CN104341360A - A rufinamide preparing method - Google Patents
A rufinamide preparing method Download PDFInfo
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- CN104341360A CN104341360A CN201310330813.2A CN201310330813A CN104341360A CN 104341360 A CN104341360 A CN 104341360A CN 201310330813 A CN201310330813 A CN 201310330813A CN 104341360 A CN104341360 A CN 104341360A
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- rufinamide
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
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Abstract
The invention belongs to the field of medicine synthesis and provides a rufinamide preparing method. 2,6-difluorobenzylalcohol is adopted as an initial raw material, and is reacted with an azidation agent diphenylphosphoryl azide to produce a critical intermediate 2,6-difluorobenzylazide, the 2,6-difluorobenzylazide is reacted with propargyl ester, and then the rufinamide is obtained by an ammonolysis reaction. The method has advantages of low toxicity, low pollution, high safety, short production period, simple and convenient operation, and the like, and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of preparation method of Rufinamide.
Background technology
Rufinamide is the antiepileptic drug of new generation developed by Novartis of Switzerland.In January, 2007 goes on the market in European Union, and commodity are called Inovelon, and in November, 2008 goes on the market in the U.S., and commodity are called BANZEL.Rufinamide is used for assisting therapy focal seizures and Lennox-Gastaut syndrome, is applicable to children and the adult patients of more than 4 years old.Clinical study shows, epileptic is good to the tolerance of Rufinamide assisting therapy, and epileptic seizures number of times reduces, and still produces effect to the local or general Patients with Epilepsy for the treatment of tolerance, can Combined Preparation or individually dosed.The pharmacokinetics of Rufinamide on Carbamzepine, Phenytoin Sodium Salt and valproate does not affect, therefore, when share with other antiepileptic drugs without the need to adjusting the dosage of Rufinamide.The main adverse reaction of this medicine is spared nerve systemic symptom, as tired out, sleepy, drowsiness etc.
The chemistry of Rufinamide is called 1-(2,6-difluorobenzyl)-1H-[1,2,3]-triazole-4-methane amide, belongs to triazole class compounds, and its chemical structure is different from the antiepileptic drug gone on the market at present.
It is key intermediate synthesis that the synthetic method of the Rufinamide of current bibliographical information is mainly with 2,6-difluorobenzyl nitrine.Occupy (the synthesis of Rufinamide such as Wen Jian, " Chinese Journal of Pharmaceuticals ", 2010, 41(4), synthetic route 247-248) reported is with 2, 6-difluoro toluene is starting raw material, generation 2 is reacted with N-bromo-succinimide under Diisopropyl azodicarboxylate catalysis, 6-difluorobenzyl bromide, 2, 6-difluorobenzyl bromide and reaction of sodium azide generate 2, 6-difluorobenzyl nitrine, 2, 6-difluorobenzyl nitrine and Methyl propiolate are obtained by reacting 1-[(2, 6-difluorophenyl) methyl]-1H-1, 2, 3-triazole-4-methyl-formiate, 0 DEG C of stirring reaction, 24 hours obtained Rufinamides in the last methanol solution saturated at ammonia.The shortcoming of this synthetic method is reagent N-bromo-succinimide and azo isobutyronitrile is expensive, toxicity is larger; The explosive danger of sodiumazide, affect production security, and the hydrazoic acid generated has genetoxic, need strictly control; Production cycle is long.
(the synthesis of antiepileptic drug Rufinamide such as Wang Junmin, " Yanbian University's medical journal ", 2004, 27(4), synthetic route 264-266) reported is with 2, 6-difluorobenzyl alcohol is starting raw material, 2 are obtained by reacting with sulfur oxychloride in anhydrous diethyl ether, 6-bis-fluorobenzyl chloride, 2, 6-bis-fluorobenzyl chloride and sodiumazide are at N, generation 2 is reacted in dinethylformamide, 6-difluorobenzyl nitrine, 2, 6-difluorobenzyl nitrine and ethyl propiolate react and generate 1-[(2, 6-difluorophenyl) methyl]-1H-1, 2, 3-triazole-4-ethyl formate, stirring at room temperature 52 hours obtained Rufinamides in the last methanol solution saturated at ammonia.The shortcoming of this synthetic method is that the toxicity of sulfur oxychloride reagent is large, corrodibility strong, causes serious environmental pollution; The explosive danger of sodiumazide, affect production security, and the hydrazoic acid generated has genetoxic, need strictly control; Production cycle is long.
Therefore, in order to improve drug safety quality better, improve the environment friendly produced and shorten the production cycle, a kind of method preparing Rufinamide developing hypotoxicity, low stain, security high, with short production cycle, easy and simple to handle is very necessary.
Summary of the invention
The object of the present invention is to provide a kind of method preparing Rufinamide that hypotoxicity, low stain, security are high, with short production cycle, easy and simple to handle.
Shown in the following reaction formula of method preparing Rufinamide (I) provided by the invention:
Wherein, R=(CH
2) nCH
3, n=0 ~ 6, preferred n=0 or 1;
Specifically comprise following sequential steps:
(1) 2,6-difluorobenzyl alcohol (II) and the azide reagent react being selected from diphenyl phosphate azide are obtained 2,6-difluorobenzyl nitrine (III);
(2) compound III and propiolate are obtained by reacting compound IV;
(3) compound IV is obtained by reacting target product Rufinamide (I) in the alcoholic solution of ammonia.
The reaction of described step (1) is carried out under organic solvent, and described organic solvent is be selected from one or more in aprotic solvent toluene, benzene, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, methyl tertiary butyl ether etc., preferred toluene or hexanaphthene; The molar ratio example of 2,6-difluorobenzyl alcohol and diphenyl phosphate azide is 1:1 ~ 1:10, preferred 1:1 ~ 1:5, more preferably 1:2 or 1:1.1; Temperature of reaction is back flow reaction; Reaction times is 1 ~ 24 hour, preferably 1 ~ 10 hour.
The reaction of described step (1) is carried out in toluene, and temperature of reaction is 90 ~ 110 DEG C, and the reaction times is 1 ~ 10 hour.
Organic solvent in described step (2) is selected from methyl alcohol, ethanol, Virahol, preferred alcohol; Temperature of reaction is back flow reaction; Reaction times is 1 ~ 24 hour, preferably 1 ~ 10 hour.
Alcohol in described step (3) is methyl alcohol; Temperature of reaction is more than 40 DEG C, preferably 40 ~ 60 DEG C; Reaction pressure is 1 ~ 16 normal atmosphere, preferably 1 ~ 8 normal atmosphere, more preferably 1 ~ 4 normal atmosphere; Reaction times is 1 ~ 24 hour, preferably 1 ~ 10 hour.
Beneficial effect of the present invention: the preparation method of Rufinamide provided by the invention is directly with 2,6-difluorobenzyl alcohol is starting raw material, key intermediate 2 can be generated through single step reaction, 6-difluorobenzyl nitrine, without the need to using the sodiumazide of high malicious halide reagent and explosive severe toxicity, not only security is high, environmental protection, and the reaction times shortens greatly; Temperature of reaction raises by the step preparing Rufinamide, and the reaction times shortens, production cycle shortening.
Specific embodiment
Following embodiment is specific preferred embodiment in order to demonstrate the invention, the protection domain be not meant to limit the present invention.
In all embodiments, TLC is silica gel H SGF254 plate, and ultimate analysis adopts ElementarVarioELIII type elemental analyser, and mass spectrum adopts AGILENT1100LC/MS mass spectrograph,
1h-NMR adopts BRUKERAV-500 type nuclear magnetic resonance analyser, and fusing point adopts YRT-3 melting point apparatus, and HPLC adopts and wears peace system.
The preparation of embodiment 12,6-difluorobenzyl nitrine (III)
2,6-difluorobenzyl alcohol (72.06g, content 98%, 0.50mol), diphenyl phosphate azide (151.36g, 0.55mol) and toluene (600mL) is added in 1L there-necked flask.Be heated to backflow under stirring, react 6 hours.Add purified water 200mL, under stirring, adjust pH to 12 with sodium hydroxide.Separatory extracts, and water layer 100mL toluene extracts 1 time.Merge organic layer, organic layer saturated common salt water washing, anhydrous magnesium sulfate (100g) drying.Filter, filtrate reduced in volume, reclaim toluene, obtain oily liquids 77.81g, yield 92.0%.ESI-MS (m/z): 170.1 [M+H]
+; HPLC purity: 97.5%.
The preparation of embodiment 22,6-difluorobenzyl nitrine (III)
2,6-difluorobenzyl alcohol (72.06g, content 98%, 0.50mol), diphenyl phosphate azide (275.2g, 1.0mol) and toluene (600mL) is added in 1L there-necked flask.Be heated to backflow under stirring, react 6 hours.Add purified water 200mL, under stirring, adjust pH to 12 with sodium hydroxide.Separatory extracts, and water layer 100mL toluene extracts 1 time.Merge organic layer, organic layer saturated common salt water washing, anhydrous magnesium sulfate (100g) drying.Filter, filtrate reduced in volume, reclaim toluene, obtain oily liquids 78.35g, yield 93.0%.ESI-MS (m/z): 170.1 [M+H]
+; HPLC purity: 97.5%.
The preparation of embodiment 3 1-(2,6-difluorophenyl)-1H-1,2,3-triazole-4-ethyl formate
Embodiment 1 product (76.11g, 0.45mol) is joined in the there-necked flask of 500mL, adds 300mL dehydrated alcohol, stir lower dissolving completely.Add ethyl propiolate (88.29g, 0.90mol), heating reflux reaction 4 hours.Be cooled to room temperature, separate out solid.Filter, filter cake dehydrated alcohol is cleaned, and obtains faint yellow solid 106.89g, yield 88.9%.ESI-MS (m/z): 268.0 [M+H]
+; HPLC purity: 97.2%.
The preparation of embodiment 4 1-(2,6-difluorophenyl)-1H-1,2,3-triazole-4-methyl-formiate
Embodiment 2 product (76.11g, 0.45mol) is joined in the there-necked flask of 500mL, adds 300mL dehydrated alcohol, stir lower dissolving completely.Add Methyl propiolate (75.66g, 0.90mol), heating reflux reaction 4 hours.Be cooled to room temperature, separate out solid.Filter, filter cake dehydrated alcohol is cleaned, and obtains faint yellow solid 96.05g, yield 84.3%.ESI-MS (m/z): 254.1 [M+H]
+; HPLC purity: 96.8%.
The preparation of embodiment 5 Rufinamide (I)
In 1L there-necked flask, add the product (106.89g) of 0.5L ammonia-methanol solution (about 5% (m/V)), embodiment 3, be stirred to solid and dissolve completely.Be heated to 50 DEG C, insulated and stirred reacts 4 hours.Naturally cool to room temperature, filter, lower dry 4 hours of filter cake decompression (vacuum tightness≤0.015MPa, temperature 40 ± 2 DEG C) obtains white solid 87.07g, yield 91.4%.
1h-NMR (DMSO-d
6, 500MHz) and δ 5.7676 (2H, s), 7.1937 (2H, m), 7.4706 (1H, brs), 7.5313 (1H, m), 7.8219 (1H, brs), 8.5755 (1H, s); ESI-MS (m/z): 239.1 [M+H]
+; The practical measurement value of ultimate analysis C, H, N content is: C:50.27%, H:3.25%, N:23.70%, and theoretical value is: with C
10h
8f
2n
4o calculates C:50.52%, H:3.57%, N:23.41%; DSC figure occurs an endotherm(ic)peak in 240.3 DEG C (onset) left and right, should be the process of melting, corresponding TG figure obviously starts to reduce about 200 DEG C weight, should be the process of decomposes.
The preparation of embodiment 6 Rufinamide (I)
In 2L stainless steel autoclave, add the product (96.05g) of methyl alcohol (about 800mL), embodiment 4, be stirred to solid W and dissolve completely.Pass into ammonia, be forced into 2 normal atmosphere, be heated to 50 DEG C, insulated and stirred reacts 2 hours.Naturally cool to room temperature, filter, lower dry 4 hours of filter cake decompression (vacuum tightness≤0.015MPa, temperature 40 ± 2 DEG C) obtains white solid 85.12g, yield 94.2%.
1h-NMR (DMSO-d
6, 500MHz) and δ 5.7676 (2H, s), 7.1937 (2H, m), 7.4706 (1H, brs), 7.5313 (1H, m), 7.8219 (1H, brs), 8.5755 (1H, s); ESI-MS (m/z): 239.1 [M+H]
+; The practical measurement value of ultimate analysis C, H, N content is: C:50.27%, H:3.25%, N:23.70%, and theoretical value is: with C
10h
8f
2n
4o calculates C:50.52%, H:3.57%, N:23.41%; DSC figure occurs an endotherm(ic)peak in 240.3 DEG C (onset) left and right, should be the process of melting, corresponding TG figure obviously starts to reduce about 200 DEG C weight, should be the process of decomposes.
Claims (10)
1. prepare a method of Rufinamide (I), as shown in following reaction formula:
Wherein, R=(CH
2) nCH
3, n=0 ~ 6, preferred n=0 or 1;
Specifically comprise following sequential steps:
(1) 2,6-difluorobenzyl alcohol (II) and the azide reagent react being selected from diphenyl phosphate azide are obtained 2,6-difluorobenzyl nitrine (III);
(2) compound III and propiolate are obtained by reacting compound IV;
(3) compound IV is obtained by reacting target product Rufinamide (I) in the alcoholic solution of ammonia.
2. the method for claim 1, it is characterized in that the reaction of described step (1) is carried out under organic solvent, described organic solvent is be selected from one or more in aprotic solvent toluene, benzene, dimethylbenzene, hexanaphthene, normal hexane, normal heptane, methyl tertiary butyl ether etc., preferred toluene or hexanaphthene.
3. the method for claim 1, it is characterized in that the molar ratio example of 2,6-difluorobenzyl alcohol and diphenyl phosphate azide is 1:1 ~ 1:10, preferred 1:1 ~ 1:5, is more preferably 1:2 or 1:1.1.
4. the method for claim 1, is characterized in that the temperature of reaction in step (1) is back flow reaction.
5. the method for claim 1, is characterized in that the reaction times in step (1) is 1 ~ 24 hour, preferably 1 ~ 10 hour.
6. method as claimed in claim 3, it is characterized in that described organic solvent is toluene, temperature of reaction is 90 ~ 110 DEG C, and the reaction times is 1 ~ 10 hour.
7. the method for claim 1, is characterized in that reaction solvent in step (2) is for being selected from methyl alcohol, ethanol, Virahol, the organic solvent of preferred alcohol; Temperature of reaction is back flow reaction.
8. the method for claim 1, is characterized in that the alcohol described in step (3) is methyl alcohol.
9. method as claimed in claim 8, is characterized in that the temperature of reaction in step (3) is more than 40 DEG C, preferably 40 ~ 60 DEG C.
10. method as claimed in claim 8, is characterized in that the reaction pressure in step (3) is 1 ~ 16 normal atmosphere, preferably 1 ~ 8 normal atmosphere, more preferably 1 ~ 4 normal atmosphere.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310330813.2A CN104341360A (en) | 2013-07-31 | 2013-07-31 | A rufinamide preparing method |
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| CN201310330813.2A CN104341360A (en) | 2013-07-31 | 2013-07-31 | A rufinamide preparing method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573388A (en) * | 2017-08-30 | 2018-01-12 | 中国石油大学(华东) | The preparation method of Azide deoxyribonucleoside and the method that amido modified deoxyribonucleoside is prepared using Azide deoxyribonucleoside |
| CN114369070A (en) * | 2021-08-31 | 2022-04-19 | 海南医学院 | Preparation process of rufinamide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126992A (en) * | 1993-07-08 | 1996-07-17 | 麦克公司 | Alcohol to azide SN2 conversion |
| WO2012093101A1 (en) * | 2011-01-04 | 2012-07-12 | Novartis Ag | Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd) |
-
2013
- 2013-07-31 CN CN201310330813.2A patent/CN104341360A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126992A (en) * | 1993-07-08 | 1996-07-17 | 麦克公司 | Alcohol to azide SN2 conversion |
| WO2012093101A1 (en) * | 2011-01-04 | 2012-07-12 | Novartis Ag | Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd) |
Non-Patent Citations (1)
| Title |
|---|
| 居文建等: "卢非酰胺的合成", 《中国医药工业杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573388A (en) * | 2017-08-30 | 2018-01-12 | 中国石油大学(华东) | The preparation method of Azide deoxyribonucleoside and the method that amido modified deoxyribonucleoside is prepared using Azide deoxyribonucleoside |
| CN114369070A (en) * | 2021-08-31 | 2022-04-19 | 海南医学院 | Preparation process of rufinamide |
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Application publication date: 20150211 |