CN103539750A - Synthesis process of rufinamide - Google Patents
Synthesis process of rufinamide Download PDFInfo
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- CN103539750A CN103539750A CN201210235864.2A CN201210235864A CN103539750A CN 103539750 A CN103539750 A CN 103539750A CN 201210235864 A CN201210235864 A CN 201210235864A CN 103539750 A CN103539750 A CN 103539750A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- POGQSBRIGCQNEG-UHFFFAOYSA-N rufinamide Chemical compound N1=NC(C(=O)N)=CN1CC1=C(F)C=CC=C1F POGQSBRIGCQNEG-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 229960003014 rufinamide Drugs 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims abstract description 12
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims abstract description 10
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940112669 cuprous oxide Drugs 0.000 claims abstract description 9
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 150000001875 compounds Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004809 thin layer chromatography Methods 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 229910052728 basic metal Inorganic materials 0.000 claims description 5
- 150000003818 basic metals Chemical group 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 3
- JSZUBPHMRHROHZ-UHFFFAOYSA-N 2-(azidomethyl)-1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1CN=[N+]=[N-] JSZUBPHMRHROHZ-UHFFFAOYSA-N 0.000 claims description 2
- LSXJPJGBWSZHTM-UHFFFAOYSA-N 2-(bromomethyl)-1,3-difluorobenzene Chemical group FC1=CC=CC(F)=C1CBr LSXJPJGBWSZHTM-UHFFFAOYSA-N 0.000 claims description 2
- MJXRENZUAQXZGJ-UHFFFAOYSA-N 2-(chloromethyl)-1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1CCl MJXRENZUAQXZGJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 7
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- -1 2, 6-difluorobenzyl halide Chemical class 0.000 abstract description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000908 ammonium hydroxide Substances 0.000 abstract 1
- 150000001540 azides Chemical class 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- 125000006508 2,6-difluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C(F)=C1[H])C([H])([H])* 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 0 C=*Cc(c(N)ccc1)c1N Chemical compound C=*Cc(c(N)ccc1)c1N 0.000 description 2
- 201000006792 Lennox-Gastaut syndrome Diseases 0.000 description 2
- 229910000365 copper sulfate Inorganic materials 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- XVEURJOWGBWEPY-UHFFFAOYSA-N COC(c1c[n](Cc(c(F)ccc2)c2F)nn1)=O Chemical compound COC(c1c[n](Cc(c(F)ccc2)c2F)nn1)=O XVEURJOWGBWEPY-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229940000221 banzel Drugs 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides an improved synthesis process for synthesizing rufinamide. The process comprises the following steps of a, reacting 2, 6-difluorobenzyl halide with azide and tetrabutylammonium chloride to obtain 2-(azide methyl)-1,3-difluorobenzene; b, reacting 2-(azide methyl)-1, 3-difluorobenzene with methyl propiolate under the catalyzing of nano-cuprous oxide (Cu2O) to obtain 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl formate; and c, reacting 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl formate with ammonium hydroxide to obtain rufinamide. The process has the advantages of short reaction time and high catalytic efficiency, and is simple and safe to operate.
Description
Technical field
The present invention relates to the synthesis technique of Rufinamide, belong to pharmaceutical chemistry field.
Background technology
Rufinamide (formula (I) compound), English Rufinamide by name, the exploitation of commodity Banzel ，You by name Switzerland Novartis Co.,Ltd, and obtain FDA approval in U.S.'s listing, for the assisting therapy of epilepsy Lennox-Gastaut syndrome (LGS) in November, 2008.Its chemical name is 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methane amide, and structural formula is as follows:
At present domesticly develop, there is no the producer of formal this medicine of production.The production technique of existing Rufinamide is first to utilize 2,6-difluorobenzyl halogenide, reacts in the aqueous solution with sodiumazide.Then the trinitride making is reacted with Methyl propiolate under the effect of copper sulfate and xitix, prepare intermediate 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl-formiate.Subsequently above-mentioned intermediate is carried out to ammonia solution with ammoniacal liquor, make Rufinamide.Prepare and in trinitride process, need to carry out reacting by heating, and will be through extraction, the steps such as underpressure distillation, complex operation, reduces yield and is unfavorable for safety in production.At preparation 1-(2,6-difluorobenzyl)-1H-1, in the process of 2,3-triazole-4-methyl-formiate the reaction times longer, need reaction overnight, catalytic efficiency is lower.
Summary of the invention
Be directed to complex operation in the production line of existing Rufinamide, dangerous, long reaction time, problem that catalytic efficiency is low, the present invention makes improvements, and a kind of simple, safe, fast, efficient Rufinamide synthetic route is provided.
Rufinamide synthetic route of the present invention comprises the steps:
A. make formula (II) compound 2,6-difluorobenzyl halogenide reacts the formula of obtaining (III) compound 2-(azido-methyl)-1,3-difluorobenzene with trinitride, tetrabutylammonium chloride;
B. make formula (III) compound and Methyl propiolate at nano cuprous oxide (Cu
2o) under catalysis, reaction obtains formula (IV) compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl-formiate;
C. make formula (IV) compound react the formula of obtaining (I) compound Rufinamide with ammoniacal liquor.
In one embodiment, described 2,6-difluorobenzyl halogenide is 2,6-difluoro benzyl bromide, and the X in formula (II) compound is Br.In another embodiment, described 2,6-difluorobenzyl halogenide is 2,6-difluorobenzyl chlorine, and the X in formula (II) compound is Cl.
In one embodiment, described trinitride (that is, Y-N
3) be basic metal trinitride.In a preferred embodiment, described basic metal trinitride is sodiumazide, and Y is Na.In a further advantageous embodiment, described basic metal trinitride is potassium azide, and Y is K.
In one embodiment, the reaction of described step a is to carry out as solvent in the situation that take water and acetonitrile.In a preferred embodiment, described step a is the aqueous solution and the halid acetonitrile solution reaction of 2,6-difluorobenzyl that makes trinitride and tetrabutylammonium chloride.Because acetonitrile and the sodiumazide aqueous solution are by layering, make fully contact reacts of 2,6-difluorobenzyl halogenide and azides ion, therefore add tetrabutylammonium chloride as phase-transfer catalyst, make reactant fully contact and to react, improve speed of reaction.And the existence of acetonitrile, greatly increased reactant 2, the halid solubleness of 6-difluorobenzyl, reaction can be carried out under the room temperature condition of 15-30 ℃, reduced the step heating in ordinary method, improved security and shortened the reaction times, the reaction system due to lower step is also acetonitrile in addition, can avoid loaded down with trivial details aftertreatment, directly carry out next step reaction.
In one embodiment, step a implements in the temperature range of 15～40 ℃, more preferably in the temperature range of 25～30 ℃, implements.
In one embodiment, the reaction times of step a is approximately 1～4 hour, more preferably approximately 1.5～2.5 hours.
Advantageously, step a is without purify intermediates formula (III) compound 2-(azido-methyl)-1 to the reaction of step b, in the situation of 3-difluorobenzene, carries out.This has just been avoided the steps such as extraction, underpressure distillation, simplification of flowsheet.
In one embodiment, the nano cuprous oxide described in step b is reacted and obtains with sodium borohydride by Polyvinylpyrolidone (PVP) (PVP), neutralized verdigris.More specifically, in reaction vessel (such as there-necked flask), add Polyvinylpyrolidone (PVP) (PVP), neutralized verdigris and water, under agitation, sodium borohydride solution is dropped in neutralized verdigris solution, after dropping finishes, stirring reaction 2h.Above-mentioned reaction solution is carried out to centrifugal abandoning supernatant, add water washing, recentrifuge obtains black solid, is nano cuprous oxide.
A favourable part of the present invention is to provide the improvement technique of preparing Rufinamide with nano cuprous oxide.The use of nano cuprous oxide has been accelerated reaction process with respect to other catalyzer in prior art (as copper sulfate and xitix), reduces the reaction times, reduces temperature of reaction, and has improved widely catalytic efficiency.
In one embodiment, step b implements in the temperature range of 15～40 ℃, more preferably in the temperature range of 25～30 ℃, implements.
In one embodiment, the reaction times of step b is approximately 2～5 hours, more preferably approximately 2.5～3.5 hours.
In one embodiment, by thin-layer chromatography, come the reaction of monitoring step a and step b whether complete.Wherein: for step a, it is sherwood oil that described thin-layer chromatography is monitored developping agent used: ethyl acetate=30: 1; And for step b, it is methylene dichloride that described thin-layer chromatography is monitored developping agent used: methyl alcohol=30: 1.
Embodiment
In conjunction with following preparation and embodiment, describe in more detail the present invention, thereby can more completely understand all respects of the present invention.Be appreciated that these preparations and embodiment are only the objects of explanation, and do not limit in any form the present invention.
Prepare the preparation of 1 nano cuprous oxide catalyzer
In 1000ml three-necked bottle, add 1.6g PVP, 0.44g neutralized verdigris, 200ml water, under vigorous stirring, the 40ml sodium borohydride solution containing sodium borohydride 0.75g is slowly dropped in neutralized verdigris solution, after dropping finishes, continue vigorous stirring 2h.Upper step reaction solution is carried out to centrifugal (6000rpm) abandoning supernatant, add water washing, recentrifuge (6000rpm) obtains the about 2g of black solid, and wherein copper content is about 60%.
The preparation of embodiment 1 Rufinamide
In 100ml there-necked flask, add 2.88g sodiumazide, 0.9g tetrabutylammonium chloride, 10ml water, at room temperature stir, after solid all dissolves, add containing 3g 2 the 20ml acetonitrile solution of 6-difluoro benzyl bromide.By mixture stirring reaction at room temperature, and utilize TLC to monitor (sherwood oil: ethyl acetate=30: 1).React completely and approximately need 2 hours.Stop stirring, stratification, separates acetonitrile layer, obtains 2-(azido-methyl)-1, the acetonitrile solution of 3-difluorobenzene.Under nitrogen protection, to 2-(azido-methyl)-1, in the acetonitrile solution of 3-difluorobenzene, add 1.4ml Methyl propiolate and nanometer Cu
2o (0.01 equivalent, 0.034g), and stirring at room reaction under nitrogen protection, utilize TLC to monitor (methylene dichloride: methyl alcohol=30: 1).React completely and approximately need 3 hours.Stop stirring, with petroleum ether-ethyl acetate (20: 1), carry out recrystallization, obtain 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl-formiate sterling 3.37g, now yield is 92.1%.
Then in two mouthfuls of flasks of 100ml, add 1.43g 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl-formiate, adds 10ml methyl alcohol and 30ml ammoniacal liquor.Be heated to 65 ℃.Utilize TLC monitoring reaction (methylene dichloride: methyl alcohol=30: 1), react completely and approximately need 3 hours.Stop heating, be cooled to room temperature, suction filtration, first water will leach thing washing to neutral, then with ethyl acetate washing, obtain the Rufinamide 1.16g of white solid, and the yield of this step reaction is 87%.
For clear and understandable object, explanation and embodiment have described the present invention in detail by way of example.Be appreciated that specification sheets is above intended to, for explanation rather than for restriction, therefore can in the scope of subsidiary claim, change and revise.
Claims (10)
1. a technique for synthesis type (I) compound Rufinamide, described technique comprises:
A. make formula (II) compound 2,6-difluorobenzyl halogenide reacts the formula of obtaining (III) compound 2-(azido-methyl)-1,3-difluorobenzene with trinitride, tetrabutylammonium chloride;
B. make formula (III) compound and Methyl propiolate at nano cuprous oxide (Cu
2o) under catalysis, reaction obtains formula (IV) compound 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-methyl-formiate;
C. make formula (IV) compound react the formula of obtaining (I) compound Rufinamide with ammoniacal liquor.
2. technique according to claim 1, wherein, the reaction of described step a is to carry out as solvent in the situation that take water and acetonitrile.
3. technique according to claim 1, wherein, described formula (II) compound 2,6-difluorobenzyl halogenide is 2,6-difluoro benzyl bromide or 2,6-difluorobenzyl chlorine.
4. technique according to claim 1, wherein, described trinitride is basic metal trinitride.
5. technique according to claim 4, wherein, described basic metal trinitride is sodiumazide or potassium azide.
6. technique according to claim 1, wherein, described nano cuprous oxide is reacted and obtains with sodium borohydride by Polyvinylpyrolidone (PVP) (PVP), neutralized verdigris.
7. technique according to claim 1, wherein, step a is without purifying formula (III) compound 2-(azido-methyl)-1 to the reaction of step b, in the situation of 3-difluorobenzene, carries out.
8. technique according to claim 1, wherein, the reaction of step a and step b is all to carry out under the temperature range of 15-30 ℃.
9. technique according to claim 1, wherein, by the reaction of thin-layer chromatography monitoring step a and step b.
10. technique according to claim 9, wherein:
For step a, it is sherwood oil that described thin-layer chromatography is monitored developping agent used: ethyl acetate=30: 1; And
For step b, it is methylene dichloride that described thin-layer chromatography is monitored developping agent used: methyl alcohol=30: 1.
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| CN201210235864.2A CN103539750A (en) | 2012-07-09 | 2012-07-09 | Synthesis process of rufinamide |
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| CN201210235864.2A CN103539750A (en) | 2012-07-09 | 2012-07-09 | Synthesis process of rufinamide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014121383A1 (en) * | 2013-02-11 | 2014-08-14 | Apotex Technologies Inc. | A process for the preparation of rufinamide and intermediates thereof |
| CN107141235A (en) * | 2017-06-21 | 2017-09-08 | 云南民族大学 | A kind of blue light excites the method and its medicine of lower synthesis benzyl azide |
| CN109438374A (en) * | 2018-10-10 | 2019-03-08 | 凯莱英医药集团（天津）股份有限公司 | Rufinamide is continuously synthesizing to method |
| CN114369070A (en) * | 2021-08-31 | 2022-04-19 | 海南医学院 | Preparation process of rufinamide |
| CN117105873A (en) * | 2023-08-24 | 2023-11-24 | 宿州亿帆药业有限公司 | A kind of preparation method of rufinamide intermediate |
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| WO2010043849A1 (en) * | 2008-10-13 | 2010-04-22 | Cipla Limited | Process for the preparation of rufinamide |
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2012
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014121383A1 (en) * | 2013-02-11 | 2014-08-14 | Apotex Technologies Inc. | A process for the preparation of rufinamide and intermediates thereof |
| CN107141235A (en) * | 2017-06-21 | 2017-09-08 | 云南民族大学 | A kind of blue light excites the method and its medicine of lower synthesis benzyl azide |
| CN109438374A (en) * | 2018-10-10 | 2019-03-08 | 凯莱英医药集团（天津）股份有限公司 | Rufinamide is continuously synthesizing to method |
| CN109438374B (en) * | 2018-10-10 | 2020-10-30 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of rufinamide |
| CN114369070A (en) * | 2021-08-31 | 2022-04-19 | 海南医学院 | Preparation process of rufinamide |
| CN117105873A (en) * | 2023-08-24 | 2023-11-24 | 宿州亿帆药业有限公司 | A kind of preparation method of rufinamide intermediate |
| CN117105873B (en) * | 2023-08-24 | 2026-01-30 | 宿州亿帆药业有限公司 | A method for preparing a loufeamide intermediate |
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