CN102924369A - Method for synthesizing 3,5-dibromo-4-iodopyridine by one step - Google Patents
Method for synthesizing 3,5-dibromo-4-iodopyridine by one step Download PDFInfo
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- CN102924369A CN102924369A CN2012104562422A CN201210456242A CN102924369A CN 102924369 A CN102924369 A CN 102924369A CN 2012104562422 A CN2012104562422 A CN 2012104562422A CN 201210456242 A CN201210456242 A CN 201210456242A CN 102924369 A CN102924369 A CN 102924369A
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Abstract
The invention discloses a synthesis method of halogenated pyridine 3,5-dibromo-4-iodopyridine. The synthesis method comprises the following steps: taking 3,5-dibromo-4-aminopyridine as an initial raw material to perform diazotization to obtain 3,5-dibromo-4-iodopyridine by one step. Compared with the disclosed prior art, the process provided by the invention is simple to operate, high in reaction yield (65-83%) and good in reaction in selectivity, industrial production can be easily implemented, and the product does not contain isomerides difficult to separate.
Description
Technical field
The present invention relates to a kind of synthetic method of haloperidid, particularly 3, the synthetic method of 5-two bromo-4-iodine pyridines.
Background technology
Haloperidid is important fine-chemical intermediate, is widely used at medicine, pesticide field.Haloperidid brominated and iodine is used very extensive especially in fields such as agricultural chemicals, medicine, functional materialss.3,5-, two bromo-4-iodine pyridines are because its synthetic difficulty is larger, both at home and abroad to the synthetic report of 3,5-, two bromo-4-iodine pyridines seldom, only document (
Chemistry--A European Journal Vol.17; Nb. 47; 2011; P. 13284-13297) its synthetic method is disclosed: with 3, the 5-dibromo pyridine is raw material, take tetrahydrofuran (THF), normal hexane as solvent, generate active carbanion intermediate 0 ℃ of lower reaction with n-Butyl Lithium and Tetramethyl Ethylene Diamine zinc dichloride, this carbanion intermediate at room temperature, again with Iod R, generate 3,5-two bromo-4-iodine pyridines, reaction yield only has 8%(to generate 22% 3,5-, two bromo-2-iodine pyridine isomerss), and isomer 3 appears in the product, 5-two bromo-2-iodine pyridines so that separate, the purifying difficulty is large.In this reaction, use in a large number expensive n-Butyl Lithium (mol ratio of n-Butyl Lithium and 3,5-dibromo pyridine is 1.5:1), so that manufacturing cost is high; The use of n-Butyl Lithium is so that technique anhydrous and oxygen-free operational condition is harsh simultaneously, and the through engineering approaches difficulty is large.In sum, prior art exists that yield is excessively low, a large amount of isomerss occur in the product so that the problem of the needs solution such as separation and purification is difficult, process conditions is harsh, be not easy to accomplish scale production.The document reaction equation is as follows:
Summary of the invention
The object of the present invention is to provide that a kind of synthesis step is short, yield is high, selectivity is good, simple to operate 3,5-two bromo-4-iodine pyridine synthetic methods.
The technical solution used in the present invention is as follows:
A kind of 3, the synthesis technique of 5-two bromo-4-iodine pyridines, the starting raw material that adopts are 3,5-, two bromo-4-aminopyridines.
Synthetic 3,5-, the two bromo-4-iodine pyridine chemical reaction processes of the present invention are as follows:
Above-mentioned 3, the synthetic concrete technology step of 5-two bromo-4-iodine pyridines is:
In three-necked bottle, add 30-60% sulfuric acid, under 15 ℃, add in batches reference literature (
Synthesis; Nb. 14; 2001; P. 2175 reach
Chemistry--A European Journal; Vol
.18; Nb. 20; 2012; P. 6328, see embodiment 1 for details) preparation 3,5-two bromo-4-aminopyridines, heating is fully stirred and is made its dissolving, after reaction flask is as cold as room temperature, bathes cooling with cryosel, slowly drip sodium nitrite in aqueous solution, drip the process control certain temperature, after dripping, stirred 15 minutes, then in reaction system, drip the diazotization iodination reagent, drip 0～5 ℃ of process temperature control, drip rear rapid heating and be warmed up to certain temperature, keep this temperature, stirred 2 hours.Post-reaction treatment: pour in the frozen water after the reaction solution cooling, fully stir, Precipitation light yellow 3,5-two bromo-4-iodine pyridine crude products, filter gained filtrate with the 10% aqueous sodium hydroxide solution pH=6.0 that neutralizes, use chloroform extraction, separatory, organic phase is again with the 5% aqueous sodium hydroxide solution pH=7.5 that neutralizes, separatory, organic phase is used the saturated common salt water washing once, separatory, gained organic layer anhydrous sodium sulfate drying, filter, revolve to steam and remove the solvent trichloromethane, obtain yellow 3,5-, two bromo-4-iodine pyridine crude products.Filter the gained filter cake, oven dry moisture merges two portions solid, uses the normal hexane recrystallization, obtains white 3,5-two bromo-4-iodine pyridine sterlings, yield 65～83%, liquid content 95～99%.
In the described reaction, sulfuric acid concentration is 20-60%, preferred 40%.
In the described reaction, 3,5-, two bromo-4-aminopyridines and Sodium Nitrite mol ratio are preferably 1:1～1.5.
In the described reaction, the temperature that drips sodium nitrite in aqueous solution is-20～30 ℃, is preferably 0～5 ℃.
In the described reaction, the diazotization iodination reagent is potassiumiodide, sodium iodide, cesium iodide, cuprous iodide one-component or its any both compositions, is preferably potassiumiodide and cuprous iodide, is preferably the 2:1 mixture of potassiumiodide and cuprous iodide again.
In the described reaction, 3,5-, two bromo-4-aminopyridines and diazotization iodination reagent mol ratio are preferably 1:1～3.
In the described reaction, drip the diazotization iodination reagent after, intensification is 20～130 ℃, is preferably 80～100 ℃.
Compare with existing public technology, the present invention has following advantage:
1, do not use this class technique anhydrous and oxygen-free operational condition of n-Butyl Lithium harsh, the reagent that the through engineering approaches difficulty is large, technological operation of the present invention is simple, is easy to realize through engineering approaches.
2, reaction yield high (65～83%).
3, good reaction selectivity, the impure isomers that is being difficult to separate in the product.
Therefore, the present invention has good economic benefit and social benefit in sum.
Embodiment
Embodiment 1
3, synthesizing of 5-two bromo-4-aminopyridines: in the 2000ml three-necked bottle, add successively solvent tetracol phenixin 900ml, 4-aminopyridine 94.11g(1.0mol), Diisopropyl azodicarboxylate etc. (AIBN) 0.82g, under 20 ℃, add N-bromo-succinimide (NBS) 391.56g(2.2mol) in batches, room temperature reaction 24 hours, controlling/monitoring all is converted into target product 3 to raw material 4-aminopyridine and intermediate 3-bromo-4-aminopyridine in the liquid phase, behind the 5-two bromo-4-aminopyridines, and stopped reaction.Post-reaction treatment: behind the lower cool to room temperature of reaction solution stirring, pour in the 1000ml tetracol phenixin, stir, filter, filter cake washs 2 times with the 2*200ml tetracol phenixin, and filtrate with the sodium bicarbonate aqueous solution washing once, the saturated common salt water washing is once revolved steaming and is eliminated solvent tetracol phenixin, gained 3, the thick product of 5-two bromo-4-aminopyridines is used the normal hexane recrystallization, obtains white 3,5-two bromo-4-aminopyridine 225.6g, yield 89.6%, liquid content 97.8%, this product can be directly used in next step reaction.
Embodiment 2
In the 1000ml three-necked bottle, add 40% sulfuric acid, under 15 ℃, add in batches with above-described embodiment 1 method synthetic 3,5-two bromo-4-aminopyridine 126.0g(0.50mol), be heated to 45 ℃ of abundant stirrings and make its dissolving, after reaction flask is as cold as room temperature, bathe cooling with cryosel, slowly drip and contain 38.5g(0.56mol) sodium nitrite solution of Sodium Nitrite and 150g water, drip 0～3 ℃ of process control, after dripping, stirred 15 minutes, then drip simultaneously in the reaction system and contain potassiumiodide 83.0g(0.5mol, 1.0eq) saturated aqueous solution and contain cuprous iodide 47.6g(0.25mol, 0.5eq) 30% sulphuric acid soln, drip 0～5 ℃ of process temperature control, drip rear rapid heating and be warmed up to 80 ℃ of interior temperature, keep this temperature, stirred 2 hours.Post-reaction treatment: pour in the 2000ml frozen water after the reaction solution cooling, fully stir, Precipitation light yellow 3,5-two bromo-4-iodine pyridine crude products, filter gained filtrate with the 10% aqueous sodium hydroxide solution pH=6.0 that neutralizes, use chloroform extraction, separatory, organic phase is again with the 5% aqueous sodium hydroxide solution pH=7.5 that neutralizes, separatory, organic phase is used the saturated common salt water washing once, separatory, gained organic layer anhydrous sodium sulfate drying, filter, revolve to steam and remove the solvent trichloromethane, obtain yellow 3,5-, two bromo-4-iodine pyridine crude products.Filter the light yellow filter cake of gained, oven dry moisture merges two portions crude product, uses the normal hexane recrystallization, obtain light yellow 3,5-two bromo-4-iodine pyridine sterling 141.3g, yield 78.0%, liquid content 98.8%.
Embodiment 3
In the described reaction, initial sulfuric acid concentration is 30%, other biconditional operations embodiment 2.
Operate according to embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 125.0 grams, yield 69.0%, content 98.2%.
Embodiment 4
In the described reaction, initial sulfuric acid concentration is 50%, other biconditional operations embodiment 2.
Operate according to embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 139.9 grams, yield 77.2%, content 98.5%.
Embodiment 5
In the described reaction, the Sodium Nitrite consumption is 34.3g(0.50mol), other operate according to embodiment with embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 133.9 grams, content 98.2%, yield 73.9%.
Embodiment 6
In the described reaction, the diazotization iodination reagent is for containing potassiumiodide 83.0g(0.5mol, 1.5eq) saturated aqueous solution, other operate according to embodiment with embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 121.7 grams, content 98.3%, yield 67.2%.
Embodiment 7
In the described reaction, the diazotization iodination reagent is for containing sodium iodide 75.0g(0.5mol, 1.0eq) saturated aqueous solution and contain cuprous iodide 47.6g(0.25mol, 0.5eq), other operate according to embodiment with embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 117.9 grams, content 97.6%, yield 65.1%.
Embodiment 8
In the described reaction, drip the diazotization iodination reagent after, the temperature reaction temperature is 100 ℃, other operate according to embodiment with embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 150.0 grams, content 99.3%, yield 82.8%.
Embodiment 9
In the described reaction, drip the diazotization iodination reagent after, the temperature reaction temperature is 60 ℃, other operate according to embodiment with embodiment 2, obtain light yellow 3,5-two bromo-4-iodine pyridine sterlings 129.1 grams, content 98.9%, yield 71.3%.
Claims (7)
1.3 the synthetic method of 5-two bromo-4-iodine pyridines is characterized in that with 3,5-, two bromo-4-aminopyridines be main starting raw material, through diazotization reaction, a step obtains target product, and chemical reaction process is as follows:
The concrete technology step is:
In three-necked bottle, add 30-60% sulfuric acid, under 15 ℃, add 3 of reference literature preparation, 5-two bromo-4-aminopyridines in batches, heating is fully stirred and is made its dissolving, after reaction flask is as cold as room temperature, bathes cooling with cryosel, slowly drip sodium nitrite in aqueous solution, drip the process control certain temperature, after dripping, stirred 15 minutes, then in reaction system, drip the diazotization iodination reagent, drip 0～5 ℃ of process temperature control, drip rear rapid heating and be warmed up to certain temperature, keep this temperature, stirred 2 hours; Post-reaction treatment: pour in the frozen water after the reaction solution cooling, fully stir, Precipitation light yellow 3,5-two bromo-4-iodine pyridine crude products, filter gained filtrate with the 10% aqueous sodium hydroxide solution pH=6.0 that neutralizes, use chloroform extraction, separatory, organic phase is again with the 5% aqueous sodium hydroxide solution pH=7.5 that neutralizes, separatory, organic phase is used the saturated common salt water washing once, separatory, gained organic layer anhydrous sodium sulfate drying, filter, revolve to steam and remove the solvent trichloromethane, obtain yellow 3,5-, two bromo-4-iodine pyridine crude products; Filter the gained filter cake, oven dry moisture merges two portions solid, uses the normal hexane recrystallization, obtains white 3,5-two bromo-4-iodine pyridine sterlings, yield 65～83%, liquid content 95～99%.
2. in the described reaction, sulfuric acid concentration is 20-60%, preferred 40%.
3. in the described reaction, 3,5-, two bromo-4-aminopyridines and Sodium Nitrite mol ratio are preferably 1:1～1.5.
4. in the described reaction, the temperature that drips sodium nitrite in aqueous solution is-20～30 ℃, is preferably 0～5 ℃.
5. in the described reaction, the diazotization iodination reagent is potassiumiodide, sodium iodide, cesium iodide, cuprous iodide one-component or its any both compositions, is preferably potassiumiodide and cuprous iodide, is preferably the 2:1 mixture of potassiumiodide and cuprous iodide again.
6. in the described reaction, 3,5-, two bromo-4-aminopyridines and diazotization iodination reagent mol ratio are preferably 1:1～3.
7. in the described reaction, drip the diazotization iodination reagent after, intensification is 20～130 ℃, is preferably 80～100 ℃.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103420903A (en) * | 2013-09-03 | 2013-12-04 | 天津安锦科技发展有限公司 | Method for synthesizing 5-Bromo-2, 4-dichloropyridine |
| CN106467488A (en) * | 2016-09-28 | 2017-03-01 | 贵州大学 | A kind of preparation technology of 2 iodine, 3 bromine 5 chloropyridine |
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| US20100160641A1 (en) * | 2008-12-19 | 2010-06-24 | Jubilant Organosys Ltd. | Process for producing dihalopyridines |
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| CN1807414A (en) * | 2006-02-06 | 2006-07-26 | 南京广通医药化工有限责任公司 | 2,3-dichloropyridine synthesis method |
| US20100160641A1 (en) * | 2008-12-19 | 2010-06-24 | Jubilant Organosys Ltd. | Process for producing dihalopyridines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103420903A (en) * | 2013-09-03 | 2013-12-04 | 天津安锦科技发展有限公司 | Method for synthesizing 5-Bromo-2, 4-dichloropyridine |
| CN106467488A (en) * | 2016-09-28 | 2017-03-01 | 贵州大学 | A kind of preparation technology of 2 iodine, 3 bromine 5 chloropyridine |
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Application publication date: 20130213 |