CN110922409A - Method for preparing BTK inhibitor zebritinib - Google Patents
Method for preparing BTK inhibitor zebritinib Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 37
- 229940124291 BTK inhibitor Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 150000001875 compounds Chemical class 0.000 claims description 152
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 54
- 238000003756 stirring Methods 0.000 claims description 40
- 239000000706 filtrate Substances 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000012046 mixed solvent Substances 0.000 claims description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 17
- 229940125782 compound 2 Drugs 0.000 claims description 17
- 229940125904 compound 1 Drugs 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 229940126214 compound 3 Drugs 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000010898 silica gel chromatography Methods 0.000 claims description 14
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 229940125898 compound 5 Drugs 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 7
- 235000011152 sodium sulphate Nutrition 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- 239000000376 reactant Substances 0.000 description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
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- 230000036632 reaction speed Effects 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 241000249820 Lipotes vexillifer Species 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
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- 239000011541 reaction mixture Substances 0.000 description 1
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- 238000007363 ring formation reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing a BTK inhibitor zerewitinib. The method uses an easily-obtained and cheap intermediate to obtain a target product through 5 steps of reaction.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a method for preparing a BTK inhibitor zetinib.
Background
Zebrintinib (Zanbutritinib) is a potent BTK inhibitor that has been used as a single agent or in combination with other therapies to develop clinical trials in the treatment of a variety of lymphomas. In 2018, 8 and 10 months, the application of zebritinib to NMPA for the new drug marketing in the treatment of relapsed or refractory Mantle Cell Lymphoma (MCL) and relapsed refractory Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) was filed in baiji state, and both were incorporated into the priority channel. On 15/11/2019, the U.S. FDA approved zebritinib developed in baiji state, a chinese company, as "breakthrough therapy" for its "priority rating" to be marketed under the trade designation BRUKINSA, which is a capsule with a dosage form of 80 mg.
The chemical structure of zetinib is shown as formula I:
the preparation method of the zerewitinoib at present 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 novel process of zerewitinoib and a preparation method thereof, wherein the process is simple, the yield is high, the reaction condition is mild, and the process can be effectively industrialized.
In one aspect of the invention, the invention provides a process for preparing a compound of 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 the compound represented by the formula 3 with D- (+) -dibenzoyltartaric acid (D-DBTA), Pd/C and hydrogen to obtain a compound represented by the formula 4;
(3) contacting a compound represented by formula 4 with HCl/dioxane to obtain a compound represented by formula 5;
(4) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(5) contacting a compound of formula 7 with methanesulfonic acid (MsOH) to obtain a compound of formula I zetidine,
the inventor finds that the compound shown in the formula I can be quickly and effectively prepared by using the method, and compared with the prior art, the method has the advantages of simple synthetic route and reaction steps, no need of extremely low temperature reaction, mild reaction conditions and easiness in industrial industrialization.
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 an embodiment of the present invention, the above method for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, and the compound represented by formula I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the starting materials for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, the compound represented by formula I is not particularly limited, and it may be prepared by any known method or commercially available.
According to an embodiment of the present invention, in step (1), the contacting manner of the compound represented by formula 1 and the compound represented by formula 2 is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 1 and the compound shown in the formula 2 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: compound 1, compound 2, AcOH and toluene were added in sequence. Under the protection of nitrogen, gradually heating and stirring until the reaction is finished. Cooling to room temperature, concentrating the filtrate, and subjecting the residue to silica gel column chromatography to obtain the compound represented by 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 (1), the molar ratio of the compound 1 to the compound 2 is 1 (1.0-1.5), and the molar ratio of the compound 1 to the compound 2 is preferably 1: 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 (1), the column chromatography purification is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (30-60): 1, and preferably, the column chromatography purification is performed by using a mixed solvent of dichloromethane and methanol in a volume ratio of 50: 1.
According to the embodiment of the present invention, in the step (1), the compound 1 and the compound 2 may be contacted and reacted at 80 to 95 ℃ for 2 to 3 hours, and preferably, the compound 1 and the compound 2 may be contacted and reacted at 90 ℃ for 2 hours and 15 minutes.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: compound 1(27.6g,0.1mol), Compound 2(33.9g,0.12mol), AcOH (30mL), and toluene (480mL) were added sequentially at room temperature. Under the protection of nitrogen, the temperature is gradually increased to 90 ℃ by stirring, and the reaction is carried out for 2 hours and 15 minutes by stirring. After the reaction, the reaction mixture was cooled to room temperature, the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 50: 1), and the collected objective filtrate was concentrated to dryness to obtain a compound represented by formula 3 as an off-white solid in an amount of 42.1g with a yield of 85.3%. Thus, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to an embodiment of the present invention, in step (2), the compound represented by formula 3 is reacted with D-DBTA, 10% Pd/C, and H2The contact manner of (3) is not particularly limited. Preferably, the solvent of the reaction is a THF solution. Thus, the compound represented by the formula 3 can be promoted with D-DBTA, 10% Pd/C, and H2The contact efficiency is improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the following steps are included: to a stirred THF solution of Compound 3 was added D-DBTA and 10% Pd/C, and H was bubbled through2Stirring is carried out until the reaction is finished. Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3Washing, recrystallizing with methanol and petroleum ether, and post-treating to obtain the compound shown in 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 (2), the molar ratio of the compound 3 to the D-DBTA is 1 (1.0-1.5), and the molar ratio of the compound 3 to the D-DBTA is preferably 1: 1.1. 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 mass ratio of the compound 3 to 10% Pd/C is 1: 0.05. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in step (2), the compound 3, D-DBTA, 10% Pd/C and H can be reacted at 35-40 deg.C2And (3) carrying out contact and stirring reaction for 2-2.5 hours.
According to an embodiment of the invention, in step (2), H is introduced2The pressure of (2 atm).
According to a specific embodiment of the present invention, in the step (2), the following steps are included: to a THF solution (200mL) of Compound 3(5.0g,0.01mol) were added D-DBTA (4.0g,0.011mol) and 10% Pd/C (0.25g), the mixture was replaced with nitrogen 3 times, and H was further introduced2(2atm), and stirring and reacting for 2 hours and 10 minutes at 35-40 ℃.Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3After washing, the product was recrystallized from methanol and petroleum ether, the resultant was further subjected to reverse-phase column chromatography, and the filtrate was concentrated under reduced pressure to dryness to give 3.9g of a brown oily substance which was the compound represented by formula 4 in a yield of 78.0%.
According to an embodiment of the present invention, the contacting manner of the compound represented by formula 4 with HCl/dioxane in step (3) is not particularly limited. Therefore, the efficiency of contacting the compound shown as the formula 4 with HCl/dioxane can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown as the formula 5 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the following steps are included: HCl/dioxane was added to a stirred solution of compound 4 in tetrahydrofuran at 0 ℃ and the reaction was stirred. And (5) carrying out post-treatment on the reaction solution to obtain the compound shown in the formula 5. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: to a stirred solution of Compound 4(35g, 0.07mol) in tetrahydrofuran (1000mL) was added HCl/dioxane (4M,2000mL) at 0 deg.C and the reaction was stirred for 0.5 h. The reaction was concentrated, ethyl acetate (1000mL) was added and saturated NaHCO was used3The solution was washed, dried and the organic phase was concentrated to obtain 26.6g of a white solid, which was the compound represented by formula 5 with a yield of 95%.
According to an embodiment of the present invention, in step (4), the compound represented by formula 5 is reacted with NaHCO3The contact manner of the compound represented by formula 6 is not particularly limited. Preferably, the solvent of the reaction is CH3CN and water. Thus, the compound of formula 5 can be promoted with NaHCO3And the efficiency of contacting the compound shown in the formula 6 accelerates the reaction speed, and further improves the efficiency of preparing the compound shown in the formula 7 by using the method.
According to an embodiment of the present invention, in the step (4), the following steps are included: dissolving the compound 5 in CH at-5 to 0 DEG C3CN solution and H2To O, NaHCO is added3Dropwise adding CH of compound 6 under the protection of nitrogen3CN solution, stirring after drippingAnd (5) finishing the reaction. Separating organic phase, adding ethyl acetate into water phase for extraction, adding sodium sulfate for drying, filtering, and concentrating the filtrate to obtain the compound shown in formula 7 as light yellow solid. This can further improve the efficiency of producing the compound represented by formula 7 by this method.
According to an embodiment of the present invention, in step (4), a compound represented by formula 5, NaHCO3The molar ratio of the compound shown in the formula 6 is 1 (2.0-3.5) to (1.1-1.4), preferably the compound shown in the formula 5 and NaHCO3The molar ratio of the compound represented by formula 6 is 1:2.5: 1.1. 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 (4), the compound represented by formula 5, NaHCO, may be reacted at-2 deg.C to 5 deg.C3And the compound shown in the formula 6 is contacted and stirred for reaction for 50 to 65 minutes.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: compound 5(40g,0.1mol) was dissolved in CH3CN (200mL) and H2O (200mL) at-5 deg.C, NaHCO3(21g,0.25mol) was added, and a solution of Compound 6(10g,0.11mol) in CH3CN (100mL) was added dropwise under nitrogen, after which the reaction was completed by stirring at 0 deg.C for 1 hour. The organic phase was separated, and ethyl acetate (200mL) was added to the aqueous phase for extraction, followed by addition of sodium sulfate, drying, filtration, and concentration of the filtrate to obtain 41.6g of a pale yellow solid, which is the compound represented by formula 7, in 91.7% yield.
According to an embodiment of the present invention, in step (5), the contacting manner of the compound represented by formula 7 with MsOH is not particularly limited.
According to an embodiment of the present invention, in the step (5), the following steps are included: adding the compound 7 into MsOH at room temperature, heating to 80-90 ℃, and stirring for 2-2.5 hours until the reaction is finished. Dropwise addition of H2O, stirring for 10 hours at 35-40 ℃, and adding CH into the reaction solution2Cl2Extracting, slowly adding a proper amount of 20% NaOH solution into the organic phase, and adjusting the pH value to 11-12. Concentrating the organic phase, drying, and performing silica gel column chromatography to obtain the compound zetinib shown in the formula I. Therefore, the method for preparing the compound shown in the formula I can be further improvedEfficiency of zebritinib.
According to an embodiment of the present invention, in the step (5), the mass-to-volume ratio of the compound represented by formula 7 to MsOH is 1:25 (g/v). 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 (5), the mixed solvent of dichloromethane and methanol with the volume ratio of (30-60): 1 is adopted for column chromatography, and preferably, the mixed solvent of dichloromethane and methanol with the volume ratio of 50:1 is adopted for column chromatography.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: compound 7(20g, 0.044mol) was added to MsOH (500mL) at room temperature, and the reaction was stirred for 2 hours and 15 minutes at 85 ℃. Cooling to room temperature, and then dropwise adding H2O (800mL), heating to 35-40 ℃, stirring for 10 hours, and adding CH into the reaction liquid2Cl2Extracting, slowly adding appropriate amount of 20% NaOH solution into organic phase, and adjusting pH to 11-12. Concentrating the organic phase, drying, purifying by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 50: 1), concentrating the filtrate to dryness to obtain the compound zeutinib shown in the formula I with the amount of 1.80g, the yield of 89.2% and the HPLC purity of 99.7%.
According to embodiments of the present invention, the synthetic route of the compound zetidine of formula I can be as follows:
compared with the prior art, the novel process and the preparation method of the zerewitinoib have the following beneficial effects: according to the method, the starting material is hydrogenated after ring closing reaction, then the Boc protecting group of secondary amine is removed, then alkylation is carried out, and finally cyano reduction is carried out to obtain the target compound Zebrintinib. Compared with the existing synthetic route, the reaction steps are all more than 10 steps, the route uses easily-obtained and cheap intermediates (such as a compound 1 as an intermediate and a compound 2 as an intermediate), and the target product is obtained through 5 steps of reaction, so that the reaction steps are greatly reduced, the total yield of the reaction is improved, and the industrial production of the product is favorably realized.
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
At room temperature, adding the compound 1(27.6g,0.1mol), the compound 2(33.9g,0.12mol), AcOH (120mL) and toluene (600mL) in sequence, stirring and gradually raising the temperature to 90 ℃ under the protection of nitrogen, stirring and reacting for 2 hours and 15 minutes, cooling to room temperature, concentrating the filtrate, purifying the residue by silica gel column chromatography (eluting by using a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1), and concentrating the collected target filtrate to dryness to obtain the compound shown in the formula 3, wherein the compound is an off-white solid, the yield is 42.1g, and the yield is 85.3%.
LC-MS(APCI):m/z＝494.3(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
At room temperature, adding the compound 1(27.6g,0.1mol), the compound 2(28.2g,0.10mol), AcOH (120mL) and toluene (600mL) in sequence, stirring and gradually raising the temperature to 95 ℃ under the protection of nitrogen, stirring and reacting for 2 hours, cooling to room temperature, concentrating the filtrate, purifying the residue by silica gel column chromatography (eluting by using a mixed solvent of dichloromethane and methanol with a volume ratio of 60: 1), and concentrating the collected target filtrate to dryness to obtain the compound shown in the formula 3, wherein the compound is an off-white solid, the yield is 37.7g, and the yield is 76.3%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
Compound 1(27.6g,0.1mol), Compound 2(42.4g,0.15mol), AcOH (130mL), and toluene (660mL) were added sequentially at room temperature. Under the protection of nitrogen, the temperature is gradually increased to 80 ℃ by stirring, and the reaction is carried out for 3 hours by stirring. Cooling to room temperature, concentrating the filtrate, purifying the residue by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 30: 1), and concentrating the collected target filtrate to dryness to obtain the compound shown in formula 3 as an off-white solid with a yield of 40.7g and 82.5%.
Example 4 Synthesis of Compound represented by formula 4
To a THF solution (200mL) of Compound 3(5.0g,0.01mol) were added D-DBTA (3.6g,0.01mol) and 10% Pd/C (0.25g), the mixture was replaced with nitrogen 3 times, and H was further introduced2(2atm), and stirring and reacting for 2 hours at 35-40 ℃. Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3After washing, the product was recrystallized from methanol and petroleum ether, the resultant was further subjected to reverse-phase column chromatography, and the filtrate was concentrated under reduced pressure to dryness to give 3.6g of a brown oily substance which was a compound represented by formula 4 in a yield of 72.1%.
LC-MS(APCI):m/z＝500.3(M+1)+。
EXAMPLE 5 Synthesis of Compound represented by formula 4
To a THF solution (200mL) of Compound 3(5.0g,0.01mol) were added D-DBTA (4.0g,0.011mol) and 10% Pd/C (0.25g), the mixture was replaced with nitrogen 3 times, and H was further introduced2(2atm), and stirring and reacting for 2 hours and 10 minutes at 35-40 ℃. Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3After washing, the product was recrystallized from methanol and petroleum ether, the resultant was further subjected to reverse-phase column chromatography, and the filtrate was concentrated under reduced pressure to dryness to give 3.9g of a brown oily substance which was the compound represented by formula 4 in a yield of 78.0%. EXAMPLE 6 Synthesis of Compound represented by formula 4
To a THF solution (200mL) of Compound 3(5.0g,0.01mol) were added D-DBTA (5.0g,0.015mol) and 10% Pd/C (0.25g), and the mixture was replaced with nitrogen 3 times, followed by feeding H2(2atm), and stirring and reacting for 2.5 hours at 35-40 ℃. Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3After washing, the product was recrystallized from methanol and petroleum ether, the resultant was further subjected to reverse-phase column chromatography, and the filtrate was concentrated under reduced pressure to dryness to give 3.8g of a brown oily substance which was a compound represented by formula 4 in a yield of 76.1%.
Example 7 Synthesis of Compound represented by formula 5
Stirring at 0 deg.CTo a solution of Compound 4(35g, 0.07mol) in tetrahydrofuran (1000mL) was added HCl/dioxane (4M,2000mL) and the reaction was stirred for 0.5 h. The reaction was concentrated, ethyl acetate (1000mL) was added and saturated NaHCO was used3The solution was washed, dried and the organic phase was concentrated to obtain 26.6g of a white solid, which was the compound represented by formula 5 with a yield of 95%.
LC-MS(APCI):m/z＝400.5(M+1)+。
EXAMPLE 8 Synthesis of Compound represented by formula 7
Compound 5(40g,0.1mol) was dissolved in CH at-5 deg.C3CN (200mL) and H2O (200mL), NaHCO was added3(21g,0.25mol), Compound 6(10g,0.11mol) CH was added dropwise under nitrogen protection3CN (100mL) solution was added dropwise, and the reaction was completed by stirring at 0 ℃ for 1 hour. The organic phase was separated, and ethyl acetate (200mL) was added to the aqueous phase for extraction, followed by addition of sodium sulfate, drying, filtration, and concentration of the filtrate to obtain 41.6g of a pale yellow solid, which is the compound represented by formula 7, in 91.7% yield.
LC-MS(APCI):m/z＝454.3(M+1)+。
Example 9 Synthesis of Compound represented by formula 7
Compound 5(40g,0.1mol) was dissolved in CH at-2 deg.C3CN (200mL) and H2O (200mL), NaHCO was added3(16.8g,0.2mol), Compound 6(10.9g,0.12mol) CH was added dropwise under nitrogen3CN (100mL) solution was added dropwise, and the mixture was stirred at-2 ℃ for 65 minutes to complete the reaction. The organic phase was separated, and ethyl acetate (200mL) was added to the aqueous phase for extraction, followed by addition of sodium sulfate, drying, filtration, and concentration of the filtrate to obtain 40.9g of a pale yellow solid, which is the compound represented by formula 7, in a yield of 90.1%. EXAMPLE 10 Synthesis of Compound represented by formula 7
Compound 5(40g,0.1mol) was dissolved in CH at 0 deg.C3CN (200mL) and H2O (200mL), NaHCO was added3(29.4g,0.35mol), CH of Compound 6(12.7g,0.14mol) was added dropwise under nitrogen3CN (100mL) solution was added dropwise, and the reaction was terminated by stirring at 5 ℃ for 50 minutes. Separating organic phase, extracting water phase with ethyl acetate (200mL), adding sodium sulfate, drying, filtering, concentrating filtrate to obtain light yellow solid 41.4g which is compound shown in formula 7, and collectingThe rate was 91.2%. EXAMPLE 11 Synthesis of Compound of formula I
Compound 7(20g, 0.044mol) was added to MsOH (500mL) at room temperature, and the reaction was stirred for 2 hours and 15 minutes at 85 ℃. Cooling to room temperature, and then dropwise adding H2O (800mL), heating to 35-40 ℃, stirring for 10 hours, and adding CH into the reaction liquid2Cl2Extracting, slowly adding appropriate amount of 20% NaOH solution into organic phase, and adjusting pH to 11-12. Concentrating the organic phase, drying, purifying by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 50: 1), concentrating the filtrate to dryness to obtain the compound zeutinib shown in the formula I with the amount of 1.80g, the yield of 89.2% and the HPLC purity of 99.7%.
LC-MS(APCI):m/z＝458.6(M+1)+。
EXAMPLE 12 Synthesis of Compound of formula I
Compound 7(20g, 0.044mol) was added to MsOH (500mL) at room temperature, and the reaction was stirred for 2.5 hours at 80 ℃. Cooling to room temperature, and then dropwise adding H2O (800mL), heating to 35-40 ℃, stirring for 10 hours, and adding CH into the reaction liquid2Cl2Extracting, slowly adding appropriate amount of 20% NaOH solution into organic phase, and adjusting pH to 11-12. Concentrating the organic phase, drying, purifying by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 30: 1), concentrating the filtrate to dryness to obtain the compound zeutinib shown in the formula I with the amount of 1.75g, the yield of 86.7% and the HPLC purity of 99.5%. EXAMPLE 13 Synthesis of Compound of formula I
Compound 7(20g, 0.044mol) was added to MsOH (500mL) at room temperature, and the reaction was stirred for 2 hours while increasing the temperature to 90 ℃. Cooling to room temperature, and then dropwise adding H2O (800mL), heating to 35-40 ℃, stirring for 10 hours, and adding CH into the reaction liquid2Cl2Extracting, slowly adding appropriate amount of 20% NaOH solution into organic phase, and adjusting pH to 11-12. Concentrating the organic phase, drying, purifying by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 60: 1), concentrating the filtrate to dryness to obtain the compound zeutinib shown in the formula I with the amount of 1.77g, the yield of 87.8% and the HPLC purity of 99.3%.
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 process for preparing a compound of formula I, comprising:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting the compound represented by the formula 3 with D- (+) -dibenzoyltartaric acid, Pd/C and hydrogen to obtain a compound represented by the formula 4;
(3) contacting the compound represented by formula 4 with HCl/dioxane to obtain a compound represented by formula 5;
(4) contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(5) contacting the compound of formula 7 with methanesulfonic acid to obtain the compound zebritinib of formula I,
2. the method according to claim 1, wherein in step (1), the following steps are included: sequentially adding the compound 1, the compound 2, AcOH and toluene, gradually heating and stirring under the protection of nitrogen until the reaction is finished, cooling to room temperature, concentrating the filtrate, and performing silica gel column chromatography on the residue to obtain a compound shown in a formula 3;
optionally, the molar ratio of the compound 1 to the compound 2 is 1 (1.0-1.5);
optionally, the molar ratio of compound 1 to compound 2 is 1: 1.2;
optionally, eluting by using a mixed solvent of dichloromethane and methanol in a volume ratio of (30-60): 1 for column chromatography purification, preferably, using a mixed solvent of dichloromethane and methanol in a volume ratio of 50:1 for column chromatography purification;
optionally, the compound 1 and the compound 2 are contacted and reacted for 2 to 3 hours at the temperature of 80 to 95 ℃, preferably, the compound 1 and the compound 2 are contacted and reacted for 2 hours and 15 minutes at the temperature of 90 ℃.
3. The method of claim 2, wherein in step (1), the following steps are included: compound 1(27.6g,0.1mol), Compound 2(33.9g,0.12mol), AcOH (30mL), and toluene (480mL) were added sequentially at room temperature. Under the protection of nitrogen, the temperature is gradually increased to 90 ℃ by stirring, and the reaction is carried out for 2 hours and 15 minutes by stirring. After the reaction is finished, cooling to room temperature, concentrating the filtrate, purifying the residue by silica gel column chromatography (eluting by using a mixed solvent of dichloromethane and methanol with the volume ratio of 50: 1), and concentrating the collected target filtrate to be dry to obtain the compound shown in the formula 3.
4. The method of claim 1, wherein in step (2), the following steps are included: to a stirred THF solution of Compound 3 was added D-DBTA and 10% Pd/C, and H was bubbled through2Stirring is carried out until the reaction is finished. Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3Washing, recrystallizing with methanol and petroleum ether, and post-treating to obtain compound shown in formula 4;
optionally, the molar ratio of the compound 3 to the D-DBTA is 1 (1.0-1.5), preferably the molar ratio of the compound 3 to the D-DBTA is 1: 1.1;
optionally, the mass ratio of the compound 3 to 10% Pd/C is 1: 0.05;
optionally, the compounds 3, D-DBTA, 10% Pd/C and H are reacted at 35 ℃ to 40 ℃2Contacting and stirring for reaction for 2-2.5 hours;
optionally, said passing H2The pressure of (2 atm).
5. The method of claim 4, wherein in step (2), the following steps are included: to a THF solution (200mL) of Compound 3(5.0g,0.01mol) were added D-DBTA (4.0g,0.011mol) and 10% Pd/C (0.25g), the mixture was replaced with nitrogen 3 times, and H was further introduced2(2atm), and stirring and reacting for 2 hours and 10 minutes at 35-40 ℃. Filtering the reaction solution, concentrating the filtrate, and using saturated NaHCO for the remainder3After washing, the product was recrystallized from methanol and petroleum ether, the resultant was further subjected to reverse phase column chromatography, and the filtrate was concentrated under reduced pressure to dryness to give 3.9g of a brown oily substance which was a compound represented by formula 4.
6. The method of claim 1, wherein in step (3), the following steps are included: HCl/dioxane was added to a stirred solution of compound 4 in tetrahydrofuran at 0 ℃ and the reaction was stirred. And (5) carrying out post-treatment on the reaction solution to obtain the compound shown in the formula 5.
7. The method of claim 6, wherein in step (3), the following steps are included: to a stirred solution of Compound 4(35g, 0.07mol) in tetrahydrofuran (1000mL) was added HCl/dioxane (4M,2000mL) at 0 deg.C and the reaction was stirred for 0.5 h. The reaction was concentrated, ethyl acetate (1000mL) was added and saturated NaHCO was used3The solution was washed, dried and the organic phase was concentrated to obtain 26.6g of a white solid, which was the compound represented by formula 5.
8. The method according to claim 1, wherein in step (4), the following steps are included: -5Dissolve Compound 5 in CH at-0 deg.C3CN solution and H2To O, NaHCO is added3Dropwise adding CH of compound 6 under the protection of nitrogen3And after the dripping of the CN solution is finished, stirring the solution for reaction till the reaction is finished. Separating organic phase, adding ethyl acetate into water phase for extraction, adding sodium sulfate for drying, filtering, and concentrating filtrate to obtain compound shown in formula 7;
optionally, the compound shown in the formula 5 and NaHCO3The molar ratio of the compound shown in the formula 6 is 1 (2.0-3.5) to (1.1-1.4), preferably the compound shown in the formula 5 and NaHCO3The molar ratio of the compound represented by formula 6 is 1:2.5: 1.1.
Optionally, the compound shown as the formula 5 and NaHCO are used at the temperature of-2 ℃ to 5 DEG C3The compound shown in the formula 6 is contacted and stirred for reaction for 50 to 65 minutes;
optionally, in the step (4), the following steps are included: compound 5(40g,0.1mol) was dissolved in CH3CN (200mL) and H2O (200mL) at-5 deg.C, NaHCO3(21g,0.25mol) was added, and a solution of Compound 6(10g,0.11mol) in CH3CN (100mL) was added dropwise under nitrogen, after which the reaction was completed by stirring at 0 deg.C for 1 hour. The organic phase was separated, and ethyl acetate (200mL) was added to the aqueous phase for extraction, followed by addition of sodium sulfate, drying, filtration, and concentration of the filtrate to obtain 41.6g of a pale yellow solid, which is a compound represented by formula 7.
9. The method according to claim 1, wherein in step (5), the following steps are included: adding the compound 7 into MsOH at room temperature, heating to 80-90 ℃, and stirring for 2-2.5 hours until the reaction is finished. Dropwise addition of H2O, stirring for 10 hours at 35-40 ℃, and adding CH into the reaction solution2Cl2Extracting, slowly adding appropriate amount of 20% NaOH solution into organic phase, and adjusting pH to 11-12. Concentrating the organic phase, drying, and performing silica gel column chromatography to obtain the compound zetinib shown in the formula I.
Optionally, the mass-to-volume ratio of the compound represented by formula 7 to MsOH is 1: 25.
Optionally, the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (30-60): 1, and preferably, the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 50: 1.
10. The method of claim 9, wherein in step (5), the steps of: compound 7(20g, 0.044mol) was added to MsOH (500mL) at room temperature, and the reaction was stirred for 2 hours and 15 minutes at 85 ℃. Cooling to room temperature, and then dropwise adding H2O (800mL), heating to 35-40 ℃, stirring for 10 hours, and adding CH into the reaction liquid2Cl2Extracting, slowly adding appropriate amount of 20% NaOH solution into organic phase, and adjusting pH to 11-12. Concentrating the organic phase, drying, purifying by silica gel column chromatography (eluting with a mixed solvent of dichloromethane and methanol at a volume ratio of 50: 1), concentrating the filtrate to dryness to obtain the compound zeutinib shown in the formula I with the amount of 1.80g, the yield of 89.2% and the HPLC purity of 99.7%.
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