CN1202083C - Method of preparing 4-dimethylamino pyridine - Google Patents
Method of preparing 4-dimethylamino pyridine Download PDFInfo
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- CN1202083C CN1202083C CN 03117604 CN03117604A CN1202083C CN 1202083 C CN1202083 C CN 1202083C CN 03117604 CN03117604 CN 03117604 CN 03117604 A CN03117604 A CN 03117604A CN 1202083 C CN1202083 C CN 1202083C
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title claims abstract description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 92
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 50
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000010992 reflux Methods 0.000 claims abstract description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 18
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000000376 reactant Substances 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- 238000012805 post-processing Methods 0.000 claims description 6
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 claims description 3
- 239000002024 ethyl acetate extract Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 230000001186 cumulative effect Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000002027 dichloromethane extract Substances 0.000 claims 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000047 product Substances 0.000 description 18
- 239000012043 crude product Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 230000018044 dehydration Effects 0.000 description 8
- 238000006297 dehydration reaction Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000010025 steaming Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000008118 PEG 6000 Substances 0.000 description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 2
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 pyridines compound Chemical class 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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Abstract
The present invention relates to a method for preparing 4-dimethyl aminopyridine, which is characterized in that conventional used amino reagents, such as DMF or dimethylamine hydrochloride, etc. are directly added into reaction system solution to continuously carry out the subsequent reaction after pyridine is used as raw materials in an ethyl acetate reaction medium to carry out conventional reflux reaction with thionyl chloride. Then, a reactant is conventionally post-processed so that the compound product (4-dimethyl aminopyridine) is obtained. Compared with the existing traditional methods, the method can greatly simplify the operation, shorten a reaction cycle, reduce cost, and increase the yield.
Description
Technical field
What the present invention relates to is improvement to 4-Dimethylamino pyridine compounds process for production thereof.
Background technology
4-Dimethylamino pyridine (DMAP) is a kind of new and effective acylation catalyst, can be in the acidylate and the transesterification reaction of alcohol, phenol, amine, and the aspects such as surface reaction of anti-phase phase-transfer catalyst obtain widely applying.Be characterized in that speed of response is fast, mild condition, solvent applicatory is extensive, and product yield is more high, and especially the acidylate for big hindered alcohols has better effect.At present more to the relevant preparation method of DMAP, but all adopt the two-step reaction that independently carries out by respectively, promptly finish by pyridine and thionyl chloride after the first step reaction obtains the double pyridines compound intermediate, earlier this intermediate is isolated from reactive system, and then continue to carry out next step reaction, and finally obtain said DMAP product with corresponding aminated reagent with the intermediate after separating.This kind preparation method except that exist to some extent raw material seldom, go back the ubiquity severe reaction conditions and be difficult to grasp, complex operation, and cause shortcomings such as product yield is low and second-rate.
For example, people such as Sun Shunneng are at " chemical reagent " (Vol.12,1989 (6), 363-364,357) among the corresponding preparation method who introduces in " the synthetic synthetic and application of using research (the III)-DMAP of chemical reagent of DNA ", in with the acetic acid ethyl reaction medium, be that raw material and thionyl chloride carry out after back flow reaction obtains the midbody compound of double amidopyridine salt hydrochlorate form with the pyridine, continuing with N, dinethylformamide is that aminated reagent carries out before next step the reaction, adopt to steam earlier and remove ethyl acetate and unreacted pyridine and thionyl chloride and after obtaining being the semi-solid thing of stiff shape black, handle with dehydrated alcohol again and obtain double amidopyridine salt hydrochlorate solid intermediate.Find in the practice that these operations are difficulty relatively, and this double amidopyridine salt hydrochlorate solid instability of gained, under as the effect of external force such as stirring, can decompose.Carrying out second step reaction input N, behind the dinethylformamide (DMF), need it be dissolved fully again, continue at then under the high temperature and reacted 2 hours, steam pyridine and the water that removes the reaction generation again.Therefore, for a long time the too high meeting of temperature causes side reaction to increase, and makes reaction time long and operate loaded down with trivial detailsly, and influences the yield of product.
Zheng Qihuang and once people such as Gansu Province plum at " Chinese Journal of Pharmaceuticals " (Vol.22,1991 (7), 318-319) among the preparation method who introduces in " synthesizing of 4-dimethylamino pyridine ", after preparing corresponding double pyridines compound intermediate in a similar manner, before carrying out next step reaction as aminated reagent with Dimethylammonium chloride, equally also steam earlier and remove ethyl acetate and unreacted pyridine and thionyl chloride, separate and obtain stiff shape black semisolid, and then after adding ethyl acetate and Dimethylammonium chloride, continued back flow reaction 3 hours.Comprise again afterwards and add alkali aqueous solution and steam pyridine and the water that produces except that reaction, steam again except that methylene dichloride and residual water after adding methylene dichloride, and the adding acetic acid ethyl dissolution, with aftertreatment such as concentrating behind the decolorizing with activated carbon again, obtain the crude product of DMAP product.Can also carry out the purification process of recrystallization again with the ethyl acetate equal solvent to resulting DMAP crude product, obtain the highly finished product product at last.Its operation is equally all very loaded down with trivial details and unnecessary, and distill repeatedly can cause the increase of side reaction, the quality of reduction yield and product equally.
Summary of the invention
At above-mentioned situation, the present invention will provide a kind of method for preparing 4-Dimethylamino pyridine (DMAP) in a continuous manner, to overcome above-mentioned preparation method's at present commonly used deficiency, to simplify the operation, shorten reaction time, and can avoid long high-temperature reaction process, thereby can also reach the purpose that improves DMAP product yield and quality.
The present invention prepares the method for 4-Dimethylamino pyridine, what adopt is to be after raw material and thionyl chloride carry out the back flow reaction of routine with pyridine in the acetic acid ethyl reaction medium, aminated reagent is directly added reactive system solution and proceeds follow-up reaction, then reactant is carried out conventional aftertreatment, promptly obtain said DMAP product.Wherein said aminated reagent, can adopt at present commonly used as N, compounds such as dinethylformamide (DMF) or Dimethylammonium chloride.Its reaction process can be shown below:
Double amidopyridine salt hydrochlorate DMAP
In above-mentioned preparation method, the first step is the same reaction of carrying out with usual manner, and obtains the midbody compound of double amidopyridine salt hydrochlorate form equally.But this moment, the inventive method did not need this midbody compound is carried out any separating treatment, promptly directly drops into second and go on foot required aminated reagent and proceed and finish the reaction process in second step in former reactive system solution.Experimental result shows, after in former reactive system, dropping into aminated reagent, can be on the completed reaction of the first step basis, both can realize destroying the running balance of former completed the first step reaction, and impel reaction to carry out, and help avoiding reaction system to be in oversize purpose of time under the condition of high temperature again to the second step direction of expection, and can obviously simplify operation, shorten reaction time, and reduced the generation of side reaction, thereby helped improving the quality of finished product.Experimental result shows, adopts preparation method of the present invention, generally can make the yield of finished product improve 5%-17% than traditional preparation method.
At above-mentioned employing DMF during as aminated reagent, the preferable preparation method of reference when but a kind of sacrificial vessel body is implemented, be adopt usual manner with pyridine and thionyl chloride in the acetic acid ethyl reaction medium after the back flow reaction, the DMF that is about to conventional amount used directly joins in the reactive system solution, and promptly begins to steam pyridine and the water that is produced except that in ethyl acetate in the reaction system and the reaction process to add the thermal distillation mode after adding.Can the residue post processing mode routinely after the distillation with alkali aqueous solution dissolving and adjusting pH12-14, be used dichloromethane extraction again and concentrate after the filtration then, obtain said DMAP product crude product.If necessary, after with dichloromethane extraction, after also can handling, concentrate again and obtain the crude product of said 4-Dimethylamino pyridine product, and/or with isopropyl ether etc. resulting DMAP crude product is carried out the purification process of recrystallization again the decolouring that extracting solution is earlier made usual manner with activated carbon etc.
Another kind when can be used as concrete implement is a Dimethylammonium chloride in a usual manner, as anhydrous hydrochloric acid dimethylamine commonly used aminated reagent as the reaction of second step with reference to mode.After carrying out the first step reaction with above-mentioned same or similar fashion, can be in former reactive system the direct solid Dimethylammonium chloride of input conventional amount used, and proceed back flow reaction.Wherein preferably reflux time is 3-4 hour.Reaction finishes, and equally also can obtain said DMAP product after conventional mode is carried out post-processing operation.
The Dimethylammonium chloride that adopts the latter finishes the reaction of second step as aminated reagent after, a kind of preferred post processing mode of reference in the time of can also further can supplying to implement, be after reactant is cooled to room temperature, add alkali aqueous solution and regulator solution pH13-14, standing demix is to the ethyl acetate extraction of water layer reusable heat.Wherein, the temperature that is used to extract the hot ethyl acetate of water layer is preferably 40 ℃-60 ℃.Acetic acid ethyl acetate extract after merging is concentrated into 1/5～1/6 of its cumulative volume, and routine stirs following crystallization and obtains said compound product.If necessary, after equally also can handling, carry out said concentrating again to the decolouring that the acetic acid ethyl acetate extract after the said merging be made usual manner earlier.
No matter adopt which kind of above-mentioned method, that all need carry out in said aftertreatment handles with buck, and purpose is for the acid in the neutralization reaction system, and makes DMAP dissociate out.Therefore, the alkali aqueous solution of said use generally can be selected the aqueous solution of alkali metal hydroxide commonly used such as the sodium hydroxide that is easy to get, potassium hydroxide for use.
Because in preparation method of the present invention, after having carried out the first step reaction in a usual manner and obtaining the midbody compound of two pyridines, need not to carry out the operation that the steaming among the present preparation method removes reaction solvent and isolates this midbody compound, but adopted the aminated reagent that DMF or Dimethylammonium chloride etc. are commonly used directly to add former reaction system, and proceed next step reaction.Be that aminated reagent is when carrying out second step reaction especially wherein adopting DMF, more can be further will carry out and finish the process of second step reaction, and merge into an operation with the still-process that steams the pyridine that produces in the ethyl acetate removed in the reaction system and the reaction and water and carry out simultaneously.Because the former reaction system before adding DMF is a homogeneous system, need not after the adding to dissolve with high temperature again, only need pass through to steam the ethyl acetate in the system of removing and react the pyridine of generation and the process of water in heating, can destroy the running balance of former the first step reaction, impel reaction to carry out to the direction of expection.Therefore, above-mentioned preparation method of the present invention has simplified operation greatly, and has obviously shortened reaction time, can also avoid the long time under the condition of high temperature simultaneously, has reduced the generation of side reaction, is the major reason that product yield and quality are improved.
On the basis of foregoing,,, can also make modification, replacement or the change of various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Description of drawings
Fig. 1 is the IR contrast collection of illustrative plates that the DMAP product for preparing with the inventive method and outsourcing reference substance (ACROS) are done.
Embodiment
Mechanical stirrer is being housed, thermometer, add ethyl acetate 900ml successively in the 3000ml there-necked flask of reflux, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol), oil bath was heated to gentle reflux after 2 hours, add DMF 640ml (8.3mol), change back stream and be distillation, steam the pyridine and the water of solvent and generation in 180 ℃ of following temperature, finish, raffinate is chilled to about 100 ℃, stirring 5 premium on currency that will contain 400g sodium hydroxide down pours into wherein, dissolving back suction filtration, filtrate is used dichloromethane extraction, organic phase washes with water 3 times, anhydrous sodium sulfate drying dehydration, small amount of activated decolouring, filter, steaming desolventizes to such an extent that 4-Dimethylamino pyridine (DMAP) crude product 352g gets colourless tabular crystal 282g elaboration through the isopropyl ether recrystallization.Yield 62.2%.Mp112.3-113 ℃ (WRS-1A numeral fusing point instrument); IR and nuclear magnetic spectrum are consistent with reference substance (ACROS. content is more than 99%) collection of illustrative plates.The contrast collection of illustrative plates of IR as shown in Figure 1; The related data of nucleus magnetic resonance is as follows:
1H-NMR：δ2.96(2.95，S，6H)；δ6.47(6.48，d，2H)；δ8.26(8.26，d，2H)。
Mechanical stirrer is being housed, thermometer, add ethyl acetate 900ml successively in the 3000ml there-necked flask of reflux, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol), oil bath was heated to gentle reflux after 2 hours, add DMF640ml (8.3mol), change back stream and be distillation, steam the pyridine and the water of solvent and generation in 180 ℃ of following temperature, finish, raffinate is chilled to room temperature, get a brown-black solid, after blending, 5 premium on currency that will contain 400g sodium hydroxide are poured into wherein, treat solid dissolving back suction filtration, filtrate is used dichloromethane extraction, organic phase washes with water 3 times, anhydrous sodium sulfate drying dehydration, small amount of activated decolouring, filter, steaming desolventizes to such an extent that 4-Dimethylamino pyridine (DMAP) crude product 357g gets colourless tabular crystal 286g elaboration through the isopropyl ether recrystallization.Yield 63%, mp112-113.4 ℃ (WRS-1A numeral fusing point instrument).
Embodiment 3
Mechanical stirrer is being housed, thermometer, add ethyl acetate 900ml successively in the 3000ml there-necked flask of reflux, anhydrous pyridine 600ml (7.2mol), thionyl chloride 540ml (7.2mol), oil bath was heated to gentle reflux after 2 hours, add DMF640ml (8.3mol), change back stream and be distillation, steam the pyridine and the water of solvent and generation in 180 ℃ of following temperature, finish, raffinate is chilled to about 100 ℃, stirring 5 premium on currency that will contain 400g sodium hydroxide down pours into wherein, dissolving back suction filtration, filtrate is used dichloromethane extraction, organic phase washes with water 3 times, anhydrous sodium sulfate drying dehydration, small amount of activated decolouring, filter, steaming desolventizes to such an extent that 4-Dimethylamino pyridine (DMAP) crude product 348g gets colourless tabular crystal 265g elaboration through the isopropyl ether recrystallization.Yield 58.5%, mp111.9-113.1 ℃ (WRS-1A numeral fusing point instrument).
Embodiment 4
Mechanical stirrer is being housed, thermometer, add ethyl acetate 900ml successively in the 3000ml there-necked flask of reflux, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol), oil bath was heated to gentle reflux after 2 hours, add DMF580ml (7.5mol), change back stream and be distillation, steam the pyridine and the water of solvent and generation in 180 ℃ of following temperature, finish, raffinate is chilled to about 100 ℃, stirring 5 premium on currency that will contain 400g sodium hydroxide down pours into wherein, dissolving back suction filtration, filtrate is used dichloromethane extraction, organic phase washes with water 3 times, anhydrous sodium sulfate drying dehydration, small amount of activated decolouring, filter, steaming desolventizes to such an extent that 4-Dimethylamino pyridine (DMAP) crude product 35g gets colourless tabular crystal 268g elaboration through the isopropyl ether recrystallization.Yield 59.1%, mp112.1-113.2 ℃ (WRS-1A numeral fusing point instrument).
Embodiment 5
Mechanical stirrer is being housed, thermometer, add ethyl acetate 900ml successively in the 3000ml there-necked flask of reflux, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol), oil bath was heated to gentle reflux after 2 hours, add Dimethylammonium chloride 300g (3.6mol), sodium bicarbonate 300g (3.6mol), PEG6000 180g (0.3mol) continues backflow 3-4 hour, be chilled to room temperature and transfer pH to 13.5-14 with 20% sodium hydroxide water liquid, standing demix, the water layer ethyl acetate extraction, the combined ethyl acetate layer, with the anhydrous sodium sulfate drying dehydration, the small amount of activated decolouring is filtered, when being concentrated into residue 1/5th volumes, ethyl acetate stirs cooling crystallization, get the light yellow tabular crystal of 308g, yield 67.9%, mp110-113.2 ℃ (WRS-1A numeral fusing point instrument).The related data of nucleus magnetic resonance is as follows:
1H-NMR：δ2.95(2.95，S，6H)；δ6.50(6.48，d，2H)；δ8.25(8.26，d，2H)
Embodiment 6
Mechanical stirrer is being housed, thermometer, add ethyl acetate 900ml successively in the 3000ml there-necked flask of reflux, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol), oil bath was heated to gentle reflux after 2 hours, add Dimethylammonium chloride 330g (3.96mol), sodium bicarbonate 300g (3.6mol), PEG6000 180g (0.3mol) continues to reflux 3.5 hours, be chilled to room temperature and transfer pH to 13.5-14 with 20% sodium hydroxide water liquid, standing demix, the water layer ethyl acetate extraction, the combined ethyl acetate layer, with the anhydrous sodium sulfate drying dehydration, the small amount of activated decolouring is filtered, when being concentrated into residue 1/5th volumes, ethyl acetate stirs cooling crystallization, get the light yellow tabular crystal of 291g, yield 64.2%, mp110-113.4 ℃ (WRS-1A numeral fusing point instrument).
Embodiment 7
In being housed, the 3000ml there-necked flask of mechanical stirrer, thermometer, reflux adds ethyl acetate 900ml, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol) successively, oil bath was heated to gentle reflux after 2 hours, add Dimethylammonium chloride 330g (3.96mol), sodium bicarbonate 300g (3.6mol).Continue to reflux about 4 hours, be chilled to room temperature and transfer pH to 13.5-14, standing demix, water layer ethyl acetate extraction with 20% sodium hydroxide water liquid, the combined ethyl acetate layer, with the anhydrous sodium sulfate drying dehydration, the small amount of activated decolouring is filtered, when being concentrated into residue 1/5th volumes, ethyl acetate stirs cooling crystallization, get the light yellow tabular crystal of 256g, yield 56.4%, mp110-113.3 ℃ (WRS-1A numeral fusing point instrument).
Embodiment 8
In being housed, the 3000ml there-necked flask of mechanical stirrer, thermometer, reflux adds ethyl acetate 900ml, anhydrous pyridine 600ml (7.2mol), thionyl chloride 450ml (6mol) successively, oil bath was heated to gentle reflux after 2 hours, add Dimethylammonium chloride 330g (3.96mol), sodium bicarbonate 300g (3.6mol).Continue to reflux 3.5 hours, be chilled to room temperature and transfer pH to 13.5-14, standing demix, water layer ethyl acetate extraction with 20% sodium hydroxide water liquid, the combined ethyl acetate layer, with the anhydrous sodium sulfate drying dehydration, the small amount of activated decolouring is filtered, when being concentrated into residue sixth volume, ethyl acetate stirs cooling crystallization, get the light yellow tabular crystal of 323g, yield 71.2%, mp109-113.6 ℃ (WRS-1A numeral fusing point instrument).
Claims (10)
1. the method for preparing the 4-Dimethylamino pyridine, it is characterized in that in the acetic acid ethyl reaction medium with pyridine be after raw material and thionyl chloride carry out conventional back flow reaction, after aminated reagent directly added reactive system solution, steam ethyl acetate of removing in the reaction system and the pyridine that reacts generation and the mode or the reflux type of water with heating and proceed follow-up reaction, then reactant is carried out conventional aftertreatment, promptly obtain said compound product.
2. preparation method as claimed in claim 1, it is characterized in that said aminated reagent is the N of conventional amount used, dinethylformamide, and in said reactive system solution, adding N, behind the dinethylformamide, promptly begin to heat and steam pyridine and the water that the ethyl acetate removed in the reaction system and reaction produce, to the residue after the distillation routinely post processing mode with the alkali aqueous solution dissolving and regulate pH12-14, again with dichloromethane extraction with after concentrating, obtain said compound product after the filtration.
3. preparation method as claimed in claim 2, it is characterized in that to resulting dichloromethane extract can decolour earlier handle after, concentrating.
4. preparation method as claimed in claim 2 is characterized in that can carrying out with isopropyl ether resulting compound product the purification process of recrystallization again.
5. preparation method as claimed in claim 1, it is characterized in that said aminated reagent is the Dimethylammonium chloride of conventional amount used, and after in said reactive system solution, adding Dimethylammonium chloride, continue back flow reaction, reaction finishes, carry out post-processing operation in the usual way, obtain said compound product.
6. preparation method as claimed in claim 5 is characterized in that the reactant continuation backflow behind the said adding Dimethylammonium chloride was reacted in 3-4 hour.
7. preparation method as claimed in claim 5, it is characterized in that in said post-processing operation, after earlier reaction soln being cooled to room temperature, add alkali aqueous solution and regulator solution pH13-14 again, behind the standing demix, the water layer ethyl acetate extraction of heat, the combined ethyl acetate extracting solution also is concentrated into 1/5～1/6 of its cumulative volume, and stirring and crystallizing obtains said compound product.
8. preparation method as claimed in claim 7 is characterized in that the said temperature that is used to extract the hot ethyl acetate of water layer is 40 ℃-60 ℃.
9. preparation method as claimed in claim 7, it is characterized in that acetic acid ethyl acetate extract after said being combined decolour earlier handle after, carry out said concentrating again.
10. as the described preparation method of one of claim 1 to 9, it is characterized in that the alkali aqueous solution of using in the said aftertreatment is the aqueous solution of alkali metal hydroxide.
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| CN 03117604 CN1202083C (en) | 2003-04-03 | 2003-04-03 | Method of preparing 4-dimethylamino pyridine |
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| CN 03117604 CN1202083C (en) | 2003-04-03 | 2003-04-03 | Method of preparing 4-dimethylamino pyridine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2733717C1 (en) * | 2020-03-25 | 2020-10-06 | федеральное государственное автономное образовательное учреждение высшего образования «Национальный исследовательский Томский политехнический университет» | Method for producing 4-n,n-dimethylaminopyridine |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101845015B (en) * | 2010-06-04 | 2012-09-05 | 安徽省郎溪县联科实业有限公司 | Refining separation and drying method of 4-dimethylamino naphthyridine |
| CN104496892A (en) * | 2014-11-13 | 2015-04-08 | 安徽国星生物化学有限公司 | Novel technology for synthesizing 4-dimethylamino-pyridine |
-
2003
- 2003-04-03 CN CN 03117604 patent/CN1202083C/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2733717C1 (en) * | 2020-03-25 | 2020-10-06 | федеральное государственное автономное образовательное учреждение высшего образования «Национальный исследовательский Томский политехнический университет» | Method for producing 4-n,n-dimethylaminopyridine |
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| CN1442408A (en) | 2003-09-17 |
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