CN114736205B - Preparation method of compound Tomivosertib - Google Patents
Preparation method of compound Tomivosertib Download PDFInfo
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- CN114736205B CN114736205B CN202210346083.4A CN202210346083A CN114736205B CN 114736205 B CN114736205 B CN 114736205B CN 202210346083 A CN202210346083 A CN 202210346083A CN 114736205 B CN114736205 B CN 114736205B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 230
- HKTBYUWLRDZAJK-UHFFFAOYSA-N 6-[(6-aminopyrimidin-4-yl)amino]-8-methylspiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione Chemical compound NC1=CC(=NC=N1)NC1=CC(=C2N(C1=O)C1(NC2=O)CCCCC1)C HKTBYUWLRDZAJK-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 229940121341 tomivosertib Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 126
- 238000000034 method Methods 0.000 claims abstract description 66
- 239000002994 raw material Substances 0.000 claims abstract description 34
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 147
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 111
- 239000000243 solution Substances 0.000 claims description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 42
- 239000003208 petroleum Substances 0.000 claims description 30
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 28
- 239000012046 mixed solvent Substances 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- 239000012141 concentrate Substances 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 20
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 18
- 239000000741 silica gel Substances 0.000 claims description 18
- 229910002027 silica gel Inorganic materials 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 14
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 239000012267 brine Substances 0.000 claims description 7
- 239000012074 organic phase Substances 0.000 claims description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 8
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000036632 reaction speed Effects 0.000 description 10
- 239000007858 starting material Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000005658 halogenation reaction Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102100026299 MAP kinase-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 1
- 101710139011 MAP kinase-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 1
- 102100033610 MAP kinase-interacting serine/threonine-protein kinase 2 Human genes 0.000 description 1
- 101710138999 MAP kinase-interacting serine/threonine-protein kinase 2 Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 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
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a kinase inhibitor compound Tomivosertib. Compared with the prior art, the preparation method has the advantages that the cyclohexanone is creatively added in the step (2), and then intramolecular dehydration condensation cyclization is carried out to obtain the target product, and compared with the problem of low selectivity when halogenated reaction is adopted to generate the product in other documents, the method not only simplifies the reaction steps, but also improves the reaction yield and is beneficial to reaction and purification. The preparation method of the compound Tomivosertib adopts commercial raw materials, is prepared by 5 steps of reaction, has higher overall yield of the route, mild reaction conditions, simple operation and simple purification process, and is suitable for the requirement of industrial mass production of the raw material medicines.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a preparation method of a kinase inhibitor compound Tomivosertib.
Background
The eFFECTATOR treatment company is developing Tomivosertib (EFT-508), a potent MNK1 and MNK2 kinase selective inhibitor, for oral treatment of cancer. At present, the clinical trial indications cover: diffuse large B-cell lymphoma, head and neck tumors, hepatocellular carcinoma, hormone refractory prostate cancer, lymphoma, metastatic breast cancer, metastatic colorectal cancer, non-small cell lung cancer, transitional cell carcinoma, solid tumors, all of which are currently in phase 2 clinical research, with the exception of metastatic breast cancer in phase 2 clinical research in canada, the remaining indications in phase 2 clinical research in the united states.
The chemical structure of Tomivosertib is specifically shown as formula I:
however, the current new preparation method of the compound Tomivosertib remains to be improved.
Disclosure of Invention
The present invention is directed to solving, at least in part, one of the technical problems in the related art. To this end, an object of the present invention is to propose a novel process for the preparation of the compound Tomivosertib. Compared with the prior art, the preparation method provided by the invention adopts commercially available raw materials, is prepared by 5 steps of reaction, has the advantages of higher overall yield of the route, mild reaction conditions, simplicity in operation and simple purification process, and is suitable for the requirement of industrial mass production of the raw material medicines. In the step (1), the carboxylic acid protecting group is removed by ammonia water, and then the amidation reaction is carried out simultaneously, so that the reaction steps are reduced, the yield is high, and the reaction time can be effectively shortened and the reaction efficiency is improved by adopting a sealed tube as a reaction container. Compared with the problem of low selectivity when products are generated by adopting a halogenation reaction in other documents, the method not only simplifies the reaction steps, but also can improve the reaction yield and is beneficial to reaction and purification. And (4) a catalyst and a ligand are added to carry out a specific halogenation reaction, so that the selectivity of the reaction is effectively improved, and side reactions are reduced.
In one aspect of the present invention, the present invention provides a process for the preparation of the compound Tomivosertib of formula I. According to an embodiment of the invention, the method comprises:
(1) Contacting the compound represented by formula 1 with ammonia water to obtain a compound represented by formula 2;
(2) Contacting the compound represented by formula 2 with cyclohexanone (the compound represented by formula 3) to obtain a compound represented by formula 4;
(3) Contacting the compound represented by formula 4 with Pd/C to obtain a compound represented by formula 5;
(4) Contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(5) Contacting the compound of formula 7 with Pd/C to obtain the compound of formula I,
the synthetic route of the invention adopts commercial raw materials (wherein the cas number of the compound shown in the formula 1 is 1509897-31-7, the cas number of the compound shown in the formula 3 is 108-94-1, and the cas number of the compound shown in the formula 6 is 126827-19-8), and the compound Tomivosertib shown in the formula I is prepared through 5 steps of reaction. The inventor finds that the preparation method has the advantages of high overall yield of the route, mild reaction conditions, simple operation and simple purification process, and is suitable for the requirement of industrial mass production of the bulk drugs.
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.
The terms "first", "second" and "first" are used herein for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
According to an embodiment of the present invention, the above method for preparing the compound represented by formula 2, the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, and the compound represented by formula I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the starting materials for preparing the compound represented by formula 2, the compound represented by formula 4, the compound represented by formula 5, the compound represented by formula 7, and the compound represented by formula I is not particularly limited, and it may be prepared by any known method or commercially available.
According to an embodiment of the present invention, in the step (1), the manner of contacting the compound represented by formula 1 with aqueous ammonia is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 and ammonia water can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 2 by using the method is further improved.
According to an embodiment of the present invention, in the step (1), the following steps are included: adding the compound shown in the formula 1 into methanol at room temperature, adding ammonia water into a sealed tube, stirring the mixture, heating the mixture at 60-68 ℃ for 2-45-3-30 minutes for reaction, wherein TLC shows that the raw materials are completely consumed, cooling the reaction liquid to room temperature, extracting the mixed liquid for three times by using ethyl acetate, combining organic phases, washing by using brine, concentrating, and using the volume ratio of a concentrate to be (8-12): purifying the product by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 2. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 and ammonia water can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 2 by using the method is further improved.
According to an embodiment of the present invention, in step (1), the mass-to-volume ratio of the compound represented by formula 1 to aqueous ammonia is 1 (30 to 40) (g/v), and preferably the mass-to-volume ratio of the compound represented by formula 1 to aqueous ammonia is 1. Therefore, the utilization rate of the reactants is high, the waste of raw materials and actual raw materials is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (1), it is preferable that the reaction temperature of the compound represented by formula 1 and aqueous ammonia is 65 ℃ and the reaction time is 3 hours. Therefore, the utilization rate of the reactants is high, the waste of raw materials and actual raw materials is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in step (1), the solvent for silica gel column chromatography is preferably 10:1, a mixed solvent of petroleum ether and ethyl acetate.
According to a specific embodiment of the present invention, in the step (1), the following steps are included: the compound of formula 1 (5.0 g, 0.0221mol) was added to methanol (15 mL) at room temperature, aqueous ammonia (180 mL) was added to a 500mL sealed tube, the mixture was stirred and heated at 65 ℃ for reaction for 3 hours, TLC showed complete consumption of the starting material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 90 mL), the organic phases were combined, washed with brine (90 mL) and concentrated, and the concentrate was diluted with 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 2 in an amount of 4.0g with a yield of 91.8%.
According to an embodiment of the present invention, in the step (2), the contact manner of the compound represented by formula 2 with the compound represented by formula 3, and the dioxane hydrochloride solution is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and the dioxane hydrochloride solution 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: adding a 4M dioxane hydrochloride solution into anhydrous dioxane solutions of a compound shown as a formula 2 and a compound shown as a formula 3 at room temperature in a sealed tube, heating to 100 ℃, reacting for 10 hours in the sealed tube, wherein TLC shows that raw materials are completely consumed, and after the reaction solution is concentrated under reduced pressure, the concentrate is prepared by using a solvent with a volume ratio of (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 4. Therefore, the efficiency of the contact reaction of the compound shown in the formula 2, the compound shown in the formula 3 and the dioxane hydrochloride solution 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 4M dioxane hydrochloride solution is prepared by: weighing a certain amount of dioxane, introducing dry HCl gas, weighing to a calculated amount, and stopping introducing the gas to obtain the dioxane.
According to an embodiment of the present invention, in step (2), the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 1 (1.0 to 1.2), and preferably the molar ratio of the compound represented by formula 2 to the compound represented by formula 3 is 1.0. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in the step (2), the mass-to-volume ratio of the compound represented by formula 2 to the anhydrous dioxane solution and the dioxane hydrochloride solution is 1. Thus, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in the step (2), it is preferable that the solvent for silica gel column chromatography is a solvent having a volume ratio of 10:1, a mixed solvent of petroleum ether and ethyl acetate.
According to a specific embodiment of the present invention, in the step (2), the following steps are included: after adding a 4M dioxane hydrochloride solution (200 mL) to an anhydrous dioxane solution (200 mL) of a compound represented by formula 2 (19.7g, 0.1mol) and a compound represented by formula 3 (9.8g, 0.1mol) at room temperature in a sealed tube, heating to 100 ℃ and reacting for 10 hours in the sealed tube, TLC showed complete consumption of the starting material, and after concentrating the reaction solution under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using the mixed solvent of petroleum ether/ethyl acetate of 1, to give 23.7g of the compound represented by formula 4 in 85.5% yield.
According to an embodiment of the present invention, the contacting manner of the compound represented by formula 4 with Pd/C in step (3) is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 and Pd/C can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the following steps are included: adding Pd/C into a methanol solution containing the compound shown in the formula 4 under the protection of nitrogen, replacing for 2-5 times by using hydrogen under vacuum, keeping the reaction liquid at 2.0-3.0 atmospheric pressure, keeping the temperature of 20-25 ℃, stirring and reacting, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to be dry to obtain a crude solid of the compound shown in the formula 5. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 and Pd/C can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 5 by using the method is further improved.
According to the embodiment of the invention, in the step (3), the Pd/C is 5-20% Pd/C, and preferably the Pd/C is 5% Pd/C, 10% Pd/C or 20% Pd/C.5% to 20% Pd/C is used as a catalyst for the catalytic hydrogenation, for example, 5% Pd/C means that the content of metallic Pd in the Pd/C mixture is 5%, and 10% Pd/C means that the content of metallic Pd in the Pd/C mixture is 10%.
According to an embodiment of the present invention, in step (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 10% Pd/C is 1. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to an embodiment of the present invention, in step (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 5% Pd/C is 1. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to an embodiment of the present invention, in step (3), it is preferable that the mass ratio of the compound represented by formula 4 to the 20% Pd/C is 1. Thus, the efficiency of preparing the compound represented by formula 5 using this method can be further improved.
According to a specific embodiment of the present invention, in the step (3), the following steps are included: 10% Pd/C (380 mg) was added to a methanol (150 ml) solution containing a compound represented by formula 4 (3.8g, 0.0137mol) under nitrogen protection, and the mixture was replaced with hydrogen gas under vacuum for 3 times, the reaction solution was maintained at 2.5 atmospheres, and stirred at 20 ℃ to 25 ℃ for reaction, after TLC showed complete consumption of the raw material, the reaction solution was filtered to remove Pd/C, and the filtrate was concentrated to dryness to give a crude solid represented by formula 5 (3.25 g), with a yield of 95.9%, which was used directly in the next reaction.
According to an embodiment of the present invention, in the step (4), the compound represented by the formula 5 is reacted with the compound represented by the formula 6 and Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The contact manner of (3) is not particularly limited. Thus, the compounds represented by the formula 5 and the compounds represented by the formula 6, and Pd (OAc) can be increased 2 、Xantphos、Cs 2 CO 3 The efficiency of the contact reaction is improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.
In accordance with an embodiment of the present invention,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 1,4-dioxane at room temperature, stirring uniformly, adding Pd (OAc) 2 Xantphos and Cs 2 CO 3 Heating the reaction solution under the protection of nitrogen and keeping the temperature at 96-100 ℃ for 4h, filtering the reaction solution after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of a concentrate is (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 7. Thus, the compounds represented by the formula 5 and the compounds represented by the formula 6, and Pd (OAc) can be increased 2 、Xantphos、Cs 2 CO 3 The efficiency of the contact reaction is improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 7 by using the method is further improved.
According to an embodiment of the present invention, in the step (4), the compound represented by the formula 5 is reacted with the compound represented by the formula 6 and Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1 (1.0-1.2): (0.12-0.2): 2.5-5, preferably 5 and 6, and Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1.05. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (4), it is preferable that the solvent for silica gel column chromatography is 10:1, a mixed solvent of petroleum ether and ethyl acetate.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: adding the compound of formula 5 (24.7g, 0.1mol) and the compound of formula 6 (16.7g, 0.105mol) to 1,4-dioxane (500 mL) at room temperature, stirring well, adding Pd (OAc) 2 (3.4g, 0.015mol), xantphos (14.4g, 0.015mol) and Cs 2 CO 3 (117.3 g, 0.36mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reaction for 4 hours, filtering the reaction solution after the reaction is finished, concentrating the reaction solution under reduced pressure, and concentrating the concentrate by using a volume ratio of 10: purifying the product of the petroleum ether/ethyl acetate mixed solvent of 1 on silica gel column chromatography to obtain the compound shown in the formula 7, and obtaining the amount34.6g, yield 93.4%.
According to an embodiment of the present invention, in step (5), the manner of contacting the compound represented by formula 7 with Pd/C is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 7 and Pd/C 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 (5), the following steps are included: adding Pd/C into a methanol solution containing the compound shown in the formula 7 under the protection of nitrogen, replacing for 2-5 times by hydrogen under vacuum, keeping the reaction solution at 2.0-3.0 atmospheric pressure, keeping the temperature at 20-25 ℃, stirring for reaction, filtering the reaction solution to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude product solid of the compound shown in the formula I, and recrystallizing the crude product to obtain a refined product solid of the compound shown in the formula I. Therefore, the efficiency of the contact reaction of the compound shown in the formula 7 and Pd/C 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 (5), the Pd/C is 5% -20% Pd/C, preferably the Pd/C is 5% Pd/C, 10% Pd/C, or 20% Pd/C. In the present invention, 5% to 20% Pd/C is used as a catalyst for catalytic hydrogenation, for example, 5% Pd/C means that the content of metallic Pd in the Pd/C mixture is 5%, and 10% Pd/C means that the content of metallic Pd in the Pd/C mixture is 10%.
According to an embodiment of the present invention, in step (5), it is preferable that the mass ratio of the compound represented by formula 7 to be reacted with the 10% Pd/C is 1. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to an embodiment of the present invention, in step (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 5% Pd/C is 1. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to an embodiment of the present invention, in step (5), it is preferable that the mass ratio of the compound represented by formula 7 to the 20% Pd/C is 1. Therefore, the efficiency of preparing the compound shown in the formula I by using the method can be further improved.
According to a specific embodiment of the present invention, in the step (5), the following steps are included: adding 10% Pd/C (300 mg) into a methanol (30 mL) solution containing a compound (3.0 g, 0.0081mol) shown in formula 7 under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, keeping the reaction solution at 2.5 atmospheric pressure, keeping the temperature of 20-25 ℃ and stirring for reaction, filtering the reaction solution to remove the Pd/C after TLC shows that raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in formula I, and recrystallizing the crude product (the solvent for recrystallization is petroleum ether/ethyl acetate =5/1, the crude product is about 2.8g, and the dosage ratio of the solvent is 1g/10mL (28 mL of the used crystallization solvent)) to obtain a refined solid of the compound shown in formula I, wherein the HPLC (HPLC) yield is 2.50g, the yield is 90.7%, and the purity is 99.8%.
According to embodiments of the present invention, the synthetic route for the compounds of formula I may be as follows:
compared with the prior art, the preparation method disclosed by the invention at least has the following beneficial effects: according to the method, the compound Tomivosertib shown in the formula I is prepared by using commercially available raw materials through 5 reaction steps. In the step 1, the amidation reaction is carried out simultaneously after the carboxylic acid protecting group is removed by using ammonia water, so that the reaction steps are reduced, and the yield is high. The reaction vessel is a sealed tube, so that the reaction time can be effectively shortened, and the reaction efficiency can be improved. Compared with the problem of low selectivity when halogenated reaction is adopted to generate products in other documents, the method not only simplifies the reaction steps, but also can improve the reaction yield and is beneficial to reaction and purification. Step 3 is a nitro reduction reaction. And 4, a catalyst and a ligand are added to carry out a specific halogenation reaction, so that the selectivity of the reaction is effectively improved, and side reactions are reduced. Step 3 is a nitro reduction reaction without purification. According to the preparation method, 2 steps (step 3 and step 5) in the 5-step reaction belong to a nitro reduction reaction, the nitro compound is selected as a raw material, so that the sites in the reaction can be reduced, the cyclization and halogenation reactions can be selectively carried out, and the reaction yield of each step can be effectively improved; the method has the advantages of high overall yield of the route, mild reaction conditions, simple operation and simple purification process, and is suitable for the requirement of industrial mass production of the raw material medicines.
Detailed Description
The following describes in detail embodiments of the present invention. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
EXAMPLE 1 Synthesis of Compound represented by formula 2
The compound of formula 1 (5.0 g, 0.0221mol) was added to methanol (15 mL) at room temperature, aqueous ammonia (180 mL) was added to a 500mL sealed tube, the mixture was stirred and heated at 65 ℃ for reaction for 3 hours, TLC showed complete consumption of the starting material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 90 mL), the organic phases were combined, washed with brine (90 mL) and concentrated, and the concentrate was diluted with 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 2 in an amount of 4.0g with a yield of 91.8%.
LC-MS(APCI):m/z＝198.2(M+1) + 。
Example 2 Synthesis of Compound represented by formula 2
The compound of formula 1 (5.0 g, 0.0221mol) was added to methanol (15 mL) at room temperature, aqueous ammonia (150 mL) was added to a 500mL sealed tube, the mixture was stirred and heated at 60 ℃ for reaction for 3 hours and 30 minutes, TLC showed complete consumption of the starting material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 90 mL), the organic phases were combined, washed with brine (90 mL) and concentrated, and the concentrate was diluted with 8: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 2 in an amount of 3.8g with a yield of 87.2%.
EXAMPLE 3 Synthesis of Compound represented by formula 2
At room temperature, the compound represented by formula 1 (5.0 g, 0.0221mol) was added to methanol (15 mL), aqueous ammonia (200 mL) was added to a 500mL sealed tube, the mixture was stirred and heated at 68 ℃ for 2 hours and 45 minutes, TLC showed complete consumption of the starting material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 90 mL), the organic phases were combined, washed with brine (90 mL) and concentrated, and the concentrate was concentrated using a volume ratio of 12: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 2 in an amount of 3.9g with a yield of 89.5%.
Example 4 Synthesis of Compound represented by formula 4
After adding a 4M dioxane hydrochloride solution (200 mL) to an anhydrous dioxane solution (200 mL) of a compound represented by formula 2 (19.7g, 0.1mol) and a compound represented by formula 3 (9.8g, 0.1mol) at room temperature in a sealed tube, heating to 100 ℃ and reacting for 10 hours in the sealed tube, TLC showed complete consumption of the starting material, and after concentrating the reaction solution under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 4 in an amount of 23.7g with a yield of 85.5%.
LC-MS(APCI):m/z＝278.3(M+1) + 。
EXAMPLE 5 Synthesis of Compound represented by formula 4
To an anhydrous dioxane solution (200 mL) of a compound represented by formula 2 (19.7 g,0.1 mol) and a compound represented by formula 3 (10.3 g, 0.105mol) was added a dioxane solution (200 mL) of 4M hydrochloric acid at room temperature in a sealed tube, and then the mixture was heated to 100 ℃ to react in the sealed tube for 10 hours, TLC showed complete consumption of the starting material, and after the reaction solution was concentrated under reduced pressure, the concentrate was concentrated with a volume ratio of 10: the product was purified by column chromatography on silica gel using the mixed solvent of petroleum ether/ethyl acetate of 1, to give 23.6g of the compound represented by formula 4 in 85.1% yield.
Example 6 Synthesis of Compound represented by formula 4
After adding a 4M dioxane hydrochloride solution (200 mL) to an anhydrous dioxane solution (200 mL) of a compound represented by formula 2 (19.7g, 0.1mol) and a compound represented by formula 3 (11.8g, 0.12mol) at room temperature in a sealed tube, heating to 100 ℃ and reacting in the sealed tube for 10 hours, wherein TLC shows complete consumption of the raw materials, and after the reaction solution is concentrated under reduced pressure, the concentrate is concentrated by a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 4 in an amount of 22.7g with a yield of 81.9%.
Example 7 Synthesis of Compound represented by formula 5
To a solution of the compound represented by formula 4 (3.8g, 0.0137mol) in methanol (150 ml) under nitrogen protection was added 10% Pd/C (380 mg), and the mixture was replaced with hydrogen gas 3 times under vacuum, the reaction solution was maintained at 2.5 atmospheres, and the reaction was stirred at 20 ℃ to 25 ℃, and TLC showed that the raw material was completely consumed, the reaction solution was filtered to remove Pd/C, and the filtrate was concentrated to dryness to give a crude solid of the compound represented by formula 5 (3.25 g), with a yield of 95.9%, which was used as it was in the next reaction.
LC-MS(APCI):m/z＝248.3(M+1) + 。
EXAMPLE 8 Synthesis of Compound represented by formula 5
To a solution of the compound represented by the formula 4 (3.8g, 0.0137mol) in methanol (150 ml) under nitrogen protection was added 5% Pd/C (760 mg), and the mixture was replaced with hydrogen gas 2 times under vacuum, the reaction solution was maintained at 2.0 atmospheres, and the reaction was stirred at 20 ℃ to 25 ℃, and after TLC showed complete consumption of the raw materials, the reaction solution was filtered to remove Pd/C, and the filtrate was concentrated to dryness to give a crude solid of the compound represented by the formula 5 (3.21 g, yield 94.8%, which was used as it was in the next reaction.
Example 9 Synthesis of Compound represented by formula 5
After adding 20% Pd/C (190 mg) to a methanol (150 ml) solution containing the compound represented by the formula 4 (3.8g, 0.0137mol) under nitrogen protection, replacing 5 times with hydrogen in vacuo, maintaining the reaction solution at 3.0 atm, maintaining 20 ℃ to 25 ℃ and stirring for reaction, after TLC showed complete consumption of the raw materials, filtering the reaction solution to remove Pd/C, and concentrating the filtrate to dryness, 3.22g of a crude solid of the compound represented by the formula 5 was obtained, with a yield of 95.1%, and the crude product was directly used in the next reaction.
EXAMPLE 10 Synthesis of Compound represented by formula 7
Adding the compound of formula 5 (24.7g, 0.1mol) and the compound of formula 6 (16.7g, 0.105mol) to 1,4-dioxane (500 mL) at room temperature, stirring well, adding Pd (OAc) 2 (3.4g, 0.015mol), xantphos (14.4g, 0.015mol) and Cs 2 CO 3 (117.3 g, 0.36mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reaction for 4 hours, filtering the reaction solution after the reaction is finished, concentrating the reaction solution under reduced pressure, and concentrating the concentrate by using a volume ratio of 10: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 7 in an amount of 34.6g with a yield of 93.4%.
LC-MS(APCI):m/z＝371.3(M+1) + 。
EXAMPLE 11 Synthesis of Compound represented by formula 7
At room temperature, the compound represented by formula 5 (24.7g, 0.1mol) and the compound represented by formula 6 (15.9g, 0.10mol) were added to 1,4-dioxane (500 mL), and stirred well, and Pd (OAc) was added 2 (2.7 g, 0.012mol), xantphos (11.5g, 0.012mol) and Cs 2 CO 3 (81.5 g, 0.25mol), heating the reaction liquid under the protection of nitrogen, keeping the temperature at 96 ℃ for reacting for 4h, filtering the reaction liquid after the reaction is finished, concentrating under reduced pressure, and mixing the concentrate with a solvent with a volume ratio of 8: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give the compound represented by formula 7 in an amount of 34.1g with a yield of 92.1%.
EXAMPLE 12 Synthesis of Compound represented by formula 7
Adding the compound represented by formula 5 (24.7g, 0.1mol) and the compound represented by formula 6 (19.1g, 0.12mol) to 1,4-dioxane (650 mL) at room temperature, stirring well, adding Pd (OAc) 2 (4.5g, 0.02mol), xantphos (19.2g, 0.02mol) and Cs 2 CO 3 (163.0 g,0.5 mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 98 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, concentrating under reduced pressure, and concentrating the concentrate by using a volume ratio of 12: the product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether/ethyl acetate of 1 to give a compound represented by formula 7 in an amount of 33.6g with a yield of 90.7%.
EXAMPLE 13 Synthesis of Compound of formula I
Adding 10% Pd/C (300 mg) into a methanol (30 mL) solution containing a compound (3.0 g, 0.0081mol) shown in formula 7 under the protection of nitrogen, replacing the solution with hydrogen for 3 times under vacuum, maintaining the reaction solution at 2.5 atmospheric pressure, keeping the temperature to 25 ℃ and stirring for reaction, filtering the reaction solution to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude solid of the compound shown in formula I, and recrystallizing the crude product (the solvent for crude recrystallization is petroleum ether/ethyl acetate =5/1 (v/v), the crude product is about 2.8g, and the using amount ratio of the solvent is 1g/10mL (28 mL of the used crystallization solvent)) to obtain a refined solid of the compound shown in formula I, wherein the yield is 2.53g, the yield is 91.8%, and the HPLC purity is 99.8%.
LC-MS(APCI):m/z＝341.2(M+1) + 。
EXAMPLE 14 Synthesis of Compound of formula I
20% of Pd/C (150 mg) was added to a methanol (30 ml) solution containing the compound represented by the formula 7 (3.0 g, 0.0081mol) under nitrogen protection, the mixture was replaced with hydrogen gas 5 times under vacuum, the reaction mixture was maintained at 3.0 atmospheres, the mixture was stirred and reacted at 20 ℃ to 25 ℃, TLC showed that the raw materials were completely consumed, the reaction mixture was filtered to remove Pd/C, the filtrate was concentrated to dryness to obtain a crude solid of the compound represented by the formula I, and the crude product was recrystallized (the same recrystallization method as in example 13) to obtain a refined solid of the compound represented by the formula I, the yield was 2.50g, the yield was 90.7%, and the HPLC purity was 99.5%.
EXAMPLE 15 Synthesis of Compound of formula I
Adding 5% Pd/C (600 mg) to a methanol (30 ml) solution containing the compound represented by formula 7 (3.0 g, 0.0081mol) under nitrogen protection, replacing 2 times with hydrogen under vacuum, maintaining the reaction solution at 2.0 atmospheres, maintaining the temperature of 20-25 ℃ and stirring for reaction, after TLC shows that the raw materials are completely consumed, filtering the reaction solution to remove Pd/C, concentrating the filtrate to dryness to obtain a crude solid of the compound represented by formula I, and recrystallizing the crude product (the same as in example 13) to obtain a refined solid of the compound represented by formula I, wherein the yield is 2.44g, the yield is 88.7% and the HPLC purity is 99.4%.
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 (28)
1. A method for preparing a compound of formula I, tomivosertib, comprising:
(1) Contacting the compound represented by formula 1 with ammonia water to obtain a compound represented by formula 2;
(2) Contacting a compound represented by formula 2 with a compound represented by formula 3 to obtain a compound represented by formula 4;
(3) Contacting the compound represented by formula 4 with Pd/C to obtain a compound represented by formula 5;
(4) Contacting a compound represented by formula 5 with a compound represented by formula 6 to obtain a compound represented by formula 7;
(5) Contacting the compound of formula 7 with Pd/C to obtain the compound of formula I,
2. the method according to claim 1, wherein in step (1), the following steps are included: adding the compound shown in the formula 1 into methanol at room temperature, adding ammonia water into a sealed tube, stirring the mixture, heating the mixture at 60-68 ℃ for 2-45-3-30 minutes for reaction, wherein TLC shows that the raw materials are completely consumed, cooling the reaction liquid to room temperature, extracting the mixed liquid for three times by using ethyl acetate, combining organic phases, washing by using brine, concentrating, and using the volume ratio of a concentrate to be (8-12): purifying the product by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 2.
3. The method according to claim 2, wherein in the step (1), the mass-to-volume ratio of the compound represented by the formula 1 to the aqueous ammonia is 1 (30 to 40) g/v.
4. The method according to claim 3, wherein in step (1), the mass-to-volume ratio of the compound represented by formula 1 to aqueous ammonia is 1.
5. The method according to claim 2, wherein the reaction temperature of the compound represented by formula 1 with aqueous ammonia in step (1) is 65 ℃ and the reaction time is 3 hours.
6. The method as claimed in claim 2, wherein in the step (1), the solvent for silica gel column chromatography is 10:1, a mixed solvent of petroleum ether and ethyl acetate.
7. The method of claim 1, wherein in step (2), the method comprises the steps of: adding a 4M dioxane hydrochloride solution into anhydrous dioxane solutions of a compound shown as a formula 2 and a compound shown as a formula 3 at room temperature in a sealed tube, heating to 100 ℃, reacting for 10 hours in the sealed tube, wherein TLC shows that raw materials are completely consumed, and after the reaction solution is concentrated under reduced pressure, the concentrate is prepared by using a solvent with a volume ratio of (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 4.
8. The method according to claim 7, wherein in the step (2), the compound represented by the formula 2 is reacted with the compound represented by the formula 3 in a molar ratio of 1 (1.0 to 1.2).
9. The method according to claim 8, wherein in step (2), the compound represented by formula 2 is reacted with the compound represented by formula 3 at a molar ratio of 1.
10. The method according to claim 7, wherein in step (2), the mass-to-volume ratio of the compound represented by formula 2 to the anhydrous dioxane solution and the dioxane hydrochloride solution is 1.
11. The method as claimed in claim 7, wherein in the step (2), the solvent for silica gel column chromatography is 10:1, a mixed solvent of petroleum ether and ethyl acetate.
12. The method of claim 1, wherein in step (3), the following steps are included: adding Pd/C into a methanol solution containing the compound shown in the formula 4 under the protection of nitrogen, replacing for 2-5 times by hydrogen under vacuum, keeping the reaction solution at 2.0-3.0 atmospheric pressure, keeping the temperature at 20-25 ℃, stirring for reaction, filtering the reaction solution to remove Pd/C after TLC shows that the raw materials are completely consumed, and concentrating the filtrate to dryness to obtain a crude solid of the compound shown in the formula 5.
13. The method of claim 12, wherein in step (3), the Pd/C is 5% to 20% Pd/C.
14. The method of claim 13, wherein in step (3), the Pd/C is 5%,10%, or 20% Pd/C.
15. The method according to claim 12, wherein, in the step (3), the compound represented by formula 4 is reacted with 10% Pd/C in a mass ratio of 1.
16. The method according to claim 12, wherein, in step (3), the compound represented by formula 4 is reacted with 5% Pd/C in a mass ratio of 1.
17. The method according to claim 12, wherein, in the step (3), the compound represented by formula 4 is reacted with 20% Pd/C in a mass ratio of 1.
18. The method according to claim 1, wherein in step (4), the following steps are included: adding the compound shown in formula 5 and the compound shown in formula 6 into 1,4-dioxane at room temperature, stirring uniformly, adding Pd (OAc) 2 Xantphos and Cs 2 CO 3 Heating the reaction solution under the protection of nitrogen and keeping the temperature at 96-100 ℃ for 4h, filtering the reaction solution after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of a concentrate is (8-12): the product is purified by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1, and the compound shown in the formula 7 is obtained.
19. The method according to claim 18, wherein in the step (4), the compound represented by the formula 5 is reacted with the compound represented by the formula 6 and with Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1 (1.0-1.2) (0.12-0.2) to (2.5-5).
20. The method according to claim 19, wherein in step (4), the compound represented by formula 5 is reacted with the compound represented by formula 6 and with Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1.05.
21. The method as claimed in claim 18, wherein in the step (4), the solvent for silica gel column chromatography is 10:1, a mixed solvent of petroleum ether and ethyl acetate.
22. The method of claim 1, wherein the step (5) comprises the steps of: adding Pd/C into a methanol solution containing the compound shown in the formula 7 under the protection of nitrogen, replacing for 2-5 times by using hydrogen under vacuum, keeping the reaction liquid at 2.0-3.0 atmospheric pressure, keeping the temperature of 20-25 ℃, stirring for reaction, filtering the reaction liquid to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to dryness to obtain a crude product solid of the compound shown in the formula I, and recrystallizing the crude product to obtain a refined product solid of the compound shown in the formula I.
23. The method of claim 22, wherein in step (5), the Pd/C is 5% -20% Pd/C.
24. The method of claim 23, wherein in step (5), the Pd/C is 5%,10%, or 20% Pd/C.
25. The method according to claim 22, wherein, in step (5), the compound represented by formula 7 is reacted with 10% Pd/C in a mass ratio of 1.
26. The method according to claim 22, wherein, in the step (5), the compound represented by formula 7 is reacted with 5% Pd/C in a mass ratio of 1.
27. The method according to claim 22, wherein, in the step (5), the compound represented by formula 7 is reacted with 20% Pd/C in a mass ratio of 1.
28. The method according to claim 1, wherein in step (1), the following steps are included: adding 5.0g of the compound represented by formula 1 to 15mL of methanol at room temperature, adding 180mL of ammonia water to 500mL of a sealed tube, stirring the mixture and reacting at 65 ℃ for 3 hours, TLC shows complete consumption of the raw material, cooling the reaction solution to room temperature, extracting the mixture with 3X 90mL of ethyl acetate three times, combining the organic phases, washing with 90mL of brine, concentrating, and concentrating the concentrate with a volume ratio of 10: purifying the product of the petroleum ether/ethyl acetate mixed solvent of 1 on silica gel column chromatography to obtain a compound shown as a formula 2, wherein the yield is 4.0g and 91.8%;
in the step (2), the method comprises the following steps: adding 200mL of 4M dioxane hydrochloride solution into 200mL of anhydrous dioxane solution of 19.7g of the compound shown in the formula 2 and 9.8g of the compound shown in the formula 3 at room temperature, heating to 100 ℃, reacting for 10 hours in a sealed tube, wherein TLC shows that the raw materials are completely consumed, and after the reaction solution is concentrated under reduced pressure, the concentrate is prepared by using a solvent with the volume ratio of 10: purifying the product by column chromatography on silica gel with the mixed solvent of petroleum ether and ethyl acetate of 1 to obtain the compound shown in the formula 4, wherein the yield is 23.7g and 85.5%;
in the step (3), the method comprises the following steps: adding 380mg 10% Pd/C into 150ml methanol solution containing 3.8g of the compound represented by the formula 4 under nitrogen protection, replacing 3 times with hydrogen under vacuum, maintaining the reaction solution at 2.5 atm, maintaining 20-25 deg.C, stirring for reaction, after TLC shows complete consumption of the raw materials, filtering the reaction solution to remove Pd/C, concentrating the filtrate to dryness to obtain 3.25g of a crude solid of the compound represented by the formula 5, with a yield of 95.9%, wherein the crude product can be directly used in the next reaction;
in the step (4), the method comprises the following steps: 24.7g of the compound represented by the formula 5 and 16.7g of the compound represented by the formula 6 were added to 500mL of 1, 4-dioxane at room temperature, stirred well, and 3.4g of Pd (OAc) was added 2 14.4g Xantphos and 117.3g Cs 2 CO 3 Heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reacting for 4 hours, filtering the reaction solution after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of a concentrate is 10: purifying the product of the mixed solvent of petroleum ether and ethyl acetate of 1 on silica gel column chromatography to obtain a compound shown as a formula 7, wherein the yield is 34.6g and 93.4%;
in the step (5), the method comprises the following steps: adding 300mg 10% of Pd/C into 30mL of methanol solution containing 3.0g of the compound shown in the formula 7 under the protection of nitrogen, replacing 3 times by using hydrogen under vacuum, keeping the reaction solution at 2.5 atmospheric pressures, stirring and reacting at 20-25 ℃, filtering the reaction solution to remove Pd/C after TLC shows that the raw materials are completely consumed, concentrating the filtrate to be dry to obtain a crude solid of the compound shown in the formula I, recrystallizing the crude product, wherein the crude product recrystallization solvent is petroleum ether/ethyl acetate with the volume ratio of 5/1, the crude product is about 2.8g, the dosage ratio of the solvent is 1g/10mL, and 28mL of the crystallization solvent is used to obtain a refined solid of the compound shown in the formula I with the yield of 2.50g and the HPLC purity of 99.8%.
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| US20180228803A1 (en) * | 2017-02-14 | 2018-08-16 | Effector Therapeutics, Inc. | Piperidine-Substituted Mnk Inhibitors and Methods Related Thereto |
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