CN114853756B - Preparation process of compound Tomivosertib - Google Patents
Preparation process of compound Tomivosertib Download PDFInfo
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- CN114853756B CN114853756B CN202210344413.6A CN202210344413A CN114853756B CN 114853756 B CN114853756 B CN 114853756B CN 202210344413 A CN202210344413 A CN 202210344413A CN 114853756 B CN114853756 B CN 114853756B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 193
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 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 14
- 229940121341 tomivosertib Drugs 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- 238000000034 method Methods 0.000 claims abstract description 39
- 239000002994 raw material Substances 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 54
- 239000000243 solution Substances 0.000 claims description 42
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 35
- 238000003756 stirring Methods 0.000 claims description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 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
- 239000003208 petroleum Substances 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- 238000004440 column chromatography Methods 0.000 claims description 20
- 239000012141 concentrate Substances 0.000 claims description 20
- 239000000741 silica gel Substances 0.000 claims description 20
- 229910002027 silica gel Inorganic materials 0.000 claims description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 19
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 19
- 239000012295 chemical reaction liquid Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 239000012267 brine Substances 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- 238000010898 silica gel chromatography Methods 0.000 claims description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 7
- 238000001816 cooling Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 16
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 238000005658 halogenation reaction Methods 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 150000001408 amides Chemical class 0.000 abstract description 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 229940043355 kinase inhibitor Drugs 0.000 abstract description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000036632 reaction speed Effects 0.000 description 8
- 239000000376 reactant Substances 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 3
- 230000026030 halogenation Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- 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
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003247 decreasing effect Effects 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
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000003446 ligand Substances 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
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation process of a kinase inhibitor compound Tomivosertib, which is obtained by a halogenation reaction, an amide reaction, a halogenation reaction and a deprotection synthesis, wherein the total steps are 4 steps of reaction. Compared with the method in the prior art, the preparation method provided by the invention has the advantages that the synthesis steps are more, the process steps for synthesizing the compound Tomivosertib shown in the formula I are simplified by using the preparation process method, the total steps of the route are less, the conditions are simple and easy to operate, the selectivity of each step is good, the total yield is higher, and the method 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 process of a kinase inhibitor compound Tomivosertib.
Background
The eFECTOR 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 new process for the preparation of the compound Tomivosertib is still in need of improvement.
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 method in the prior art, the preparation method provided by the invention has the advantages that the synthesis steps are more, the process steps for synthesizing the compound Tomivosertib shown in the formula I are simplified by using the preparation process method, the total steps of the route are less, the conditions are simple and easy to operate, the selectivity of each step is good, the total yield is higher, and the method is suitable for the requirement of industrial mass production of the raw material medicines.
In one aspect of the invention, the invention provides a process for preparing a compound of formula I, tomivosertib. According to an embodiment of the invention, the method comprises:
(1) Contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) Contacting the compound represented by formula 3 with ammonia water to obtain a compound represented by formula 4;
(3) Contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula 6;
(4) Contacting the compound of formula 6 with a HCl/dioxane solution to obtain a compound of formula I,
the synthetic route adopts a preparation process of a commercial raw material (wherein the cas number of the compound shown in the formula 1 is 1509897-36-2, and the cas number of the compound shown in the formula 2 is 1849595-31-8) and a compound Tomivosertib, the compound shown in the formula 1 and the compound shown in the formula 2 are used as starting materials, and after a halogenation reaction and an amide reaction, a halogenation reaction is carried out again, and finally a deprotection group is synthesized into a target molecule, and the overall step is a 4-step reaction. The inventor finds that compared with the prior literature, the preparation method provided by the invention has more steps, simplifies the process steps for synthesizing the compound Tomivosertib shown in the formula I, has fewer overall steps, simple and easy-to-operate conditions, good selectivity of each step and higher overall yield, and is suitable for the requirement of industrial mass production of raw material medicines.
The term "contacting" as used herein is to be understood broadly and can be any means that enables at least two reactants to react chemically, e.g. mixing of two reactants under suitable conditions. The reactants to be contacted may be mixed with stirring as needed, 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 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 6, the compound represented by formula I may further have at least one of the following additional technical features:
the chemical reactions described herein may be performed according to any method known in the art, according to embodiments of the present invention. The source of the raw materials for preparing the compound represented by formula 3, the compound represented by formula 4, the compound represented by formula 6, and the compound represented by formula I is not particularly limited, and it may be prepared by any known method, or may be commercially available.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1 is reacted with the compound represented by formula 2, K 2 CO 3 The contact manner of (2) is not particularly limited. Thus, the compound represented by the formula 1, the compound represented by the formula 2, and K can be promoted 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 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: adding the compound shown in the formula 1 and the compound shown in the formula 2 into stirring dioxane at room temperature, and adding K under the condition of continuous stirring 2 CO 3 Reacting the mixture for 2 hours at 95-100 ℃ under the protection of nitrogen, filtering the reaction liquid after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of the 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 3 is obtained. Thus, the compound represented by the formula 1, the compound represented by the formula 2, and K can be promoted 2 CO 3 Effect of contact reactionThe reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to an embodiment of the present invention, in step (1), the compound represented by formula 1 is reacted with the compound represented by formula 2, K 2 CO 3 The molar ratio of (1) to (1.05-1.3) to (1.1-1.5), preferably the compound represented by the formula 1 to the compound represented by the formula 2, and K 2 CO 3 1.1, 1.2. 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 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 represented by formula 1 (19.6 g, 0.1mol) and the compound represented by formula 2 (25.3 g, 0.11mol) were added to a stirring dioxane (200 mL) at room temperature, and K was added under continued stirring 2 CO 3 (16.6 g, 0.12mol), keeping the mixture at 95-100 ℃ for reacting for 2h under the protection of nitrogen, filtering the reaction solution after the reaction is finished, concentrating 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 3 in an amount of 34.8g with a yield of 89.4%.
According to an embodiment of the present invention, in the step (2), the manner of contacting the compound represented by formula 3 with aqueous ammonia is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 3 and ammonia water 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 compound shown as a formula 3 into methanol at room temperature, adding ammonia water into the methanol, placing the mixture into a sealed tube, stirring the mixture, heating the mixture at 60-68 ℃ for reaction for 2-45-3-30 minutes, 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 the organic phases by using brine, concentrating, and using the volume ratio of a concentrate to the mixture 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 3 and ammonia water can be improved, the reaction speed is accelerated, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to an embodiment of the present invention, in the step (2), the mass-to-volume ratio of the compound represented by formula 3 to aqueous ammonia is 1 (30 to 40) (g/v), and preferably the mass-to-volume ratio of the compound represented by formula 3 to aqueous ammonia is 1. Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to an embodiment of the present invention, in the step (2), it is preferable that the reaction temperature of the compound represented by formula 3 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 reality is avoided, and the yield of the target compound is high.
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: at room temperature, the compound represented by formula 3 (6.0 g, 0.0154mol) was added to methanol (20 mL), aqueous ammonia (200 mL) was further 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 raw material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with brine (100 mL) and concentrated, and 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 5.1g of the compound represented by formula 4 in 91.9% yield.
According to an embodiment of the present invention, in step (3), the compound represented by formula 4 is reacted with the compound represented by formula 5 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 4, the compounds represented by the formula 5, and Pd (OAc) can be increased 2 、Xantphos、Cs 2 CO 3 The efficiency of contact reaction is improved, the reaction speed is accelerated, and the utilization of the method is further improvedThe method has high efficiency of preparing the compound shown in the formula 6.
According to an embodiment of the present invention, in the step (3), the following steps are included: adding the compound shown in the formula 4 and the compound shown in the formula 5 into 1, 4-dioxane at room temperature, stirring uniformly, and 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 6. Thus, the compounds represented by the formula 4, the compounds represented by the formula 5, 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 6 by using the method is further improved.
According to an embodiment of the present invention, in the step (3), the compound represented by the formula 4 is reacted with the compound represented by the formula 5, and with Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1 (1.0-1.3): (0.12-0.2): 3.5-5, preferably the compound of formula 4 and the compound of formula 5, 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 (3), it is preferable that the silica gel column chromatography is performed using 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 (3), the following steps are included: the compound represented by formula 4 (36.0g, 0.1mol) and the compound represented by formula 5 (35.3g, 0.105mol) were added to 1, 4-dioxane (720 mL) at room temperature, and stirred well, followed by addition of Pd (OAc) 2 (3.4 g, 0.015mol), xantphos (14.4 g, 0.015mol) and Cs 2 CO 3 (130.3 g,0.4 mol), heating the reaction solution under the protection of nitrogen, keeping the temperature at 100 ℃ for reacting for 4h, filtering the reaction solution after the reaction is finished, concentrating the reaction solution under reduced pressure, and using the volume ratio of a concentrate to a concentrated solution of 10:1 ofThe product was purified by column chromatography on silica gel using a mixed solvent of petroleum ether and ethyl acetate to give 35.3g of the compound of formula 6 in 80.1% yield.
According to an embodiment of the present invention, the contacting manner of the compound represented by formula 6 with the HCl/dioxane solution in step (4) is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown as the formula 6 and the HCl/dioxane solution can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown as 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: adding 4MHCl/dioxane solution into the compound shown in the formula 6 at 0 ℃ under stirring, keeping the temperature at 0 ℃ for reaction for 0.5h after the addition is finished, and concentrating the reaction liquid under reduced pressure to be solid after the reaction is finished to obtain the compound shown in the formula I. Therefore, the efficiency of the contact reaction of the compound shown as the formula 6 and the HCl/dioxane solution can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown as the formula I by using the method is further improved.
According to an embodiment of the present invention, in the step (4), 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 (4), the mass-to-volume ratio of the compound represented by formula 6 to the 4MHCl/dioxane solution is 1 (8 to 11) (g/v), and preferably the mass-to-volume ratio of the compound represented by formula 6 to the 4MHCl/dioxane solution is 1 (g/v). Therefore, the utilization rate of the reactants is high, the waste of raw materials and reality is avoided, and the yield of the target compound is high.
According to a specific embodiment of the present invention, in the step (4), the following steps are included: at 0 ℃, under stirring, adding 4M HCl/dioxane solution (440 mL) into the compound (44.0 g, 0.1mol) shown in the formula 6, keeping the temperature at 0 ℃ for reaction for 0.5h after the addition is finished, and after the reaction is finished, concentrating the reaction liquid under reduced pressure to solid to obtain the compound shown in the formula I, wherein the yield is 32.3g, and the HPLC purity is 99.7%.
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, commercial raw materials are adopted in the route, and after a halogenation reaction and an amide reaction, the target molecule is synthesized through a halogenation reaction and deprotection, and the total steps are 4. In the first step of halogenation, the compound shown in the formula 1 contains two amino groups (primary amine and secondary amine), and the compound shown in the formula 2 also contains an amino group, so that the compound shown in the formula 2 with protected amino groups is selected as a raw material, and in order to avoid the secondary amine in the compound shown in the formula 1 participating in the halogenation reaction, the reaction temperature is set to be lower (such as 95-100 ℃), and an inorganic base such as K is adopted 2 CO 3 As a reaction reagent, higher yield is ensured. And in the second step, after the carboxylic acid protecting group is removed by using ammonia water, amidation reaction is simultaneously carried out, so that the reaction steps are reduced, and the yield is high. The tube sealing is used as a reaction container, so that the reaction time can be effectively shortened, and the reaction efficiency is improved. And in the third step, the sites of raw material halogenation are more, and a catalyst and a ligand are added to carry out specific halogenation, so that the reaction selectivity is effectively improved, and side reactions are reduced. And step four, removing the amino protecting group by using dioxane solution of hydrochloric acid, wherein the reaction yield is high, the operation is simple, and purification is not required. Compared with the existing literature, the preparation process has the advantages of fewer overall steps, simple conditions, easy operation, good selectivity of each step, high overall yield and suitability 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 3
The compound represented by formula 1 (19.6 g, 0.1mol) and the compound represented by formula 2 (25.3 g, 0.11mol) were added to a stirring dioxane (200 mL) at room temperature, and K was added under continued stirring 2 CO 3 (16.6 g, 0.12mol), keeping the mixture at 95-100 ℃ for reacting for 2h under the protection of nitrogen, filtering the reaction liquid after the reaction is finished, concentrating under reduced pressure, and mixing the concentrate with a solvent with the 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 3 in an amount of 34.8g with a yield of 89.4%.
LC-MS(APCI):m/z＝390.2(M+1) + 。
EXAMPLE 2 Synthesis of Compound represented by formula 3
The compound represented by the formula 1 (19.6 g,0.1 mol) and the compound represented by the formula 2 (24.1 g, 0.105mol) were added to a stirring dioxane (200 mL) at room temperature, and K was added under continued stirring 2 CO 3 (15.2g, 0.11mol), keeping the mixture at 95-100 ℃ under the protection of nitrogen for reacting for 2h, 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 a compound represented by formula 3 in an amount of 34.0g with a yield of 87.3%.
Example 3 Synthesis of Compound represented by formula 3
The compound represented by the formula 1 (19.6 g, 0.1mol) and the compound represented by the formula 2 (29.9 g, 0.13mol) were added to a stirring dioxane (200 mL) at room temperature, and while continuing stirring, K was added 2 CO 3 (20.7 g, 0.15mol), keeping the mixture at 95-100 ℃ under the protection of nitrogen, reacting for 2h, filtering the reaction liquid after the reaction is finished, concentrating under reduced pressure, and using the volume ratio of the concentrate to be 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 3 in an amount of 34.6g with a yield of 88.8%.
Example 4 Synthesis of Compound represented by formula 4
At room temperature, the compound represented by formula 3 (6.0 g, 0.0154mol) was added to methanol (20 mL), aqueous ammonia (200 mL) was further 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 raw material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with brine (100 mL) and concentrated, and 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 5.1g of the compound represented by formula 4 in 91.9% yield.
LC-MS(APCI):m/z＝361.2(M+1) + 。
EXAMPLE 5 Synthesis of Compound represented by formula 4
The compound represented by formula 3 (6.0 g, 0.0154mol) was added to methanol (20 mL) at room temperature, aqueous ammonia (180 mL) was further 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 raw material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with brine (100 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 4 in an amount of 4.9g with a yield of 88.3%.
EXAMPLE 6 Synthesis of Compound represented by formula 4
The compound represented by formula 3 (6.0 g, 0.0154mol) was added to methanol (20 mL) at room temperature, aqueous ammonia (240 mL) was further 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 raw material, the reaction solution was cooled to room temperature, the mixture was extracted three times with ethyl acetate (3 × 100 mL), the organic phases were combined, washed with brine (100 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 a compound represented by formula 4 in an amount of 5.0g with a yield of 90.5%.
Example 7 Synthesis of Compound represented by formula 6
The compound represented by formula 4 (36.0g, 0.1mol) and the compound represented by formula 5 (35.3g, 0.105mol) were added to 1, 4-dioxane (720 mL) at room temperature, and stirred well, followed by addition of Pd (OAc) 2 (3.4g, 0.015mol), xantphos (14.4g, 0.015mol) and Cs 2 CO 3 (130.3g,0.4mol)，And (2) 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: 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 6 in an amount of 35.3g with a yield of 80.1%.
LC-MS(APCI):m/z＝441.3(M+1) + 。
EXAMPLE 8 Synthesis of Compound represented by formula 6
The compound represented by formula 4 (36.0g, 0.10mol) and the compound represented by formula 5 (33.6g, 0.10mol) were added to 1, 4-dioxane (700 mL) at room temperature, and stirred uniformly, and Pd (OAc) was added 2 (2.7 g, 0.012mol), xantphos (11.5g, 0.012mol) and Cs 2 CO 3 (114.0 g, 0.35mol), the reaction solution is heated and kept at 96 ℃ for 4 hours of reaction under the protection of nitrogen, after the reaction is finished, the reaction solution is filtered and then concentrated under reduced pressure, and the concentrate is prepared by using a solvent with the volume ratio of 8: the product was purified by column chromatography on silica gel using the mixed solvent of petroleum ether/ethyl acetate of 1, to give the compound represented by formula 6 in an amount of 34.6g with a yield of 78.5%.
Example 9 Synthesis of Compound represented by formula 6
The compound represented by formula 4 (36.0g, 0.1mol) and the compound represented by formula 5 (40.3g, 0.12mol) were added to 1, 4-dioxane (850 mL) at room temperature, and stirred well, followed by addition of 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 the compound represented by formula 6 in an amount of 35.1g with a yield of 79.7%.
EXAMPLE 10 Synthesis of Compound of formula I
At 0 ℃, under stirring, adding 4MHCl/dioxane solution (440 mL) into the compound (44.0 g, 0.1mol) shown in the formula 6, keeping the temperature at 0 ℃ for reaction for 0.5h after the addition is finished, and after the reaction is finished, concentrating the reaction liquid under reduced pressure to solid to obtain the compound shown in the formula I, wherein the yield is 32.3g, and the HPLC purity is 99.7 percent.
LC-MS(APCI):m/z＝341.2(M+1) + 。
EXAMPLE 11 Synthesis of Compound of formula I
At 0 ℃, under stirring, adding 4MHCl/dioxane solution (350 mL) into the compound (44.0 g, 0.1mol) shown in the formula 6, keeping the temperature at 0 ℃ for reaction for 0.5h after the addition is finished, and after the reaction is finished, concentrating the reaction liquid under reduced pressure to solid to obtain the compound shown in the formula I, wherein the yield is 32.1g, and the HPLC purity is 99.4 percent.
EXAMPLE 12 Synthesis of Compound of formula I
At 0 ℃, under stirring, adding 4MHCl/dioxane solution (480 mL) into the compound (44.0 g, 0.1mol) shown in the formula 6, keeping the temperature at 0 ℃ for reaction for 0.5h after the addition is finished, and after the reaction is finished, concentrating the reaction liquid under reduced pressure to solid to obtain the compound shown in the formula I, wherein the yield is 32.0g, and the HPLC purity is 99.5 percent.
EXAMPLE 13 Synthesis of Compound of formula I
At 0 ℃, under stirring, adding 4MHCl/dioxane solution (880 mL) into the compound shown in the formula 6 (44.0 g, 0.1mol), keeping the temperature at 10 ℃ for reaction for 1h after the addition is finished, and after the reaction is finished, concentrating the reaction liquid under reduced pressure to solid to obtain the compound shown in the formula I, wherein the yield is 31.0g, and the HPLC purity is measured to be 97.8%.
Example 13 is a comparative example in which the inventors adjusted the mass-to-volume ratio of the compound represented by formula 6 to a 4MHCl/dioxane solution to 1 (g/v), and adjusted the temperature and time of the incubation reaction to 1h at the holding temperature of 10 ℃. The results show that comparative example 13 gives a product having a significantly lower HPLC purity than examples 10 to 12, and the yield of the objective compound obtained by the method of example 13 is not improved but rather decreased, as compared with examples 10 to 12 of the present invention, in terms of technical effects.
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 (18)
1. A process for preparing Tomivosertib, a compound of formula I, comprising:
(1) Contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) Contacting the compound represented by formula 3 with ammonia water to obtain a compound represented by formula 4;
(3) Contacting a compound represented by formula 4 with a compound represented by formula 5 to obtain a compound represented by formula 6;
(4) Contacting the compound of formula 6 with a solution of HCl/1, 4-dioxane to obtain a compound of formula I,
2. the production process according to claim 1, characterized by comprising, in step (1), the steps of: adding the compound shown in the formula 1 and the compound shown in the formula 2 into the stirred 1, 4-dioxane at room temperature, and adding K under the condition of continuous stirring 2 CO 3 Reacting the mixture at 95-100 deg.c for 2 hr under the protection of nitrogen, filtering the reacted liquid, decompression concentrating and concentratingThe volume ratio of the condensate 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 3 is obtained.
3. The process according to claim 2, wherein in step (1), the compound represented by formula 1 is reacted with the compound represented by formula 2, K 2 CO 3 The molar ratio of (1) to (1.05-1.3) to (1.1-1.5).
4. The process according to claim 3, wherein in the step (1), the compound represented by the formula 1 is reacted with the compound represented by the formula 2, K 2 CO 3 1.1, 1.2.
5. The preparation process according to claim 2, wherein in the step (1), 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.
6. The production process according to claim 1, characterized by comprising, in step (2), the steps of: adding a compound shown in a formula 3 into methanol at room temperature, adding ammonia water into a sealed tube, stirring the mixture, heating and reacting for 2 hours 45 minutes to 3 hours 30 minutes at 60 ℃ to 68 ℃, 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, merging organic phases, washing by using brine, concentrating, and using a concentrate 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.
7. The process according to claim 6, wherein in the step (2), the mass-to-volume ratio of the compound represented by the formula 3 to aqueous ammonia is 1 (30 to 40) g/mL.
8. The production process according to claim 7, wherein in the step (2), the mass-to-volume ratio of the compound represented by formula 3 to aqueous ammonia is 1.
9. The process according to claim 6, wherein in the step (2), the reaction temperature of the compound represented by the formula 3 with aqueous ammonia is 65 ℃ and the reaction time is 3 hours.
10. The preparation process according to claim 6, wherein in the step (2), 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.
11. The production process according to claim 1, characterized by comprising, in step (3), the steps of: adding the compound shown in the formula 4 and the compound shown in the formula 5 into 1, 4-dioxane at room temperature, stirring uniformly, and 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 6 is obtained.
12. The process according to claim 11, wherein in the step (3), the compound represented by the formula 4 is reacted with the compound represented by the formula 5 and with Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1 (1.0-1.3), (0.12-0.2), (3.5-5).
13. The process according to claim 12, wherein in the step (3), the compound represented by the formula 4 is reacted with the compound represented by the formula 5 and with Pd (OAc) 2 、Xantphos、Cs 2 CO 3 The molar ratio of the reaction is 1.05.
14. The preparation process according to claim 11, wherein in the step (3), 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.
15. The production process according to claim 1, characterized by comprising, in step (4), the steps of: adding 4M HCl/1, 4-dioxane solution into the compound shown in the formula 6 at 0 ℃ under stirring, keeping the temperature at 0 ℃ for reaction for 0.5h after the addition is finished, and concentrating the reaction liquid under reduced pressure to be solid after the reaction is finished to obtain the compound shown in the formula I.
16. The preparation process of claim 15, wherein in the step (4), the mass-to-volume ratio of the compound represented by the formula 6 to the 4M HCl/1, 4-dioxane solution is 1 (8-11) g/mL.
17. The process according to claim 16, wherein in step (4), the mass-to-volume ratio of the compound represented by formula 6 to the 4M HCl/1, 4-dioxane solution is 1.
18. The production process according to claim 1, characterized by comprising, in step (1), the steps of: 19.6g of the compound represented by the formula 1 and 25.3g of the compound represented by the formula 2 were added to 200mL of 1, 4-dioxane while stirring at room temperature, and 16.6g of K was added while continuing stirring 2 CO 3 And keeping the mixture at 95-100 ℃ for reacting for 2h under the protection of nitrogen, filtering the reaction liquid after the reaction is finished, and concentrating under reduced pressure, wherein the volume ratio of the concentrate is 10: purifying the product of the petroleum ether/ethyl acetate mixed solvent of 1 by column chromatography on silica gel to obtain a compound shown in a formula 3, wherein the yield is 34.8g and 89.4%;
in the step (2), the method comprises the following steps: adding 6.0g of the compound represented by the formula 3 into 20mL of methanol at room temperature, adding 200mL of ammonia water into a 500mL sealed tube, stirring the mixture and heating at 65 ℃ for reaction for 3 hours, TLC shows that the raw materials are completely consumed, cooling the reaction solution to room temperature, extracting the mixed solution with 3X 100mL of ethyl acetate for three times, combining organic phases, washing with 100mL of brine, concentrating, 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 a compound shown as a formula 4, wherein the yield is 5.1g and 91.9%;
in the step (3), the method comprises the following steps: at room temperature, 36.0g of the compound represented by formula 4 and 35.3g of the compound represented by formula 5 were added to 720mL of 1, 4-dioxane, stirred well, and 3.4g of Pd (OAc) was added 2 14.4g Xantphos and 130.3g 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 petroleum ether/ethyl acetate mixed solvent of 1 by column chromatography on silica gel to obtain a compound shown in a formula 6, wherein the yield is 35.3g and 80.1%;
in the step (4), the method comprises the following steps: 440mL of 4M HCl/1, 4-dioxane solution is added into 44.0g of the compound shown as the formula 6 under stirring at 0 ℃, the temperature is kept at 0 ℃ for reaction for 0.5h after the addition is finished, and after the reaction is finished, the reaction liquid is decompressed and concentrated to be solid to obtain the compound shown as the formula I, wherein the yield is 32.3g, and the HPLC purity is 99.7%.
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Denomination of invention: Preparation process of compound Tomivosertib Granted publication date: 20230328 Pledgee: Agricultural Bank of China Co.,Ltd. Wuhan Branch Business Department Pledgor: Wuhan Jiuzhou Yumin Medical Technology Co.,Ltd. Registration number: Y2024980025475 |
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