CN101066987B - Preparation process of brivudine - Google Patents
Preparation process of brivudine Download PDFInfo
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- CN101066987B CN101066987B CN200710041980A CN200710041980A CN101066987B CN 101066987 B CN101066987 B CN 101066987B CN 200710041980 A CN200710041980 A CN 200710041980A CN 200710041980 A CN200710041980 A CN 200710041980A CN 101066987 B CN101066987 B CN 101066987B
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Abstract
The present invention relates to medicine technology, and is especially preparation process of brivudine. The preparation process includes the following steps: reaction between the 2'-deoxy uracil material and paraformaldehyde to obtain 5-methylol-2'-deoxy uracil; oxidizing 5-methylol-2'-deoxy uracil with manganese dioxide to prepare 5-formyl-2'-deoxy uracil; condensation of 5-formyl-2'-deoxy uracil and malonic acid to prepare (E)-5-(2-carboxyl vinyl)-2'-deoxy uracil; and reaction of (E)-5-(2-carboxyl vinyl)-2'-deoxy uracil and N-bromo succimide under the action of potassium acetate to obtain the ultimate product. The present invention has greatly lowered cost, simple operation, high yield, environment friendship and easy use in industrial production.
Description
Technical field
That the present invention relates to is a kind of preparation method of medical technical field, specifically is a kind of preparation method of brivudine.
Technical background
Brivudine: (E)-5-(2-bromo vinyl)-2 '-Brdurd, be called for short BVDU, be Pyrmidine nucleoside derivatives.This compound is the strongest active at present anti-varicella-zoster virus (VZV) medicine, and its effectiveness is 1000 times of acyclovir.Brivudine is mainly used in the caused innate immunity hypofunction of the simple venereal disease poison of zoster, varicella virus dermatoses and I type; Or Secondary cases immunodeficiency patient carries out immunosuppression (after organ transplantation); Or cytostatics when treatment the skin and the mucosal infections that occur.The serious zoster that has confirmed oral BVDU (125mg/ time, 3 times/day, logotype 5 days) treatment cancer patient at present is effective.Brivudine is as the regeneration product of antiviral, than previously used other drug safety and reliability, and also easy to use, have considerable application prospect.
Finding by prior art documents, is raw material with 2 '-deoxyuridine, obtains organo-metallic mercury intermediate through polystep reaction, and this intermediate is again through Li
2PdCl
4(E)-5-(2-carboxyl vinyl) Brdurd has finally selectively been synthesized in catalysis.Name of document is: The Synthesis of the PotentAnti-herpes Virus Agent, E-5 (2-Bromovinyl)-2 '-Deoxyuridine and RelatedCompounds, (effectively Anti-virus agent E-5 (2-bromo vinyl)-2 '-Brdurd and related compound is synthetic), A.S.Jones, G.Verhelst and R.T.Walker, Tetrahedron Letters (tetrahedron wall bulletin), 1979,45 volumes, the 4415-4418 page or leaf.This method not only reactions steps is long, raw materials used and used metal reagent Li
2PdCl
4Cost an arm and a leg the production cost height.Not only increase isolating difficulty, and had a strong impact on productive rate.The purifying of multiple intermediate all will be used column chromatography technology in this synthetic method, is not suitable for suitability for industrialized production.In a word, the suitability for industrialized production difficult point of brivudine has three: the one, and the cis-trans isomerism problem during synthetic (E)-5-(2-bromo vinyl) uridylic; The 2nd, glucosides has the isomerization problem when being connected with bromo pyrimi piperidine; The 3rd, the issues of purification of intermediate and final product.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of preparation method of brivudine is provided.Synthetic route of the present invention is short, yield is high, simple to operate, convenient separation, production cost are low, be easy to the new process of production of industrialized antiviral brivudine, be raw material promptly, make brivudine through four-step reaction with all industrialized 2 '-Brdurd both at home and abroad.The present invention is reasonable in design, and is easy to operate, and production cost is low and be applicable to the preparation technology of industrialization brivudine.
The present invention is achieved by the following technical solutions, the present invention includes following four big steps:
(1) be that raw material and Paraformaldehyde 96 react in the aqueous solution of triethylamine and make 5-methylol-2 '-Brdurd with 2 '-Brdurd.
(2) 5-methylol-2 '-Brdurd makes 5-aldehyde radical-2 '-Brdurd with the Manganse Dioxide selective oxidation.
(3) 5-aldehyde radical-2 '-Brdurd and propanedioic acid generation Knoevenagel (brain literary composition lattice) condensation reaction makes (E)-5-(2-carboxyl vinyl)-2 '-Brdurd.
(4) (E)-5-(2-carboxyl vinyl)-2 '-Brdurd and NBS (N-bromo-succinimide) react under the effect of Potassium ethanoate and obtain final product (E)-5-(2-bromo vinyl)-2 '-Brdurd.
In the first step, described raw material adopts the mode of recrystallizing methanol to carry out purifying, gets 5-methylol-2 '-Brdurd.
Described second step is specially: 5-methylol-2 '-Brdurd in solvent by the Manganse Dioxide oxidation.The consumption of Manganse Dioxide is 4 equivalents (eq.)-23 equivalent of substrate, and temperature of reaction is 10 ℃-65 ℃, and the reaction times is 6 hours-4 days.Reaction at first helps filter with diatomite after finishing, and gained filtrate concentrates, and recrystallization makes 5-aldehyde radical-2 '-Brdurd in methyl alcohol.
Described second step, solvent are methyl alcohol or N, dinethylformamide or dimethyl sulfoxide (DMSO).Described solvent is preferably methyl alcohol.
In the described reaction times, be preferably 6 hours.
Described temperature of reaction is preferably 30 ℃.
The consumption of described Manganse Dioxide is preferably 4 equivalents into substrate.
In second step, describedly help filter with diatomite, gained filtrate gets 5-aldehyde radical-2 '-Brdurd with recrystallizing methanol.
Described third step is specially: condensation reaction takes place in 5-aldehyde radical-2 '-Brdurd and propanedioic acid in the exsiccant solvent under the catalysis of piperidines.Temperature of reaction is 100 ℃, and the reaction times is 2 hours.After reaction finishes, revolve and boil off except that pyridine, after handling again (E)-5-(2-carboxyl vinyl)-2 '-Brdurd.
Described solvent is meant pyridine.
The consumption of described propanedioic acid is 1 equivalent of substrate.
The consumption of described catalyzer piperidines is 0.22 equivalent of substrate.
In the third step, described processing, its detailed process is: with the sodium hydroxide solution dilution of 2M, be 3 with the 1M hcl acidifying to pH again, suction filtration, water washes out solid, i.e. (E)-5-(2-carboxyl vinyl)-2 '-Brdurd.
The synthetic route of the inventive method is as follows:
The present invention is that raw material synthesizes with β-2 '-Brdurd that domestic and international all industrialization are produced directly, has so just solved the isomerization problem.Simultaneously, avoided the use of expensive raw material and chemical reagent on synthetic, on industrial separation, avoided refining modes such as column chromatography, for the industrial applications of this route provides reliable guarantee.This method has not only shortened the step of reaction, and aftertreatment is very easy, has simplified operation greatly, for the industrial applications of this route further provides strong assurance.The present invention has selected for use when oxidation has better selectivity oxygenant Manganse Dioxide to vinyl carbinol, thereby has reduced the process of last protection and deprotection, has avoided trivial step, has reduced production cost, has improved overall yield.
The present invention has following advantage: 1) when keeping yield, greatly reduce cost, simplified operation; 2) the purifying mode of employing recrystallization is easy to suitability for industrialized production; 3) raw material sources are convenient, and reaction yield height, synthetic cost are low; 4) required reagent is cheap in synthetic, and environmentally friendly.
Embodiment
Below embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
(1) preparation of 5-methylol-2 '-Brdurd (I)
2 '-Brdurd (5.25g, 23.1mmol) and Paraformaldehyde 96 (3.11g 103.5mmol) is dissolved in the aqueous solution (80ml) of 0.5M triethylamine, is warming up to 60 ℃, reacts four days, every other day adds Paraformaldehyde 96 (4.49g, 149.5mmol one time; 3.21g 105.8mmol), a triethylamine (1ml) and water (10ml) are added in the centre, concentrate at last, recrystallization obtains the 4.11g white solid in methyl alcohol, that is: 5-methylol-2 '-Brdurd (I), and productive rate is 70%.
Its characterization parameter is:
1H NMR (400MHz, DMSO-d6) δ: 11.34 (s, 1H, N-H), 7.71 (s, 1H, 6-H), 6.17 (t, J=6.8Hz, 1H, 1 '-H), 5.26 (s, 1H, 3 '-OH), 4.97 (s, 2H, 5 '-OH andCH
2O-H), 4.20 (q, J=3.2Hz, 1H, 4 '-H), 4.10 (s, 2H, 5-H), 3.75 (q, J=3.2Hz, 1H, 3 '-H), 3.57-3.47 (m, 2H, 5 '-H), 2.09-1.99 (m, 2H, 2 '-H)).
(2) by compound (I) preparation 5-aldehyde radical-2 '-Brdurd (II)
(I) (0.70g, 2.7mmol) and freshly prepd Manganse Dioxide (0.94g, 10.9mmol) (23 equivalent eq.) in 10ml methyl alcohol, 30 ℃ are reacted after 6 hours down, help filter with diatomite, gained filtrate concentrates, and recrystallization makes 0.56g 5-aldehyde radical-2 '-Brdurd (II) in methyl alcohol, productive rate is 80%, and transformation efficiency is 81%.Manganse Dioxide is prepared under the sodium hydroxide effect by potassium permanganate and Manganous sulfate monohydrate.
Its characterization parameter is:
1H NMR (400MHz, DMSO-d6) δ: 11.76 (s, 1H, N-H), 9.73 (s, 1H ,-CHO), 8.71 (s, 1H, 6-H), 6.07 (t, J=6.2Hz, 1H, 1 '-H), 5.28 (s, 1H, 3 '-OH), 5.13 (s, 1H, 5 '-OH), 4.21 (q, J=4Hz, 1H, 4 '-H), 3.83 (q, J=3.2Hz, 1H, 3 '-OH), 3.61 (q, J=4Hz, 1H, 5 '-H), 3.54 (q, J=4Hz, 1H, 5 '-H), 2.22 (q, J=8Hz, 1H, 2 '-H), 2.15 (q, J=8Hz, 1H, 2 '-H).
(3) by compound (II) preparation (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III)
(II) (O.30mg, 1.2mmol) and propanedioic acid (O.12g, 1.2mmol) (1eq) at piperidines (O.02ml, 0.26mmol) under (0.22eq) the catalysis, be solvent with pyridine (5ml), 100 ℃ the Knoevenagel condensation reactions take place down, reacted about 3 hours, after concentrating, with the sodium hydroxide solution dissolving of 9ml 2M, be about 3 with the 1M hcl acidifying to pH again, filter, washing gets the 0.24g solid, i.e. (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III), productive rate is 69%.
Its characterization parameter is:
1H NMR (400MHz, DMSO-d6) δ: 12.11 (bs, 1H ,-COOH), 11.6 (s, 1H ,-NH), 8.37 (s, 1H, 6-H), 7.28 (d, J=15.2Hz, 1H, vinyl), 6.75 (d, J=15.2Hz, 1H, vinyl), 6.12 (t, J=6.4Hz, 1H, 1 '-H), 5.23 (s, 1H, 3 '-OH), 5.15 (s, 1H, 5 '-OH), 4.24 (q, J=4Hz, 1H, 4 '-H), 3.78 (q, J=4Hz, 1H, 3 '-H), 3.67-3.54 (m, 2H, 5 '-H), 2.12-2.09 (m, 2H, 2 '-H).
(4) by compound (III) preparation (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV)
(III) (0.30g, 1.0mmol) and Potassium ethanoate (0.20g 2.0mmol) uses water dissolution, be warming up to 60 ℃, add NBS (0.19g, 1.05mmol) after, reduce to room temperature, react about 3h, with ethyl acetate and water extraction, after organic layer concentrated, recrystallization got the 0.30g white solid in methyl alcohol, be final product (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV), productive rate is 89%.m.p.：167℃(dec.)
Its characterization parameter is:
1H NMR (400MHz, DMSO-d6) δ: 11.55 (s, 1H, N-H), 8.06 (s, 1H, 6-H), 7.23 (d, J=13.2Hz, 1H, vinyl), 6.83 (d, J=13.2Hz, 1H, vinyl), 6.11 (t, J=12.8Hz, 1H, 1 '-H), 5.23 (d, J=4Hz, 1H, 3 '-OH), 5.07 (t, J=9.6Hz, 1H, 5 '-OH), 4.23 (m, 1H, 4 '-H), 3.77 (m, 1H, 3 '-H), 3.64-3.52 (m, 2H, 5 '-H), 2.14-2.09 (m, 2H, 2 '-H).
Embodiment 2
(1) preparation of 5-methylol-2 '-Brdurd (I)
2 '-Brdurd (15.25g, 69.3mmol) and Paraformaldehyde 96 (9.96g 311.9mmol) is dissolved in the aqueous solution (240ml) of 0.5M triethylamine, is warming up to 60 ℃, reacts four days, every other day adds Paraformaldehyde 96 (14.38g, 450.5mmol afterwards one time; 10.18g 318.8mmol), a triethylamine (3ml) and water (30ml) are added in the centre, concentrate at last, use recrystallizing methanol, obtain 10.01g 5-methylol-2 '-Brdurd (I), productive rate is 56%.
(2) by compound (I) preparation 5-aldehyde radical-2 '-Brdurd (II)
(I) (1.01g, 3.9mmol) and Manganse Dioxide (7.78g, 89.5mmol) at 20ml DMF (N, dinethylformamide) in, 10 ℃ are reacted after 4 days down, help filter with diatomite, and gained filtrate concentrates, recrystallization makes 0.60g 5-aldehyde radical-2 '-Brdurd (II) in methyl alcohol, and productive rate is 61%.
(3) by compound (II) preparation (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III)
(II) (0.50g, 2.0mmol) and propanedioic acid (0.20g, 2.0mmol) (1eq) is at piperidines (0.04ml, 0.4mmol) under (0.22eq) the catalysis, be solvent with pyridine (5ml), 100 ℃ the Knoevenagel condensation reactions take place down, reacted about 2 hours, after concentrating,, be about 3 with the 1M hcl acidifying to pH again with the sodium hydroxide solution dissolving of 3ml 2M, filter, washing gets 0.37g (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III), and productive rate is 63%.
(4) by compound (III) preparation (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV)
(III) (0.10mg, 0.3mmol) and Potassium ethanoate (0.07g 0.7mmol) uses water dissolution, be warming up to 60 ℃, (0.07g is cooled to room temperature after 0.3mmol), reacts about 3 hours to add NBS (N-bromo-succinimide), with ethyl acetate and water extraction, organic layer concentrate white solid, use ethyl acetate: sherwood oil=the mistake post got the pure products point in 2: 1, heavily was 0.06g, be final product (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV), productive rate is 51%.
Embodiment 3
(1) preparation of 5-methylol-2 '-Brdurd (I)
This synthetic method is with reference to (1) among the embodiment 1.
(2) by compound (I) preparation 5-aldehyde radical-2 '-Brdurd (II)
(I) (0.20g, 0.8mmol) and Manganse Dioxide (1.54g, 8mmol) (10eq.) is at 5ml DMF (N, dinethylformamide) in, 10 ℃ are reacted after 9 hours down, remove Manganse Dioxide with the diatomite suction filtration, concentrate, cross post with ethyl acetate, make 0.08g 5-aldehyde radical-2 '-Brdurd (II), productive rate is 42%.
(3) by compound (II) preparation (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III)
This synthetic method is with reference to (3) among the embodiment 1.
(4) by compound (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV)
This synthetic method is with reference to (4) among the embodiment 1.
Embodiment 4
(1) preparation of 5-methylol-2 '-Brdurd (I)
This synthetic method is with reference to (1) among the embodiment 1.
(2) by compound (I) preparation 5-aldehyde radical-2 '-Brdurd (II)
(I) (0.17g, 0.7mmol) and freshly prepd Manganse Dioxide (1.30g, 15.0mmol) (21eq.) at 5ml N, dinethylformamide (DMF), behind the reaction 6h, help filter with diatomite under the room temperature, gained filtrate concentrates, recrystallization makes 0.11g 5-aldehyde radical-2 '-Brdurd (II) in methyl alcohol, and productive rate is 66%.
(3) prepare this synthetic method of (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III) with reference to (3) among the embodiment 1 by compound (II).
(4) by this synthetic method of compound (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV) with reference to (4) among the embodiment 1.
Embodiment 5
(1) preparation of 5-methylol-2 '-Brdurd (I)
This synthetic method is with reference to (1) among the embodiment 1.
(2) by compound (I) preparation 5-aldehyde radical-2 '-Brdurd (II)
(I) (0.70g, 2.7mmol) and freshly prepd Manganse Dioxide (5.39g, 62.6mmol) (23eq.) in 13ml methyl alcohol, reflux (65 ℃,) down behind the reaction 12h, use the diatomite suction filtration, gained filtrate is concentrated, recrystallization obtains 0.41g 5-aldehyde radical-2 '-Brdurd (II) in methyl alcohol, and productive rate is 59%.
(3) prepare this synthetic method of (E)-5-(2-carboxyl vinyl)-2 '-Brdurd (III) with reference to (3) among the embodiment 1 by compound (II).
(4) by compound (E)-5-(2-bromo vinyl)-2 '-Brdurd (IV)
This synthetic method is with reference to (4) among the embodiment 1.
In the above example, short with the reaction times among the embodiment 1, the yield height, easy to operate, be preferred reaction scheme.
Claims (9)
1. the preparation method of a brivudine specifically comprises following four big steps:
(1) is raw material with 2 '-Brdurd, adds Paraformaldehyde 96 and in the aqueous solution of triethylamine, react and make 5-methylol-2 '-Brdurd;
(2) 5-methylol-2 '-Brdurd makes 5-aldehyde radical-2 '-Brdurd with the Manganse Dioxide oxidation;
(3) 5-aldehyde radical-2 '-Brdurd and propanedioic acid generation condensation reaction make (E)-5-(2-carboxyl vinyl)-2 '-Brdurd;
(4) (E)-5-(2-carboxyl vinyl)-2 '-Brdurd and N-bromo-succinimide react under the effect of Potassium ethanoate and obtain final product (E)-5-(2-bromo vinyl)-2 '-Brdurd.
2. the preparation method of brivudine as claimed in claim 1 is characterized in that, in the first step, described raw material adopts the mode of recrystallizing methanol to carry out purifying.
3. the preparation method of brivudine as claimed in claim 1, it is characterized in that described second step is specially: 5-methylol-2 '-Brdurd in solvent by the Manganse Dioxide oxidation, the consumption of Manganse Dioxide is 4 equivalents-23 equivalent of substrate, temperature of reaction is 10 ℃-65 ℃, and the reaction times is 6 hours-4 days, after reaction finishes, at first help filter with diatomite, get filtrate, concentrate, recrystallization makes 5-aldehyde radical-2 '-Brdurd.
4. the preparation method of brivudine as claimed in claim 3 is characterized in that, described solvent is methyl alcohol or N, dinethylformamide or dimethyl sulfoxide (DMSO).
5. the preparation method of brivudine as claimed in claim 3 is characterized in that, the temperature of reaction described in second step is 30 ℃.
6. the preparation method of brivudine as claimed in claim 3 is characterized in that, described concentrating is meant: with final 5-aldehyde radical-the 2 '-Brdurd that gets of recrystallizing methanol.
7. the preparation method of brivudine as claimed in claim 1, it is characterized in that, described third step is specially: condensation reaction takes place in substrate 5-aldehyde radical-2 '-Brdurd and propanedioic acid in the exsiccant pyridine solvent under the catalysis of piperidines, temperature of reaction is 100 ℃, reaction times is 2 hours, after reaction finishes, revolves and boils off except that pyridine, handle again, get (E)-5-(2-carboxyl vinyl)-2 '-Brdurd.
8. the preparation method of brivudine as claimed in claim 7 is characterized in that, the consumption of described propanedioic acid is 1 equivalent of substrate 5-aldehyde radical-2 '-Brdurd, and described piperidines consumption is 0.22 equivalent of substrate 5-aldehyde radical-2 '-Brdurd.
9. the preparation method of brivudine as claimed in claim 7 is characterized in that, described processing again, detailed process is: with the sodium hydroxide solution dilution of 2M, be 3 with the 1M hcl acidifying to pH again, and suction filtration, water washes out solid, i.e. (E)-5-(2-carboxyl vinyl)-2 '-Brdurd.
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| CN102432655A (en) * | 2011-10-28 | 2012-05-02 | 河南师范大学 | Method for synthesizing 5-((E)-2-bromovinyl)-2'-deoxyuridine (brivudine) |
| CN104497083B (en) * | 2014-05-12 | 2017-07-07 | 河南师范大学 | Nucleosides phenylpropen ketone hybrid with Antiparasitic Activity and its preparation method and application |
| CN113234112B (en) * | 2021-04-15 | 2022-08-19 | 湖南华纳大药厂科技开发有限公司 | Novel synthesis process of brivudine and brivudine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1420773A (en) * | 1999-07-21 | 2003-05-28 | 耶鲁大学 | 5-(E)-bromovinyl uracil analogues and related pyrimidine nucleosides as anti-viral agents and methods of use |
| CN1494550A (en) * | 2001-02-28 | 2004-05-05 | ж� | Process for preparation of (E)-5-(2-bromovinyl) -2'-deoxyuridine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1420773A (en) * | 1999-07-21 | 2003-05-28 | 耶鲁大学 | 5-(E)-bromovinyl uracil analogues and related pyrimidine nucleosides as anti-viral agents and methods of use |
| CN1494550A (en) * | 2001-02-28 | 2004-05-05 | ж� | Process for preparation of (E)-5-(2-bromovinyl) -2'-deoxyuridine |
Non-Patent Citations (4)
| Title |
|---|
| A.S.Jones,et al.the synthesis of the potent antiherpes virus agent,E-5(2-bromovinyl)-2＇-deoxyuridine and related compounds.tetrahedron letters 45.1979,(45),4415-4418. |
| A.S.Jones,et al.the synthesis of the potent antiherpes virus agent,E-5(2-bromovinyl)-2＇-deoxyuridine and related compounds.tetrahedron letters 45.1979,(45),4415-4418. * |
| 吴瑞芳.赫尔品片.中国新药杂志3 6.1994,3(6),24. |
| 吴瑞芳.赫尔品片.中国新药杂志3 6.1994,3(6),24. * |
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