CN111362923A - Method for preparing RET inhibitor pracetib, intermediate of pracetib and preparation method of pracetib - Google Patents
Method for preparing RET inhibitor pracetib, intermediate of pracetib and preparation method of pracetib Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 title abstract description 11
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 title abstract description 11
- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 216
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 105
- 238000006243 chemical reaction Methods 0.000 claims description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 66
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 48
- 238000004440 column chromatography Methods 0.000 claims description 40
- 238000003756 stirring Methods 0.000 claims description 38
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 31
- 239000012074 organic phase Substances 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 23
- 239000012046 mixed solvent Substances 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 19
- 239000007821 HATU Substances 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 18
- 238000005406 washing Methods 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 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 16
- 235000011152 sodium sulphate Nutrition 0.000 claims description 16
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 15
- 239000003480 eluent Substances 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 229940125782 compound 2 Drugs 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 238000006069 Suzuki reaction reaction Methods 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 3
- 238000006482 condensation reaction Methods 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 238000007142 ring opening reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 10
- 229940125898 compound 5 Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 239000012450 pharmaceutical intermediate Substances 0.000 description 4
- 230000036632 reaction speed Effects 0.000 description 4
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- GBLBJPZSROAGMF-RWYJCYHVSA-N 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 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-RWYJCYHVSA-N 0.000 description 2
- -1 Hexafluorophosphate Chemical compound 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 229940125905 RET kinase inhibitor Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 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
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- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 229940121597 pralsetinib Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
The invention relates to a method for preparing RET inhibitor prasutinib, an intermediate of prasutinib and a preparation method thereof. The method can rapidly and effectively prepare and obtain the prasutinib through four steps of Suzuki reaction, ring-opening reaction, deprotection and amide condensation reaction.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a method for preparing RET inhibitor pracetib, an intermediate of pracetib and a preparation method thereof.
Background
RET receptor tyrosine kinases are oncogenes that appear in a variety of cancers, including non-small cell lung cancer (NSCLC), Medullary Thyroid Carcinoma (MTC), and the like, whose abnormal 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.
Currently, no selective and specific drug and therapy for RET has been approved by regulatory agencies such as FDA. Pralsetinib (BLU-667, prasutinib) developed by Blueprint medicins as a highly selective Ret kinase inhibitor, including Ret kinase fusions and mutations (including drug resistant mutations), for oral treatment of NSCLC and MTC, including unresectable or metastatic. Currently, the phase 3 clinical completion of this drug is achieved, in 1 month 2020, the company submits pracetinib to the us FDA for NDA treatment for RET fusion positive MTC patients, currently in the drug 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 3, the compound shown in the formula 4 and the compound shown in the formula 5 are respectively intermediate compounds used for synthesizing and preparing the prasutinib, the 3 intermediate compounds are all new compounds, and the compound shown in the formula 3, the compound shown in the formula 4, the compound shown in the formula 5 and the preparation method thereof are not reported in documents. The structures of the compound shown in the formula 3, the compound shown in the formula 4 and the compound shown in the formula 5 are respectively as follows:
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 the RET inhibitor prasutinib, and an intermediate of the prasutinib and a preparation method thereof. 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, good quality of the obtained products and high purity.
In a first aspect of the invention, the invention provides a process for the preparation of the RET inhibitor pracetinib, 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 a compound represented by formula 3 with hydrochloric acid to obtain a compound represented by formula 4;
(3) reacting a compound represented by the formula 4 with CHBr3KOH and MeOH 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 I,
the inventor finds that the compound pracetib shown in the formula I can be quickly and effectively prepared by four steps of Suzuki reaction, ring-opening reaction, deprotection and amide condensation reaction by using the method, and the HPLC determination purity of the final pracetib raw material medicine product can reach more than 99.5%.
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 6, e.g., "compound of formula 2" may also be referred to herein as "compound 2".
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to embodiments of the present invention, the above-described method for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 5, 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, 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 compounds represented by the general formula 1, the compounds represented by the general formula 2 and the compounds represented by the general formula 6 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 1106871-37-7, 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), the compound represented by formula 1, the compound represented by formula 2, K2CO3And tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) The contact manner of (3) is not particularly limited. Thus, the compound represented by the formula 1, the compound represented by the formula 2, and K can be promoted2CO3And Pd (PPh)3)4The contact efficiency is improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: n is a radical of2Under protection, compound 1, compound 2 and K are mixed2CO3Toluene and H were added2Adding Pd (PPh) into the mixture, mixing the mixture evenly and adding the Pd (PPh)3)4Stirring, heating, refluxing, reacting, separating, extracting, washing, drying, concentrating, and purifying by column chromatography 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 step (1), the compound represented by formula 1, the compound represented by formula 2, K2CO3And Pd (PPh)3)4In a molar ratio of 1: (1.0-1: 5): (2.0-4.0): (0.01 to 0.02), preferably a compound represented by the formula 1, a compound represented by the formula 2, and K2CO3And Pd (PPh)3)4Is 1:1:2.5: 0.012. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to embodiments of the present inventionIn the step (1), the compound represented by the formula 1, the compound represented by the formula 2, and K may be reacted at 120 ℃2CO3And Pd (PPh)3)4Contact and stir for 2-2.5 hours.
According to a specific embodiment of the present invention, the compound represented by formula 1, the compound represented by formula 2, and K are preferably reacted at 120 ℃2CO3And Pd (PPh)3)4The contact reaction was carried out for 2 hours.
According to the embodiment of the invention, in the step (1), the column chromatography adopts a mixed solvent of dichloromethane and methanol in a volume ratio of (5-20): 1.
According to an embodiment of the present invention, in step (1), it is preferable that the column chromatography uses a mixed solvent of dichloromethane and methanol in a volume ratio of 10: 1.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: n is a radical of2Under protection, compound 1(26.8g, 0.1mol), compound 2(26.8g, 0.1mol) and K2CO3(34.6g, 0.25mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with Pd (PPh)3)4(1.39g, 0.0012mol), stirring, heating to 120 ℃, refluxing and reacting for 2h, cooling the reaction solution after the reaction is finished, separating out an organic phase, adding EA (100mL) into an aqueous phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 10:1 for elution), filtering the collected target eluent, and concentrating in vacuum 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 hydrochloric acid is not particularly limited. Preferably, the solvent of the reaction is selected from dioxane. Therefore, the contact efficiency of the compound shown in the formula 3 and the hydrochloric acid can be improved, the reaction speed is increased, and the preparation efficiency of 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 dioxane at room temperature, adding a hydrochloric acid solution, keeping the room temperature, stirring for reaction, and concentrating a reaction solution after the reaction is finished 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 hydrochloric acid is 1 (20-35), and preferably the molar ratio of the compound shown in the formula 3 to the hydrochloric acid is 1: 25. 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 invention, in step (2), the hydrochloric acid is formulated as a hydrochloric acid solution.
According to the embodiment of the invention, in the step (2), the compound shown in the formula 3 and the hydrochloric acid solution can be stirred and reacted for 9-12 hours at room temperature. Therefore, the contact efficiency of the compound 3 and the hydrochloric acid can be improved, and the efficiency of preparing the compound shown in 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 hydrochloric acid for reaction for 10 hours at room temperature. Therefore, the efficiency of contacting the compound 3 with the hydrochloric acid can be improved, and the efficiency of preparing the compound shown in the formula 4 by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: compound 3(8.0g, 0.0243mol) was placed in dioxane (80mL) at room temperature, 6M HCl solution (100mL) was added, the mixture was stirred at room temperature for 10 hours, and after completion of the reaction, the reaction mixture was concentrated to give the compound represented by formula 4.
According to an embodiment of the present invention, in step (3), the compound represented by formula 4 is reacted with the CHBr3The contact mode of KOH and MeOH is not particularly limited. Thus, the compound represented by the formula 4 and the CHBr can be elevated3KOH and MeOH, thereby accelerating the reaction speed and further improving the efficiency of preparing the compound shown in the formula 5 by using the method.
According to an embodiment of the present invention, in the step (3), the following steps are included: will be provided withCompound 4 with addition of CHBr3Adding KOH in MeOH slowly and dropwise at 0 ℃, stirring at 0 ℃ for reaction, heating to room temperature, and adding H2And stirring the reaction solution for reaction for 2 hours, adjusting the pH value of the reaction solution to 7 by using a 6M HCl solution, then generating white precipitate, filtering and drying to obtain the compound shown in the formula 5. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound shown in the formula 4 to the KOH is 1 (2.5-4), and preferably the molar ratio of the compound shown in the formula 4 to the KOH is 1: 3. 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 (3), the compound represented by formula 4 is reacted with CHBr3KOH and MeOH are stirred at 0 ℃ for 9-12 hours, preferably 10 hours. Thus, the contact efficiency can be improved, and the efficiency of preparing the compound represented by formula 5 by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: compound 4(28.5g, 0.1mol) was added to CHBr3(280mL), KOH (16.8g, 0.3mol) in MeOH (600mL) was slowly added dropwise at 0 deg.C, the reaction was stirred at 0 deg.C for 10H, warmed to room temperature, and H was added2O (570mL) was stirred for an additional 2 h. The reaction solution was adjusted to pH 7 with 6M HCl solution to form white precipitate, which was then filtered and dried to obtain the compound represented by formula 5.
According to an embodiment of the present invention, in the step (4), the contacting manner of the compound represented by formula 5, the compound represented by formula 6, 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 5 with the compound shown in the formula 6 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 an embodiment of the present invention, in the step (4), the following steps are included: reacting a compound represented by the formula 5 with a compound represented by the formula 6 at room temperatureAdding the compound into DMF, stirring, adding HATU and DIPEA, stirring at room temperature for reaction, and adding H after HPLC detection reaction2And (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 an embodiment of the present invention, in the step (4), the molar ratio of the compound represented by the formula 5, the compound represented by the formula 6, HATU, and DIPEA is 1 (1.0-1.3): 1.1-1.6, and preferably the molar ratio of the compound represented by the formula 5, the compound represented by the formula 6, HATU, and DIPEA is 1:1.0:1.0: 1.2. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (4), the compound represented by formula 5, the compound represented by formula 6, HATU, and DIPEA are contacted and reacted for 2 to 3 hours.
According to an embodiment of the present invention, in the step (4), the compound represented by formula 5, the compound represented by formula 6, HATU, and DIPEA may be contacted and reacted at room temperature for 2 hours.
According to the embodiment of the invention, in the step (4), the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of (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 a specific embodiment of the present invention, in the step (4), the following steps are included: adding the compound shown in the formula 5 (34.5g, 0.1mol) and the compound shown in the formula 6 (20.6g, 0.1mol) into DMF (350mL) at room temperature, stirring uniformly, adding HATU (38.0g, 0.1mol) and DIPEA (15.5g, 0.12mol), stirring and reacting for 2H while keeping the room temperature, and adding H after HPLC detection reaction2Extracting with O (300mL) and EA (300mL), washing the organic phase with saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography is eluted with a mixed solvent of dichloromethane and methanol at a volume ratio of 20: 1), filtering the collected target eluent, and vacuum concentrating to obtain solidThe compound is the pracetib shown in the formula I.
In a second aspect of the invention, the invention provides a pharmaceutical intermediate compound shown as a formula 3 for preparing prasutinib
In a third aspect of the invention, the invention provides a pharmaceutical intermediate compound shown as a formula 4 for preparing prasutinib
In a fourth aspect of the invention, the invention provides a pharmaceutical intermediate compound shown as a formula 5 for preparing prasutinib
The compound shown in the formula 3, the compound shown in the formula 4 and the compound shown in the formula 5 are all medical intermediate compounds used for synthesizing and preparing the prasutinib, the 3 intermediate compounds are all new compounds, and the preparation methods are not reported in documents.
As a pharmaceutical intermediate for the preparation of prasutinib: the preparation methods of the compound shown in the formula 3, the compound shown in the formula 4 and the compound shown in the formula 5 are respectively described in the specification of the invention.
According to embodiments of the present invention, the synthetic route for the compound prasutinib of formula I can be as follows:
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 6) to synthesize the target molecule prasutinib through four steps of Suzuki reaction, ring opening reaction, deprotection and amide condensation reaction.
2. The preparation method of the invention completes the original two-step protection reaction in one step in the process from the compound 4 to the compound 5 in the step 3, thereby reducing the reaction steps. The post-treatment of the compound 5 utilizes the characteristic of poor product solubility, and utilizes the pH adjustment to separate out the product, thereby improving the operability of the reaction.
3. The invention develops 3 medical intermediates for synthesizing and preparing the prasutinib, the medical intermediates are all new compounds, and the 3 compounds and the preparation method thereof are not reported in documents.
4. 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 final pracetinic raw material medicine has good quality, the product purity can reach more than 99.5 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
N2Under protection, compound 1(26.8g, 0.1mol), compound 2(26.8g, 0.1mol) and K2CO3(34.6g, 0.25mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with tetrakis (triphenylphosphine) palladium (Pd (PPh)3)4) (1.39g, 0.0012mol), stirring, heating to 120 ℃, refluxing and reacting for 2h, cooling the reaction solution after the reaction is finished, separating out an organic phase, adding EA (100mL) into an aqueous phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 10:1 for elution), filtering the collected target eluent, and concentrating in vacuum to obtain the compound shown in the formula 3, wherein the yield is 28.5g and 86.5%.
LC-MS(APCI):m/z＝330.3(M+1)+。
EXAMPLE 2 Synthesis of Compound represented by formula 3
N2Under protection, compound 1(26.8g, 0.1mol), compound 2(29.5g, 0.11mol) and K2CO3(27.6g, 0.2mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with Pd (PPh)3)4(1.16g, 0.001mol), stirring, heating to 120 ℃, refluxing for reaction for 2 hours and 15 minutes, cooling the reaction liquid after the reaction is finished, separating out an organic phase, adding EA (100mL) into a water phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 5:1 for elution), filtering the collected target eluent, and concentrating in vacuum to obtain the compound shown in the formula 3, wherein the yield is 27.0g and 82.0 percent.
EXAMPLE 3 Synthesis of Compound represented by formula 3
N2Under protection, compound 1(26.8g, 0.1mol), compound 2(26.8g, 0.15mol) and K2CO3(34.6g, 0.4mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with Pd (PPh)3)4(1.39g, 0.002mol), stirring, heating to 120 ℃, refluxing for reaction for 2.5 hours, cooling the reaction liquid after the reaction is finished, separating out an organic phase, adding EA (100mL) into an aqueous phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, and purifying the obtained oily substance by column chromatography (the column chromatography adopts dichloromethane and methanol in a volume ratio of 20: 1)Mixed solvent elution), filtering the collected target eluent, and concentrating in vacuum to obtain the compound shown in the formula 3, wherein the yield is 27.7g and 84.1%.
Example 4 Synthesis of Compound represented by formula 3
N2Under protection, compound 1(26.8g, 0.1mol), compound 2(26.8g, 0.16mol) and K2CO3(34.6g, 0.5mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with Pd (PPh)3)4(1.39g, 0.0024mol), stirring, heating to 120 ℃, refluxing for reaction for 2h, cooling the reaction solution after the reaction is finished, separating out an organic phase, adding EA (100mL) into an aqueous phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 10:1 for elution), filtering the collected target eluent, and concentrating in vacuum to obtain the compound shown in the formula 3, wherein the yield is 26.0g and 78.9%.
EXAMPLE 5 Synthesis of Compound represented by formula 3
N2Under protection, compound 1(26.8g, 0.1mol), compound 2(26.8g, 0.095mol) and K2CO3(34.6g, 0.2mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with Pd (PPh)3)4(1.39g, 0.001mol), stirring, heating to 120 ℃, refluxing for reaction for 2h, cooling the reaction solution after the reaction is finished, separating out an organic phase, adding EA (100mL) into an aqueous phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 10:1 for elution), filtering the collected target eluent, and concentrating in vacuum to obtain the compound shown in the formula 3, wherein the yield is 22.0g and 66.8%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
Compound 3(8.0g, 0.0243mol) was placed in dioxane (80mL) at room temperature, 6M HCl solution (100mL) was added, the mixture was stirred at room temperature for 10 hours, and after completion of the reaction, the reaction mixture was concentrated to give the compound represented by formula 4 in an amount of 7.7g with a yield of 96.2%.
LC-MS(APCI):m/z＝286.4(M+1)+。
Example 7 Synthesis of Compound represented by formula 4
Compound 3(8.0g, 0.0243mol) was placed in dioxane (80mL) at room temperature, 6M HCl solution (100mL) was added, the mixture was stirred at room temperature for reaction for 9 hours, and after completion of the reaction, the reaction mixture was concentrated to give the compound represented by formula 4 in an amount of 7.3g with a yield of 91.2%.
EXAMPLE 8 Synthesis of Compound represented by formula 4
Compound 3(8.0g, 0.0243mol) was placed in dioxane (80mL) at room temperature, 6M HCl solution (100mL) was added, the mixture was stirred at room temperature for 12 hours, and after completion of the reaction, the reaction mixture was concentrated to give the compound represented by formula 4 in an amount of 7.5g with a yield of 93.7%.
Example 9 Synthesis of Compound represented by formula 5
Compound 4(28.5g, 0.1mol) was added to CHBr3(280mL), KOH (16.8g, 0.3mol) in MeOH (600mL) was slowly added dropwise at 0 deg.C, the reaction was stirred at 0 deg.C for 10H, warmed to room temperature, and H was added2O (570mL) was stirred for an additional 2 h. The reaction mixture was adjusted to pH 7 with 6M HCl solution to form white precipitate, which was then filtered and dried to obtain 30.4g of the compound represented by formula 5, with a yield of 88.0%.
LC-MS(APCI):m/z＝346.4(M+1)+。
EXAMPLE 10 Synthesis of Compound represented by formula 5
Compound 4(28.5g, 0.1mol) was added to CHBr3(250mL), KOH (14g, 0.25mol) in MeOH (600mL) was added slowly dropwise at 0 deg.C, the reaction was stirred at 0 deg.C for 9H, warmed to room temperature, and H was added2O (550mL) was stirred for an additional 2 h. The reaction mixture was adjusted to pH 7 with 6M HCl solution to form white precipitate, which was then filtered and dried to obtain 29.7g of the compound represented by formula 5, with a yield of 86.0%.
EXAMPLE 11 Synthesis of Compound represented by formula 5
Compound 4(28.5g, 0.1mol) was added to CHBr3(350mL), KOH (22.4g, 0.4mol) in MeOH (660mL) was added slowly and dropwise at 0 deg.C, the reaction was stirred at 0 deg.C for 12h, warmed to room temperature,addition of H2The reaction was stirred for an additional 2h with O (600 mL). The reaction mixture was adjusted to pH 7 with 6M HCl solution to form white precipitate, which was then filtered and dried to obtain 29.3g of the compound represented by formula 5, with a yield of 84.8%.
Example 12 Synthesis of Prasetinib Compound of formula I
Adding compound 4(34.5g, 0.1mol) and compound 5(20.6g, 0.1mol) into DMF (350mL) 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 HPLC, adding H2Extracting with O (300mL) and EA (300mL), washing the organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the 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 the collected target eluent, and concentrating in vacuum to obtain a solid, namely the compound pracetib shown in the formula I, wherein the yield is 67.3%, and the HPLC purity 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 (350mL) 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, and adding H after HPLC detection2Extracting with O (300mL) and EA (300mL), washing the organic phase with saturated NaCl aqueous solution, drying with sodium sulfate, filtering and concentrating, purifying the obtained oily matter by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with the volume ratio of 10:1 for elution), filtering the collected target eluent, and concentrating in vacuum to obtain a solid, namely the compound pracetib shown in the formula I, wherein the yield is 64.1%, and the HPLC purity is 99.6%.
Example 14 Synthesis of a Compound of formula I, Prasetinib
Compound 4(34.5g, 0.1mol), Compound 5(26.8g, 0.13mol) was added to DMF at room temperature(350mL) was stirred well, HATU (49.4g, 0.13mol) and DIPEA (20.7g, 0.16mol) were added, the reaction was stirred at room temperature for 3H, and H was added after HPLC check2Extracting with O (300mL) and EA (300mL), washing the organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the 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 the collected target eluent, and concentrating in vacuum to obtain a solid, namely the compound pracetib shown in the formula I, wherein the yield is 63.6%, and the HPLC purity 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 (350mL) 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, and adding H after HPLC detection2Extracting with O (300mL) and EA (300mL), washing the organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the 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 the collected target eluent, and concentrating in vacuum to obtain a solid, namely the compound pracetib shown in the formula I, wherein the yield is 54.2%, and the HPLC purity is 93.5%.
EXAMPLE 16 Synthesis of Prasetinib Compound of formula I
Adding compound 4(34.5g, 0.1mol) and compound 5(20.6g, 0.15mol) into DMF (350mL) at room temperature, stirring uniformly, adding HATU (38.0g, 0.15mol) and DIPEA (15.5g, 0.18mol), stirring at room temperature for reaction for 2.5H, and adding H after HPLC detection2Extracting with O (300mL) and EA (300mL), washing the organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the 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 the collected target eluent, and concentrating in vacuum to obtain a solid, namely the compound pracetib shown in the formula I, wherein the yield is 57.8 g, and the HPLC purity 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 hydrochloric acid to obtain a compound represented by formula 4;
(3) reacting a compound represented by the formula 4 with CHBr3KOH and MeOH 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 I,
2. the method of claim 1, wherein the method is performed in a batch processThe step (1) comprises the following steps: n is a radical of2Under protection, compound 1, compound 2 and K are mixed2CO3Toluene and H were added2Adding Pd (PPh) into the mixture, mixing the mixture evenly and adding the Pd (PPh)3)4Stirring, heating, refluxing for reaction, performing post-treatment of separation, extraction, washing and drying after the reaction is finished, and purifying the obtained oily substance by column chromatography after the oily substance is concentrated to obtain a compound shown in a formula 3;
the step (2) comprises the following steps: placing the compound 3 in dioxane at room temperature, adding a hydrochloric acid solution, keeping the room temperature, stirring for reaction, and concentrating a reaction solution after the reaction is finished to obtain a compound shown in a formula 4;
in the step (3), the method comprises the following steps: adding Compound 4 to CHBr3Adding KOH in MeOH slowly and dropwise at 0 ℃, stirring at 0 ℃ for reaction, heating to room temperature, and adding H2Stirring the reaction solution for reaction for 2 hours, adjusting the pH of the reaction solution to 7 by using a 6M HCl solution, then generating white precipitate, filtering and drying to obtain a compound shown in a formula 5;
in the step (4), the method comprises the following steps: adding the compound shown in the formula 5 and the compound shown in the formula 6 into DMF at room temperature, stirring uniformly, adding HATU and DIPEA, keeping the room temperature for stirring reaction, adding H after HPLC detection reaction is finished2And (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.
3. The method according to claim 2, wherein in the step (1), the compound represented by formula 1, the compound represented by formula 2, K2CO3And Pd (PPh)3)4In a molar ratio of 1: (1.0-1: 5): (2.0-4.0): (0.01 to 0.02), preferably a compound represented by the formula 1, a compound represented by the formula 2, and K2CO3And Pd (PPh)3)4In a molar ratio of 1:1:2.5: 0.012;
optionally, in the step (1), the compound shown as the formula 1, the compound shown as the formula 2 and K are reacted at 120 DEG C2CO3And Pd (PPh)3)4Contact and stir for 2-2.5 hours; preferably, the compound represented by formula 1, the compound represented by formula 2, and K are reacted at 120 deg.C2CO3And Pd (PPh)3)4Contact reaction is carried out for 2 hours;
optionally, in the step (1), a mixed solvent of dichloromethane and methanol in a volume ratio of (5-20): 1 is adopted for column chromatography, and preferably, a mixed solvent of dichloromethane and methanol in a volume ratio of 10:1 is adopted for column chromatography.
4. The method according to claim 2, wherein in the step (2), the molar ratio of the compound shown in formula 3 to the hydrochloric acid is 1 (20-35), preferably the molar ratio of the compound shown in formula 3 to the hydrochloric acid is 1: 25;
optionally, in the step (2), the compound shown in the formula 3 is reacted with the hydrochloric acid solution at room temperature for 9-12 hours under stirring, and preferably, the compound shown in the formula 3 is contacted with the hydrochloric acid at room temperature for 10 hours.
5. The method according to claim 2, wherein in the step (3), the molar ratio of the compound represented by formula 4 to the KOH is 1 (2.5-4), preferably the molar ratio of the compound represented by formula 4 to the KOH is 1: 3;
optionally, in the step (3), the compound shown as the formula 4 is reacted with CHBr3KOH and MeOH are stirred at 0 ℃ for 9 to 12 hours, preferably at 0 ℃ for 10 hours.
6. The method according to claim 2, wherein in the step (4), the molar ratio of the compound represented by the formula 5, the compound represented by the formula 6, HATU and DIPEA is 1 (1.0-1.3) to (1.1-1.6), preferably the molar ratio of the compound represented by the formula 5, the compound represented by the formula 6, HATU and DIPEA is 1:1.0:1.0: 1.2;
optionally, in the step (4), the contact reaction time of the compound shown in the formula 5, the compound shown in the formula 6, HATU and DIPEA at room temperature is 2-3 hours; preferably, the compound represented by the formula 5, the compound represented by the formula 6, HATU and DIPEA are contacted and reacted at room temperature for 2 hours,
optionally, in the step (4), 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.
7. The method according to claims 1-6, wherein in step (1), the method comprises the steps of: n is a radical of2Under protection, compound 1(26.8g, 0.1mol), compound 2(26.8g, 0.1mol) and K2CO3(34.6g, 0.25mol) toluene (270mL) and H were added2O (55mL), mixed well, and added with Pd (PPh)3)4(1.39g, 0.0012mol), stirring, heating to 120 ℃, refluxing and reacting for 2h, cooling the reaction solution after the reaction is finished, separating out an organic phase, adding EA (100mL) into an aqueous phase for extraction, combining the organic phases, washing with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the obtained oily substance by column chromatography (the column chromatography adopts a mixed solvent of dichloromethane and methanol with a volume ratio of 10:1 for elution), filtering the collected target eluent, and concentrating in vacuum to obtain the compound shown in formula 3;
the step (2) comprises the following steps: placing the compound 3(8.0g, 0.0243mol) in dioxane (80mL) at room temperature, adding 6M HCl solution (100mL), keeping the room temperature, stirring and reacting for 10h, and concentrating the reaction solution after the reaction is finished to obtain the compound shown in the formula 4;
in the step (3), the method comprises the following steps: compound 4(28.5g, 0.1mol) was added to CHBr3(280mL), KOH (16.8g, 0.3mol) in MeOH (600mL) was slowly added dropwise at 0 deg.C, the reaction was stirred at 0 deg.C for 10H, warmed to room temperature, and H was added2Stirring O (570mL) for reacting for 2h, adjusting the pH of the reaction solution to 7 with 6M HCl solution to obtain white precipitate, filtering and drying to obtain the compound shown in the formula 5;
in the step (4), the method comprises the following steps: the compound represented by the formula 5 (34.5g, 0.1mol) and the compound represented by the formula 6 (20.6g, 0.1mol) were added to DMF (350mL) at room temperatureStirring well, adding HATU (38.0g, 0.1mol) and DIPEA (15.5g, 0.12mol), stirring at room temperature for 2H, after HPLC detection, adding H2Extracting with O (300mL) and EA (300mL), washing the organic phase with a saturated NaCl aqueous solution, drying with sodium sulfate, filtering, concentrating, purifying the 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 the collected target eluent, and concentrating in vacuum to obtain a solid, namely the compound pracetitinib shown in the formula I.
8. A compound shown as a formula 3, which is used for synthesizing a medical intermediate for preparing prasutinib,
9. a compound shown as a formula 4, which is used for synthesizing a medical intermediate for preparing prasutinib,
10. a compound shown as a formula 5, which is used for synthesizing a medical intermediate for preparing prasutinib,
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