Method and production system for continuous hydrodechlorination of 6-chloro substituted purine nucleoside analogue
By using microchannel reaction technology and ammonium formate as hydrogen source in the dechlorination and hydrogenation process of 6-chloro-substituted purine nucleoside analogs, the problems of high operation difficulty, high toxicity and low mass transfer efficiency in the prior art are solved. An efficient and safe hydrogenation dechlorination reaction is achieved, which improves the yield and purity of the reaction.
Patent Information
- Application Number
- CN202411614338.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-13
- Publication Date
- 2025-02-21
AI Technical Summary
The existing dechlorination and hydrogenation process of 6-chloro-substituted purine nucleoside analogs has problems such as difficult operation, high toxicity, harsh reaction conditions, low mass transfer efficiency, and low yield and purity.
Using microchannel reaction technology, ammonium formate is used as the hydrogen source, and the palladium catalyst is solidly loaded in the microchannel reactor, and reacted by a mixed solvent of alcohol solvent, water and epoxy ether to achieve continuous hydrogenation and dechlorination.
The reaction conditions are simplified, the mass transfer efficiency is improved, the use of toxic materials is reduced, the reaction time is shortened, and the reaction yield and purity are improved.
Smart Images
Figure CN119490549A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of compound intermediate production, in particular to a method and a production system for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs. Background Art
[0002] The compounds formed by dechlorination and hydrogenation of 6-chloro-substituted purine nucleoside analogs are important intermediates in drug synthesis. Therefore, researchers have continuously developed and improved the dechlorination and hydrogenation process of 6-chloro-substituted purine nucleoside analogs. However, the existing dechlorination and hydrogenation still have many problems, such as (1) using AIBN and tetra-n-butyltin as dechlorination conditions, the reaction conditions are harsh, requiring anhydrous and oxygen-free conditions, and the operation is difficult. In addition, tetra-n-butyltin is highly toxic and easily endangers the health of operators; (2) the reaction conditions are difficult to achieve, such as the reaction temperature is as high as 80°C and the reaction time is as long as 6h; (3) when a conventional reactor is used for hydrogenation, hydrogen is prone to leakage and is more dangerous. When hydrogen is used, the reaction system is three-phase and the reaction mass transfer efficiency is low; (4) the reaction yield is low. Therefore, an improved hydrogenation dechlorination method is urgently needed to improve the above problems at the same time.
[0003] In view of this, the present invention is proposed. Summary of the invention
[0004] The object of the present invention is to provide a method and a production system for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs. The reaction conditions of the hydrogenation and dechlorination method provided in the embodiment of the present invention are easy to implement, avoid the use of highly toxic materials, the reaction system is two-phase, the mass transfer efficiency of the reaction is high, and the yield and purity of the reaction are both high.
[0005] The present invention is achieved in that:
[0006] In a first aspect, the present invention provides a method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, comprising: reacting ammonium formate, a palladium catalyst, a 6-chloro-substituted purine nucleoside analog and a solvent using a microchannel reaction technology.
[0007] In an optional embodiment, the palladium catalyst is immobilized in the reaction channel of the microchannel reaction.
[0008] In an optional embodiment, the palladium catalyst is selected from palladium hydroxide on carbon or palladium aluminum oxide.
[0009] In an optional embodiment, the amount of the catalyst used is 5-10% of the mass of the 6-chloro-substituted purine nucleoside analog.
[0010] In an optional embodiment, the solvent is selected from at least one of an alcohol solvent, water and an epoxy ether;
[0011] Preferably, the alcohol solvent is selected from methanol;
[0012] The epoxy ether is selected from 1,4-dioxane.
[0013] In an optional embodiment, the volume ratio of the alcohol solvent, the epoxy ether and the water is (10-40):(0-20):(0-1).
[0014] In an optional embodiment, 20-210 ml of the solvent is added per mole of the 6-chloro-substituted purine nucleoside analog.
[0015] In an optional embodiment, the reaction time is 3.5-30 min; the temperature is 25-60°C.
[0016] In a second aspect, the present invention provides a production system for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, wherein the production system for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs is used to implement the method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs as described in any of the aforementioned embodiments, and comprises a microchannel reactor for performing microchannel reaction.
[0017] In an optional embodiment, it includes a raw material mixer for mixing and dissolving ammonium formate, 6-chloro-substituted purine nucleoside analogs and a solvent to form a mixed solution, an injection pump for injecting the mixed solution, a heat exchange unit for preliminarily heating the mixed solution and a microchannel reactor for performing a microchannel reaction, which are connected in sequence; a palladium catalyst is immobilized in the microchannel reactor; and a heating device is arranged outside the heat exchange unit and the microchannel reactor.
[0018] The present invention has the following beneficial effects: an embodiment of the present invention provides a method for hydrogenation dechlorination, which adopts a microchannel reaction to carry out the reaction and can realize a continuous reaction, and adopts ammonium formate as a hydrogen source, so that the reaction system has only two phases, thereby improving the mass transfer efficiency of the reaction, and the whole method does not adopt highly toxic raw materials, and the conditions of the method are also easy to implement, and high temperature does not need to be adopted, the reaction time is shortened, and the yield and purity of the whole reaction are improved. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.
[0020] Figure 1 A schematic diagram of the results of the production system of continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs provided in an embodiment of the present invention.
[0021] Icon: 100-6-chloro-substituted purine nucleoside analogue continuous hydrogenation and dechlorination production system; 110-raw material mixer; 120-injection pump; 130-heat exchange unit; 140-microchannel reactor; 141-filter sieve plate; 150-reaction liquid collection tank; 160-heating device. DETAILED DESCRIPTION
[0022] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.
[0023] In a first aspect, the present invention provides a method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, comprising: reacting ammonium formate, a palladium catalyst, a 6-chloro-substituted purine nucleoside analog and a solvent using a microchannel reaction technology.
[0024] The embodiment of the present invention adopts ammonium formate as a hydrogen source, and ammonium formate is easy to sublimate. If a conventional reactor is used for reaction, there are certain safety hazards. And after the ammonium formate sublimates, it causes an equivalent change in the reaction system, and then blocks the reflux pipe, which is easy to cause a safety accident. When the embodiment of the present invention adopts microchannel reaction technology for reaction, ammonium formate is not easy to sublimate, which can not only ensure production safety, but also ensure that the amount of material in the reaction system remains unchanged, thereby ensuring production efficiency.
[0025] At the same time, the embodiment of the present invention adopts the above raw materials to carry out the reaction, and the reaction system is two-phase. Compared with the dechlorination and hydrogenation using hydrogen, the mass transfer efficiency can be improved, and no post-treatment is required after the reaction is completed.
[0026] Furthermore, the palladium catalyst is immobilized in the reaction pipe of the microchannel reaction. The method provided by the embodiment of the present invention can reduce the amount of catalyst used, but increase the equivalent of the catalyst participating in the reaction.
[0027] Furthermore, the catalyst is selected from palladium hydroxide on carbon or palladium aluminum oxide. The amount of the catalyst used is 5-10% of the mass of the 6-chloro substituted purine nucleoside analog.
[0028] Furthermore, 20-210 ml of the solvent is added for each mole of the 6-chloro-substituted purine nucleoside analog. Specifically, the solvent is selected from at least one of an alcohol solvent, water and an epoxy ether; for example, the alcohol solvent includes but is not limited to methanol; the epoxy ether includes but is not limited to 1,4-dioxane. The volume ratio of the above-mentioned alcohol solvent, the epoxy ether and the water is (10-40): (0-20): (0-1), that is, water and / or 1,4-dioxane may not be used as a solvent, and is specifically adjusted according to the solubility of the reactants.
[0029] Furthermore, the reaction time is 3.5-30 min and the temperature is 25-60° C. The preparation method provided by the embodiment of the present invention can significantly shorten the reaction time, reduce the reaction temperature, and improve the reaction yield and purity.
[0030] The present invention is described in detail by referring to the following synthesis path:
[0031]
[0032] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.
[0033] Example 1
[0034] See also Figure 1 The embodiment of the present invention provides a production system 100 for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, which is used to implement a method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs. Specifically, it includes a raw material mixer 110, which is used to mix and dissolve ammonium formate, 6-chloro-substituted purine nucleoside analogs and a solvent to form a mixed solution. The raw material mixer 110 can adopt a stirring tank in the prior art.
[0035] It also includes a syringe pump 120 for injecting the mixed solution. The syringe pump 120 can adopt an existing pressure pump. The syringe pump 120 transports the mixed solution to subsequent equipment for transportation or reaction.
[0036] It also includes a heat exchange unit 130 for preliminarily heating the mixed solution. The heat exchange unit 130 is used to heat the mixed solution to reach the reaction temperature. Then, when the mixed solution enters the microchannel reaction, it can directly contact and react with the catalyst, thereby shortening the reaction time and improving the reaction efficiency.
[0037] The invention also includes a microchannel reactor 140 for performing microchannel reaction; a palladium catalyst is immobilized in the microchannel reactor 140; and the heated mixed solution is passed into the microchannel reactor 140 and then contacts and reacts with the immobilized palladium catalyst. Filter sieve plates 141 are respectively provided at both ends of the microchannel reactor 140 to prevent the catalyst from being taken out of the microchannel reactor 140.
[0038] It also includes a reaction liquid collecting tank 150 , which is connected to the outlet of the microchannel reactor 140 .
[0039] It should be noted that during the reaction process, the mixed solution is continuously introduced into the microchannel reactor 140 until the mixed solution is completely introduced.
[0040] The microchannel reactor 140 may be a cylindrical reaction pipe.
[0041] That is, the raw material mixer 110, the injection pump 120, the heat exchange unit 130 and the microchannel reactor 140 are connected in sequence.
[0042] Furthermore, a heating device 160 is disposed outside the heat exchange unit 130 and the microchannel reactor 140 .
[0043] Example 2
[0044] This embodiment provides a method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, using the production system 100 for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs provided in Example 1, comprising:
[0045] The synthesis was carried out according to the following synthesis route:
[0046] The catalyst palladium hydroxide carbon is immobilized in the microchannel reactor 140, and ammonium formate, methanol, water, dioxane and compound A are mixed to form a mixed solution, which is then heated to the reaction temperature through a heat exchanger and then introduced into the microchannel reactor for reaction.
[0047] The reaction conditions are as follows: 1.0 g A and 10 eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (10V / 10V / 1V, 21 ml), temperature 60°C, reaction time 5 min, concentration to obtain a white solid, UPLC: 95.81% A1, yield: 92.6%.
[0048] Example 3-12
[0049] Examples 3-12 were reacted with reference to the synthesis method of Example 2, with specific synthesis conditions being different, as follows:
[0050] Example 3: Reactants: 1.0 g A and 5 eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41 ml), temperature 25°C, reaction time 10 min, concentration to obtain a white solid, UPLC: 97.95% A1, yield: 94.8%.
[0051] Example 4: Reactants: 1.0 g A and 10 eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41 ml), temperature 50°C, reaction time 30 min, concentration to obtain a white solid, UPLC: 96.34% A1, yield: 93.3%.
[0052] Example 5: Reactants: 5.0 g A and 10 eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 205 ml), temperature 50°C, reaction time 5 min, concentration to obtain a white solid, UPLC: 95.00%, yield: 97.5%.
[0053] Example 6: Reactants: 1.0 g C and 10 eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41 ml), temperature 25°C, reaction time 30 min, concentrated to obtain a white solid, UPLC: 89.11% C1, yield: 96.2%. The structural formula of C is:
[0054] Example 7: Reactants: 1.0 g C and 10 eq ammonium formate, 5% palladium aluminum oxide, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41 ml), temperature 25°C, reaction time 17.5 min, concentration to obtain a white solid, UPLC: 91.06% C1, yield: 93.2%.
[0055] Example 8: Reactants: 1.0 g C and 10 eq ammonium formate, 5% palladium aluminum oxide, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41 ml), temperature 50°C, reaction time 7 min, concentration to obtain a white solid, UPLC: 92.90% C1, yield: 94.7%.
[0056] Example 9: Reactants: 1.0 g C and 10 eq ammonium formate, 5% palladium aluminum oxide, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41 ml), temperature 50°C, reaction time 5 min, concentration to obtain a white solid, UPLC: 94.00% C1, yield: 96.2%.
[0057] Example 10: Reactants: 1.0 g D and 10 eq ammonium formate, 5% palladium aluminum oxide, solvent: MeOH (40V, 40 ml), temperature 50°C, reaction time 3.5 min, collect 27.5 ml of effluent, concentrate to obtain a white solid, UPLC: 93.58% D1, yield: 93.2%, wherein the structural formula of D is:
[0058] Example 11: Reactants: 1.0 g D and 15 eq ammonium formate, 5% palladium aluminum oxide, solvent: MeOH (40 V, 40 ml), temperature 50° C., reaction time 7 min, concentrated to obtain a white solid, UPLC: 98.13% D1, yield: 91.5%.
[0059] Example 12: Reactants: 1.0 g B and 15 eq ammonium formate, 5% palladium aluminum oxide, solvent: MeOH (40V, 40 ml), temperature 60°C, reaction time 5 min, collect 27.5 ml of effluent, concentrate to obtain a white solid, UPLC: 94.80% B1, yield: 91.8%. The structural formula of B is as follows:
[0060] Comparative Example 1
[0061] This comparative example is synthesized by referring to the preparation method of Example 3, except that the reaction equipment of Example 1 used in Example 3 is replaced by a reaction kettle.
[0062] Specifically, 1.0 g A and 5 eq ammonium formate, catalyst: 10% palladium hydroxide on carbon (0.3 eq), solvent: MeOH / Dioxane / H2O (20 V / 20 V / 1 V, 41 ml), temperature 25°C, reaction time 10 min, UPLC: 65% A1, 25% A, yield: 78%. It can be seen that more raw materials are not completely reacted in the autoclave reaction.
[0063] Comparative Example 2
[0064] This comparative example was synthesized by referring to the preparation method of Example 3, except that the solvent was different. The specific conditions were as follows:
[0065] 1.0g A and 5eq ammonium formate, 10% palladium hydroxide on carbon, solvent: EtOH / Dioxane / H2O (60V / 20V / 1V, 81ml), temperature 25°C, reaction time 10min, concentrated to obtain a white solid, UPLC: 75% A1, 15% A, yield: 80%. It can be seen that after replacing methanol with ethanol, the solvent in ethanol is poor, more solvent is needed, and more raw materials are not reacted completely.
[0066] Comparative Example 3
[0067] This comparative example was synthesized by referring to the preparation method of Example 3, except that the reaction time was different. The specific conditions were as follows:
[0068] 1.0g A and 5eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41ml), temperature 25°C, reaction time 60min, concentrated to obtain a white solid, UPLC: 80% A1, 16% over-hydrogenation by-products, yield: 82%. It can be seen that after extending the time to 60min, the reaction purity decreased and over-hydrogenation by-products were generated.
[0069] Comparative Example 3
[0070] This comparative example was synthesized by referring to the preparation method of Example 3, except that the reaction temperature was different. The specific reaction conditions were as follows:
[0071] 1.0g A and 5eq ammonium formate, 10% palladium hydroxide on carbon, solvent: MeOH / Dioxane / H2O (20V / 20V / 1V, 41ml), temperature 80℃, reaction time 10min, concentrated to obtain white solid, UPLC: 78% A1, 18% over-hydrogenation by-product, yield: 85%. It can be seen that after increasing the reaction temperature, the reaction purity decreased and over-hydrogenation by-products were generated.
[0072] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, characterized in that: include: Ammonium formate, a palladium catalyst, a 6-chloro-substituted purine nucleoside analog and a solvent are reacted by using a microchannel reaction technology.
2. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 1, characterized in that: The palladium catalyst is immobilized in the reaction channel of the microchannel reaction.
3. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 1, characterized in that: The palladium catalyst is selected from palladium hydroxide on carbon or palladium aluminum oxide.
4. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 1, characterized in that: The amount of the catalyst used is 5-10% of the mass of the 6-chloro substituted purine nucleoside analog.
5. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 1, characterized in that: The solvent is selected from at least one of an alcohol solvent, water and epoxy ether; Preferably, the alcohol solvent is selected from methanol; The epoxy ether is selected from 1,4-dioxane.
6. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 5, characterized in that: The volume ratio of the alcohol solvent, the epoxy ether and the water is (10-40):(0-20):(0-1).
7. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 1, characterized in that: 20-210 ml of the solvent is added for each mole of the 6-chloro substituted purine nucleoside analog.
8. The method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 1, characterized in that: The reaction time is 3.5-30 minutes; the temperature is 25-60°C.
9. A production system for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs, characterized in that: The production system for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs is used to implement the method for continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to any one of claims 1 to 8, and comprises a microchannel reactor for performing microchannel reaction.
10. The production system of continuous hydrogenation and dechlorination of 6-chloro-substituted purine nucleoside analogs according to claim 9, characterized in that: The invention comprises a raw material mixer for mixing and dissolving ammonium formate, 6-chloro-substituted purine nucleoside analogs and a solvent to form a mixed solution, an injection pump for injecting the mixed solution, a heat exchange unit for preliminarily heating the mixed solution and a microchannel reactor for performing microchannel reaction, which are connected in sequence; a palladium catalyst is immobilized in the microchannel reactor; and a heating device is arranged outside the heat exchange unit and the microchannel reactor.