CN101514184A - Synthetic method for 5-bromine-2-methylpyridine - Google Patents
Synthetic method for 5-bromine-2-methylpyridine Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- UENBBJXGCWILBM-UHFFFAOYSA-N 6-methylpyridin-3-amine Chemical compound CC1=CC=C(N)C=N1 UENBBJXGCWILBM-UHFFFAOYSA-N 0.000 claims abstract description 16
- FEWVINDUUUHRKM-UHFFFAOYSA-N ethyl 6-methylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=C(C)N=C1 FEWVINDUUUHRKM-UHFFFAOYSA-N 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- IJXDURUAYOKSIS-UHFFFAOYSA-N 6-methylpyridine-3-carboxamide Chemical compound CC1=CC=C(C(N)=O)C=N1 IJXDURUAYOKSIS-UHFFFAOYSA-N 0.000 claims abstract description 12
- RZOKQIPOABEQAM-UHFFFAOYSA-N 6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=N1 RZOKQIPOABEQAM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- OFKWIQJLYCKDNY-UHFFFAOYSA-N 5-bromo-2-methylpyridine Chemical compound CC1=CC=C(Br)C=N1 OFKWIQJLYCKDNY-UHFFFAOYSA-N 0.000 claims description 23
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 229910019093 NaOCl Inorganic materials 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 229910052811 halogen oxide Inorganic materials 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 3
- 238000005915 ammonolysis reaction Methods 0.000 abstract description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000013019 agitation Methods 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UQOCEEQQGFOLRM-UHFFFAOYSA-N 2-methylideneimidazole Chemical compound C=C1N=CC=N1 UQOCEEQQGFOLRM-UHFFFAOYSA-N 0.000 description 1
- AIPWPTPHMIYYOX-UHFFFAOYSA-N 3-bromo-2-methylpyridine Chemical compound CC1=NC=CC=C1Br AIPWPTPHMIYYOX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- ZNOLRTPMNMPLHY-UHFFFAOYSA-N n-(6-chloro-7-methoxy-9h-pyrido[3,4-b]indol-8-yl)-2-methylpyridine-3-carboxamide Chemical compound COC1=C(Cl)C=C2C3=CC=NC=C3NC2=C1NC(=O)C1=CC=CN=C1C ZNOLRTPMNMPLHY-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- -1 pyridine ring compound Chemical class 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthetic method for 5-bromine-2-methylpyridine: using 6-methyl-3-picolinic acid as the raw material to react with ethyl alcohol to generate 6-methyl-3-picolinic acid ethyl ester; carrying out ammonolysis reaction by aqueous ammonia on the 6-methyl-3-picolinic acid ethyl ester to generate 6-methyl-3-pyridine carboxamide; carrying out Hofmann degradation reaction to obtain 6-methyl-3-aminopyridine; and finally reacting the 6-methyl-3-aminopyridine with a bromizing reagent to generate 5-bromine-2-methylpyridine. In the method, the process reaction condition is mild, the yield is high, the raw material is available, the cost is lower, and no 3-subsidary products are generated in the whole process, the load of post separation is eliminated and the prospect of industrialization is good.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of synthetic method of 5-bromo-2-picoline.
Background technology
Pyridine and derivative thereof are distributed in nature widely.All contain the pyridine ring compound in the structure of many plant constituents such as alkaloid etc.Their purposes is very extensive, can be used for the fine chemical product of production high added value, occupies critical role in pharmaceutical industry, pesticide industry and chemical industry.They are the bases that produce many important compound, are indispensable important source material during medicine, agricultural chemicals, fuel, tensio-active agent, rubber ingredients, fodder additives, foodstuff additive, tackiness agent, synthetic materials etc. are produced.5-bromo-2-picoline is a kind of important pharmacy intermediate, has broad prospects in the production of cardiovascular medicament and respiratory drugs, and market potential is huge.Its synthetic method that mainly adopts is direct bromo method at present, owing to relate to substituent orientation effect, the isomer that has 3 when reaction generates, its ratio is 45: 55, and its boiling point only differs 1.5 ℃, is difficult to separate purification by traditional methods such as rectifying, the report of general document purifies how to separate the pure product that obtain with column chromatography to it, this method is promptly lost time, and increases cost, and is not suitable for large-scale industrial production
[1～4]
Reference:
[1]Li，Yuexian；Plesescu，Mihaela；Prakash，Shimoga?R.Synthesis?of?C-14?and?C-13，H-2-labeled?IKK?inhibitor：[14C]?and?[13C4，D3]N-(6-chloro-7-methoxy-9H-pyrido[3，4-b]indol-8-yl)-2-methyl-3-pyridinecarboxamide..Journal?of?Labelled?Compounds?andRadioph-armaceuticals(2006)，49(9)，789-799.
[2]Jagusch，Carsten；Negri，Matthias；Hille，Ulrike?E.；Hu，Qingzhong；Bartels，Marc；Jahn-Hoffmann，Kerstin；Pinto-Bazurco?Mendieta，Mariano?A.E.；Rodenwaldt，Barbara；Mueller-Vieira，Ursula；Schmidt，Dirk；Lauterbach，Thomas；Recanatini，Maurizio；Cavalli，Andrea；Hartmann，Rolf?W.Synthesis，biological?evaluation?and?molecular?modellingstudies?of?methyleneimidazole?substituted?biaryls?as?inhibitors?of?human17-hydroxylase-17，20-lyase(CYP?17).Heterocyclic?modifications?of?the?core?structure.，Germany.Bioorganic?&?Medicinal?Chemistry(2008)，16(4)，1992-2010.
[3]Guthikonda，Ravindra?Nath；Cama，L.D.；Quesada，M.；Woods，M.F.；Salzmann，T.N.；Christensen，B.G.Structure-activity?relationships?in?the?2-arylcarbapenem?series.Synthesisof?1-methyl-2-arylcarbapenems.Journal?of?Medicinal?Chemistry(1987)，30(5)，871-80.
[4] Du Zhenxia, Liu behaviour, 5-bromo-2-methyl-pyridine separates and preparation Beijing University of Chemical Technology's journal 20023 (3): 79-81 with 3-bromo-2-methyl-pyridine
Summary of the invention
Technical problem to be solved by this invention provides a kind of synthetic method of new 5-bromo-2-picoline, generates to avoid its isomer of 3, reduces segregational load.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of synthetic method of 5-bromo-2-methyl-pyridine comprises the steps:
(1) utilizes 6-methyl-3-pyridine carboxylic acid to be raw material, in the presence of acid, react generation 6-methyl-3-pyridine carboxylic acid ethyl ester down at 30～80 ℃ with ethanol;
(2) 6-methyl-3-pyridine carboxylic acid ethyl ester is added in the ammoniacal liquor, reacted 4～10 hours down, obtain 6-methyl-3-pyridine carboxamide at-5～60 ℃;
(3) with 6-methyl-3-pyridine carboxamide in containing the sodium hydroxide solution of halogen, temperature is 20～100 ℃ of down reactions 1～6 hour, obtains 6-methyl-3-aminopyridine;
(4) 6-methyl-3-aminopyridine is added in the HBr solution, in the presence of the CuBr of catalytic amount, drip NaNO
2Solution, temperature are controlled at-10～20 ℃, react 1～6 hour, get 5-bromo-2-picoline.
Acid described in the step (1) is hydrochloric acid, sulfuric acid or SOCl
2
In the step (1), in the ethanol of every 100mL, add the 6-methyl-3-pyridine carboxylic acid of 5～10g and the acid of 3～10mL.
In the step (2), the mass percent concentration of described ammonia concn is 25～28%.
In the step (2), in every 100mL ammoniacal liquor, the add-on of 6-methyl-3-pyridine carboxylic acid ethyl ester is 10～25g.
In the step (3), described halogen is Cl
2, Br
2, NaOCl or NaOBr.
In the step (3), the mol ratio of 6-methyl-3-pyridine carboxamide, halogen and sodium hydroxide is 1: 1～1.3: 2～5, and the mass percent concentration of NaOH solution is 3～10%.
In the step (4), the mass percent concentration of described halogen acid solution is 40～50%.
In the step (4), the mol ratio of 6-methyl-3-aminopyridine and CuBr is 1: 1.0～1.5, and in every 100mL HBr solution, 6-methyl-3-aminopyridine add-on is 10～20g, saturated NaNO
2The add-on of solution is 15～30mL.
The reaction equation of the inventive method is:
Wherein, X=Cl, Br
Beneficial effect: the synthetic method of 5-bromo-2-picoline of the present invention, at first, a large amount of 3 by products generations in the traditional preparation process method have been avoided, the waste and the isolating load of later stage of raw material have been reduced, secondly, the water-soluble bad method of directly from water, separating out of utilization 6-methyl-3-pyridine carboxamide in the reaction of preparation acid amides, thereby adopt the acyl chlorides synthesis method when avoiding the traditional preparation process acid amides, the problem that environmental pollution is serious, and avoid owing to the violent bad control very of acyl chlorides ammonolysis reaction stays the potential safety hazard that causes splash easily.Route reaction mild condition of the present invention, yield height, and raw material is easy to get, cost is lower, and whole process do not have 3 by products and generate, and has reduced isolating load of later stage, has industrialization prospect.
Description of drawings
Fig. 1 is according to the 5-bromo-2-picoline of the method for embodiment 1 preparation
1H NMR collection of illustrative plates;
Fig. 2 is the MS collection of illustrative plates according to the 5-bromo-2-picoline of the method preparation of embodiment 1.
Embodiment:
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to illustrate the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:
In the 500mL there-necked flask of agitator, thermometer is housed, add the 320mL dehydrated alcohol, add then and add 25.6g (0.19mol) 6-methyl-3-pyridine carboxylic acid, 20mLSOCl respectively
2, load onto reflux condensing tube, oil bath heats up and is controlled at 50～60 ℃, follows the tracks of reaction up to reacting completely.Solvent is spin-dried for, and solid is poured the saturated NaCO of 200mL into
3In the solution, use CH
2Cl
2Extract (100mL*2), merge organic layer, use the 20g anhydrous sodium sulfate drying, filter, be spin-dried for the brown liquid 6-methyl-3-pyridine carboxylic acid ethyl ester 28g of solvent, productive rate is 91%, 116～117 ℃ of b.p.
In the 250mL single port flask of magnetic agitation is housed, add 176mL ammoniacal liquor (concentration 25%), with 22g (0.13mol) 6-methyl-3-pyridine carboxylic acid ethyl ester, drop in the single port bottle and stirred 6～7 hours down for 10～15 ℃, be put into and spend the night in the refrigerator, allow white crystal fully separate out in room temperature, filter, wash (50mL*2) with water, get white crystal 6-methyl-3-pyridine carboxamide 16.7g, productive rate is 92%.m.p：199～200℃。
In being housed, the 500mL there-necked flask of agitator, thermometer adds 300mL NaOH (concentration 5%) solution, slowly add 17.3g (0.1mol) bromine again, methyl-the 3-pyridine carboxamide slowly adds in the there-necked flask with 13g (0.1mol) 6-then, stirred 20 minutes, solution temperature is controlled at 0～5 ℃.Oil bath is warmed up to 70～80 ℃ of maintenances 4 hours, reaction solution CH then
2Cl
2(100mL*2) extract, wash (100mL*2) again with water, use the 30g anhydrous sodium sulfate drying, filter, be spin-dried for, at normal hexane-CH
2Cl
2Recrystallization in (1: 1) filters, and gets brown powder 6-methyl-3-aminopyridine 9.4g, and productive rate is 91%.m.p：95～96℃。
The HBr that in the 100mL there-necked flask of agitator, thermometer is housed, adds 20mL 48%, 3.1g (0.022mol) CuBr is dissolved in the HBr solution, ice bath keeps temperature slowly to add 3g (0.02mol) 6-methyl-3-aminopyridine for 0～5 ℃, keep temperature 10 minutes, and slowly dripped saturated NaNO
2Solution 4.8mL adds the back and stirs 1h, and to pH=7～8, water steam steams white products 5-bromo-2-picoline 3g with 10% sodium hydroxide solution neutralization reaction liquid, and productive rate is 63%.m.p：33～34℃。
1H?NMR(300MHz，CDCl
3)δ：2.44(3H，s)，δ：7.25(1H，s，J＝8Hz)，δ：7.91(1H，q，J＝10Hz)，δ：8.55(1H，d，J＝2.4Hz).MS(m/z)：172/174[M+H]
+。
Embodiment 2:
In the 500mL there-necked flask of agitator, thermometer is housed, add the 300mL dehydrated alcohol, add then and add 25.6g (0.19mol) 6-methyl-3-pyridine carboxylic acid respectively, the 20mL concentrated hydrochloric acid, load onto reflux condensing tube, oil bath heats up and is controlled at 70～80 ℃, follows the tracks of reaction up to reacting completely.Solvent is spin-dried for, and solid is poured the saturated NaCO of 200mL into
3In the solution, use CH
2Cl
2Extract (100mL*2), merge organic layer, use the 20g anhydrous sodium sulfate drying, filter, be spin-dried for the brown liquid 6-methyl-3-pyridine carboxylic acid ethyl ester 25g of solvent, productive rate is 81%, 116～117 ℃ of b.p.
In the 250mL single port flask of magnetic agitation is housed, add 100mL ammoniacal liquor (concentration 28%), with 22g (0.13mol) 6-methyl-3-pyridine carboxylic acid ethyl ester, drop in the single port bottle and stirred 4～5 hours down for 0～10 ℃, be put into and spend the night in the refrigerator, allow white crystal fully separate out in room temperature, filter, wash (50mL*2) with water, get white crystal 6-methyl-3-pyridine carboxamide 13g, productive rate is 71.6%.m.p：199～200℃。
In being housed, the 500mL there-necked flask of agitator, thermometer adds 300mL NaOH (concentration 5%) solution, slowly add 11.9g (0.1mol) NaOBr again, methyl-the 3-pyridine carboxamide slowly adds in the there-necked flask with 13g (0.1mol) 6-then, stirred 20 minutes, solution temperature is controlled at-5～5 ℃.Oil bath is warmed up to 60～70 ℃ of maintenances 4 hours, reaction solution CH then
2Cl
2(100mL*2) extract, wash (100mL*2) again with water, use the 30g anhydrous sodium sulfate drying, filter, be spin-dried for, at normal hexane-CH
2Cl
2Recrystallization in (1: 1) filters, and gets brown powder 6-methyl-3-aminopyridine 9.8g, and productive rate is 95%.m.p：95～96℃。
In being housed, the 100mL there-necked flask of agitator, thermometer adds HBr as 25mL48%, 4.0g (0.028mol) CuBr is dissolved in the HBr solution, ice bath keeps temperature slowly to add 3g (0.02mol) 6-methyl-3-aminopyridine for 0～10 ℃, keep temperature 10 minutes, and slowly dripped saturated NaNO
2Solution 5.2mL adds the back and stirs 1h, and to pH=7～8, water steam steams white products 5-bromo-2-picoline 3g with 10% sodium hydroxide solution neutralization reaction liquid, and productive rate is 67.2%.m.p：33～34℃。
1H?NMR(300MHz，CDCl
3)δ：2.44(3H，s)，δ：7.25(1H，s，J＝8Hz)，δ：7.91(1H，q，J＝10Hz)，δ：8.55(1H，d，J＝2.4Hz).MS(m/z)：172/174[M+H]
+。
Embodiment 3:
In the 500mL there-necked flask of agitator, thermometer is housed, add the 350mL dehydrated alcohol, add then and add 25.6g (0.19mol) 6-methyl-3-pyridine carboxylic acid, 15mLH respectively
2SO
4, load onto reflux condensing tube, oil bath heats up and is controlled at 70～80 ℃, follows the tracks of reaction up to reacting completely.Solvent is spin-dried for, and solid is poured the saturated NaCO of 200mL into
3In the solution, use CH
2Cl
2Extract (100mL*2), merge organic layer, use the 20g anhydrous sodium sulfate drying, filter, be spin-dried for the brown liquid 6-methyl-3-pyridine carboxylic acid ethyl ester 26g of solvent, productive rate is 84.5%, 116～117 ℃ of b.p.
In the 250mL single port flask of magnetic agitation is housed, add 200mL ammoniacal liquor (concentration 25%), with 22g (0.13mol) 6-methyl-3-pyridine carboxylic acid ethyl ester, drop in the single port bottle and stirred 7～8 hours down for 15～25 ℃, be put into and spend the night in the refrigerator, allow white crystal fully separate out in room temperature, filter, wash (50mL*2) with water, get white crystal 6-methyl-3-pyridine carboxamide 17g, productive rate is 94%.m.p：199～200℃。
In being housed, the 500mL there-necked flask of agitator, thermometer adds 300mL NaOH (5%) solution, slowly add 7.45g g (0.1mol) NaOCl again, methyl-the 3-pyridine carboxamide slowly adds in the there-necked flask with 13g (0.1mol) 6-then, stirred 20 minutes, solution temperature is controlled at 0～5 ℃.Oil bath is warmed up to 60～70 ℃ of maintenances 5 hours, reaction solution CH then
2Cl
2(100mL*2) extract, wash (100mL*2) again with water, use the 30g anhydrous sodium sulfate drying, filter, be spin-dried for, at normal hexane-CH
2Cl
2Recrystallization in (1: 1) filters, and gets brown powder 6-methyl-3-aminopyridine 9.2g, and productive rate is 89%.m.p：95～96℃。
In being housed, the 100mL there-necked flask of agitator, thermometer adds HBr as 22mL 48%, 3.7g (0.026mol) CuBr is dissolved in the HBr solution, ice bath keeps temperature-3～5 ℃ slow 3g (0.02mol) of adding 6-methyl-3-aminopyridine, keep temperature 10 minutes, and slowly dripped saturated NaNO
2Solution 5mL adds the back and stirs 1h, and to pH=7～8, water steam steams white products 5-bromo-2-picoline 2.4g with 10% sodium hydroxide solution neutralization reaction liquid, and productive rate is 50%.m.p：33～34℃。
1H?NMR(300MHz，CDCl
3)δ：2.44(3H，s)，δ：7.25(1H，s，J＝8Hz)，δ：7.91(1H，q，J＝10Hz)，δ：8.55(1H，d，J＝2.4Hz).MS(m/z)：172/174[M+H]
+。
Embodiment 4:
With the preparation method of embodiment 3, different is: in the 500mL there-necked flask of agitator, thermometer is housed, add the 300mL dehydrated alcohol, add then and add 15g 6-methyl-3-pyridine carboxylic acid, 9mLH respectively
2SO
4, load onto reflux condensing tube, oil bath heats up and is controlled at 40～50 ℃, follows the tracks of reaction up to reacting completely.
Embodiment 5:
With the preparation method of embodiment 3, different is: in the 250mL single port flask of magnetic agitation is housed, add 200mL ammoniacal liquor (concentration 25%), with 50g 6-methyl-3-pyridine carboxylic acid ethyl ester, drop in the single port bottle and stirred 4～5 hours down for 40～50 ℃ in room temperature.
Embodiment 6:
Preparation method with embodiment 3, different is: add 300mLNaOH (5%) solution in the 500mL there-necked flask of agitator, thermometer is housed, slowly add 0.13mol NaOCl again, slowly add 0.1mol 6-methyl-3-pyridine carboxamide in the there-necked flask then, stirred 20 minutes, solution temperature is controlled at 0～5 ℃.Oil bath is warmed up to 30～40 ℃ of maintenances 5 hours then.
Claims (9)
1, a kind of synthetic method of 5-bromo-2-methyl-pyridine is characterized in that this method comprises the steps:
(1) utilizes 6-methyl-3-pyridine carboxylic acid to be raw material, in the presence of acid, react generation 6-methyl-3-pyridine carboxylic acid ethyl ester down at 30～80 ℃ with ethanol;
(2) 6-methyl-3-pyridine carboxylic acid ethyl ester is added in the ammoniacal liquor, reacted 4～10 hours down, obtain 6-methyl-3-pyridine carboxamide at-5～60 ℃;
(3) with 6-methyl-3-pyridine carboxamide in containing the sodium hydroxide solution of halogen, temperature is 20～100 ℃ of down reactions 1～6 hour, obtains 6-methyl-3-aminopyridine;
(4) 6-methyl-3-aminopyridine is added in the HBr solution, in the presence of the CuBr of catalytic amount, drip NaNO
2Solution, temperature are controlled at-10～20 ℃, react 1～6 hour, get 5-bromo-2-picoline.
2, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1, it is characterized in that: the acid described in the step (1) is hydrochloric acid, sulfuric acid or SOCl
2
3, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 and 2 is characterized in that: in the step (1), in the ethanol of every 100mL, add the 6-methyl-3-pyridine carboxylic acid of 5～10g and the acid of 3～10mL.
4, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 is characterized in that: in the step (2), the mass percent concentration of described ammoniacal liquor is 25～28%.
5, according to the synthetic method of claim 1 or 4 described 5-bromo-2-methyl-pyridines, it is characterized in that: in the step (2), in every 100mL ammoniacal liquor, the add-on of 6-methyl-3-pyridine carboxylic acid ethyl ester is 10～25g.
6, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 is characterized in that: in the step (3), described halogen is Cl
2, Br
2, NaOCl or NaOBr.
7, according to the synthetic method of claim 1 or 6 described 5-bromo-2-methyl-pyridines, it is characterized in that: in the step (3), the mol ratio of 6-methyl-3-pyridine carboxamide, halogen and sodium hydroxide is 1: 1～1.3: 2～5, and the mass percent concentration of NaOH solution is 3～10%.
8, the synthetic method of 5-bromo-2-methyl-pyridine according to claim 1 is characterized in that: in the step (4), the mass percent concentration of described HBr solution is 40～50%.
9, according to the synthetic method of claim 1 or 8 described 5-bromo-2-methyl-pyridines, it is characterized in that: in the step (4), the mol ratio of 6-methyl-3-aminopyridine and CuBr is 1: 1.0～1.5, in every 100mL HBr solution, 6-methyl-3-aminopyridine add-on is 10～20g, saturated NaNO
2The add-on of solution is 15～30mL.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102977009A (en) * | 2012-11-09 | 2013-03-20 | 杭州澳赛诺化工有限公司 | Synthesizing method of 2-trifluoromethyl-3-fluoropyridin |
| CN105061301A (en) * | 2015-09-07 | 2015-11-18 | 陈吉美 | Synthesis method of 2,5-dibromopyridine |
| CN106146386A (en) * | 2015-04-21 | 2016-11-23 | 江苏威凯尔医药科技有限公司 | A kind of new technology preparing prucalopride intermediate |
| CN107011255A (en) * | 2017-06-08 | 2017-08-04 | 安徽星宇化工有限公司 | A kind of method and its purification process that aminopyridine is prepared by picoline |
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2009
- 2009-04-07 CN CNA2009100292282A patent/CN101514184A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102977009A (en) * | 2012-11-09 | 2013-03-20 | 杭州澳赛诺化工有限公司 | Synthesizing method of 2-trifluoromethyl-3-fluoropyridin |
| CN102977009B (en) * | 2012-11-09 | 2015-07-29 | 杭州澳赛诺生物科技有限公司 | A kind of synthetic method of 2-trifluoromethyl-3-fluorine pyridine |
| CN106146386A (en) * | 2015-04-21 | 2016-11-23 | 江苏威凯尔医药科技有限公司 | A kind of new technology preparing prucalopride intermediate |
| CN105061301A (en) * | 2015-09-07 | 2015-11-18 | 陈吉美 | Synthesis method of 2,5-dibromopyridine |
| CN107011255A (en) * | 2017-06-08 | 2017-08-04 | 安徽星宇化工有限公司 | A kind of method and its purification process that aminopyridine is prepared by picoline |
| CN107011255B (en) * | 2017-06-08 | 2019-06-21 | 安徽星宇化工有限公司 | A kind of method and its purification process preparing aminopyridine by picoline |
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