CN102219735A - Method for preparing 2-sulfydryl-5-bromine-N-pyridine oxide - Google Patents
Method for preparing 2-sulfydryl-5-bromine-N-pyridine oxide Download PDFInfo
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- CN102219735A CN102219735A CN2011100932360A CN201110093236A CN102219735A CN 102219735 A CN102219735 A CN 102219735A CN 2011100932360 A CN2011100932360 A CN 2011100932360A CN 201110093236 A CN201110093236 A CN 201110093236A CN 102219735 A CN102219735 A CN 102219735A
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Abstract
The invention discloses a method for preparing 2-sulfydryl-5-bromine-N-pyridine oxide, which comprises the following steps of: dissolving 2-aminopyridine in glacial acetic acid or acetic anhydride, dripping liquid bromine, hydrolyzing, oxidizing by using hydrogen peroxide, diazotizing, performing mercaptoethylation and the like to prepare the 2-sulfydryl-5-bromine-N-pyridine oxide. The invention has the advantages that raw materials are cheap, reaction conditions are mild, and the method is easy and convenient to operate, environment-friendly and high in yield.
Description
Technical field
The present invention relates to the preparation method of 2-sulfydryl-5-bromo-N-pyridine oxide compound.
Technical background
The 2-aminopyridine is a kind of basic chemical industry raw material, has following structure:
Because of the structural relation of amino and pyridine, make it that diazotization reaction, substitution reaction and oxidizing reaction easily take place, can prepare 2-sulfydryl-5-bromo-N-pyridine oxide with bromizating agent, oxygenant and mercapto agent and its stepping action under certain condition.
2-sulfydryl-N-pyridine oxide (PTO) because the uniqueness of its structure and replacement atom or functional group has antibacterial, the sterilization biological activity of wide spectrum, can be used as good industrial chemicals, is a kind of efficient, safe medicine intermediate.
Summary of the invention
The objective of the invention is to the 2-aminopyridine is raw material, through bromination, oxidation, diazotization, and reaction such as sulfhydrylation Synthetic 2-sulfydryl-5-bromo-N-pyridine oxide.
Technical scheme of the present invention is as follows:
The preparation method of a kind of 2-sulfydryl-5-bromo-N-pyridine oxide is a raw material with the 2-aminopyridine, through bromination, oxidation, diazotization, and reaction such as sulfhydrylation Synthetic 2-sulfydryl-5-bromo-N-pyridine oxide, concrete steps are as follows:
Step 1. is dissolved in the 2-aminopyridine in Glacial acetic acid or the diacetyl oxide, drips the liquid bromine solutions that is dissolved in acetate, under 10-20 ℃, reacts 3-6 hour.
Step 2. adds water in the reactant of step 1, the NaOH neutralization, and the gained solid refluxes in sherwood oil, and suction filtration gets the amino 5-bromopyridine of 2-.
Step 3. is dissolved in diacetyl oxide with 2-amino-5-bromopyridine, under 40-50 ℃, drips superoxol, under 60-70 ℃, reacts 1-4 hour.
Step 4. is cooled off step 3 reaction solution, decompressing and extracting, and washing with alcohol gets 2-acetyl ammonia-5-bromopyridine.
Step 5. is water-soluble with 2-acetyl ammonia-5-bromopyridine, neutralizes, and refluxes, and concentrates, and filters, and washing gets 2-amino-5-bromo-N-pyridine oxide.
The reaction solution of step 6. 2-amino-5-bromo-N-pyridine oxide is water-soluble and concentrated hydrochloric acid under 0-5 ℃, drips NaNO
2The aqueous solution reacted 0.5-2 hour,
Step 7. is transferred to the reaction solution of step 6 in the hydrochloric acid soln under 95-100 ℃, reacted 1-2 hour,
Step 8. is neutralized to alkalescence with step 7 reacting liquid filtering, drips sodium sulfide solution, under 85-90 ℃, reacted 1-4 hour,
To acidity, normal temperature reacted 1-2 hour down step 9. with step 8 reaction solution adjust pH, filter, and washing, recrystallization gets 2-sulfydryl-5-bromo-N-pyridine oxide.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the liquid bromine solutions that is dissolved in acetate described in the step 1, the consumption of its liquid bromine and acetate are 1.0 ± 0.2 milliliters of acetate of every gram liquid bromine, temperature is no more than 20 ℃ in the dropping process.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide adds water described in the step 2 in reactant, the consumption of its 2-aminopyridine and water is 10.0 ± 0.2 milliliters of every gram 2-aminopyridine waters.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the consumption of 2-amino-5-bromopyridine described in the step 3 and acetic anhydride is 3 ± 0.2 milliliters of diacetyl oxides of every gram 2-amino-5-bromopyridine; The concentration of superoxol is 45%～65%.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the consumption that 2-acetyl ammonia-5-bromopyridine is water-soluble described in the step 5 is 10.0 ± 0.2 milliliters of every gram 2-acetyl ammonia-5-bromopyridine water.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the consumption of 2-amino-5-bromo-N-pyridine oxide described in the step 6 and aqueous hydrochloric acid (1: 1) is 3.0 ± 0.2 milliliters of aqueous hydrochloric acids of every gram 2-amino-5-bromo-N-pyridine oxide.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the NaNO described in the step 6
2The aqueous solution is every gram NaNO
2Solid is dissolved in 2.0 ± 0.2 milliliters.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the consumption of the hydrochloric acid soln described in the step 7 is every gram 2-amino-5-bromo-N-pyridine oxide with 1.2 ± 0.2 milliliters of 20% hydrochloric acid solns.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the solution described in the step 8 is neutralized to alkalescence, its pH=8～9; Dripping the sodium sulfide solution consumption is every gram 2-amino-5-bromo-N-pyridine oxide Na
2S9H
2O 1.55 ± 0.2 grams.
The preparation method of above-mentioned 2-sulfydryl-5-bromo-N-pyridine oxide, the accent pH described in the step 9 is to acidity, its pH=2～3.
The invention has the beneficial effects as follows: the raw material cheapness, the reaction conditions gentleness, easy and simple to handle, productive rate is higher, environmental friendliness.
Embodiment
Further describe the present invention by following examples, but should notice that scope of the present invention is not influenced by any of these embodiment.
Embodiment 1
1.12-amino-5-bromopyridine is synthetic
8.46g (0.09mol) 2-aminopyridine and 15mL Glacial acetic acid are added in the 150mL round-bottomed flask, behind the stirring reaction 30min, are cooled to 10 ℃ under the normal temperature.To be dissolved in 4.62mL (0.09mol) the liquid bromine solutions of 15mL acetic acid, and slowly be added drop-wise in the above-mentioned system, temperature is no more than 20 ℃, reaction 3h.In system, add water 50mL, treat solid dissolving after, drip 40% sodium hydroxide solution, produce white precipitate, continue reaction 30min.Suction filtration, gained solid are added in the 20mL sherwood oil, and backflow 20min, suction filtration while hot, solid be with the petroleum ether of heat 2～3 times, drying, product 13.5g, productive rate 85.7%.m.p.133-135℃。React as follows:
1.2 2-amino-5-bromo-N-pyridine oxide is synthetic
16.6g (0.09mol) 2-amino-5-bromopyridine and 30mL diacetyl oxide are added in the 250mL round-bottomed flask, and 60-70 ℃ was reacted 1-2 hour down, is cooled to 40 ℃.With 20mL 48%H
2O
2Slowly be added drop-wise in the above-mentioned system, temperature is no more than 40 ℃, and 60-70 ℃ is continued reaction 2h down.Cooling, decompressing and extracting adds dehydrated alcohol, filters, washing, drying gets acylate 18.2g.m.p.164-166℃。Acylate is dissolved in the 160mL water, adds NaOH 3.0g and refluxed 1 hour, be concentrated into 40mL, cooling gradually has a large amount of faint yellow precipitations to separate out.Filter, washing, drying gets product 14.3g, productive rate 78.6%.m.p.183-185℃。
1.3 2-sulfydryl-5--bromo-N-pyridine oxide (HL) is synthetic
Under 0-5 ℃, 2-amino-5-bromo-N-pyridine oxide 9.45g (0.05mol) is dissolved in the mixed solution of 15mL water and 15mL concentrated hydrochloric acid.To be dissolved in the NaNO in the 10mL cold water
23.45g (0.05mol), slowly be added drop-wise in the above-mentioned reaction solution.Behind the 10-30min, 1/3 of reaction solution is transferred to (oil bath 95-100 ℃) in the 100mL flask that fills 8ml 20%HCl, add concentrated hydrochloric acid 4mL, residual reaction liquid has been shifted, continue to react to N
2All emit.Cooling is filtered, and is extremely alkaline with the NaOH neutralization filtrate.N
2Protection is added drop-wise to the aqueous solution of sodium sulphite 14.4g (0.06mol) in the above-mentioned solution down, under 85-90 ℃, reacts 0.5-1 hour.Cooling, enriching HCl solution adjust pH are filtered to 2-3, get solid, water, absolute ethanol washing, oven dry.Get product 7.20g, productive rate 70.6%.Fusing point is 110-112 ℃.Ultimate analysis C
5H
4BrNOS: calculated value (%): C, 29.16; H, 1.96; N, 6.80.Experimental value (%): C, 28.87; H, 1.86; N, 6.54.IR(KBr)cm
-1：3063，2359，1600，1576，1429，1411，1281，1240，1186，1162，1085，1053958，943，816，774，759，701。
This Compound I R spectrogram is seen accompanying drawing.
Embodiment 2
2.12-amino-5-bromopyridine is synthetic
16.9g (0.18mol) PA and 30mL glacial acetic acid are added in the 150mL round-bottomed flask, behind the stirring reaction 30min, are cooled to 10 ℃ under the normal temperature. To be dissolved in 9.25mL (0.18mol) the bromine solution of 15mL acetic acid, and slowly be added drop-wise in the above-mentioned system, temperature is no more than 20 ℃, reaction 5h. In system, add water 100mL, treat dissolution of solid after, drip 40% sodium hydroxide solution, produce white precipitate, continue reaction 1h. Suction filtration, gained solid are added in the 40mL benzinum, backflow 30min, and suction filtration while hot, solid are with the petroleum ether of heat 2～3 times, and drying gets product 26.7g, productive rate 84.7%. M.p.132-134 ℃.
42.3g (0.45mol) PA and 75mL glacial acetic acid are added in the 250mL round-bottomed flask, behind the stirring reaction 45min, are cooled to 10 ℃ under the normal temperature. To be dissolved in 23.2mL (0.45mol) the bromine solution of 60mL acetic acid, and slowly be added drop-wise in the above-mentioned system, temperature is no more than 20 ℃, reaction 4h. In system, add water 250mL, treat dissolution of solid after, drip 40% sodium hydroxide solution, produce white precipitate, continue reaction 1h. Suction filtration, gained solid are added in the 100mL benzinum, backflow 30min, and suction filtration while hot, solid are with the petroleum ether of heat 2～3 times, and drying gets product 68.8g, productive rate 87.4%. M.p.132.5-134.5 ℃.
2.2 2-amino-5-bromine-N-pyridine oxide is synthetic
26.7g (0.144mol) 2-amino-5-bromopyridine and 48mL acetic anhydride are added in the 250mL round-bottomed flask, and 60-70 ℃ of lower the reaction 2 hours is cooled to 40 ℃. With 30mL 56%H2O
2Slowly be added drop-wise in the above-mentioned system, temperature is no more than 40 ℃, the 60-70 ℃ of lower reaction 2h that continues. Cooling, decompressing and extracting adds absolute ethyl alcohol, filters, washing, drying gets acylate 30.3g. M.p.163-165 ℃. Acylate is dissolved in the 160mL water, adds NaOH 3.0g and refluxed 1 hour, be concentrated into 40mL, cooling gradually has a large amount of faint yellow Precipitations. Filter, washing, drying gets product 24.0g, productive rate 82.3%. M.p.182-184 ℃.
2.3 2-sulfydryl-5--bromine-N-pyridine oxide is synthetic
Under 0-5 ℃, 2-amino-5-bromine-N-pyridine oxide 24.0g (0.126mol) is dissolved in the mixed liquor of 38mL water and 38mL concentrated hydrochloric acid. To be dissolved in the NaNO in the 25mL cold water28.70g (0.126mol), slowly be added drop-wise in the above-mentioned reactant liquor. Behind the 10-30min, 1/3 of reactant liquor is transferred to (oil bath 95-100 ℃) in the 100mL flask that fills 20ml 20%HCl, add concentrated hydrochloric acid 10mL, residual reaction liquid has been shifted, continue to react to N2All emit. Cooling is filtered, and is extremely alkaline with the NaOH neutralization filtrate. N2Protection is lower, and the aqueous solution of vulcanized sodium 36.3g (0.15mol) is added drop-wise in the mentioned solution, under 85-90 ℃, reacts 1-1.5 hour. Cooling, enriching HCl solution adjust pH are filtered to 2-3, get solid, water, and absolute ethanol washing, oven dry gets product 19.0g, productive rate 72.5%. Fusing point is 110-111.5 ℃. Elementary analysis C5H
4BrNOS: calculated value (%): C, 29.16; H, 1.96; N, 6.80. Experiment value (%): C, 28.82; H, 1.82; N, 6.62. IR (KBr) cm-1：3064，2360，1598，1575，1429，1410，1281，1241，1186，1162，1086，1053，958，943，815，774，759，702。
Conclusion
1. the method for this preparation 2-seleno-N-pyridine oxide, after the concentration of hydrogen peroxide that uses improves, productive rate increases, and is obvious dose-effect relationship;
2. the method for this preparation 2-seleno-N-pyridine oxide, the raw material cheapness, the reaction conditions gentleness, productive rate is higher, environmental friendliness.
Claims (8)
1. the preparation method of 2-sulfydryl-5-bromo-N-pyridine oxide is characterized in that with the 2-aminopyridine be raw material, through bromination, oxidation, diazotization, and mercaptolation Synthetic 2-sulfydryl-5-bromo-N-pyridine oxide, concrete steps are as follows:
Step 1, the 2-aminopyridine is dissolved in Glacial acetic acid or the diacetyl oxide, drips the liquid bromine solutions that is dissolved in acetate, temperature of reaction is 10-20 ℃, reacts 3-6 hour;
Step 2, with the neutralization of the mixture of step 1, the gained solid refluxes in sherwood oil, suction filtration, the amino 5-bromopyridine of 2-;
Step 3,2-amino-5-bromopyridine is dissolved in the diacetyl oxide, 40-50 ℃ drips superoxol down, under 60-70 ℃, continues reaction 1-4 hour;
Step 4, cooling, decompressing and extracting, washing with alcohol gets 2-acetyl ammonia-5-bromo-N-pyridine oxide;
Step 5, the product of step 4 is water-soluble neutralizes, and refluxes, and concentrates, and filters, and washing gets 2-amino-5-bromo-N-pyridine oxide;
The reaction solution of step 6, step 5 product is water-soluble and concentrated hydrochloric acid under 0-5 ℃, drips NaNO
2The aqueous solution reacted 0.5-2 hour;
Step 7, the reaction solution of step 6 is transferred in the hydrochloric acid soln under 95-100 ℃, reacted 1-2 hour;
Step 8, step 7 solution is neutralized to alkalescence, drips sodium sulfide solution, under 85-90 ℃, reacted 1-4 hour;
Step 9, with step 8 solution adjust pH to acid, normal temperature reaction 1-2 hour is down filtered, washing, recrystallization, 2-sulfydryl-5-bromo-N-pyridine oxide.
2. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide is characterized in that: the dropping described in the step 1 is dissolved in the liquid bromine solutions of acetate, and temperature is cooled to 10 ℃ earlier, is no more than 20 ℃ in the dropping process; The consumption of liquid bromine and acetic acid solution is per 1 1.0 ± 0.2 milliliters of acetate of gram liquid bromine.
3. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide is characterized in that: the concentration of the described superoxol of step 3 is 45%～65%.
4. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide is characterized in that: the consumption of 2-amino-5-bromo-N-pyridine oxide described in the step 6 and aqueous hydrochloric acid (1: 1) is per 1 gram 2-amino-3.0 ± 0.2 milliliters of aqueous hydrochloric acids of 5-bromo-N-pyridine oxide.
5. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide is characterized in that: the NaNO described in the step 6
2The aqueous solution is per 1 gram NaNO
2Solid is dissolved in 2.0 ± 0.2 milliliters.
6. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide is characterized in that: the consumption of the hydrochloric acid soln described in the step 7 is per 1 gram 2-amino-5-bromo-N-pyridine oxide with 1.2 ± 0.2 milliliters of 20% hydrochloric acid solns.
7. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide, it is characterized in that: the solution described in the step 8 is neutralized to alkalescence, its pH=8～9; Dripping the sodium sulfide solution consumption is per 1 gram 2-amino-5-bromo-N-pyridine oxide Na
2S9H
2O 1.55 ± 0.2 grams.
8. the preparation method of 2-sulfydryl according to claim 1-5-bromo-N-pyridine oxide is characterized in that: the accent pH described in the step 9 is to acidity, its pH=2～3.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4080329A (en) * | 1976-04-02 | 1978-03-21 | Ciba-Geigy Corporation | Process for the manufacture of 2-mercapto pyridine-1-oxides |
| WO2003011292A1 (en) * | 2001-07-26 | 2003-02-13 | U.S. Army Medical Research And Materiel Command | Antivesicant compounds and methods of making and using thereof |
| US20030055090A1 (en) * | 2001-07-25 | 2003-03-20 | Lin Ai J. | Antivesicant compounds and methods of making and using thereof |
-
2011
- 2011-04-07 CN CN2011100932360A patent/CN102219735A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4080329A (en) * | 1976-04-02 | 1978-03-21 | Ciba-Geigy Corporation | Process for the manufacture of 2-mercapto pyridine-1-oxides |
| US20030055090A1 (en) * | 2001-07-25 | 2003-03-20 | Lin Ai J. | Antivesicant compounds and methods of making and using thereof |
| WO2003011292A1 (en) * | 2001-07-26 | 2003-02-13 | U.S. Army Medical Research And Materiel Command | Antivesicant compounds and methods of making and using thereof |
Non-Patent Citations (2)
| Title |
|---|
| 方永勤 等: "2-氨基-5-溴吡啶的合成", 《精细石油化工》, vol. 27, no. 4, 31 July 2010 (2010-07-31), pages 4 - 6 * |
| 赵瑛琛: "2-巯基氧化吡啶钠盐的合成及抑菌性能研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》, no. 3, 15 March 2009 (2009-03-15), pages 17 - 22 * |
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Application publication date: 20111019 |