CN1935791A - Method for preparing 3-methyl quinolines-8-sulfochlorides - Google Patents
Method for preparing 3-methyl quinolines-8-sulfochlorides Download PDFInfo
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- CN1935791A CN1935791A CN 200610046254 CN200610046254A CN1935791A CN 1935791 A CN1935791 A CN 1935791A CN 200610046254 CN200610046254 CN 200610046254 CN 200610046254 A CN200610046254 A CN 200610046254A CN 1935791 A CN1935791 A CN 1935791A
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- toluquinoline
- sulphuryl chloride
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Abstract
The invention belongs to the producing field of fine industrial products, especially relating to a 3-methylquinoline-8-sulfonyl chloride preparing method, comprising the steps of: making 3-methylquinoline react with chlorosulfonic acid and sulfonating assistant to produce mixture of sulfonated and chlorosulfonated compounds of 3-methylquinoline and, making the mixture further react with at least one chloridizing agent of thionyl chloride, and phosphoracyl chlorine or phosphorus pentachloride, and thus making it. And the invention has simple and convenient operating process, raw materials easy to get, and low cost, beneficial to scale production, and able to meet high yield and high purity requirements in chemical and medical fields.
Description
Technical field
The invention belongs to the production field of fine chemical product, the preparation method of particularly a kind of 3-toluquinoline-8-SULPHURYL CHLORIDE.
Background technology
The present invention relates to prepare the method for 3-toluquinoline-8-SULPHURYL CHLORIDE, 3-toluquinoline 8-SULPHURYL CHLORIDE is the important fine chemicals that is used for synthetic medicine, agricultural chemicals etc.
3-toluquinoline-8-SULPHURYL CHLORIDE has the chemical structure of be shown below (1).(American Chemical Society, CAS) the CAS registration number of this compound of Fa Hang summary magazine " " chemical abstracts " (Chemical Abstracts, CA) " is: " [74863-82-4] " in American Chemical Society.
At existing patent (US4201863, EP8746, JP81-15267) introduced a kind of chemosynthesis process that is used for the newtype drug-argatroban (Argatrban) of acute ischemic cerebral apoplexy treatment in, and 3-toluquinoline-8-SULPHURYL CHLORIDE is applied to this process as a kind of key intermediate.
Disclose the method for a kind of 3-of preparation toluquinoline-8-SULPHURYL CHLORIDE as existing method Japanese Patent (JP59-184161), this is the unique known references that retrieves at present, is not resolved but still exist some problems in the method for the disclosure.Containing a large amount of isomer (3-toluquinoline-5-SULPHURYL CHLORIDE, the chemical structure of be shown below (2)) in the product that obtains, and contain other impurity, is yellow to making product, is difficult to satisfy the requirement as the medical chemistry product.
The purpose of this invention is to provide the method for a kind of high yield, prepared in high purity 3-toluquinoline-8-SULPHURYL CHLORIDE, effectively prevented the generation of impurity, to satisfy the requirement of medical production field.
Summary of the invention
The present invention aims to provide that a kind of operating process is easy, and raw material is easy to get, and cost is low, helps the high yield of large-scale production, the preparation method of high purity 3-toluquinoline-8-SULPHURYL CHLORIDE.
The technology of the present invention solution can realize according to following mode:
The preparation method of a kind of 3-toluquinoline-8-SULPHURYL CHLORIDE, it may further comprise the steps:
1) 3-toluquinoline and chlorsulfonic acid are reacted;
2) step 1) gained reaction product is changed in the mixture of ice and water;
3) with step 2) products therefrom filters, washes, is drying to obtain target product.
The present invention is in above-mentioned steps 1) reaction finish after, can add chlorizating agent again and react.
In addition, the present invention also can add the sulfonation auxiliary agent and reacts in described step 1).
As a kind of preferred version, chlorizating agent of the present invention is one or more the mixture in thionyl chloride, phosphorus oxychloride, the phosphorus pentachloride.
The mol ratio of 3-toluquinoline of the present invention, chlorsulfonic acid and sulfonation auxiliary agent is followed successively by: 1: 1～6: 0.01～0.15.
As another kind of preferred version, sulfonation auxiliary agent of the present invention is one or more the mixture in sodium sulfate, ammonium sulfate, the ammonium chloride.
The mol ratio of 3-toluquinoline of the present invention, chlorsulfonic acid, sulfonation auxiliary agent and chlorizating agent is followed successively by: 1: 1～6: 0.01～0.15: 0.8～5.
In the first step of the present invention reaction, under preferred condition, make the transformation efficiency of raw material 3-toluquinoline near 100%, mainly generate the mixture of 3-toluquinoline-8-sulfonic acid and 3-toluquinoline-8-SULPHURYL CHLORIDE.
Reaction principle is:
In second step reaction of the present invention, the first step reaction mixture that obtains and at least a chlorizating agent that is selected from thionyl chloride, phosphorus oxychloride and the phosphorus pentachloride are further reacted, thereby make the 3-toluquinoline-8-sulfonic acid that generates in the above-mentioned reaction be converted into 3-toluquinoline-8-SULPHURYL CHLORIDE effectively.
Reaction principle is:
The present invention has following advantage compared with the prior art:
1) 3-toluquinoline provided by the invention-8-SULPHURYL CHLORIDE preparation method can be fit to chemical industry, the high yield of medicine and other fields, requirement of high purity.
2) 3-toluquinoline-8-SULPHURYL CHLORIDE of obtaining of the present invention is the off-white color crystallization, and purity can be greater than 98.5%.
3) preparation process of 3-toluquinoline provided by the invention-8-SULPHURYL CHLORIDE is easy and simple to handle, and raw material is easy to get, and cost is low, helps large-scale production.
Description of drawings
Below in conjunction with embodiment operational path of the present invention is described in detail.
Fig. 1 is the prepared product liquid-phase chromatographic analysis figure of the present invention.
Embodiment
In 500 milliliters of four-hole reaction flasks that have mechanical stirrer, thermometer, reflux condensing tube and charging opening, add chlorsulfonic acid (233 grams, 2.0 moles), under 25 ℃, splash into 3-toluquinoline (143 grams, 1.0 mole), add sodium sulfate (14 grams, 0.1 mole) then.The reinforced back of finishing is warmed up to 120 ℃ then 25 ℃ of isothermal reactions 1 hour, reacts 4 hours.Cool to 50 ℃, splash into thionyl chloride (119 grams, 1.0 moles), and be warming up to 70 ℃, reacted 2 hours.Cooling is transferred to it in mixing frozen water of 1000 gram trash ices and 500 gram water lentamente, and filtration, washing, drying obtain faint yellow 3-toluquinoline-8-SULPHURYL CHLORIDE crude product 178 grams, and yield is 74%.The toluene recrystallization obtains pure product 162 grams of off-white color, and yield is 91%.Fusing point is: 161-162 ℃.
The content of liquid-phase chromatographic analysis 3-toluquinoline-8-SULPHURYL CHLORIDE is 98.80%.
The test condition of liquid chromatography is as follows:
Chromatographic instrument: Jasco 880-PU
Chromatographic column: 250 * 4.6mm SS EXSIL ODS, 5 μ m
Moving phase: methanol=9: 1
Column temperature: 25 ℃
Flow velocity: 0.5 ml/min
Detector (wavelength): Jasco 870-UV (254nm)
The method of area normalization is adopted in cubage.
Embodiment 2
In 500 milliliters of four-hole reaction flasks that have mechanical stirrer, thermometer, reflux condensing tube and charging opening, add chlorsulfonic acid (233 grams, 2.0 moles), under 25 ℃, splash into 3-toluquinoline (143 grams, 1.0 mole), add ammonium chloride (5 grams, 0.1 mole) then.The reinforced back of finishing is warmed up to 120 ℃ then 25 ℃ of isothermal reactions 1 hour, reacts 4 hours.Cool to 50 ℃, splash into thionyl chloride (119 grams, 1.0 moles), and be warming up to 70 ℃, reacted 2 hours.The last handling process of reaction obtains faint yellow 3-toluquinoline-8-SULPHURYL CHLORIDE crude product 169 grams with embodiment 1, and yield is 70%.The toluene recrystallization obtains pure product 152 grams of off-white color, and yield is 90%.Fusing point is: 161-162 ℃.
The content of liquid-phase chromatographic analysis 3-toluquinoline-8-SULPHURYL CHLORIDE is 98.61%.
In 500 milliliters of four-hole reaction flasks that have mechanical stirrer, thermometer, reflux condensing tube and charging opening, add chlorsulfonic acid (233 grams, 2.0 moles), under 25 ℃, splash into 3-toluquinoline (143 grams, 1.0 mole), add sodium sulfate (14 grams, 0.1 mole) then.The reinforced back of finishing is warmed up to 120 ℃ then 25 ℃ of isothermal reactions 1 hour, reacts 4 hours.Cool to 50 ℃, splash into phosphorus pentachloride (177 grams, 1.0 moles), and be warming up to 80 ℃, reacted 3 hours.The last handling process of reaction obtains faint yellow 3-toluquinoline-8-SULPHURYL CHLORIDE crude product 193 grams with embodiment 1, and yield is 80%.The toluene recrystallization obtains pure product 181 grams of off-white color, and yield is 94%.Fusing point is: 161-162 ℃.
The content of liquid-phase chromatographic analysis 3-toluquinoline-8-SULPHURYL CHLORIDE is 98.69%.
Comparative example 1
In 500 milliliters of four-hole reaction flasks that have mechanical stirrer, thermometer, reflux condensing tube and charging opening, add chlorsulfonic acid (233 grams, 2.0 moles), under 25 ℃, splash into 3-toluquinoline (143 grams, 1.0 moles).The reinforced back of finishing is warmed up to 120 ℃ then 30 ℃ of isothermal reactions 1 hour, reacts 4 hours.The last handling process of reaction obtains yellow 3-toluquinoline-8-SULPHURYL CHLORIDE crude product 101 grams with embodiment 1, and yield is 42%.
Comparative example 2
In 500 milliliters of four-hole reaction flasks that have mechanical stirrer, thermometer, reflux condensing tube and charging opening, add chlorsulfonic acid (233 grams, 2.0 moles), under 20 ℃, splash into 3-toluquinoline (143 grams, 1.0 moles).The reinforced back of finishing is warmed up to 120 ℃ then 30 ℃ of isothermal reactions 1 hour, reacts 4 hours.Cool to 50 ℃, splash into thionyl chloride (119 grams, 1.0 moles), and be warming up to 70 ℃, reacted 2 hours.Cooling is transferred to it in frozen water, and filtration, washing, drying obtain faint yellow 3-toluquinoline-8-SULPHURYL CHLORIDE crude product 130 grams, and yield is 54%.
Protection scope of the present invention will not only be confined to above-mentioned embodiment, and any reaction with 3-toluquinoline and chlorsulfonic acid is that the preparation 3-toluquinoline-8-SULPHURYL CHLORIDE operational path of principal character all should be regarded as and fall within protection scope of the present invention.
Claims (7)
1, the preparation method of a kind of 3-toluquinoline-8-SULPHURYL CHLORIDE is characterized in that may further comprise the steps:
1) 3-toluquinoline and chlorsulfonic acid are reacted;
2) step 1) gained reaction product is changed in the mixture of ice and water;
3) with step 2) products therefrom filters, washes, is drying to obtain target product.
2, according to the preparation method of the described 3-toluquinoline of claim 1-8-SULPHURYL CHLORIDE, it is characterized in that: after described step 1) reaction is finished, add chlorizating agent again and react.
3, according to the preparation method of the described 3-toluquinoline of claim 2-8-SULPHURYL CHLORIDE, it is characterized in that: in described step 1), add the sulfonation auxiliary agent and react.
4, according to the preparation method of claim 2 or 3 described 3-toluquinoline-8-SULPHURYL CHLORIDE, it is characterized in that: described chlorizating agent is one or more the mixture in thionyl chloride, phosphorus oxychloride, the phosphorus pentachloride.
5, according to the preparation method of the described 3-toluquinoline of claim 3-8-SULPHURYL CHLORIDE, it is characterized in that: the mol ratio of described 3-toluquinoline, chlorsulfonic acid and sulfonation auxiliary agent is followed successively by: 1: 1～6: 0.01～0.15.
6, according to the preparation method of the described 3-toluquinoline of claim 4-8-SULPHURYL CHLORIDE, it is characterized in that: described sulfonation auxiliary agent is one or more the mixture in sodium sulfate, ammonium sulfate, the ammonium chloride.
7, according to the preparation method of the described 3-toluquinoline of claim 5-8-SULPHURYL CHLORIDE, it is characterized in that: the mol ratio of described 3-toluquinoline, chlorsulfonic acid, sulfonation auxiliary agent and chlorizating agent is followed successively by: 1: 1～6: 0.01～0.15: 0.8～5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100462542A CN100422154C (en) | 2006-04-07 | 2006-04-07 | Method for preparing 3-methyl quinolines-8-sulfochlorides |
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|---|---|---|---|
| CNB2006100462542A CN100422154C (en) | 2006-04-07 | 2006-04-07 | Method for preparing 3-methyl quinolines-8-sulfochlorides |
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| CN1935791A true CN1935791A (en) | 2007-03-28 |
| CN100422154C CN100422154C (en) | 2008-10-01 |
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| CNB2006100462542A Expired - Fee Related CN100422154C (en) | 2006-04-07 | 2006-04-07 | Method for preparing 3-methyl quinolines-8-sulfochlorides |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483254A (en) * | 2012-06-12 | 2014-01-01 | 华东师范大学 | Method for synthesizing 3-methylquinoline-8-sulfonyl chloride |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59184161A (en) * | 1983-03-31 | 1984-10-19 | Tokyo Kasei Kogyo Kk | Production of sulfonyl chloride |
| CN1143844C (en) * | 2001-04-30 | 2004-03-31 | 浙江大学 | Prepn of nitrobenzene sulfonyl chloride |
| JP2005139149A (en) * | 2003-11-10 | 2005-06-02 | Taoka Chem Co Ltd | Method for producing quinoline-8-sulfonyl chloride |
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- 2006-04-07 CN CNB2006100462542A patent/CN100422154C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483254A (en) * | 2012-06-12 | 2014-01-01 | 华东师范大学 | Method for synthesizing 3-methylquinoline-8-sulfonyl chloride |
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Granted publication date: 20081001 Termination date: 20180407 |