CN104402799B - A kind of N-(3-chloropropyl) piperidines process for purification - Google Patents
A kind of N-(3-chloropropyl) piperidines process for purification Download PDFInfo
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- CN104402799B CN104402799B CN201410734773.2A CN201410734773A CN104402799B CN 104402799 B CN104402799 B CN 104402799B CN 201410734773 A CN201410734773 A CN 201410734773A CN 104402799 B CN104402799 B CN 104402799B
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- chloropropyl
- piperidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/067—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a kind of N (3 chloropropyl) piperidines process for purification, particularly as follows: it is by N (3 chloropropyl) piperidines crude product with alkaline or neutral desiccant dryness overnight first, then carry out dried crude product heating high vacuum rectification, remove low boiling and high boiling impurity, collect the fraction of required temperature range, i.e. can get the fine work of N (3 chloropropyl) piperidines, the present invention can remove the moisture in N (3 chloropropyl) piperidines crude product and other impurity efficiently, the fine work enabling refined gained safely and effectively carries out grignard reaction, and the inventive method is simple, easy and simple to handle, with low cost, it is suitable for pharmacy corporation to use.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to the process for purification of pharmaceutical intermediate, particularly to a kind of N-(3-chloropropyl) piperidines process for purification.
Background technology
N-(3-chloropropyl) piperidines is the important intermediate of synthesis dizziness drug withdrawal difenidol hydrochloride, carries out, for raw material, the important reaction that grignard reaction is synthetic hydrochloric acid diphenidol medicine with this material.Wherein, the Grignard reagent that grignard reaction is used is a kind of organo-magnesium compound, is that in absolute ether or THF and magnesium metal effect generates alkyl halide magnesium RMgX to halogenated hydrocarbons.Grignard reagent is especially sensitive to water, this is because containing Labile protons in the middle of water, these Labile protons can react with Grignard reagent and make it hydrolyze the inefficacy causing Grignard reagent.Therefore with N-(3-chloropropyl) piperidines be raw material carry out grignard reaction time, the quality of this material and moisture are the key factors affecting grignard reaction success or failure and yield.
But, most enterprises is only dried process with Matrii Sulfas Exsiccatus (anhydrous sodium sulfate) to N-(3-chloropropyl) piperidines at present, the method not only can not effectively remove other impurity in N-(3-chloropropyl) piperidines crude product, and the content of N-(3-chloropropyl) piperidines is low.What is more important this method dehydrating effect is the most undesirable, still contains the moisture of 0.1% ~ 1% in N-(3-chloropropyl) piperidines obtained, and the effect preparing difenidol hydrochloride medicine for grignard reaction is the most undesirable.
Summary of the invention
It is an object of the invention to overcome the deficiencies in the prior art, offer one efficiently removes N-(3-chloropropyl) the piperidines process for purification that the moisture in N-(3-chloropropyl) piperidines crude product is simple, easy and simple to handle, with low cost with other impurity and method.
For achieving the above object, the technical solution used in the present invention is: a kind of N-(3-chloropropyl) piperidines process for purification, it is by N-(3-chloropropyl) piperidines crude product with neutral or alkaline desiccant dryness overnight first, then carry out dried crude product heating high vacuum rectification, remove low boiling and high boiling impurity, collect the fraction of required temperature range, i.e. can get the fine work of N-(3-chloropropyl) piperidines.
Described neutral desiccant or alkalescence desiccant one in anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, calcium sulfate, sodium carbonate, potassium carbonate, calcium hydride, sodium hydroxide, potassium hydroxide.
Described neutral desiccant or alkalescence 0.01 ~ 0.5 times that consumption is N-(3-chloropropyl) piperidines crude product of desiccant.
Described condition of high vacuum degree is 0 ~ 1000 Pa.
The fraction of described needs is the material of 90 DEG C of ＜ boiling point ＜ 120 DEG C.
Described low boiling impurity is the material of boiling point≤90 DEG C.
Described high-boiling-point impurity is the material of boiling point >=120 DEG C.
Described is heated to be oil bath heating.
The invention have the benefit that 1, elder generation of the present invention drying agent is dried overnight, then passes through high-vacuum rectification, it is possible to efficiently remove the moisture in N-(3-chloropropyl) piperidines crude product and other impurity；2, the present invention substantially increases the content of N-(3-chloropropyl) piperidines；3, the inventive method is simple, easy and simple to handle, with low cost, facilitates industrial applications.
Detailed description of the invention
Below in conjunction with embodiment the present invention elaborated rather than limit protection scope of the present invention.
Embodiment 1
By 20 g N-(3-chloropropyl) piperidines crude product, 5 g anhydrous sodium sulfates add in round-bottomed flask, it is stirred overnight, then by said mixture, zeolite proceeds in distilling flask, the vacuum of distilling apparatus is controlled at 300Pa ~ 400Pa with sliding vane rotary vacuum pump, collect the low-boiling point material of boiling point≤90 DEG C respectively, the high boiling substance of boiling point >=120 DEG C and the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C, the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C is gained N-(3-chloropropyl) piperidines fine work, its water content≤0.05%, content >=99.2% of N-(3-chloropropyl) piperidines.
Embodiment 2
By 20 g N-(3-chloropropyl) piperidines crude product, 4 g anhydrous magnesium sulfates add in round-bottomed flask, it is stirred overnight, then by said mixture, zeolite proceeds in distilling flask, the vacuum of distilling apparatus is controlled at 300Pa ~ 400Pa with sliding vane rotary vacuum pump, collect the low-boiling point material of boiling point≤90 DEG C respectively, the high boiling substance of boiling point >=120 DEG C and the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C, the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C is gained N-(3-chloropropyl) piperidines fine work, its water content≤0.04%, content >=99.2% of N-(3-chloropropyl) piperidines.
Embodiment 3
By 20 g N-(3-chloropropyl) piperidines crude product, 5 g anhydrous calcium chlorides add in round-bottomed flask, it is stirred overnight, then by said mixture, zeolite proceeds in distilling flask, the vacuum of distilling apparatus is controlled at 300Pa ~ 400Pa with sliding vane rotary vacuum pump, collect the low-boiling point material of boiling point≤90 DEG C respectively, the high boiling substance of boiling point >=120 DEG C and the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C, the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C is gained N-(3-chloropropyl) piperidines fine work, its water content≤0.05%, content >=99.2% of N-(3-chloropropyl) piperidines.
Embodiment 4
By 20 g N-(3-chloropropyl) piperidines crude product, 6 g potassium carbonate add in round-bottomed flask, it is stirred overnight, then by said mixture, zeolite proceeds in distilling flask, the vacuum of distilling apparatus is controlled at 300Pa ~ 400Pa with sliding vane rotary vacuum pump, collect the low-boiling point material of boiling point≤90 DEG C respectively, the high boiling substance of boiling point >=120 DEG C and the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C, the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C is gained N-(3-chloropropyl) piperidines fine work, its water content≤0.05%, content >=99.2% of N-(3-chloropropyl) piperidines.
Embodiment 5
By 20 g N-(3-chloropropyl) piperidines crude product, 3 g calcium hydrides add in round-bottomed flask, it is stirred overnight, then by said mixture, zeolite proceeds in distilling flask, the vacuum of distilling apparatus is controlled at 300Pa ~ 400Pa with sliding vane rotary vacuum pump, collect the low-boiling point material of boiling point≤90 DEG C respectively, the high boiling substance of boiling point >=120 DEG C and the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C, the positive boilers of 90 DEG C of ＜ boiling point ＜ 120 DEG C is gained N-(3-chloropropyl) piperidines fine work, its water content≤0.05%, content >=99.2% of N-(3-chloropropyl) piperidines.
Claims (5)
1. N-(3-chloropropyl) piperidines process for purification, it is characterized in that: it is by N-(3-chloropropyl) piperidines crude product with neutral or alkaline desiccant dryness overnight first, then carry out dried crude product heating high vacuum rectification, remove low boiling and high boiling impurity, collect the fraction of required temperature range, i.e. can get the fine work of N-(3-chloropropyl) piperidines, described neutral desiccant or alkalescence desiccant are selected from anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, calcium sulfate, sodium carbonate, potassium carbonate, calcium hydride, sodium hydroxide, one in potassium hydroxide, described neutral desiccant or alkalescence 0.01 ~ 0.5 times that consumption is N-(3-chloropropyl) piperidines crude product of desiccant, described condition of high vacuum degree is 0 ~ 1000 Pa.
2. a kind of N-(3-chloropropyl) piperidines process for purification as claimed in claim 1, it is characterised in that: the fraction of described needs is the material of 90 DEG C of ＜ boiling point ＜ 120 DEG C.
3. a kind of N-(3-chloropropyl) piperidines process for purification as claimed in claim 1, it is characterised in that: described low boiling impurity is the material of boiling point≤90 DEG C.
4. a kind of N-(3-chloropropyl) piperidines process for purification as claimed in claim 1, it is characterised in that: described high-boiling-point impurity is the material of boiling point >=120 DEG C.
5. a kind of N-(3-chloropropyl) piperidines process for purification as claimed in claim 1, it is characterised in that: described is heated to be oil bath heating.
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| CN201410734773.2A CN104402799B (en) | 2014-12-08 | 2014-12-08 | A kind of N-(3-chloropropyl) piperidines process for purification |
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| CN201410734773.2A CN104402799B (en) | 2014-12-08 | 2014-12-08 | A kind of N-(3-chloropropyl) piperidines process for purification |
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| CN104402799B true CN104402799B (en) | 2017-01-04 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3088869A (en) * | 1961-08-29 | 1963-05-07 | Smith Kline French Lab | Antiemetic compositions and methods of treating nausea and vomiting |
| CN101560179B (en) * | 2009-05-25 | 2012-04-18 | 浙江大学 | Azotic indole derivative with H3 receptor affinity and applications |
| CN102731415A (en) * | 2012-07-02 | 2012-10-17 | 首都师范大学 | Quinazoline-4-piperazine dithioformate and preparation method and purpose thereof |
| US20130303531A1 (en) * | 2006-10-02 | 2013-11-14 | Qingqi Chen | Tetra-substituted ndga derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use |
| CN101547689B (en) * | 2006-10-02 | 2014-02-26 | 埃里莫斯医药品有限公司 | Tetra-substituted ndga derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use |
-
2014
- 2014-12-08 CN CN201410734773.2A patent/CN104402799B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3088869A (en) * | 1961-08-29 | 1963-05-07 | Smith Kline French Lab | Antiemetic compositions and methods of treating nausea and vomiting |
| US20130303531A1 (en) * | 2006-10-02 | 2013-11-14 | Qingqi Chen | Tetra-substituted ndga derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use |
| CN101547689B (en) * | 2006-10-02 | 2014-02-26 | 埃里莫斯医药品有限公司 | Tetra-substituted ndga derivatives via ether bonds and carbamate bonds and their synthesis and pharmaceutical use |
| CN101560179B (en) * | 2009-05-25 | 2012-04-18 | 浙江大学 | Azotic indole derivative with H3 receptor affinity and applications |
| CN102731415A (en) * | 2012-07-02 | 2012-10-17 | 首都师范大学 | Quinazoline-4-piperazine dithioformate and preparation method and purpose thereof |
Non-Patent Citations (4)
| Title |
|---|
| Development of a New Class of Nonimidazole Histamine H3 Receptor Ligands with Combined Inhibitory Histamine N-Methyltransferase Activity;Joachim Apelt,等;《Journal of Medicinal Chemistry》;20020502;第45卷(第5期);第1134页化合物2的合成 * |
| First Metal-Containing Histamine H3 Receptor Ligands;Kerstin Sander,等;《Organic Letters》;20100605;第12卷(第11期);第S2页化合物P3的合成 * |
| Kojic Acid Derivatives as Histamine H3 Receptor Ligands;Kerstin SANDER,等;《Chemical & Pharmaceutical Bulletin》;20100713;第58卷(第10期);第1358页化合物P2的合成 * |
| 盐酸地芬尼多工艺改进;王金恒,等;《山东医药工业》;20021231;第21卷(第3期);第2页 * |
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Effective date of registration: 20170307 Address after: Zhang pan town of Xuchang County in Xuchang city in 461100 in Henan Province before Wang Village Patentee after: HENAN YUCHEN PHARMACEUTICAL CO., LTD. Address before: 461100 Xuchang City, Henan Province Zhang Zhen Town Industrial Park Patentee before: HENAN HUIJIN PHARMACEUTICAL CO., LTD. |