNMR:(300MHz,DMSO_d6)δ9.45(s,1H),8.53(d,J＝5.1Hz,1H),8.23(d,J＝8.1Hz,2H),8.09(d,J＝8.1Hz,2H),7.37(d,J＝5.1Hz,1H),6.93(d,J＝8.7Hz,2H),3.76-3.74(m,4H),3.07-3.04(m,4H),.
LCMS:377.2[M+H]+,375.1[M-H]-.
EXAMPLE 8 Synthesis of Compound represented by formula 6
Dissolving a compound 5(1g,2.56mmol) in a mixed solution of methanol and tetrahydrofuran (16 mL in total, the volume ratio of methanol to tetrahydrofuran is 3:1), adding sodium hydroxide (153.7mg,3.84mmol) and water (4mL), heating to 65 ℃, stirring for 2h, detecting by TLC that the reaction is complete, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water (20mL), adjusting the pH value to 3 with 10% hydrochloric acid under stirring, precipitating a large amount of solid, filtering, drying the obtained filter cake to obtain a crude product, and pulping and purifying by using methanol to obtain a compound 6, wherein the yield is 827mg and is 85.8%.
Example 9 Synthesis of Compound represented by formula 6
Dissolving a compound 5(1g,2.56mmol) in a mixed solution of methanol and tetrahydrofuran (16 mL in total, the volume ratio of methanol to tetrahydrofuran is 3:1), adding sodium hydroxide (307.3mg,7.68mmol) and water (4mL), heating to 65 ℃, stirring for 2h, detecting by TLC that the reaction is complete, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water (20mL), adjusting the pH value to 3 with 10% hydrochloric acid while stirring, wherein a large amount of solid is separated out, filtering, drying the obtained filter cake to obtain a crude product, and pulping and purifying by using methanol to obtain a compound 6, wherein the yield is 833mg and is 86.4%.
EXAMPLE 10 Synthesis of Momelaloninib, a Compound of formula I
Compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(298mg,5.32mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion of the reaction, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1) to obtain the compound mometalonib shown in the formula I, wherein the yield is 1.01g, and the purity of HPCL is 99.4%.
1HNMR:(300MHz,DMSO_d6)δ9.47(s,1H),9.32(t,J＝5.4Hz,1H),8.54(d,J＝5.1Hz,1H),8.27(d,J＝8.1Hz,2H),8.03(d,J＝8.1Hz,2H),7.67(d,J＝8.7Hz,2H),7.40(d,J＝5.1Hz,1H),6.94(d,J＝8.7Hz,2H),4.35(d,J＝5.1Hz,2H),3.77-3.74(m,4H),3.07-3.04(m,4H).
LCMS:415.1[M+H]+,437.1[M+Na]+,413.2[M-H]-.
EXAMPLE 11 Synthesis of Momelaloninib, a Compound of formula I
Compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(238mg,4.25mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with a volume ratio of 20: 1) to obtain the compound mometalonib shown in the formula I, wherein the obtained amount is 970mg, the yield is 88.0 percent, and the purity of HPCL is 99.2 percent.
EXAMPLE 12 Synthesis of Momelaloninib, a Compound of formula I
Compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(448mg,7.98mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with a volume ratio of 30: 1) to obtain the compound mometalonib shown in the formula I, wherein the obtained amount is 955mg, the yield is 86.6 percent, and the purity of HPCL is 99.6 percent.
EXAMPLE 13 Synthesis of Momelaloninib, a Compound of formula I
Compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(224mg,3.99mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with the volume ratio of 30: 1) to obtain the compound mometalonib shown in the formula I, wherein the yield is 865mg, the yield is 78.5 percent, and the purity of HPCL is 97.2 percent.
EXAMPLE 14 Synthesis of Momelaloninib, a Compound of formula I
Compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(522mg,9.31mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1) to obtain a compound represented by the formula I, namely the mometalonib, wherein the yield is 922g, the yield is 83.6 percent, and the purity of HPCL is 98.0 percent.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A method for preparing mometalonib, a compound shown as formula I, comprises the following steps:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting a compound represented by formula 3 with a compound represented by formula 4 to obtain a compound represented by formula 5;
(3) contacting a compound represented by formula 5 with the base to obtain a compound represented by formula 6;
(4) contacting a compound of formula 6 with a compound of formula 7 to obtain a compound of formula I, mometalonib,
2. the method according to claim 1, wherein in step (1), the following steps are included: dissolving a compound 1 and a compound 2 in toluene and n-propanol, sequentially adding 2M sodium carbonate and tetratriphenylphosphine palladium into a reaction solution at room temperature, refluxing and stirring the reaction system under the protection of nitrogen overnight, detecting that the compound 1 has completely reacted by TLC, cooling the reaction solution to room temperature, adding water and ethyl acetate, filtering a mixture suspension by using kieselguhr, washing by using ethyl acetate to obtain a filtrate, separating out a water phase, extracting for three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, spin-drying to obtain a crude product, and purifying the crude product by using column chromatography to obtain a compound 3.
3. The method as claimed in claim 2, wherein in the step (1), the molar ratio of the compound 1 to the compound 2 to the tetrakistriphenylphosphine palladium is 1 (1.6-3) to (0.05-0.2), preferably the molar ratio of the compound 1 to the compound 2 to the tetrakistriphenylphosphine palladium is 1:2: 0.1;
optionally, in the step (1), a mixed solvent of dichloromethane and methanol in a volume ratio of (10-30): 1 is adopted for column chromatography, and preferably, a mixed solvent of dichloromethane and methanol in a volume ratio of 10:1 is adopted for column chromatography.
4. The method according to claim 1, wherein in the step (2), the following steps are included: dissolving a compound 3 and a compound 4 in dioxane, adding p-toluenesulfonic acid under the stirring condition, heating and refluxing the reaction after the addition is finished, detecting the reaction is finished by HPLC (high performance liquid chromatography), cooling the reaction to room temperature, concentrating the mixture in vacuum, adding ethyl acetate and a 5% sodium carbonate solution into the mixture, stirring for 30 minutes to find that yellow solid is separated out, filtering to obtain a filter cake, pulping and purifying by using methanol, filtering, and drying in vacuum to obtain a product compound 5.
5. The method as claimed in claim 4, wherein in the step (2), the molar ratio of the compound 3 to the compound 4 to the p-toluenesulfonic acid is 1 (1.0-1.3) to (1.0-1.5), preferably the molar ratio of the compound 3 to the compound 4 to the p-toluenesulfonic acid is 1:1.1: 1.1;
optionally, in the step (2), the reaction time of the compound 3, the compound 4 and the p-toluenesulfonic acid in contact heating reflux is 19-22 h.
6. The method according to claim 1, wherein in step (3), the following steps are included: dissolving a compound 5 in a mixed solution of methanol and tetrahydrofuran, adding sodium hydroxide and water, heating to 65 ℃, stirring for 2 hours, detecting by TLC to complete reaction, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water, adjusting the pH value to 3 by using 10% hydrochloric acid under stirring, separating out a large amount of solids, filtering, drying the obtained filter cake to obtain a crude product, and pulping and purifying by using methanol to obtain a compound 6.
7. The method according to claim 6, wherein in the step (3), the molar ratio of the compound 5 to the base is 1 (1.5-3), preferably the molar ratio of the compound 5 to the base is 1: 2;
optionally, in the step (3), the base is an inorganic base, preferably the base is at least one selected from sodium hydroxide or potassium hydroxide;
optionally, in the step (3), the volume ratio of methanol to tetrahydrofuran in the mixed solution of methanol and tetrahydrofuran is 3: 1.
8. The method according to claim 1, wherein in step (4), the following steps are included: dissolving the compound 6 in DMF, adding triethylamine into the reaction solution, adding the compound 7 while stirring, sequentially adding HOBt and EDCI, stirring the reaction system at room temperature overnight, detecting the complete reaction by TLC, and concentrating the reaction mixture under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography to obtain the compound mometalonib shown in the formula I.
9. The method according to claim 8, wherein in the step (4), the molar ratio of the compound 6, the triethylamine, the compound 7, the HOBt and the EDCI is 1:6 (1.6-3) to 1.2:1.2, preferably the molar ratio of the compound 6, the triethylamine, the compound 7, the HOBt and the EDCI is 1:6:2:1.2: 1.2;
optionally, in the step (4), a mixed solvent of dichloromethane and methanol in a volume ratio of (20-50): 1 is adopted for column chromatography, and preferably, a mixed solvent of dichloromethane and methanol in a volume ratio of 50:1 is adopted for column chromatography.
10. The method according to claims 1-9, wherein in step (1), the following steps are included: dissolving a compound 1(1g,5.55mmol), a compound 2(1.65g,11.11mmol) in toluene (20mL) and n-propanol (6.5mL), sequentially adding 2M sodium carbonate (5mL) and tetratriphenylphosphine palladium (0.65g,0.56mmol) into a reaction solution at room temperature, refluxing and stirring the reaction system overnight under the protection of nitrogen, detecting that the compound 1 is completely reacted by TLC, cooling the reaction solution to room temperature, adding water and ethyl acetate, filtering a mixture suspension by using a Buchner funnel filled with kieselguhr, washing the ethyl acetate to obtain a filtrate, separating out a water phase, extracting three times by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and spin-drying to obtain a crude product, and purifying the crude product by using column chromatography (adopting a dichloromethane/methanol mixed solvent with a volume ratio of 10: 1) to obtain a compound 3;
the step (2) comprises the following steps: dissolving a compound 3(1g,4.02mmol) and a compound 4(788.44mg,4.42mmol) in dioxane (20mL), adding p-toluenesulfonic acid (761.74mg,4.42mmol) under stirring, heating and refluxing the reaction for 20h after the addition is finished, detecting the reaction completion by HPLC, cooling the reaction to room temperature, concentrating the mixture in vacuum, adding ethyl acetate (5mL) and a 5% sodium carbonate solution (5mL) into the mixture, stirring for 30 min, detecting that a yellow solid is separated out, filtering to obtain a filter cake, pulping and purifying by using methanol (8mL), filtering, and drying in vacuum to obtain a product compound 5;
in the step (3), the method comprises the following steps: dissolving a compound 5(1g,2.56mmol) in a mixed solution of methanol and tetrahydrofuran (16 mL in total, the volume ratio of methanol to tetrahydrofuran is 3:1), adding sodium hydroxide (204.88mg,5.12mmol) and water (4mL), heating to 65 ℃, stirring for 2h, detecting by TLC to complete reaction, cooling the reaction to room temperature, concentrating the solvent in vacuum, adding water (20mL), adjusting the pH value to 3 by using 10% hydrochloric acid under stirring, precipitating a large amount of solid, filtering, drying the obtained filter cake to obtain a crude product, and pulping and purifying by using methanol to obtain a compound 6;
in the step (4), the method comprises the following steps: compound 6(1g,2.66mmol) was dissolved in DMF (10mL), triethylamine (1.61g,15.94mmol) was added to the reaction mixture, compound 7(298mg,5.32mmol) was added with stirring, HOBt (430.78mg,3.19mmol) and EDCI (611.14mg,3.19mmol) were added sequentially, the reaction was stirred overnight at room temperature, TLC checked for completion of the reaction, and the reaction mixture was concentrated under reduced pressure. And adding DCM into the crude product to dissolve the crude product, extracting and washing the crude product by using a saturated sodium bicarbonate solution, combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the organic phases, and concentrating the organic phases under reduced pressure to obtain the crude product, and purifying the crude product by using column chromatography (adopting a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1) to obtain the compound mometalonib shown in the formula I.
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| CN103533939A (en) * | 2011-05-02 | 2014-01-22 | 澳大利亚Ym生物科学私人有限公司 | Multiple myeloma treatment |
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