A preparation method of impurity C of rizatriptan EP
Through a simplified six-step reaction method, the problem of cumbersome and low efficiency of EP impurity C synthesis route in the prior art was solved, and efficient and low-cost preparation was achieved, and high-purity test samples were provided to drugs. Research provides important application value.
Patent Information
- Application Number
- CN202410342526.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-25
- Publication Date
- 2024-12-06
- Estimated Expiration
- 2044-03-25
AI Technical Summary
The existing synthesis route of rizatriptan EP impurity C is numerous, has low efficiency and high cost, making it difficult to meet the needs of drug research and development for impurity control.
Using the six-step reaction method with intermediate I as the starting material, the synthesis route is simplified and the total collection is increased through nucleophilic substitution, benzyl bromide, phosphonium salt formation, nitro reduction, amide condensation and Vitic reaction. rate and purity.
The efficient preparation of rizatriptan EP impurity C was achieved, with a total yield of 50% to 60%, and a purity of more than 95%, reducing costs and providing high-quality test samples for drug research.
Smart Images
Figure CN118047762B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of compound synthesis, and in particular to a method for preparing impurity C of rizatriptan EP. Background Art
[0002] Rizatriptan was developed by Merck and launched in the United States in 1998. It is a selective agonist of 5-hydroxytryptamine (1B / 1D) receptors and has been shown to be superior to placebo, ergotamine and certain oral triptans, with good safety and tolerability. It is a second-generation 5-HT1B / 1D receptor agonist that normalizes dilated meningeal vessels and blocks the release of neuropeptides from perivascular trigeminal neurons, thereby inhibiting the development of neurogenic inflammation and reversing some pathophysiological mechanisms in migraine attacks. Prior to regulatory approval, more than 5,000 patients were recruited for research, more than 46,000 migraine attacks were treated, and the efficacy and safety of rizatriptan tablets and orally disintegrating tablets (ODT) formulations were demonstrated. Currently, rizatriptan is used in more than 50 countries around the world.
[0003] In recent years, China's drug regulatory agencies have proposed a series of policies and guidelines to strengthen the evaluation of drug quality, safety and efficacy before the drug is put on the market. One of the most important aspects is the control of drug impurities, which is closely related to drug quality. Drug developers and drug regulatory agencies have deeply realized that impurities are often related to drug safety, and in a few cases, they are also related to efficacy. Therefore, controlling impurity levels has received more and more attention from drug developers during the drug development process.
[0004] Several impurities are generated during the synthesis process of rizatriptan. As one of the key impurities, rizatriptan EP impurity C is a geometric isomer impurity of rizatriptan API. In the current literature, there is only one synthetic route reported by Emcure Pharmaceuticals Ltd. in India in 2012 using p-nitrobenzyl bromide as the starting material (Org. Process Res. Dev., 2012, 16, 507−511). This synthetic route uses Sonogashira coupling and acetylenic ring closure as two key reactions to construct the indole core. This route successfully provides a target impurity reference for the development of rizatriptan, but its total synthesis steps are as long as 10 steps, which is not efficient and has a correspondingly high cost. In order to address the shortcomings of the existing preparation method, we developed a route using intermediate I (3-methyl-4-nitrobenzyl bromide) as the starting material and obtaining rizatriptan EP impurity C through 6 steps of reaction. At the same time, the raw materials of this route are easily available, and the total yield is 50%~60%, which is much higher than the total yield of 20% in the literature route, and the cost is low, so it can greatly improve the research and development efficiency of rizatriptan. Summary of the invention
[0005] In view of the problems existing in the prior art, the present invention provides a method for preparing a rizatriptan EP impurity C, a method for preparing a rizatriptan EP impurity C with a more convenient synthesis method, and the purity of the target product obtained by the preparation method can reach more than 95%, which provides a test sample for rizatriptan research and has important application value.
[0006] In order to achieve the above object, the present invention provides a method for preparing rizatriptan EP impurity C, comprising the following steps:
[0007] Step S1: Take intermediate I as a raw material and dissolve it in solvent I, add base I, and then add triazole to react to obtain intermediate II. The reaction equation is as follows:
[0008]
[0009] Step S2: Dissolve intermediate II in solvent II, add NBS, and react in the presence of a free radical initiator to generate intermediate III. The reaction equation is as follows:
[0010]
[0011] Step S3: Dissolve the intermediate III in solvent three, add triphenylphosphine, and react to generate the phosphonium salt intermediate IV. The reaction equation is as follows:
[0012]
[0013] Step S4: dissolving the phosphonium salt intermediate IV in solvent IV, adding palladium carbon, and reducing with a hydrogen donor to generate an amine intermediate V. The reaction equation is as follows:
[0014]
[0015] Step S5: Dissolve the intermediate V in solvent V, add N,N-dimethyl-β-alanine, and react with an amide condensing agent to generate the intermediate VI. The reaction equation is as follows:
[0016]
[0017] Step S6: Dissolve the intermediate VI in solvent VI, and generate the target product VII through Wittig reaction under the alkaline condition of base 2. The reaction equation is as follows:
[0018] .
[0019] Preferably, the molar ratio of the intermediate I to the base one and the triazole in step S1 is 1:(1-10):(1-10); the base one is selected from one or more of sodium hydride, lithium hydroxide, sodium hydroxide, sodium carbonate or potassium carbonate; the solvent one is selected from one or more of THF, DMF, MeCN and NMP, and the reaction time of step S1 is 6-24h. More preferably, the molar ratio of the intermediate I to the base and the triazole in step S1 is 1:(1.2-1.5):(1.2-1.5); the base one is preferably potassium carbonate; the solvent one is DMF; and the reaction time is 12-18h.
[0020] Preferably, the molar ratio of intermediate II to NBS in step S2 is 1:(1-5).
[0021] Preferably, the free radical initiator in step S2 is AIBN or BPO, and the molar ratio of the free radical initiator to the intermediate II is 1:(0.02-0.05); the reaction time in step S2 is 12-24h. More preferably, the molar ratio of the intermediate II to NBS is 1:(1-2), the free radical initiator is AIBN, the reaction solvent is ethyl acetate, and the reaction time is 12-16h.
[0022] Preferably, the molar ratio of the intermediate III to triphenylphosphine in step S3 is 1:(1-5); the solvent three is selected from one or more of THF, DME, DMF, DMSO, and MeCN; and the reaction time of step S3 is 12-24 hours. More preferably, the molar ratio of the intermediate III to triphenylphosphine in step S3 is 1:(1-1.2); the solvent three is THF; and the reaction time is 12 to 16 hours.
[0023] Preferably, the mass percentage of 5% or 10% palladium on carbon in step S4 is 5% to 10% of intermediate IV.
[0024] Preferably, the hydrogen donor in step S4 is selected from one of hydrogen, formic acid, ammonium formate, and cyclohexadiene, and the molar ratio of the hydrogen donor to the intermediate VI is (1.5-5):1, the hydrogen donor is hydrogen, the pressure is 1 atmosphere to 5 atmospheres, the solvent four is selected from one or more of MeOH, EtOH, EtOAc, DMF, and DMSO; the reaction time of step S4 is 12-24h. More preferably, the palladium carbon in step S4 is 10%, the mass percentage is 5% of the intermediate IV, the hydrogen donor is hydrogen, the pressure is 1 atmosphere; the solvent four is ethyl acetate; the reaction time is 12 to 16h.
[0025] Preferably, the molar ratio of the intermediate V to N,N-dimethyl-β-alanine in step S5 is 1:(1-5).
[0026] Preferably, the amide condensation agent in step S5 is selected from one or more of HOBt / EDCI, HATU, and HBTU, and the solvent V is selected from one or more of THF, DMF, and MeCN; the reaction time in step S5 is 12-24 hours. More preferably, the molar ratio of the intermediate V to N,N-dimethyl-β-alanine in step S5 is 1:(1-1.2), the amide condensation agent is HOBt / EDCI, and the solvent V is DMF; the reaction time is 12-16 hours.
[0027] Preferably, the molar ratio of the intermediate VI to the base II in step S6 is 1: (1-5); the base II is selected from one or more of PhLi, n-BuLi, NaNH2, NaH, LiHDMS, and LDA, and the solvent VI is selected from one or more of THF, DME, DMF, DMSO, and MeCN; the reaction time of step S6 is 12-24h. More preferably, the molar ratio of the intermediate VI to the base II in step S6 is 1: (1-2); the base II is LiHDMS. The solvent VI is THF; and the reaction time is 8-12h.
[0028] The technical solution of the present invention has the following beneficial effects:
[0029] The method of the present invention obtains the impurity C of rizatriptan EP through a six-step synthesis reaction. First, the intermediate I undergoes a nucleophilic substitution reaction with triazole under alkaline conditions to obtain the intermediate II, and then NBS is used for benzylic bromination to obtain the intermediate III. The intermediate III reacts with triphenylphosphine to generate the phosphonium salt intermediate IV, and the latter undergoes nitro reduction under palladium carbon hydrogen conditions to obtain the intermediate V. The former is condensed with N, N-dimethyl-β-alanine amide to obtain the intermediate VI, and finally the Wittig reaction is closed to obtain the target molecule. The preparation method has easy-to-obtain raw materials, mild reaction conditions, and four steps are reduced compared with the reported synthesis route, which greatly improves the synthesis efficiency, and the total yield is 50% to 60%, which is much higher than the total yield of 20% in the literature route, and the cost is greatly reduced. The purity of the obtained impurity C meets the requirements, providing a test sample for rizatriptan research, and has important research value. Compared with the existing method, the preparation process design route of the rizatriptan EP impurity C of the present invention reduces four steps and is very simple, and the raw materials are easily available, the purity is high, the reaction process is controllable and the environmental protection effect is good; at the same time, the rizatriptan EP impurity C prepared by the present invention provides a high-quality test sample for the research of rizatriptan, and has important research value in clinical pharmacokinetic research. BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Figure 1 A flow chart of the preparation process of impurity C of Rizatriptan EP provided by the present invention;
[0031] Figure 2 The final product LCMS chart of the impurity C of Rizatriptan EP provided by the present invention;
[0032] Figure 3 The final product NMR image of the impurity C of Rizatriptan EP provided by the present invention;
[0033] Figure 4 This is a liquid phase diagram of the final product of impurity C of Rizatriptan EP provided by the present invention. DETAILED DESCRIPTION
[0034] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments.
[0035] Example 1
[0036] Reference Figures 1 to 4 Preparation of intermediate II: 15 g of intermediate I was dissolved in 150 mL of DMF, 10.8 g of potassium carbonate was added, and then 5.4 g of 1,2,4-triazole was added. The reaction was carried out at 25°C for 16 hours. Thin layer chromatography showed that the reaction was complete. The reaction system was cooled to zero degrees, 750 mL of water was added, and extracted with dichloromethane (750 mL * 3); the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the organic phases were spin-dried. The crude product was purified by column chromatography with petroleum ether and ethyl acetate system to obtain 13.1 g of intermediate II with a yield of 92%.
[0037]
[0038] Preparation of intermediate III: 13.1 g of intermediate II was dissolved in 130 mL of ethyl acetate, 12.8 g of NBS and 200 mg of AIBN were added, and the reaction was carried out at 60°C for 16 hours. Thin layer chromatography showed that the reaction was complete; the reaction system was cooled to room temperature, 650 mL of water was added, and extracted with ethyl acetate (650 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phases were spin-dried. The crude product was purified by column chromatography with petroleum ether and ethyl acetate system to obtain 16.0 g of intermediate III with a yield of 90%.
[0039]
[0040] Preparation of intermediate IV: 12.8 g of intermediate III was dissolved in 130 mL of THF, 11.3 g of triphenylphosphine was added, and the reaction was carried out at 50°C for 16 hours. Thin layer chromatography showed that the reaction was complete. The reaction system was cooled to room temperature, the insoluble matter was filtered out, the organic phase was spin-dried, and the crude product was purified by slurrying with petroleum ether to obtain 16.7 g of white solid intermediate IV, with a yield of 81%.
[0041]
[0042] Preparation of intermediate V: 16.7 g of intermediate IV was dissolved in 200 mL of ethyl acetate, 1.6 g of 10% palladium on carbon was added, and the mixture was reacted at room temperature for 16 hours under 1 atm H2 atmosphere. Thin layer chromatography showed that the reaction was complete. The insoluble matter was removed by filtration with diatomaceous earth, and the organic phase was spin-dried to obtain 15.1 g of white solid intermediate V with a yield of 97%.
[0043]
[0044] Preparation of intermediate VI: 15.1 g of intermediate V was dissolved in 150 mL of DMF, and then 4.7 g of N,N-dimethyl-β-alanine, 5.4 g of HOBt and 8.5 g of EDCI were added. The reaction was carried out at room temperature for 16 hours. Thin layer chromatography showed that the reaction was complete. After vacuum rotary evaporation to remove most of the DMF, ethyl acetate was added to dissolve the residue, and then an appropriate amount of silica gel was added to dry the column, and the column was purified with petroleum ether and ethyl acetate system to obtain 17.4 g of white solid intermediate VI with a yield of 95%.
[0045]
[0046] Preparation of intermediate VII: Dissolve 12.3 g of intermediate VI in 100 mL THF and cool to -78 o C, LiHDMS (22.4 mL, 1 mol in THF) was added dropwise. The mixture was heated at -78 o After continuing to stir at 40 °C for 2 hours, the mixture was warmed to room temperature and continued to stir for 12 hours. Thin layer chromatography showed that the reaction was complete. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, and the solvent was removed by rotary evaporation to obtain a crude product, which was purified by column chromatography using a petroleum ether and ethyl acetate system to obtain 5.2 g of light yellow viscous oil intermediate VII with a yield of 88%. The purity detected by liquid chromatography was 95.1% (lower Figure 4 ). The spectrum is as follows Figure 2 and Figure 3As shown, its ESI-LCMS (m / z): 269.96 (M+H)+ nuclear magnetic HNMR δ 1 H NMR (400 MHz, DMSO) δ11.12 (s, 1H), 7.82 (s, 1H), 7.41-7.33 (m, 2H), 6.99-6.97 (d, J = 8 Hz, 2H), 6.39 (s, 1H), 5.14(s, 2H), 2.90 – 2.86 (t, J = 8 Hz, 2H), 2.48 – 2.46 (m, 2H), 2.10 (s, 6H).
[0047]
[0048] Example 2
[0049] Reference Figures 1 to 4 Preparation of intermediate II: 23 g of intermediate I was dissolved in 230 mL of DMF, 16.5 g of potassium carbonate was added, and then 8.3 g of 1,2,4-triazole was added. The reaction was carried out at 25°C for 16 hours. Thin layer chromatography showed that the reaction was complete. The reaction system was cooled to zero degrees, 800 mL of water was added, and extracted with dichloromethane (800 mL * 3); the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the organic phases were spin-dried. The crude product was purified by column chromatography with petroleum ether and ethyl acetate system to obtain 20.7 g of intermediate II with a yield of 94%.
[0050]
[0051] Preparation of intermediate III: 15 g of intermediate II was dissolved in 150 mL of ethyl acetate, 14.7 g of NBS and 230 mg of AIBN were added, and the reaction was carried out at 60°C for 16 hours. Thin layer chromatography showed that the reaction was complete. The reaction system was cooled to room temperature, 700 mL of water was added, and extracted with ethyl acetate (700 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic phases were spin-dried. The crude product was purified by column chromatography with petroleum ether and ethyl acetate system to obtain 18.5 g of intermediate III with a yield of 91%.
[0052]
[0053] Preparation of intermediate IV: 15 g of intermediate III was dissolved in 150 mL of THF, 13.2 g of triphenylphosphine was added, and the reaction was carried out at 50°C for 16 hours. Thin layer chromatography showed that the reaction was complete. The reaction system was cooled to room temperature, the insoluble matter was filtered out, the organic phase was spin-dried, and the crude product was purified by slurrying with petroleum ether to obtain 20.1 g of white solid intermediate IV, with a yield of 83%.
[0054]
[0055] Preparation of intermediate V: 18 g of intermediate IV was dissolved in 200 mL of ethyl acetate, 1.7 g of 10% palladium on carbon was added, and the mixture was reacted at room temperature for 16 hours under 1 atm H2 atmosphere. Thin layer chromatography showed that the reaction was complete. The insoluble matter was removed by filtration with diatomaceous earth, and the organic phase was spin-dried to obtain 16.3 g of white solid intermediate V with a yield of 97%.
[0056]
[0057] Preparation of intermediate VI: 16.3 g of intermediate V was dissolved in 160 mL of DMF, and then 5.1 g of N,N-dimethyl-β-alanine, 5.8 g of HOBt and 9.2 g of EDCI were added. The reaction was carried out at room temperature for 16 hours. Thin layer chromatography showed that the reaction was complete. After vacuum rotary evaporation to remove most of the DMF, ethyl acetate was added to dissolve the residue, and then an appropriate amount of silica gel was added and dried on a column. The mixture was purified by column chromatography using a petroleum ether and ethyl acetate system to obtain 18.4 g of white solid intermediate VI with a yield of 93%.
[0058]
[0059] Preparation of intermediate VII: Dissolve 15 g of intermediate VI in 150 mL THF and cool to -78 o C, LiHDMS (27.3 mL, 1 mol in THF) was added dropwise. The mixture was heated at -78 o After stirring for 2 hours at 40 °C, the mixture was heated to room temperature and stirred for 12 hours. Thin layer chromatography showed that the reaction was complete. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate (150 mL * 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous Na2SO4, and the solvent was removed by rotary evaporation to obtain a crude product, which was purified by column chromatography using petroleum ether and ethyl acetate system to obtain 6.4 g of light yellow viscous oil intermediate VII with a yield of 89%. The spectrum is the same as Example 1.
[0060]
[0061] It can be seen that the method of the present invention obtains the impurity C of rizatriptan EP through a six-step synthesis reaction. First, the intermediate I undergoes a nucleophilic substitution reaction with triazole under alkaline conditions to obtain the intermediate II, and then NBS is used for benzylic bromination to obtain the intermediate III. The intermediate III reacts with triphenylphosphine to generate the phosphonium salt intermediate IV, and the latter undergoes nitro reduction under palladium carbon hydrogen conditions to obtain the intermediate V. The former is condensed with N, N-dimethyl-β-alanine amide to obtain the intermediate VI, and finally the Wittig reaction is closed to obtain the target molecule. The preparation method has easy-to-obtain raw materials, mild reaction conditions, and four steps are reduced compared with the reported synthesis route, which greatly improves the synthesis efficiency, and the total yield is between 50% and 60% (the product of each yield), which is much higher than the total yield of 20% of the literature route, greatly reducing the cost. And the purity of the impurity C obtained meets the requirements, providing a test sample for rizatriptan research, which has important research value. Compared with the existing method, the preparation process design route of the rizatriptan EP impurity C of the present invention reduces four steps and is very simple, and the raw materials are easily available, the purity is high, the reaction process is controllable and the environmental protection effect is good; at the same time, the rizatriptan EP impurity C prepared by the present invention provides a high-quality test sample for the research of rizatriptan, and has important research value in clinical pharmacokinetic research.
[0062] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent structural changes made by using the contents of the present invention specification and drawings under the inventive concept of the present invention, or directly / indirectly applied in other related technical fields are included in the patent protection scope of the present invention.
Claims
1. A method for preparing impurity C of rizatriptan EP, characterized in that: The steps include: Step S1: Take intermediate I as a raw material and dissolve it in solvent I, add base I, and then add triazole to react to obtain intermediate II. The reaction equation is as follows: Step S2: Dissolve intermediate II in solvent II, add NBS, and react in the presence of a free radical initiator to generate intermediate III. The reaction equation is as follows: Step S3: Dissolve the intermediate III in solvent three, add triphenylphosphine, and react to generate the phosphonium salt intermediate IV. The reaction equation is as follows: Step S4: dissolving the phosphonium salt intermediate IV in solvent IV, adding palladium carbon, and reducing with a hydrogen donor to generate an amine intermediate V. The reaction equation is as follows: Step S5: Dissolve the intermediate V in solvent 5, add N,N-dimethyl-β-alanine, and react with an amide condensing agent to generate the intermediate VI. The reaction equation is as follows: Step S6: Dissolve the intermediate VI in solvent VI, and generate the target product VII through Wittig reaction under the alkaline condition of base 2. The reaction equation is as follows: 。 2. The method for preparing Rizatriptan EP impurity C according to claim 1, characterized in that: The molar ratio of the intermediate I to the base I and the triazole in step S1 is 1:(1-10):(1-10); the base I is selected from one or more of sodium hydride, lithium hydroxide, sodium hydroxide, sodium carbonate or potassium carbonate; the solvent I is selected from one or more of THF, DMF, MeCN and NMP, and the reaction time of step S1 is 6-24h.
3. The method for preparing rizatriptan EP impurity C according to claim 1, characterized in that: The molar ratio of the intermediate II to NBS in step S2 is 1:(1-5).
4. The method for preparing the impurity C of rizatriptan EP according to claim 3, characterized in that: The free radical initiator in step S2 is AIBN or BPO, and the molar ratio of AIBN or BPO to intermediate II is 1:(0.02-0.05); the reaction time in step S2 is 12-24h.
5. The method for preparing Rizatriptan EP impurity C according to claim 1, characterized in that: The molar ratio of the intermediate III to triphenylphosphine in step S3 is 1:(1-5); the solvent III is selected from one or more of THF, DME, DMF, DMSO, and MeCN; and the reaction time of step S3 is 12-24 hours.
6. The method for preparing the impurity C of rizatriptan EP according to claim 1, characterized in that: The mass percentage of palladium carbon used in step S4 is 5% to 10% of intermediate IV.
7. The method for preparing the impurity C of rizatriptan EP according to claim 6, characterized in that: The hydrogen supply reagent of step S4 is selected from one of hydrogen, formic acid, ammonium formate, and cyclohexadiene, and the molar ratio of the hydrogen supply reagent to the intermediate VI is (1.5-5):1; the solvent tetrahydrofuran is selected from one or more of MeOH, EtOH, EtOAc, DMF, and DMSO; and the reaction time of step S4 is 12-24 hours.
8. The method for preparing Rizatriptan EP impurity C according to claim 1, characterized in that: The molar ratio of the intermediate V to N,N-dimethyl-β-alanine in step S5 is 1:(1-5).
9. The method for preparing Rizatriptan EP impurity C according to claim 8, characterized in that: The amide condensation agent in step S5 is selected from one or more of HOBt / EDCI, HATU, and HBTU, and the solvent five is selected from one or more of THF, DMF, and MeCN; the reaction time in step S5 is 12-24 hours.
10. The method for preparing Rizatriptan EP impurity C according to claim 1, characterized in that: The molar ratio of the intermediate VI to the base II in the step S6 is 1:(1-5); the base II is selected from one or more of PhLi, n-BuLi, NaNH2, NaH, LiHDMS, and LDA; the solvent VI is selected from one or more of THF, DME, DMF, DMSO, and MeCN; the reaction time of the step S6 is 12-24 h.