CN111440151A - Method for preparing antitumor drug prasutinib - Google Patents
Method for preparing antitumor drug prasutinib Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 35
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims description 174
- 238000003756 stirring Methods 0.000 claims description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- 238000001914 filtration Methods 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 32
- 239000000126 substance Substances 0.000 claims description 28
- 239000012074 organic phase Substances 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 24
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 22
- 239000011701 zinc Substances 0.000 claims description 22
- 229910052725 zinc Inorganic materials 0.000 claims description 22
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 21
- 238000004440 column chromatography Methods 0.000 claims description 20
- 239000007821 HATU Substances 0.000 claims description 18
- CVJHVJHLJYPOSS-UHFFFAOYSA-N oxolane;zinc Chemical compound [Zn].C1CCOC1 CVJHVJHLJYPOSS-UHFFFAOYSA-N 0.000 claims description 18
- 239000000725 suspension Substances 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 17
- 235000011152 sodium sulphate Nutrition 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- 101150003085 Pdcl gene Proteins 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- 229940126214 compound 3 Drugs 0.000 claims description 11
- 239000012046 mixed solvent Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002244 precipitate Substances 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000012267 brine Substances 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000005909 Kieselgur Substances 0.000 claims description 6
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- -1 Hexafluorophosphate Chemical compound 0.000 claims description 4
- 239000012964 benzotriazole Substances 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 238000000643 oven drying Methods 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 239000012467 final product Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 6
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- GBLBJPZSROAGMF-BATDWUPUSA-N pralsetinib Chemical compound CO[C@]1(CC[C@@H](CC1)C1=NC(NC2=NNC(C)=C2)=CC(C)=N1)C(=O)N[C@@H](C)C1=CC=C(N=C1)N1C=C(F)C=N1 GBLBJPZSROAGMF-BATDWUPUSA-N 0.000 description 3
- 229940121597 pralsetinib Drugs 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000036632 reaction speed Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 229940125905 RET kinase inhibitor Drugs 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing an anti-tumor drug prasutinib. The preparation method has the advantages that the reaction steps of the route are few, the reaction steps are greatly reduced, the total yield of the reaction is improved, and the cost of the final product is effectively reduced.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing an anti-tumor drug pracetin.
Background
RET receptor tyrosine kinases are oncogenes that occur in a variety of cancers, including non-small cell lung cancer (NSC L C), Medullary Thyroid Carcinoma (MTC), and the like, whose aberrant activation is a key driver leading to the growth and proliferation of a variety of solid tumors that are very sensitive to selective RET inhibitors.
There is currently no selective, specific drug and therapy for RET that has been approved by regulatory authorities such as FDA, the pralsetinib developed by Blueprint medicins, which is a highly selective RET kinase inhibitor, including RET kinase fusion and mutations (including drug resistance mutations) for oral treatment of NSC L C and MTC, including unresectable or metastatic, phase 3 clinical completion of this drug, year 2020, 1 month, the company filed pralsetinib with the us FDA for the treatment of NDA of RET fusion-positive MTC, currently in the Pre-registration state.
WO2017079140 discloses prasutinib compounds as RET inhibitors, the chemical structure of which is as shown in formula I
The compound shown in the formula 4 is a key intermediate for synthesizing and preparing the prasutinib, the intermediate is a new compound, the compound shown in the formula 4 and the preparation method thereof are not reported in documents, and the structure of the compound shown in the formula 4 is as follows:
the preparation method of the pracetinic acid still needs to be improved at present.
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 preparing an anti-tumor drug prasutinib. The method has the advantages of few synthesis steps, mild reaction conditions, high reaction yield in each step, simple and convenient operation, high total yield of reaction products and high purity of the obtained products.
In a first aspect of the invention, the invention provides a preparation method of the compound pracetib 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 the base to obtain a compound represented by formula 4;
(3) contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula I, pracetin,
the inventor finds that the compound pracetin shown in the formula I can be quickly and effectively prepared by three steps of halogenation, demethylation protecting group and amide condensation reaction by using the method, and the purity of the final pracetin raw material medicine product detected by HP L C can reach more than 99.6%.
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 5, 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 methods for preparing the compound of formula 3, the compound of formula 4, and the compound of formula I may further have at least one of the following additional features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the raw materials for preparing the compound represented by formula 3, the compound represented by formula 4, 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. The compound represented by the general formula 1, the compound represented by the general formula 2 and the compound represented by the general formula 5 are all conventional compounds, wherein the CAS number of the compound represented by the general formula 1 is 2054922-17-5, the CAS number of the compound represented by the general formula 2 is 2097133-18-9, and the CAS number of the compound represented by the general formula 5 is 1980023-96-8.
According to an embodiment of the present invention, in step (1), formula 1 is shownCompound, Rieke zinc, compound shown as formula 2, [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl)2(dppf)) is not particularly limited. Preferably, the solvent of the reaction is selected from DMF. Thus, the compound represented by formula 1, the compound represented by formula 2, Rieke zinc and PdCl can be promoted2The efficiency of (dppf) contact accelerates the reaction rate, further improving the efficiency of preparing the compound represented by formula 3 by using the method.
According to an embodiment of the present invention, in the step (1), the following steps are included: n is a radical of2Compound 1 was dissolved in DMF and the Rieke zinc-THF suspension (Rieke zinc dissolved in THF to make 50mg/m L Rieke zinc-THF suspension) was added rapidly under protection, stirred at room temperature for 15min, then compound 2, PdCl was added2(dppf), stirring the above mixture, heating and stirring to react; cooling the reaction liquid to room temperature, adding ethyl acetate, stirring uniformly, filtering through diatomite, then adding water into the filtrate, extracting, separating liquid, separating out an organic phase, washing the organic phase with brine, drying with sodium sulfate, filtering and concentrating to obtain an oily substance; adding 2M HCl solution into the oily matter, stirring for 10min, adding dichloromethane, extracting, separating, adjusting pH of the water phase to 10 with 2M NaOH solution to obtain a large amount of white precipitate, filtering, and oven drying to obtain the compound shown in formula 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 the step (1), the compound represented by formula 1, Rieke zinc, the compound represented by formula 2, and PdCl2(dppf) in a molar ratio of (1.0 to 1.3): (1.0-1.3): 1 (0.02-0.1), preferably a compound represented by formula 1, Rieke zinc, a compound represented by formula 2, and PdCl2The molar ratio (dppf) was 1.1:1.1:1: 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 one embodiment of the present invention, when the compound of formula 1, Rieke zinc, the compound of formula 2, and PdCl2(dppf) in a molar ratio of 1:1:1.1: 0.05; or, when the compound shown in formula 1, Rieke zinc, the compound shown in formula 2 and PdCl2(dppf) molar ratioAt 1.5:1.5:1:0.1, the yield of the compound represented by formula 3 obtained by the preparation method of the present invention is low, which causes related reaction raw materials and practical waste.
According to an embodiment of the present invention, in the step (1), the compound represented by formula 1, Rieke zinc, the compound represented by formula 2, and PdCl may be reacted at 75 to 85 deg.C2(dppf) and the reaction was stirred for 45 to 90 minutes.
According to an embodiment of the present invention, in the step (1), the compound represented by formula 1, Rieke zinc, the compound represented by formula 2, and PdCl may be reacted at 80 deg.C2(dppf) contact reaction for 1 hour.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: n is a radical of2Compound 1(29.5g, 0.11mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (7.15g, 0.11mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added quickly under protection, stirred at room temperature for 15min, then Compound 2(29.8g, 0.1mol), PdCl were added2(dppf) (3.66g, 0.005mol), heating the mixture to 80 deg.C under stirring, reacting for 1H under stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring, filtering with diatomaceous earth, and adding H into the filtrate2O (300M L), extracting, separating an organic phase, washing the organic phase by using brine, drying by using sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) into the oily substance, extracting, separating, adjusting the pH value of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain the compound shown in the formula 3.
According to an embodiment of the present invention, in step (2), the contacting manner of the compound represented by formula 3 with the base is not particularly limited. Therefore, the efficiency of contacting the compound shown in the formula 3 with the alkali can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the following steps are included: and (3) placing the compound 3 in THF at room temperature, adding the alkali solution, heating, stirring, reacting, and carrying out post-treatment 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 (2), the molar ratio of the compound shown in the formula 3 to the base is 1 (3-7.5), and preferably the molar ratio of the compound shown in the formula 3 to the base is 1: 5. Therefore, the utilization rate of reactants is high, the waste of raw materials and reality can not be caused, and the yield and the purity of the target compound are high.
According to an embodiment of the present invention, in step (2), the base is an organic base or an inorganic base, preferably an inorganic base, more preferably the inorganic base is at least one selected from the group consisting of lithium hydroxide (L iOH), sodium hydroxide, potassium hydroxide, cesium hydroxide, and cesium carbonate.
According to an embodiment of the present invention, in step (2), preferably, the base is lithium hydroxide.
According to the embodiment of the invention, in the step (2), the compound shown in the formula 3 and the alkali are stirred and reacted for 1.5-2.5 h at 56-70 ℃. Thus, the efficiency of contacting the compound 3 with the base can be improved, and the efficiency of preparing the compound represented by the formula 4 by using the method can be further improved.
According to an embodiment of the present invention, in the step (2), the compound represented by formula 3 may be contacted with the base at 60 ℃ for a reaction of 2 hours. Thus, the efficiency of contacting the compound 3 with the base can be improved, and the efficiency of preparing the compound represented by the formula 4 by using the method can be further improved.
According to one embodiment of the invention, the step (2) comprises the steps of placing the compound 3(35.9g, 0.1mol) in THF (360M L), adding 2M L iOH solution (12g, 0.5mol), keeping stirring at 60 ℃ for reaction for 2h after heating, filtering the reaction solution, and concentrating the filtrate to dryness to obtain the compound shown in the formula 4.
According to an embodiment of the present invention, in the step (3), the contacting manner of the compound represented by formula 4, the compound represented by formula 5, 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), N-Diisopropylethylamine (DIPEA) is not particularly limited. Preferably, the solvent of the reaction is selected from DMF. 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 I by using the method is further improved.
According to the embodiment of the invention, the step (3) comprises the steps of adding the compound 4 and the compound 5 into DMF at room temperature, stirring uniformly, adding HATU and DIPEA, keeping the mixture stirring at room temperature for reaction, adding H after HP L C detects that the reaction is finished, and stirring uniformly2And (3) extracting with O and EA, washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, and purifying the obtained oily substance by column chromatography to obtain the compound prasutinib shown in the formula I. Therefore, the efficiency of preparing the prasutinib by using the method can be further improved.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound represented by the formula 4, the compound represented by the formula 5, HATU and DIPEA is 1 (1.0-1.3): 1.1-1.6, preferably the molar ratio of the compound represented by the formula 4, the compound represented by the formula 5, HATU and DIPEA is 1:1.0:1.0:1.2, so that the utilization rate of reactants is high, raw materials and actual waste are not caused, the yield of the target compound is high, and the purity of HP L C can reach more than 99.6%.
According to an embodiment of the present invention, in the step (3), the compound represented by formula 4, the compound represented by formula 5, HATU, and DIPEA are contacted and reacted for 2 to 3 hours.
According to an embodiment of the present invention, in the step (3), the compound represented by formula 4, the compound represented by formula 5, HATU, and DIPEA may be contacted and reacted at room temperature for 2 hours.
According to the embodiment of the invention, in the step (3), the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (10-50): 1, and preferably, the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 20: 1.
According to an embodiment of the invention, the step (3) comprises the steps of adding the compound 4(34.5g, 0.1mol) and the compound 5(20.6g, 0.1mol) into DMF (350m L) at room temperature, stirring uniformly, and adding 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (38).0g, 0.1mol) and N, N-Diisopropylethylamine (DIPEA) (15.5g, 0.12mol), the reaction was stirred at room temperature for 2H, HP L C was added after the reaction was complete2Extracting O (300m L) and EA (300m L), washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying an obtained oily substance by column chromatography (the column chromatography is eluted by a mixed solvent of dichloromethane and methanol with the volume ratio of 20: 1), filtering a collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasutinib shown in the formula I.
In another aspect of the invention, the invention provides a pharmaceutical intermediate compound shown as a formula 4 for preparing prasutinib
The compound shown in the formula 4 is a key intermediate for synthesizing and preparing prasutinib, the intermediate is a novel compound, and the compound shown in the formula 4 and the preparation method thereof are not reported in documents. The process for producing the intermediate of formula 4 for prasutinib is as described in the specification of the present invention.
According to embodiments of the present invention, the synthetic route for the compound prasutinib of formula I can be as follows:
the preparation method of the prasutinib is described in the specification of the invention.
The beneficial effects obtained by the invention are as follows:
1. the method adopts the existing commercially available drug intermediates (the compound shown in the formula 1, the compound shown in the formula 2 and the compound shown in the formula 5) to synthesize the target molecule pracetinic through three steps of halogenation, demethylation protecting group and amide condensation reaction in which an organic zinc reagent participates.
2. According to the preparation method, when the organic zinc reagent participates in the reaction post-treatment in the first step, the product is separated and purified by utilizing the property that the salt of imine and acid is dissolved in water, so that the silica gel column separation in the prior art is avoided, and the separation and purification method effectively improves the operability of the reaction.
3. According to the preparation method disclosed by the invention, the product is extracted after pH is not required to be adjusted when the acid protecting group is decarboxylated, so that the product loss (the product contains carboxyl and methylene, and the product is extracted by adjusting proper pH difficultly) is avoided.
4. The invention develops a key intermediate for synthesizing and preparing prasutinib, the intermediate is a new compound, and the compound and the preparation method thereof are not reported in documents.
5. Compared with the existing synthetic route, the preparation method of pracetinic acid provided by the invention has the advantages that the reaction steps in the prior art are greatly reduced, the reaction steps are few, the total yield of the reaction is improved, the cost of the final product is effectively reduced, the reaction conditions are mild and controllable, the industrialization is easy to realize, and the preparation method has good economic advantages. The synthetic route and the preparation method have the advantages of fewer reaction steps and mild reaction conditions, so that the total yield of reaction products is greatly improved, the purity of the final pracetinic raw material medicine product can reach more than 99.6 percent, and the method has good economic advantages.
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
N2Compound 1(29.5g, 0.11mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (7.15g, 0.11mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added rapidly under protection, stirred at room temperature for 15min, thenThen compound 2(29.8g, 0.1mol), PdCl were added2(dppf) (3.66g, 0.005mol), heating the mixture to 80 deg.C under stirring, reacting for 1H under stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring, filtering with diatomaceous earth, and adding H into the filtrate2O (300M L), extracting, separating an organic phase, washing the organic phase by brine, drying by sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) for extracting, separating, adjusting the pH of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain the compound shown in the formula 3, wherein the white solid is an off-white solid, the yield is 28.0g, and the yield is 77.9%.
LC-MS(APCI):m/z＝360.4(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
N2Compound 1(26.8g, 0.1mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (6.5g, 0.1mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added quickly under protection, stirred at room temperature for 15min, then Compound 2(29.8g, 0.1mol), PdCl were added2(dppf) (1.83g, 0.0025mol), heating the mixture to 75 deg.C under stirring, reacting for 1.5H under stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring, filtering with diatomaceous earth, and adding H into the filtrate2O (300M L), extracting, separating an organic phase, washing the organic phase by brine, drying by sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) for extracting, separating, adjusting the pH of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain the compound shown in the formula 3, wherein the white precipitate is an off-white solid, the yield is 26.5g, and the yield is 73.7%.
EXAMPLE 3 Synthesis of Compound represented by formula 3
N2Compound 1(29.5g, 0.13mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (8.45g, 0.13mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added rapidly under protection, stirred at room temperature for 15min, thenThen compound 2(29.8g, 0.1mol), PdCl were added2(dppf) (7.32g, 0.01mol), heating the mixture to 85 deg.C under stirring, reacting for 45 min under stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring, filtering with diatomaceous earth, and adding H to the filtrate2O (300M L), extracting, separating an organic phase, washing the organic phase by brine, drying by sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) for extracting, separating, adjusting the pH of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain the compound shown in the formula 3, wherein the white solid is an off-white solid, the yield is 27.0g, and the yield is 75.1%.
Example 4 Synthesis of Compound represented by formula 3
N2Compound 1(26.8g, 0.1mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (6.5g, 0.1mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added quickly under protection, stirred at room temperature for 15min, then Compound 2(32.8g, 0.11mol), PdCl were added2(dppf) (3.66g, 0.005mol), heating the mixture to 82 deg.C under stirring, reacting for 1H under stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring, filtering with diatomaceous earth, and adding H into the filtrate2O (300M L), extracting, separating liquid, separating an organic phase, washing the organic phase by brine, drying by sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) for extracting, separating liquid, adjusting the pH of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain the compound shown in the formula 3, wherein the white solid is 15.1g of compound, and the yield is 46.2%.
EXAMPLE 5 Synthesis of Compound represented by formula 3
N2Compound 1(29.5g, 0.15mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (7.15g, 0.15mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added quickly under protection, stirred at room temperature for 15min, then Compound 2(29.8g, 0.1mol), PdCl were added2(dppf)(7.32g，0.01mol), heating the mixed solution to 78 ℃ while stirring, reacting for 1H while stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring uniformly, filtering with diatomite, and adding H into the filtrate2O (300M L), extracting, separating an organic phase, washing the organic phase by brine, drying by sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) for extracting, separating, adjusting the pH of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain the compound shown in the formula 3, wherein the compound is an off-white solid, the yield is 21.8g, and the yield is 60.7%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
Compound 3(35.9g, 0.1mol) was placed in THF (360M L) at room temperature, 2M L iOH solution (12g, 0.5mol) was added, the temperature was raised, the reaction was kept at 60 ℃ and stirred for 2 hours, the reaction solution was filtered, and the filtrate was concentrated to dryness to give the compound represented by formula 4 in an amount of 34.0g with a yield of 98.4%.
LC-MS(APCI):m/z＝346.4(M+1)+。
Example 7 Synthesis of Compound represented by formula 4
Compound 3(35.9g, 0.1mol) was placed in THF (360M L) at room temperature, 2M L iOH solution (18g, 0.75mol) was added, the temperature was raised, the reaction was kept at 56 ℃ and stirred for 2.5 hours, the reaction solution was filtered, and the filtrate was concentrated to dryness to give the compound represented by formula 4 in an amount of 32.3g with a yield of 93.5%.
EXAMPLE 8 Synthesis of Compound represented by formula 4
Compound 3(35.9g, 0.1mol) was placed in THF (360M L) at room temperature, 2M L iOH solution (7.2g, 0.3mol) was added, the temperature was raised, the reaction was kept at 70 ℃ and stirred for 1.5 hours, the reaction solution was filtered, and the filtrate was concentrated to dryness to give the compound represented by formula 4 in 31.2g, yield 90.3%.
Example 9 Synthesis of Compound represented by formula 4
Compound 3(35.9g, 0.1mol) was placed in THF (360M L) at room temperature, 2M NaOH solution (10g, 0.25mol) was added, the temperature was raised, the reaction mixture was stirred at 60 ℃ for 2 hours, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give the compound represented by formula 4 in an amount of 26.1g with a yield of 75.6%.
EXAMPLE 10 Synthesis of Compound represented by formula 4
Compound 3(35.9g, 0.1mol) was placed in THF (360M L) at room temperature, 2M L iOH solution (19.2g, 0.8mol) was added, the temperature was raised, the reaction was stirred at 60 ℃ for 2 hours, the reaction solution was filtered, and the filtrate was concentrated to dryness to give 28.9g of the compound represented by formula 4, 83.7% yield.
EXAMPLE 11 Synthesis of Compound represented by formula 4
Compound 3(35.9g, 0.1mol) was placed in THF (360M L) at room temperature, 2M NaOH solution (32g, 0.8mol) was added, the temperature was raised, the reaction mixture was stirred at 60 ℃ for 2 hours, the reaction mixture was filtered, and the filtrate was concentrated to dryness to give the compound represented by formula 4 in an amount of 23.4g with a yield of 67.8%.
EXAMPLE 12 Synthesis of Pralsetinib, a Compound of formula I
Adding the compound 4(34.5g, 0.1mol) and the compound 5(20.6g, 0.1mol) into DMF (350m L) at room temperature, stirring uniformly, adding 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (38.0g, 0.1mol) and N, N-Diisopropylethylamine (DIPEA) (15.5g, 0.12mol), stirring at room temperature for 2H, detecting by HP L C, adding H2O (300m L) and EA (300m L), washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying an obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 20:1 for elution), filtering a collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasuginib shown in the formula I, wherein the yield is 35.9g, the yield is 67.3%, and the purity of HP L C is 99.8%.
LC-MS(APCI):m/z＝534.4(M+1)+。
Example 13 Synthesis of a Compound of formula I, Prasetinib
Adding compound 4(34.5g, 0.1mol) and compound 5(22.7g, 0.11mol) into DMF (350m L) at room temperature, stirring uniformly, adding HATU (41.8g, 0.11mol) and DIPEA (14.2g, 0.11mol), stirring at room temperature for reaction for 2.5H, detecting the reaction completion by HP L C, and adding H2O (300m L) and EA (300m L), the organic phase was washed with saturated aqueous NaCl solution and dried over sodium sulfateDrying, filtering and concentrating, purifying the obtained oily substance by column chromatography (the column chromatography is eluted by a mixed solvent of dichloromethane and methanol with the volume ratio of 10: 1), filtering the collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasutinib shown in the formula I, wherein the yield is 64.1 percent, and the purity of HP L C is 99.6 percent.
Example 14 Synthesis of a Compound of formula I, Prasetinib
Adding compound 4(34.5g, 0.1mol) and compound 5(26.8g, 0.13mol) into DMF (350m L) at room temperature, stirring uniformly, adding HATU (49.4g, 0.13mol) and DIPEA (20.7g, 0.16mol), stirring at room temperature for reaction for 3H, detecting the reaction completion by HP L C, and adding H2O (300m L) and EA (300m L), washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying an obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 50:1 for elution), filtering a collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasuginib shown in the formula I, wherein the yield is 33.9g, the yield is 63.6%, and the purity of HP L C is 99.7%.
EXAMPLE 15 Synthesis of Prasetinib Compound of formula I
Adding compound 4(38.0g, 0.11mol) and compound 5(20.6g, 0.1mol) into DMF (350m L) at room temperature, stirring uniformly, adding HATU (41.8g, 0.11mol) and DIPEA (12.9g, 0.1mol), stirring at room temperature for reaction for 2H, detecting the reaction completion by HP L C, and adding H2O (300m L) and EA (300m L), washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying an obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 20:1 for elution), filtering a collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasuginib shown in the formula I, wherein the yield is 28.9g, the yield is 54.2%, and the purity of HP L C is 93.5%.
EXAMPLE 16 Synthesis of Prasetinib Compound of formula I
Compound 4(34.5g, 0.1mol), Compound 5(20.6g, 0.15mol) were added to DMF (350m L) at room temperature, stirred well, HATU (38.0g, 0.15mol) andDIPEA (15.5g, 0.18mol), stirring at room temperature for 2.5H, detecting by HP L C, adding H2O (300m L) and EA (300m L), washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying an obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 20:1 for elution), filtering a collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasuginib shown in the formula I, wherein the yield is 57.8 g, and the purity of HP L C is 96.6%.
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 prasutinib, 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 a compound represented by formula 3 with the base to obtain a compound represented by formula 4;
(3) contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula I, pracetin,
2. the method according to claim 1, wherein in step (1), the following steps are included: n is a radical of2Under protection, the compound shown in the formula 1 is dissolved in DMF, Rieke zinc-THF suspension is rapidly added, stirring is carried out for 15min at room temperature, and then the compound shown in the formula 2 and PdCl are added2(dppf), stirring the above mixture, heating and stirring to react; cooling the reaction liquid to room temperature, adding ethyl acetate, stirring uniformly, filtering through diatomite, then adding water into the filtrate, extracting, separating liquid, separating out an organic phase, washing the organic phase with brine, drying with sodium sulfate, filtering and concentrating to obtain an oily substance; adding 2M HCl solution into the oily matter, stirring for 10min, adding dichloromethane, extracting, separating, adjusting pH of the water phase to 10 with 2M NaOH solution to obtain a large amount of white precipitate, filtering, and oven drying to obtain the compound shown in formula 3.
3. The method of claim 2, wherein in step (1), the compound of formula 1, Rieke zinc, the compound of formula 2, and PdCl2(dppf) in a molar ratio of (1.0 to 1.3): (1.0-1.3): 1 (0.02-0.1), preferably a compound represented by formula 1, Rieke zinc, a compound represented by formula 2, and PdCl2(dppf) in a molar ratio of 1.1:1.1:1:0.05,
optionally, in the step (1), the concentration of the Rieke zinc-THF suspension is 50mg/m L,
optionally, in the step (1), the compound shown as the formula 1, Rieke zinc, the compound shown as the formula 2 and PdCl are reacted at the temperature of 75-85 DEG C2(dppf) reacting for 45-90 minutes under stirring,
optionally, in the step (1), the compound shown as the formula 1, Rieke zinc, the compound shown as the formula 2 and PdCl are reacted at 80 DEG C2(dppf) contact reaction for 1 hour.
4. The method according to claim 1, wherein in the step (2), the following steps are included: and (3) placing the compound shown as the formula 3 into THF at room temperature, adding the alkali solution, heating, stirring, reacting, and carrying out aftertreatment to obtain the compound shown as the formula 4.
5. The method according to claim 4, wherein in the step (2), the molar ratio of the compound represented by the formula 3 to the base is 1 (3-7.5), preferably the molar ratio of the compound represented by the formula 3 to the base is 1:5,
optionally, in step (2), the base is an organic base or an inorganic base, preferably an inorganic base, more preferably the inorganic base is at least one selected from lithium hydroxide (L iOH), sodium hydroxide, potassium hydroxide, cesium carbonate, most preferably the base is lithium hydroxide,
optionally, in the step (2), the compound shown in the formula 3 and the alkali are stirred and reacted for 1.5-2.5 h at the temperature of 56-70 ℃,
optionally, in the step (2), the compound shown as the formula 3 is contacted and reacted with the base at 60 ℃ for 2 hours.
6. The method according to claim 1, wherein the step (3) comprises the steps of adding the compound represented by formula 4 and the compound represented by formula 5 to DMF at room temperature, stirring the mixture uniformly, adding HATU and DIPEA, keeping the mixture at room temperature, stirring the mixture for reaction, detecting the reaction with HP L C, and adding H after the reaction is completed2And (3) extracting with O and EA, washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, and purifying the obtained oily substance by column chromatography to obtain the compound prasutinib shown in the formula I.
7. The method according to claim 6, wherein in the step (3), the molar ratio of the compound represented by the formula 4, the compound represented by the formula 5, HATU and DIPEA is 1 (1.0-1.3) to (1.1-1.6), and preferably the molar ratio of the compound represented by the formula 4, the compound represented by the formula 5, HATU and DIPEA is 1:1.0:1.0: 1.2.
8. The method according to claim 6, wherein in the step (3), the compound represented by the formula 4, the compound represented by the formula 5, HATU and DIPEA are contacted and reacted for 2-3 hours, and preferably, the compound represented by the formula 4, the compound represented by the formula 5, HATU and DIPEA are contacted and reacted for 2 hours at room temperature;
optionally, in the step (3), the column chromatography is eluted by using a mixed solvent of dichloromethane and methanol in a volume ratio of (10-50): 1, and preferably, the mixed solvent of dichloromethane and methanol in a volume ratio of 20:1 is used for the column chromatography.
9. The method according to claims 1-8, wherein in step (1), the method comprises the steps of: n is a radical of2Compound 1(29.5g, 0.11mol) was dissolved in DMF (300m L) and Rieke Zinc-THF suspension (7.15g, 0.11mol, Rieke Zinc dissolved in THF to make 50mg/m L Rieke Zinc-THF suspension) was added quickly under protection, stirred at room temperature for 15min, then Compound 2(29.8g, 0.1mol), PdCl were added2(dppf) (3.66g, 0.005mol), heating the mixture to 80 deg.C under stirring, reacting for 1H under stirring, cooling the reaction solution to room temperature, adding EA (300m L), stirring, filtering with diatomaceous earth, and adding H into the filtrate2O (300M L), extracting, separating liquid, separating an organic phase, washing the organic phase by saline water, drying by sodium sulfate, filtering and concentrating to obtain an oily substance, adding a 2M HCl solution (150M L) into the oily substance, stirring for 10min, adding DCM (150M L) into the oily substance, extracting, separating liquid, adjusting the pH value of an aqueous phase to 10 by using a 2M NaOH solution to generate a large amount of white precipitate, filtering and drying to obtain a compound shown in a formula 3;
the step (2) comprises the following steps of placing the compound 3(35.9g, 0.1mol) in THF (360M L) at room temperature, adding 2M L iOH solution (12g, 0.5mol), keeping at 60 ℃ after heating, stirring for reaction for 2 hours, filtering the reaction solution, and concentrating the filtrate to dryness to obtain the compound shown in the formula 4;
in the step (3), the method comprises the following steps: at the room temperature, the reaction kettle is used for heating,adding compound 4(34.5g, 0.1mol) and compound 5(20.6g, 0.1mol) into DMF (350m L), stirring uniformly, adding 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (38.0g, 0.1mol) and N, N-Diisopropylethylamine (DIPEA) (15.5g, 0.12mol), stirring at room temperature for 2H, detecting by HP L C, adding H2Extracting O (300m L) and EA (300m L), washing an organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying an obtained oily substance by column chromatography (the column chromatography is eluted by a mixed solvent of dichloromethane and methanol with the volume ratio of 20: 1), filtering a collected target eluent, and concentrating in vacuum to separate out a solid, namely the compound prasutinib shown in the formula I.
10. A compound shown as a formula 4, which is used for synthesizing a medical intermediate for preparing prasutinib,
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