A continuous flow process for the preparation of a tegoprazan intermediate
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ZHEJIANG YONGTAI TECH CO LTD
- Filing Date
- 2025-12-22
- Publication Date
- 2026-05-26
Smart Images
Figure CN122079946A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical synthesis technology and relates to a continuous flow preparation method for ticoraxan intermediates, specifically a continuous flow preparation method for ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one. Background Technology
[0002] For understanding the technical content of this invention: Tigorafenib, developed by CJ Health Care in South Korea and successfully launched in South Korea in July 2018, is primarily used to treat gastroesophageal reflux disease and erosive esophagitis. The chemical name of tigorafenib is 7-[[(4S)-5,7-difluoro-3,4-dihydro-2H-1-benzopyran-4-yl]oxy]-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide, CAS number 942195-55-3, and its chemical structure is shown in Formula I.
[0003] Formula I 5,7-Difluorobenzodihydropyran-4-one (Formula II, shown below) is a key intermediate in the preparation of ticoraxen.
[0004]
[0005] Formula II Literature (Manufacturing Process Development of Tegoprazan as a Potassium-Competitive Acid Blocker (P-CAB), Org. Process Res. Dev. A synthetic route was reported in 2024, 28, 1159-1169, as follows:
[0006] The reaction process involved 3,5-difluorophenol as the initial raw material, DMF as the solvent, and NaH as the base, reacting with 3-propanol to generate compound 25. Then, using acetonitrile / water as the solvent, 2-IBA was combined with Oxone for oxidation to generate compound 26. Finally, concentrated sulfuric acid was used for cyclization to produce the target product. The overall yield of the three-step reaction was 75%. The first step, using the NaH system, posed safety risks during both the reaction and post-processing. The second step, using the 2-iodobenzoic acid / potassium persulfate system, was relatively expensive, and the oxidation reaction carried a risk of temperature overshoot during scale-up production. The reaction time was long, resulting in a low yield. Furthermore, the use of water-miscible solvents led to a large volume of solvent used in the post-processing, making the process cumbersome.
[0007] Chinese invention patent application CN115109022A discloses a method for preparing 5,7-difluorobenzodihydropyran-4-one, the synthetic route of which is as follows:
[0008] This method produces 5,7 Difluorobenzodihydropyran 4 The overall yield of ketone (II) can reach 73%, with good product purity and stable quality. This method avoids the use of highly polluting liquid strong acids as catalysts and offers advantages such as simple operation, high efficiency, mild conditions, and environmental friendliness. However, its yield is relatively low and needs further improvement.
[0009] In solving the above problems or overcoming the above defects, the present invention encountered the following difficulties and obstacles: When synthesizing the intermediate 5,7-difluorobenzodihydropyran-4-one of tegorazine, the reaction is carried out in a conventional reactor. In the oxidation reaction process of step (2) above, the reaction is very slow at the beginning. When the internal reaction accumulates to a certain extent, it will react violently and cause a temperature surge. There is a safety risk in scaling up production. The reaction time is long and it is impossible to achieve mass production. Summary of the Invention
[0010] The purpose of this invention is to provide: A continuous flow preparation method for tegorazine intermediate 5,7-difluorobenzodihydropyran-4-one, and related technologies, to solve the technical problems of existing preparation methods, such as safety risks, long reaction time, and low yield, or combinations thereof.
[0011] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and disclosures cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.
[0012] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.
[0013] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2)" by Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06.
[0014] Unless otherwise stated, conventional methods within the scope of the art, such as the separation of the organic and aqueous layers, shall be used.
[0015] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.
[0016] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.
[0017] As used in this article, the term "microreactor" refers to a three-dimensional structural element fabricated on a solid matrix using specialized microfabrication techniques, which can be used to carry out chemical reactions. Microreactors typically contain small channel dimensions (equivalent diameter less than 500 µm) and channel diversity, in which fluids flow and where the desired reactions are required to occur. This results in a very large surface area to volume ratio in microstructured chemical devices.
[0018] The term “entering the microreactor for reaction” as used in this article refers to the continuous reaction of the reactants (liquid) at a set flow rate and at a set reaction temperature in a microreactor.
[0019] The term "discharge" as used in this article refers to the process of transferring the reaction solution to a storage tank or other device after the reaction is completed, for subsequent processing.
[0020] The term "separation" as used in this article refers to the technique of separating the organic phase and the aqueous phase in a reaction solution after the organic phase and the aqueous phase have been separated by means of standing or other methods.
[0021] The term "concentrated sulfuric acid" as used in this article refers to an aqueous solution of sulfuric acid with a mass ratio of not less than 70%.
[0022] In a first aspect, the present invention provides a continuous flow method for preparing the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one, comprising the following steps: (1) Dissolve 3,5-difluorophenol and 3-chloropropanol in an organic solvent to obtain solution 1 and solution 2; solution 1, solution 2 and organic amine are introduced into a microreactor to react, and after the reaction is completed, the material is discharged and the organic layer 1 is separated. (2) Add 2,2,6,6-tetramethylpiperidine oxide to organic layer 1, and then enter the microreactor with sodium hypochlorite solution and sodium chlorite solution for oxidation reaction. After the reaction is completed, discharge the material and separate organic layer 2. (3) Organic layer 2 is then added to a microreactor with concentrated sulfuric acid for reaction. After the reaction is complete, organic layer 3 is washed with water and separated. After concentration and recrystallization, tigorasen intermediate 5,7-difluorobenzodihydropyran-4-one is obtained.
[0023] The technical features include: organic solvent, organic amine, concentration of solution 1, concentration of solution 2, feed flow rate ratio and specific flow rate of solution 1, solution 2 and organic amine, concentration of sodium sulfite solution and sodium hypochlorite solution, flow rate ratio and specific flow rate of sodium sulfite solution, sodium hypochlorite solution and organic layer 1, feed flow rate ratio and specific flow rate of organic layer 2 and concentrated sulfuric acid, reaction temperature of each step in steps (1)-(3), feed ratio of reaction raw materials, and reaction operation separation, recrystallization, etc.
[0024] The organic solvent in this technical feature is toluene.
[0025] The organic amine in the technical feature is selected from one or more of triethylamine, N,N-diisopropylethylamine and diisopropanolamine; preferably triethylamine.
[0026] The concentration of technical feature solution 1 is selected from 2.0-4.0 mol / L, including but not limited to 2.0, 2.5, 3.0, 3.5 or 4 mol / L.
[0027] The concentration of technical feature solution 2 is selected from 4.0-7.0 mol / L, including but not limited to 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 or 7.0 mol / L.
[0028] The feed flow rate ratio of solution 1, solution 2, and organic amine, as described in the technical feature, is selected from 1-2:0.4-1:0.4-1, including but not limited to 1:0.4:0.4, 1:0.4:0.6, 1:0.4:0.8, 1:0.4:1, 1:0.6:0.4, 1:0.6:0.6, 1:0.6:0.8, 1:0.6:1, and 1:0.8:0. 4, 1:0.8:0.6, 1:0.8:0.8, 1:0.8:1, 1:1:0.4, 1:1:0.6, 1:1:0.8, 1:1:1, 1.5:0.4:0.4, 1.5:0.4:0.4, 1.5:0.4:0.6, 1.5:0.4:0.8, 1.5:0.4:1, 1.5:0.6:0.4, 1.5 :0.6:0.6, 1.5:0.6:0.8, 1.5:0.6:1, 1.5:0.8:0.4, 1.5:0.8:0.6, 1.5:0.8:0.8, 1.5:0.8:1, 1.5:1:0.4, 1.5:1:0.6, 1.5:1:0.8, 1.5:1:1, 2:0.4:0.4, 2:0.4:0.4 2:0.4:0.6, 2:0.4:0.8, 2:0.4:1, 2:0.6:0.4, 2:0.6:0.6, 2:0.6:0.8, 2:0.6:1, 2:0.8:0.4, 2:0.8:0.6, 2:0.8:0.8, 2:0.8:1, 2:1:0.4, 2:1:0.6, 2:1:0.8, 2:1:1.
[0029] The feed flow rate of technical feature solution 1 is selected from 50-100 mL / min, including but not limited to 50, 60, 70, 80, 90 or 100 mL / min.
[0030] The feed flow rate of technical feature solution 2 is selected from 20-50 mL / min, including but not limited to 20, 30, 40 or 50 mL / min.
[0031] Among them, the feed flow rate of the organic amine is 20-50 mL / min, including but not limited to 20, 30, 40 or 50 mL / min.
[0032] The molar concentration of the sodium chlorite solution is selected from 1.0-2.0 mol / L, including but not limited to 1.0, 1.2, 1.4, 1.6, 1.8 or 2 mol / L.
[0033] The molar concentration of the sodium hypochlorite solution is selected from 0.05-0.10 mol / L, including but not limited to 0.05, 0.06, 0.07, 0.08, 0.09 or 0.10 mol / L.
[0034] The flow rate ratio of the organic layer 1, the sodium hypochlorite solution, and the sodium chlorite solution is selected from 12-20:8-25:18-36, including but not limited to 12:8:18, 12:8:24, 12:8:30, 12:8:36, 12:8:18, 12:15:24, 12:15:30, 12:15:36, 12:25:18, 12:25:24, 12:25:30, 12:25:36, 16:8:18, 16:8:24, and 16:8:30. 16:8:36, 16:8:18, 16:15:24, 16:15:30, 16:15:36, 16:25:18, 16:25:24, 16:25:30, 16:25:36, 20:8:18, 20:8:24, 20:8:30, 20:8:36, 20:8:18, 20:15:24, 20:15:30, 20:15:36, 20:25:18, 20:25:24, 20:25:30, 20:25:36.
[0035] The feed flow rate of the organic layer 1 is selected from 60-100 mL / min, including but not limited to 60, 70, 80, 90 or 100 mL / min.
[0036] Among them, the feed flow rate of the sodium hypochlorite solution is selected from 40-75 mL / min, including but not limited to 40, 45, 50, 55, 60, 65, 70 or 75 mL / min.
[0037] Among them, the feed flow rate of the sodium chlorite solution is 90-180 mL / min, including but not limited to 90, 100, 110, 120, 130, 140, 150, 160, 170 or 180 mL / min.
[0038] The feed flow rate ratio of organic layer 2 to concentrated sulfuric acid is selected from 3-5:1-2.5, including but not limited to 3:1, 3:1.5, 3:2, 3:2.5, 4:1, 4:1.5, 4:2, 4:2.5, 5:1, 5:1.5, 5:2, and 5:2.5.
[0039] Among them, the feed flow rate of the organic layer 2 is 60-100 mL / min, including but not limited to 60, 65, 70, 75, 80, 85, 90, 95 or 100 mL / min.
[0040] Among them, the feed flow rate of concentrated sulfuric acid is 20-50 mL / min, including but not limited to 20, 25, 30, 35, 40, 45 or 50 mL / min.
[0041] The reaction temperature of technical feature step (1) is selected from 90-100℃, including but not limited to 90, 92, 94, 96, 98 or 100℃.
[0042] The reaction temperature of technical feature step (2) is selected from 30-40℃, including but not limited to 30, 32, 34, 36, 38 or 40℃.
[0043] The reaction temperature of technical feature step (3) is selected from 80-100℃, including but not limited to 80, 82, 84, 86, 88, 90, 92, 94, 96, 98 or 100℃.
[0044] The technical feature is that the recrystallization solvent is n-heptane in equal volume to the organic layer 2, and the crystallization temperature is preferably 0-10℃.
[0045] The technical characteristics of the reaction raw materials, such as 3,5-difluorophenol, 3-chloropropanol, organic amine, 2,2,6,6-tetramethylpiperidine oxide, and concentrated sulfuric acid, are all added in a ratio within the general adjustment range of the theoretical chemical reaction dosage according to the theoretical chemical reaction dosage ratio. For example, the molar ratio of 3,5-difluorophenol, 3-chloropropanol, and organic amine is 1:1-3:1-3; preferably 1:1-1.3:1.5; and more preferably 1:1.1:1.5. Another example is the amount of 2,2,6,6-tetramethylpiperidine oxide added, which is in a molar ratio of 0.5-5:100 to 3,5-difluorophenol; preferably 1-3:100; and more preferably 1:100. Yet another example is the amount of concentrated sulfuric acid added, which is in a molar ratio of 2-10:1 to 3,5-difluorophenol; preferably 3-6:1; and more preferably 4.75:1.
[0046] The technical feature separation is selected from conventional separation methods in the field, such as static layering and separation of organic and aqueous phases.
[0047] The technical feature of recrystallization includes: adding a poor solvent to the target product tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one, and crystallizing out the tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one by controlling the volume of the poor solvent or by cooling.
[0048] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the first aspect of the present invention includes: The first preferred solution: In step (1), the organic solvent is toluene. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "simplifying the post-processing operation after each step of the reaction, making the continuous flow reaction easier to realize".
[0049] The second preferred solution: In step (1), the concentration of solution 1 is 2.0-4.0 mol / L. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "improving the yield of tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one".
[0050] A further preferred embodiment of the second preferred embodiment: In step (1), the feed flow rate ratio of solution 1, solution 2, and organic amine is 1-2:0.4-1:0.4-1. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "further improving the yield of tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one".
[0051] A further preferred embodiment of the second preferred embodiment: the feed flow rate of solution 1 is 50-100 mL / min; and / or the feed flow rate of solution 2 is 20-50 mL / min; the feed flow rate of the organic amine is 20-50 mL / min. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "further improving the yield of the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one".
[0052] The third preferred option: Step (1) further includes: after the reaction is complete and the material is discharged, the pH of the reaction solution is adjusted to 6.0-6.5 using hydrochloric acid solution before separating the organic layer 1. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "improving the yield of tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one".
[0053] The fourth preferred option: In step (2), the molar concentration of the sodium chlorite solution is 1.0-2.0 mol / L; and / or the molar concentration of the sodium hypochlorite solution is 0.05-0.10 mol / L. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxen intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "improving the yield of the ticoraxen intermediate 5,7-difluorobenzodihydropyran-4-one".
[0054] A further preferred embodiment of the fourth preferred embodiment: the feed flow rate ratio of the organic layer 1, the hypochlorous acid solution, and the sodium chlorite solution is 12-20:8-25:18-36. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one," further solves the technical problem of "further improving the yield of the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one."
[0055] A further preferred embodiment of the fourth preferred embodiment: the feed flow rate of the organic layer 1 is 60-100 mL / min; the feed flow rate of the hypochlorous acid aqueous solution is 40-75 mL / min; and the feed flow rate of the sodium chlorite solution is 90-180 mL / min. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "further improving the yield of the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one".
[0056] The fifth preferred option: In step (3), the feed flow rate ratio of the organic layer 2 to concentrated sulfuric acid is 3-5:1-2.5. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "improving the yield of tegoragen intermediate 5,7-difluorobenzodihydropyran-4-one".
[0057] A further preferred embodiment of the fifth preferred embodiment: the feed flow rate of the organic layer 2 is 60-100 mL / min; the feed flow rate of the concentrated sulfuric acid is 20-50 mL / min. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "further improving the yield of the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one".
[0058] The sixth preferred option: In step (1), the reaction temperature is 90-100℃; and / or in step (2), the oxidation reaction temperature is 30-40℃; and / or in step (3), the reaction temperature is 80-100℃. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "improving the yield of the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one".
[0059] The seventh preferred option: the solvent used for recrystallization is n-heptane. This technical solution, based on solving the technical problem of "providing a continuous flow preparation method for the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one", further solves the technical problem of "improving the yield of the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one".
[0060] The technical feature "the organic solvent is toluene" corresponds to the toluene technical feature in Examples 1-3. Therefore, those skilled in the art can reasonably infer that the technical feature toluene, technical means substantially equivalent to toluene, and technical means that can replace toluene within the scope of conventional technical means and common knowledge based on the existing level of technology should all fall within the protection scope of this invention. For example, replacing toluene with an organic solvent of similar polarity, such as acetonitrile, while keeping other technical features unchanged, still falls within the protection scope of this invention.
[0061] The technical feature is that the organic solvent is toluene.
[0062] The technical feature "organic amine selected from one or more of triethylamine, N,N-diisopropylethylamine, and diisopropanolamine" corresponds to the triethylamine technical feature in Examples 1-3. Therefore, those skilled in the art can reasonably infer that the technical feature triethylamine, technical means substantially equivalent to triethylamine, and technical means that can replace triethylamine within the scope of conventional technical means and common knowledge based on the existing technical level should all fall within the protection scope of this invention. For example, replacing triethylamine with an organic solvent of similar polarity, such as acetonitrile, while keeping other technical features unchanged, still falls within the protection scope of this invention.
[0063] The technical feature "the concentration of solution 1 is 2.0-4.0 mol / L" is derived from the foregoing explanation and / or the corresponding technical features 2.5, 3.0 mol / L, etc., in Examples 1-3. Therefore, those skilled in the art can reasonably infer that the technical feature 2.0-4.0 mol / L and its subordinate concepts should all fall within the scope of protection of this invention. For example, replacing 2.0-4.0 mol / L with 3.5 mol / L while keeping other technical features unchanged still falls within the scope of protection of this invention.
[0064] The technical feature "the concentration of solution 2 is 4.0-7.0 mol / L" is derived from the foregoing explanation and / or the corresponding technical features 5.5, 6.6 mol / L, etc., in Examples 1-3. Therefore, those skilled in the art can reasonably infer that the technical feature 4.0-7.0 mol / L and its subordinate concepts should all fall within the scope of protection of this invention. For example, replacing 4.0-7.0 mol / L with 4.4 mol / L while keeping other technical features unchanged still falls within the scope of protection of this invention.
[0065] The technical feature “In step (1), the feed flow rate ratio of solution 1, solution 2 and organic amine is 1-2:0.4-1:0.4-1” is summarized from the above explanation and / or the corresponding technical features in Examples 1-3, such as the flow rate of toluene solution of 3,5-difluorophenol being 60, 70, 80 mL / min, the flow rate of toluene solution of 3-chloropropanol being 30, 35, 40 mL / min, and the flow rate of pure organic amine being 30, 35, 40 mL / min. Therefore, those skilled in the art can reasonably infer that the feed flow rate ratio of solution 1, solution 2, and organic amine described in the technical feature is 1-2:0.4-1:0.4-1, its subordinate concepts, technical means substantially equivalent to it, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention. For example, replacing the feed flow rate ratio of solution 1, solution 2, and organic amine from 1-2:0.4-1:0.4-1 to 1:1:1 while keeping other technical features unchanged still falls within the protection scope of this invention.
[0066] The technical feature “the feed flow rate of solution 1 is 50-100 mL / min; the feed flow rate of solution 2 is 20-50 mL / min; the feed flow rate of organic amine is 20-50 mL / min” is summarized from the foregoing explanation and / or the corresponding technical feature settings in Examples 1-3, such as the flow rate of toluene solution of 3,5-difluorophenol being 60, 70, or 80 mL / min, the flow rate of toluene solution of 3-chloropropanol being 30, 35, or 40 mL / min, and the flow rate of pure organic amine being 30, 35, or 40 mL / min. Therefore, those skilled in the art can reasonably infer that the feed flow rate ratio of solution 1, solution 2, and organic amine described in the technical feature as 1-2:0.4-1:0.4-1, and the subordinate concepts of the feed flow rate ratio of solution 1, solution 2, and organic amine as 1-2:0.4-1:0.4-1, should all fall within the protection scope of this invention. For example, if other technical features remain unchanged, replacing the feed flow rate of solution 1 as 50-100 mL / min; the feed flow rate of solution 2 as 20-50 mL / min; and the feed flow rate of organic amine as 20-50 mL / min with the feed flow rate of solution 1 as 50 mL / min; the feed flow rate of solution 2 as 50 mL / min; and the feed flow rate of organic amine as 50 mL / min, etc., still falls within the protection scope of this invention.
[0067] The technical feature “Step (1) also includes: after the reaction is completed and the material is discharged, the pH of the reaction solution is adjusted to 6.0-6.5 with hydrochloric acid solution before separating the organic layer 1” is summarized from the foregoing explanation and / or the corresponding technical features in Examples 1-3, such as adjusting the pH to 6.0-6.5 with 10% hydrochloric acid. Therefore, those skilled in the art can reasonably infer that the following technical means are essentially equivalent to adjusting the pH of the reaction solution to 6.0-6.5 with hydrochloric acid solution after the reaction is completed and the material is discharged, and then separating the organic layer 1; and any technical means that can be replaced by conventional technical means and common knowledge based on the existing technical level, should all fall within the protection scope of this invention. For example, adjusting the pH of the reaction solution to 6.0-6.5 with hydrochloric acid solution of any concentration before separating the organic layer 1 while keeping other technical features unchanged still falls within the protection scope of this invention.
[0068] The technical feature "the molar concentration of sodium chlorite aqueous solution is 1.0-2.0 mol / L" is derived from the foregoing explanation and / or the corresponding technical features of sodium chlorite aqueous solution molar concentrations of 1.2, 1.44 mol / L, etc., in Examples 1-3. Therefore, those skilled in the art can reasonably infer that the technical feature of sodium chlorite aqueous solution molar concentration of 1.0-2.0 mol / L and its subordinate concepts should all fall within the scope of protection of this invention. For example, replacing 1.0 with 1.0, etc., while keeping other technical features unchanged, still falls within the scope of protection of this invention.
[0069] The technical feature "the molar concentration of sodium hypochlorite aqueous solution is 0.05-0.10 mol / L" is derived from the foregoing explanation and / or the corresponding technical features in Examples 1-3, such as the molar concentration of sodium hypochlorite aqueous solution being 0.067 and 0.09 mol / L. Therefore, those skilled in the art can reasonably infer that the lower-level concepts of the technical feature "the molar concentration of sodium hypochlorite aqueous solution is 0.05-0.10 mol / L" and "the molar concentration of sodium hypochlorite aqueous solution is 0.05-0.10 mol / L" should all fall within the scope of protection of this invention. For example, replacing "the molar concentration of sodium hypochlorite aqueous solution is 0.05-0.10 mol / L" with "0.05" while keeping other technical features unchanged still falls within the scope of protection of this invention.
[0070] The technical feature “the feed flow rate ratio of the organic layer 1, hypochlorous acid solution, and sodium chlorite solution is 12-20:8-25:18-36” is summarized from the foregoing explanation and / or the corresponding technical features in Examples 1-3, such as the flow rate of the organic layer being 70 or 80 mL / min, the flow rate of the sodium chlorite aqueous solution being 117, 125, or 134 mL / min, and the flow rate of the sodium hypochlorite aqueous solution being 52.5, 60, or 80 mL / min. Therefore, those skilled in the art can reasonably infer that the feed flow rate ratio of the organic layer 1, hypochlorous acid solution, and sodium chlorite solution described in the technical feature is 12-20:8-25:18-36, and its subordinate concepts, technical means substantially equivalent to it, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention. For example, if the feed flow rate ratio of the organic layer 1, hypochlorous acid solution, and sodium chlorite solution is replaced with 12:8:18 while other technical features remain unchanged, it still falls within the protection scope of this invention.
[0071] The technical feature “the feed flow rate of the organic layer 1 is 60-100 mL / min; the feed flow rate of the hypochlorous acid aqueous solution is 40-75 mL / min; the feed flow rate of the sodium chlorite solution is 90-180 mL / min” is summarized from the foregoing explanation and / or the corresponding technical features in Examples 1-3, such as the flow rate of the organic layer being 70, 80 mL / min, the flow rate of the sodium chlorite aqueous solution being 117, 125, 134 mL / min, and the flow rate of the sodium hypochlorite aqueous solution being 52.5, 60, 80 mL / min. Therefore, those skilled in the art can reasonably infer that the feed flow rate of the organic layer 1 described in the technical feature is 60-100 mL / min; the feed flow rate of the hypochlorous acid aqueous solution is 40-75 mL / min; the feed flow rate of the sodium chlorite solution is 90-180 mL / min, and their subordinate concepts, essentially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge, should all fall within the protection scope of this invention. For example, if the feed flow rate of the organic layer 1 is 60-100 mL / min; the feed flow rate of the hypochlorous acid aqueous solution is 40-75 mL / min; and the feed flow rate of the sodium chlorite solution is 90-180 mL / min, and it is replaced with a feed flow rate of 100 mL / min for the organic layer 1; a feed flow rate of 75 mL / min for the hypochlorous acid aqueous solution; and a feed flow rate of 180 mL / min for the sodium chlorite solution, it still falls within the protection scope of this invention.
[0072] The technical feature "the feed flow rate ratio of the organic layer 2 to concentrated sulfuric acid is 3-5:1-2.5" is derived from the foregoing explanation and / or the corresponding technical features in Examples 1-3, such as the flow rate of the organic layer being 75 or 80 mL / min and the flow rate of concentrated sulfuric acid being 32, 35, or 41 mL / min. Therefore, those skilled in the art can reasonably infer that the feed flow rate ratio of the organic layer 2 to concentrated sulfuric acid of 3-5:1-2.5, its subordinate concepts, substantially equivalent technical means, and technical means that can replace this technical feature based on existing technology and conventional and common knowledge should all fall within the scope of protection of this invention. For example, replacing the feed flow rate ratio of the organic layer 2 to concentrated sulfuric acid of 3-5:1-2.5 with a feed flow rate ratio of 3:1 while keeping other technical features unchanged still falls within the scope of protection of this invention.
[0073] The technical feature “the feed flow rate of the organic layer 2 is 60-100 mL / min; the feed flow rate of the concentrated sulfuric acid is 20-50 mL / min” is summarized from the foregoing explanation and / or the corresponding technical features in Examples 1-3, such as the flow rate of the organic layer being 75 or 80 mL / min and the flow rate of the concentrated sulfuric acid being 32, 35, or 41 mL / min. Therefore, those skilled in the art can reasonably infer that the feed flow rate of the organic layer 2 described in the technical feature is 60-100 mL / min; the feed flow rate of the concentrated sulfuric acid is 20-50 mL / min; its subordinate concept; technical means that are substantially equivalent to it; and technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of this invention. For example, if the feed flow rate of the organic layer 2 is 60-100 mL / min and the feed flow rate of the concentrated sulfuric acid is 20-50 mL / min, and is replaced with a feed flow rate of 80 mL / min and a feed flow rate of 50 mL / min, while other technical features remain unchanged, it still falls within the protection scope of this invention.
[0074] The technical feature “in step (1), the reaction temperature is 90-100℃” is derived from the foregoing explanation and / or the corresponding technical feature of the microreactor in Examples 1-3, which states that the temperature is 90, 100℃, etc. Therefore, those skilled in the art can reasonably infer that the technical feature of the reaction temperature being 90-100℃, its subordinate concepts, the technical means substantially equivalent to it, and the technical means that can replace this technical feature based on existing technology and conventional technical means and common knowledge should all fall within the scope of protection of this invention. For example, replacing the reaction temperature of 90-100℃ with 95℃ while keeping other technical features unchanged still falls within the scope of protection of this invention.
[0075] The technical feature “in step (2), the temperature of the oxidation reaction is 30-40℃” is derived from the foregoing explanation and / or the corresponding technical feature microreactor reaction temperature of 30, 35, 40℃ in Examples 1-3. Therefore, those skilled in the art can reasonably infer that the technical feature oxidation reaction temperature of 30-40℃, its subordinate concept, the technical means that are basically equivalent to it, and the technical means that can replace this technical feature based on the existing level of technology and conventional technical means and common knowledge should all fall within the protection scope of this invention. For example, if A is replaced with A6, A7, etc. while other technical features remain unchanged, it still falls within the protection scope of this invention.
[0076] The technical feature “in step (1), the reaction temperature is 80-100℃” is derived from the foregoing explanation and / or the corresponding technical feature of the microreactor in Examples 1-3, such as 95℃ and 100℃. Therefore, those skilled in the art can reasonably infer that the reaction temperature of the technical feature is 80-100℃, its subordinate concept, the technical means that are substantially equivalent to it, and the technical means that can replace the technical feature based on the existing level of technology and conventional technical means and common knowledge, should all fall within the protection scope of this invention. For example, if the reaction temperature is replaced with 90℃ while other technical features remain unchanged, it still falls within the protection scope of this invention.
[0077] The technical feature "the solvent used for recrystallization is n-heptane" corresponds to the technical feature in Examples 1-3 where the solvent used for crystallization is n-heptane. Therefore, those skilled in the art can reasonably infer that the technical feature n-heptane, technical means substantially equivalent to n-heptane, and technical means that can replace n-heptane within the scope of conventional technical means and common knowledge based on the existing technical level should all fall within the protection scope of this invention. For example, replacing n-heptane with a polar solvent or a solvent with similar solubility to the ticograzine intermediate 5,7-difluorobenzodihydropyran-4-one, or changing the amount of n-heptane added, while keeping other technical features unchanged, still falls within the protection scope of this invention.
[0078] The beneficial effects of this invention are as follows: The present invention has at least the following beneficial effects: 1. Compared with existing technologies, this invention provides a technical solution with a different technical concept, and its technical effect is significantly improved compared with existing technologies. The difference between the technical concept of this invention and existing technologies is that it proposes for the first time the use of microreactors for continuous flow synthesis, which not only greatly shortens the reaction time, but also achieves a high yield of over 90%.
[0079] 2. Furthermore, compared with the prior art, the present invention has better technical effects in terms of reaction safety, cost, reaction efficiency, and yield.
[0080] According to experimental tests, the present invention increases the yield from more than 70% in the prior art to more than 90%.
[0081] According to experimental tests, the present invention reduces the reaction time from 15-20 hours in the prior art to 3-6 minutes, and the post-processing is simple. High-purity target products can be obtained by simply allowing the product to stand for layering and recrystallization in the last step.
[0082] Furthermore, compared with existing technologies, this invention enables continuous production, eliminates the need for a NaH system, offers high safety, and features a low-cost oxidation system with no risks such as temperature fluctuations.
[0083] Furthermore, based on the present invention: Based on the comparison between Example 1 and Comparative Example 1, the present invention purposefully selects a narrow range of organic basic compounds—organic amines—not mentioned in the prior art from the broad range of basic compounds disclosed in the prior art, thereby increasing the yield by about 15% and the purity to over 99.5%. Attached Figure Description
[0084] Figure 1 This is a synthetic route diagram of 5,7-difluorobenzodihydropyran-4-one, an intermediate of tegorazine according to the present invention; Figure 2 This is a process diagram illustrating the continuous flow preparation method using a microreactor according to the present invention. Figure 3 The mass spectrum of 5,7-difluorobenzodihydropyran-4-one prepared in this invention. Detailed Implementation
[0085] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.
[0086] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.
[0087] Example 1 The synthetic route for 5,7-difluorobenzodihydropyran-4-one provided in this embodiment is as follows: Figure 1 As shown, according to Figure 2 The synthetic route for preparing 5,7-difluorobenzodihydropyran-4-one is as follows: (1) Prepare 1 L of 2.50 mol / L 3,5-difluorophenol toluene solution and 500 mL of 5.50 mol / L 3-chloropropanol toluene solution, and take 3.75 mol (522 mL) of pure triethylamine. Set the flow rate of 3,5-difluorophenol toluene solution to 70 mL / min, the flow rate of 3-chloropropanol toluene solution to 35 mL / min, and the flow rate of pure triethylamine to 35 mL / min. At the same time, set the temperature of microreactor A to 90℃. Put the above materials into microreactor A at the same time for reaction. The residence time in microreactor A is 90 seconds. After the reaction is completed, discharge the material into storage tank 1, use 10% hydrochloric acid to adjust the pH to between 6.0 and 6.5, let it stand to separate the layers, remove the water layer and retain the organic layer. (2) Add 3.9g (0.025mol) of TEMPO to storage tank 1 and stir evenly. At the same time, prepare 2.5L of 1.20 mol / L sodium chlorite aqueous solution and 1.1L of 0.067 mol / L sodium hypochlorite aqueous solution. Set the flow rate of the organic layer in storage tank 1 to 70 mL / min, the flow rate of the sodium chlorite aqueous solution to 117 mL / min, and the flow rate of the sodium hypochlorite aqueous solution to 52.5 mL / min. Set the reaction temperature of the microreactor to 30℃. Put the above materials into microreactor B at the same time for reaction. The residence time in microreactor B is 53 seconds. After the reaction is completed, discharge the material into storage tank 2, let it stand and separate into layers, remove the water layer and keep the organic layer. (3) Set the flow rate of the organic layer in storage tank 2 to 80 mL / min, take 645 mL of concentrated sulfuric acid and set the flow rate to 35 mL / min, set the temperature of microreactor C to 100℃, and simultaneously introduce the above materials into microreactor C for reaction. The residence time in microreactor C is 110 seconds. After the reaction is completed, wash with water to separate the layers, concentrate the organic layer, and use n-heptane to crystallize to obtain 414.5 g of 5,7-difluorobenzodihydropyran-4-one, with a yield of 90% and a purity of 99.56%.
[0088] Example 2 The preparation method of 5,7-difluorobenzodihydropyran-4-one provided in this embodiment includes the following specific steps: (1) Prepare 1 L of 2.50 mol / L 3,5-difluorophenol toluene solution and 500 mL of 5.50 mol / L 3-chloropropanol toluene solution, and take 3.75 mol (522 mL) of pure triethylamine. Set the flow rate of 3,5-difluorophenol toluene solution to 80 mL / min, the flow rate of 3-chloropropanol toluene solution to 40 mL / min, and the flow rate of pure triethylamine to 40 mL / min. Set the temperature of microreactor A to 100℃. Put the above materials into microreactor A at the same time for reaction. The residence time in microreactor A is 79 s. After the reaction is completed, discharge the material into storage tank 1, use 10% hydrochloric acid to adjust the pH to between 6.0 and 6.5, let it stand to separate the layers, remove the water layer and keep the organic layer. (2) Add 3.9 g (0.025 mol) of 2,2,6,6-tetramethylpiperidine oxide (TEMPO) to storage tank 1. At the same time, prepare 2.5 L of 1.20 mol / L sodium chlorite aqueous solution and 1.1 L of 0.067 mol / L sodium hypochlorite aqueous solution. The flow rate of the organic layer in storage tank 1 is 80 mL / min, the flow rate of the sodium chlorite aqueous solution is 134 mL / min, and the flow rate of the sodium hypochlorite aqueous solution is 60.0 mL / min. Set the reaction temperature of microreactor B to 35℃. Put the above materials into microreactor B at the same time for reaction. The residence time in microreactor B is 46 s. After the reaction is completed, discharge the material into storage tank 2, let it stand and separate into layers, remove the water layer and keep the organic layer. (3) Set the flow rate of the organic layer in storage tank 2 to 75 mL / min, take 645 mL of concentrated sulfuric acid and set the flow rate to 32 mL / min, set the temperature of microreactor C to 100℃, and let the two materials enter microreactor C at the same time to react. The residence time in microreactor C is 118 s. After the reaction is completed, wash with water to separate the layers, concentrate the organic layer, and use n-heptane to crystallize 5,7-difluorobenzodihydropyran-4-one (HRMS(ESI) Calculated for C9H7F2O2) + ( [M+H) + (185.11) 423.6g, yield 92%, purity 99.58%, the mass spectrum of this compound is as follows: Figure 3 As shown.
[0089] Example 3 The preparation method of 5,7-difluorobenzodihydropyran-4-one provided in this embodiment includes the following specific steps: (1) Prepare 1 L of 3.0 mol / L 3,5-difluorophenol toluene solution and 500 mL of 6.60 mol / L 3-chloropropanol toluene solution, and take 4.5 mol (630 mL) of pure triethylamine. Set the flow rate of 3,5-difluorophenol toluene solution to 60 mL / min, the flow rate of 3-chloropropanol toluene solution to 30 mL / min, and the flow rate of pure triethylamine to 30 mL / min. Set the temperature of microreactor A to 100℃. Put the above materials into microreactor A at the same time for reaction. The residence time in microreactor A is 105 s. After the reaction is completed, discharge the material into storage tank 1, use 10% hydrochloric acid to adjust the pH to between 6.0 and 6.5, let it stand to separate the layers, remove the water layer and keep the organic layer. (2) Add 4.7g (0.03mol) of TEMPO to storage tank 1, and at the same time prepare 2.5L of 1.44 mol / L sodium chlorite aqueous solution and 1.0L of 0.09 mol / L sodium hypochlorite aqueous solution. Set the flow rate of the organic layer in storage tank 1 to 80 mL / min, the flow rate of the sodium chlorite aqueous solution to 125 mL / min, and the flow rate of the sodium hypochlorite aqueous solution to 80.0 mL / min. Set the reaction temperature of microreactor B to 40℃. Put the above materials into microreactor B at the same time for reaction. The residence time in microreactor B is 44s. After the reaction is completed, discharge the material into storage tank 2, let it stand and separate into layers, remove the water layer and keep the organic layer. (3) Set the flow rate of the organic layer in storage tank 2 to 75 mL / min, take 815 mL of concentrated sulfuric acid and set the flow rate to 41 mL / min, set the temperature of microreactor C to 95℃, and simultaneously introduce the above materials into microreactor C for reaction. The residence time in microreactor C is 109 s. After the reaction is completed, wash with water to separate the layers, concentrate the organic layer, and use n-heptane to crystallize to obtain 514 g of 5,7-difluorobenzodihydropyran-4-one, with a yield of 93% and a purity of 99.58%.
[0090] Comparative Example 1 (1) Prepare 1 L of 2.50 mol / L 3,5-difluorophenol toluene solution and 500 mL of 5.50 mol / L 3-chloropropanol toluene solution, and take 3.75 mol (517 g) of potassium carbonate and 724 g of water to prepare a solution (molar concentration of 3.81 mol / L) with a volume of 982 mL. Set the flow rate of 3,5-difluorophenol toluene solution to 80 mL / min, the flow rate of 3-chloropropanol toluene solution to 40 mL / min, and the flow rate of potassium carbonate aqueous solution to 79 mL / min. Set the temperature of microreactor A to 100℃. Put the above materials into microreactor A at the same time for reaction. The residence time in microreactor A is 79 s. After the reaction is completed, discharge the material into storage tank 1, use 10% hydrochloric acid to adjust the pH to between 6.0 and 6.5, let it stand to separate the layers, remove the water layer and keep the organic layer. (2) Add 3.9 g (0.025 mol) of 2,2,6,6-tetramethylpiperidine oxide (TEMPO) to storage tank 1. At the same time, prepare 2.5 L of 1.20 mol / L sodium chlorite aqueous solution and 1.1 L of 0.067 mol / L sodium hypochlorite aqueous solution. The flow rate of the organic layer in storage tank 1 is 80 mL / min, the flow rate of the sodium chlorite aqueous solution is 134 mL / min, and the flow rate of the sodium hypochlorite aqueous solution is 60.0 mL / min. Set the reaction temperature of microreactor B to 35℃. Put the above materials into microreactor B at the same time for reaction. The residence time in microreactor B is 46 s. After the reaction is completed, discharge the material into storage tank 2, let it stand and separate into layers, remove the water layer and keep the organic layer. (3) Set the flow rate of the organic layer in storage tank 2 to 75 mL / min, take 645 mL of concentrated sulfuric acid and set the flow rate to 32 mL / min, set the temperature of microreactor C to 100℃, and let the two materials enter microreactor C at the same time to react. The residence time in microreactor C is 118s. After the reaction is completed, wash with water to separate the layers, concentrate the organic layer, and use n-heptane to crystallize to obtain 359g of 5,7-difluorobenzodihydropyran-4-one, with a yield of 78% and a purity of 98.5%.
[0091] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.
Claims
1. A continuous flow method for preparing the ticoraxan intermediate 5,7-difluorobenzodihydropyran-4-one, characterized in that, Includes the following steps: (1) Dissolve 3,5-difluorophenol and 3-chloropropanol in an organic solvent to obtain solution 1 and solution 2; solution 1, solution 2 and organic amine are introduced into a microreactor to react, and after the reaction is completed, the material is discharged and the organic layer 1 is separated. (2) Add 2,2,6,6-tetramethylpiperidine oxide to organic layer 1, and then enter the microreactor with sodium hypochlorite solution and sodium chlorite solution for oxidation reaction. After the reaction is completed, discharge the material and separate organic layer 2. (3) Organic layer 2 is then added to a microreactor with concentrated sulfuric acid for reaction. After the reaction is complete, organic layer 3 is washed with water and separated. After concentration and recrystallization, tigorafenib intermediate 5,7-difluorobenzodihydropyran-4-one is obtained.
2. The continuous flow preparation method according to claim 1, characterized in that, In step (1), the organic solvent is toluene; and / or the organic amine is one or more of triethylamine, N,N-diisopropylethylamine and diisopropanolamine; preferably triethylamine.
3. The continuous flow preparation method according to claim 1, characterized in that, In step (1), the concentration of solution 1 is 2.0-4.0 mol / L; and / or the concentration of solution 2 is 4.0-7.0 mol / L.
4. The continuous flow preparation method according to claim 3, characterized in that, In step (1), the feed flow rate ratio of solution 1, solution 2 and organic amine is 1-2:0.4-1:0.4-1; Preferably, the feed flow rate of solution 1 is 50-100 mL / min; the feed flow rate of solution 2 is 20-50 mL / min; and the feed flow rate of the organic amine is 20-50 mL / min.
5. The continuous flow preparation method according to claim 1, characterized in that, Step (1) also includes: after the reaction is completed and the material is discharged, the pH of the reaction solution is adjusted to 6.0-6.5 using hydrochloric acid solution before separating the organic layer 1.
6. The continuous flow preparation method according to claim 1, characterized in that, In step (2), the molar concentration of the sodium chlorite aqueous solution is 1.0-2.0 mol / L, and / or the molar concentration of the sodium hypochlorite aqueous solution is 0.05-0.10 mol / L.
7. The continuous flow preparation method according to claim 6, characterized in that, The feed flow rate ratio of the organic layer 1, the hypochlorous acid solution, and the sodium chlorite solution is 12-20:8-25:18-36; Preferably, the feed flow rate of the organic layer 1 is 60-100 mL / min; the feed flow rate of the hypochlorous acid aqueous solution is 40-75 mL / min; and the feed flow rate of the sodium chlorite solution is 90-180 mL / min.
8. The continuous flow preparation method according to claim 1, characterized in that, In step (3), the feed flow rate ratio of the organic layer 2 to concentrated sulfuric acid is 3-5:1-2.5; Preferably, the feed flow rate of the organic layer 2 is 60-100 mL / min; the feed flow rate of the concentrated sulfuric acid is 20-50 mL / min.
9. The continuous flow preparation method according to claim 1, characterized in that, In step (1), the reaction temperature is 90-100℃; And / or in step (2), the temperature of the oxidation reaction is 30-40°C; And / or in step (3), the temperature of the reaction is 80-100°C.
10. The continuous flow preparation method according to claim 1, characterized in that, The solvent used for recrystallization is n-heptane.