CN103819398A - Method for synthesizing 4-amino-2-chlorine-3-nitro pyridine - Google Patents
Method for synthesizing 4-amino-2-chlorine-3-nitro pyridine Download PDFInfo
- Publication number
- CN103819398A CN103819398A CN201410034222.5A CN201410034222A CN103819398A CN 103819398 A CN103819398 A CN 103819398A CN 201410034222 A CN201410034222 A CN 201410034222A CN 103819398 A CN103819398 A CN 103819398A
- Authority
- CN
- China
- Prior art keywords
- amino
- chloro
- nitropyridine
- yield
- yellow powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000001953 recrystallisation Methods 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 11
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 claims description 60
- 239000007787 solid Substances 0.000 claims description 45
- YKWBEPUOVBMENG-UHFFFAOYSA-N 2-chloro-5-nitropyridin-4-amine Chemical compound NC1=CC(Cl)=NC=C1[N+]([O-])=O YKWBEPUOVBMENG-UHFFFAOYSA-N 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000000843 powder Substances 0.000 claims description 36
- 238000010189 synthetic method Methods 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- ZPFUWAVLEWIOEJ-UHFFFAOYSA-N 2-nitropyridin-4-amine Chemical compound NC1=CC=NC([N+]([O-])=O)=C1 ZPFUWAVLEWIOEJ-UHFFFAOYSA-N 0.000 claims description 16
- 238000006396 nitration reaction Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 7
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical compound NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 244000124209 Crocus sativus Species 0.000 claims description 5
- 235000019441 ethanol Nutrition 0.000 claims description 5
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 238000004807 desolvation Methods 0.000 claims description 4
- 229960004979 fampridine Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 5
- 239000002532 enzyme inhibitor Substances 0.000 abstract description 4
- 229940125532 enzyme inhibitor Drugs 0.000 abstract description 4
- 229940124036 Hydrolase inhibitor Drugs 0.000 abstract description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 abstract description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 abstract description 3
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000004093 hydrolase inhibitor Substances 0.000 abstract description 3
- 108010056274 polo-like kinase 1 Proteins 0.000 abstract description 3
- 229940121649 protein inhibitor Drugs 0.000 abstract description 3
- 239000012268 protein inhibitor Substances 0.000 abstract description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 abstract 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 abstract 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 abstract 1
- 229960005305 adenosine Drugs 0.000 abstract 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 241000700605 Viruses Species 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- PDQAWJXOYURKPI-UHFFFAOYSA-N 2-chloro-3-nitropyridin-4-amine Chemical compound NC1=CC=NC(Cl)=C1[N+]([O-])=O PDQAWJXOYURKPI-UHFFFAOYSA-N 0.000 description 1
- 206010010582 Congenital osteodystrophy Diseases 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 208000007652 Dysostoses Diseases 0.000 description 1
- 201000001324 Dysostosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- ZJUKTBDSGOFHSH-WFMPWKQPSA-N S-Adenosylhomocysteine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSCC[C@H](N)C(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZJUKTBDSGOFHSH-WFMPWKQPSA-N 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- -1 cyclopentenol nucleoside compound Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
The invention discloses a method for synthesizing 4-amino-2-chlorine-3-nitro pyridine. The method comprises the following steps: adopting 65% nitric acid and concentrated sulfuric acid as mixed acid for nitratlon reaction, wherein the yield of the prepared isomer 4-amino-chlorine-3-nitro pyridine and 4-amino-2-chlorine-5-nitro pyridine is 95 to 98%, the purity is 95 to 99.5%, and subsequently purifying through recrystallization, effectively separating the prepared 4-amino-2-chlorine-3-nitro pyridine and 4-amino-2-chlorine-5-nitro pyridine, wherein the yield of the prepared 4-amino-2-chlorine-3-nitro pyridine is 75 to 85%, the purity of the prepared 4-amino-2-chlorine-3-nitro pyridine is 95 to 99%, the yield of the prepared 4-amino-2-chlorine-5-nitro pyridine is 15 to 25%, and the purity of the prepared 4-amino-2-chlorine-5-nitro pyridine is 95 to 99%. The method is applicable to preparation of 4-amino-2-chlorine-3-nitro pyridine and 4-amino-2-chlorine-5-nitro pyridine, and medicines such as an E1 active enzyme inhibitor, an adenosine homocysteine hydrolase inhibitor, a PLK1 recombinant protein inhibitor and benzimidazole can be further prepared.
Description
Technical field
The invention belongs to pharmacy field, relate to the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-.
Background technology
The intermediate that the chloro-3-nitropyridine of 4-amino-2-is a kind of antiviral hydrolase inhibitor, can anti-vaccinia virus, viral, the H of variola virus, human cytomegalic inclusion disease virus, banded virus, HIV
1n
1and H
3n
2virus etc.; Or the intermediate of a kind of nucleoside derivates (E1 organized enzyme inhibitor), be used for treating cell proliferation obstacle, comprise cancer, inflammation and neurologic disorder.
4-amino-2-chloro-5-nitropyridine is the intermediate of benzimidizole derivatives, is used for the treatment of the diseases such as dysostosis; Also be a kind of intermediate of PLK1 recombinant protein inhibitor, be used for the treatment of cell proliferation disorders, particularly cancer.
In prior art, also there is part report for the preparation method of the chloro-3-nitropyridine of 4-amino-2-, but the yield of made product is lower, if world patent WO 2007047793 is methods of the synthetic of a kind of cyclopentenol nucleoside compound intermediate and treatment virus infection, adopting the chloro-4-aminopyridine of 2-is raw material, 70% nitrosonitric acid and the vitriol oil are as nitration mixture, carry out nitration reaction, adopt silica gel column chromatography to carry out product separation, obtain 70% the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine of 25%, and 5% impurity.
World patent WO 200684281 is preparations of a kind of E1 organized enzyme inhibitor nucleoside derivates, adopting the chloro-4-aminopyridine of 2-is raw material, 90% nitrosonitric acid and the vitriol oil are as nitration mixture, carry out nitration reaction, the product obtaining is the mixture of the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, adopt rapid column chromatography method to separate, the moving phase adopting is methylene dichloride: ethyl acetate is 1:4, obtain 44% the chloro-3-nitropyridine of 4-amino-2-, the yield that still obtains product is lower.And the highly volatile in air of the methylene dichloride in moving phase, may cause the proportioning of moving phase to change, separating effect is bad, column chromatography chromatogram method can not be carried out the separation of large-tonnage product, the activity of nitrosonitric acid is higher simultaneously, but its price is more expensive, this carries out suitability for industrialized production with regard to greatly having limited it.
The chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine are all very important medicine intermediates, market demand is huge, there are good market outlook, so how to synthesize the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, and the separation that realizes the two is a far reaching problem.
Summary of the invention
The technical problem to be solved in the present invention, be to provide the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, nitric acid and the vitriol oil of employing 65% carry out nitration reaction as nitration mixture, the isomer making is the mixture of the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, yield is 95～98%, and purity is 95～99.5%; After through recrystallization, it is carried out to purifying, and chloro-4-amino-2-3-nitropyridine has been carried out to effective separation with 4-amino-2-chloro-5-nitropyridine, the chloro-3-nitropyridine of 4-amino-2-making, yield is 75～85%, purity is 95～99%; The yield of 4-amino-2-chloro-5-nitropyridine is 15～25%, and purity is 95～99%.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
The synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, adopting the chloro-4-aminopyridine of 2-is raw material, 65% nitric acid and the vitriol oil carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-chloro-5-nitropyridine simultaneously, after recrystallization purifying, obtain corresponding sterling, process is as follows:
。
As a kind of restriction of the present invention, the synthetic method of the chloro-3-nitropyridine of this 4-amino-2-is carried out according to following steps order:
1) at 0 ℃, chloro-the 2-of 200 weight parts 4-aminopyridine is dissolved in the vitriol oil of 1200～2000 parts by volume, drips 65% nitric acid of 600～1400 parts by volume, after dropwising, at 15～20 ℃, react 2h, then pour in frozen water, at 0 ℃, stir, pass into NH
3regulating pH is 3, separates out white powder solid I, filters; Then,
2) white powder solid I is dissolved in the vitriol oil of 2000～2600 parts by volume, is heated to 80～100 ℃ of reaction 3h, under room temperature, stir and spend the night, then pour in frozen water, pass into NH at 0 ℃
3regulating pH value is finally 3, obtains yellow powder shape solid II, is the mixture of the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine;
Wherein, after reaction, under room temperature, stirring the object of spending the night has two: the firstth, and abundant reaction; The secondth, abundant cooling; Because the temperature of the vitriol oil is very high in reaction system, may internal temperature cooling in short period of time insufficient, the vitriol oil itself is added in water will heat release, if cooling be not exclusively added in frozen water can very exothermic, easily cause danger, so will stir the fully cooling of spending the night.
3) yellow powder shape solid II is carried out to recrystallization, adopts ethyl acetate and sherwood oil to make recrystallization reagent, be heated to reflux, after be down to 30～40 ℃, separate out yellow powder shape solid III, filter:
Gained solid is the chloro-3-nitropyridine of sterling 4-amino-2-, and yield is 75～85%, and purity is 95～99%;
Filtrate decompression desolvation, residuum 95% ethyl alcohol recrystallization, obtaining pale yellow powder shape solid IV is 4-amino-2-chloro-5-nitropyridine, and yield is 15～25%, and purity is 95～99%;
In said process, the proportionlity of weight and volume is gram: milliliter.
As further restriction:
A, use NH in described
3regulate pH value be finally 3 to the method that obtains yellow powder shape solid II be following alternative:
1. first pH is adjusted to 1.5～2, generates safran precipitation, filter, reject precipitation, filtrate is continued logical NH again
3to pH be 3, filter, obtain the mixture that yellow powder shape solid II is the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, the yield of isomer is 95～98%, purity is that the yield of the chloro-3-nitropyridine of 95～99.5%, 4-amino-2-is 75～85%.
2. use NH
3directly being adjusted to pH is 3, make solvent refluxing 10min with sherwood oil or toluene afterwards, be cooled to room temperature, filter, obtain the mixture that yellow powder shape solid II is the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, the yield of isomer is 95～98%, and purity is that the yield of the chloro-3-nitropyridine of 95～99.5%, 4-amino-2-is 75～85%.
In B, described step 3), total consumption of recrystallization reagent is 0.5～5 times of yellow powder shape solid II volume, and wherein the volume ratio of ethyl acetate and sherwood oil is 1:3～10.
Owing to having adopted above-mentioned technical scheme, compared with prior art, obtained technical progress is in the present invention:
The present invention adopts 65% nitric acid and the vitriol oil to carry out nitration reaction as nitration mixture, makes the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, and the yield of isomer is 95～98%, and purity is 95～99.5%; After through recrystallization, it is carried out to purifying, and chloro-4-amino-2-3-nitropyridine has been carried out to effective separation with 4-amino-2-chloro-5-nitropyridine, the chloro-3-nitropyridine of 4-amino-2-making, yield is 75～85%, purity is 95～99%; The yield of 4-amino-2-chloro-5-nitropyridine is 15～25%, and purity is 95～99%.
The present invention is applicable to the preparation of the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, is further used for preparing the medicines such as E1 organized enzyme inhibitor, adenosyl homocysteine hydrolase inhibitor, PLK1 recombinant protein inhibitor, benzoglyoxaline.
The present invention is described in further detail below in conjunction with Figure of description and specific embodiment.
Accompanying drawing explanation
Fig. 1 is 4-amino-2-chloro-3-nitropyridine in the embodiment of the present invention 1
1h HMR figure;
Fig. 2 is 4-amino-2-chloro-5-nitropyridine in the embodiment of the present invention 1
1h HMR figure.
Embodiment
the synthetic method of 1 one kinds of chloro-3-nitropyridines of 4-amino-2-of embodiment
The synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, adopting the chloro-4-aminopyridine of 2-is raw material, 65% nitric acid and the vitriol oil carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-chloro-5-nitropyridine simultaneously, after recrystallization purifying, obtain corresponding sterling, process is as follows:
。
Its synthetic method is carried out according to following steps order:
1) at 0 ℃, chloro-the 2-of 200g 4-aminopyridine is dissolved in the vitriol oil of 1200mL, drips 65% the nitric acid of 1000mL, after dropwising, at 15 ℃, react 2h, then pour in frozen water, stir at 0 ℃, pass into NH
3regulating pH is 3, separates out white powder solid I, filters;
2) white powder solid I is dissolved in the vitriol oil of 2000mL, is heated to 80 ℃ of reaction 3h, under room temperature, stir and spend the night, then pour in frozen water, pass into NH at 0 ℃
3first pH is adjusted to 1.5, generates safran precipitation, filter, reject precipitation, filtrate is continued logical NH again
3to pH be 3, filter, obtain the mixture that yellow powder shape solid II is the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, the yield of isomer is 98%, purity is 98%, and wherein, the yield of the chloro-3-nitropyridine of 4-amino-2-is 75%.
Wherein, after reaction, under room temperature, stirring the object of spending the night has two: the firstth, and abundant reaction; The secondth, abundant cooling; Because the temperature of the vitriol oil is very high in reaction system, may internal temperature cooling in short period of time insufficient, the vitriol oil itself is added in water will heat release, if cooling be not exclusively added in frozen water can very exothermic, easily cause danger, so will stir the fully cooling of spending the night.
3) yellow powder shape solid II is carried out to recrystallization (wherein: recrystallization reagent is ethyl acetate and sherwood oil, total consumption is 3 times of yellow powder shape solid II volume, and the volume ratio of ethyl acetate and sherwood oil is 1:5), be heated to reflux, after be down to 30 ℃, separate out yellow powder shape solid III;
Filter, solid is the chloro-3-nitropyridine of sterling 4-amino-2-; Yield is 78%, and purity is 97%; Filtrate decompression desolvation, it is sterling 4-amino-2-chloro-5-nitropyridine that residuum obtains pale yellow powder shape solid IV with 95% ethyl alcohol recrystallization, and yield is 22%, and purity is 98%.
the synthetic method of 2 one kinds of chloro-3-nitropyridines of 4-amino-2-of embodiment
The synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, adopting the chloro-4-aminopyridine of 2-is raw material, 65% nitric acid and the vitriol oil carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-chloro-5-nitropyridine simultaneously, after recrystallization purifying, obtain corresponding sterling, process is as follows:
Its synthetic method is carried out according to following steps order:
1) at 0 ℃, chloro-the 2-of 200g 4-aminopyridine is dissolved in the vitriol oil of 1800mL, drips 65% the concentrated nitric acid of 1000mL, after dropwising, at 20 ℃, react 2h, then pour in frozen water, stir at 0 ℃, pass into NH
3regulating pH is 3, separates out white powder solid I, filters; Then,
2) white powder solid I is dissolved in the vitriol oil of 2500mL, is heated to 90 ℃ of reaction 3h, under room temperature, stir and spend the night, then pour in frozen water, pass into NH at 0 ℃
3be 3 with being directly adjusted to pH, make solvent refluxing 10min with sherwood oil or toluene afterwards, be cooled to room temperature, filter, obtain the mixture that yellow powder shape solid II is the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, the yield of isomer is 98%, and purity is 99%; Wherein, the yield of the chloro-3-nitropyridine of 4-amino-2-is 80%;
Wherein, after reaction, under room temperature, stirring the object of spending the night has two: the firstth, and abundant reaction; The secondth, abundant cooling; Because the temperature of the vitriol oil is very high in reaction system, may internal temperature cooling in short period of time insufficient, the vitriol oil itself is added in water will heat release, if cooling be not exclusively added in frozen water can very exothermic, easily cause danger, so will stir the fully cooling of spending the night.
3) yellow powder shape solid II is carried out to recrystallization (recrystallization reagent adopts volume ratio be 1:8 ethyl acetate and sherwood oil, total consumption is 2 times of yellow powder shape solid II volume), is heated to reflux, after be down to 35 ℃, separate out yellow powder shape solid III;
Filter to obtain the chloro-3-nitropyridine of sterling 4-amino-2-; Yield is 85%, and purity is 97%; Filtrate decompression desolvation, it is sterling 4-amino-2-chloro-5-nitropyridine that residuum obtains pale yellow powder shape solid IV with 95% ethyl alcohol recrystallization; Yield is 15%, and purity is 96%.
the synthetic method of the chloro-3-nitropyridine of embodiment 3-12 4-amino-2-
Embodiment 3-7 is respectively the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, and they are only that from the difference of embodiment 1 technical parameter related in synthetic method is different, specific as follows shown in:
Note: isomer purity and yield refer to the chloro-3-nitropyridine of 4-amino-2-and total purity and the yield of 4-amino-2-chloro-5-nitropyridine.
Embodiment 8-12 is respectively the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, and they are only that from the difference of embodiment 2 technical parameter related in synthetic method is different, specific as follows shown in:
Note: isomer purity and yield refer to the chloro-3-nitropyridine of 4-amino-2-and total purity and the yield of 4-amino-2-chloro-5-nitropyridine.
embodiment 13 NH
3
regulate the method for pH value to select
The present invention adopts NH
3regulate pH value, replaced and in prior art, used ammoniacal liquor to regulate the method that pH value is 3, the NH of ammonia
3concentration is far away higher than ammoniacal liquor NH
3concentration, in the middle of the process of reacting with acid, so both can reduce the consumption of ammoniacal liquor, can save again the time of reaction, reduce production cost, be conducive to carry out industrialized production, remove the safran solid impurity in preparation process, thereby the purity of chloro-4-amino-2-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine is improved, therefore its method is screened, process is as follows:
As can be seen from the above table, adopt NH
3regulate stage by stage the method for pH value or regulate the pH value method of recrystallization again, can remove safran solid impurity.Logical NH
3adjust pH value of solution=1.5～2, filter, more logical NH
3adjust pH value of solution=3, or logical NH
3adjust pH value of solution=3, add again sherwood oil or refluxing toluene 10min, the method of these two kinds of aftertreatments all can obtain the mixture of the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, has alleviated like this separating difficulty, is conducive to further separate.
the selection of embodiment 14 recrystallization reagent
Because the chloro-3-nitropyridine of 4-amino-2-and two kinds of compounds of 4-amino-2-chloro-5-nitropyridine are isomers, both shapes are more similar, and the method using in prior art is column chromatography, this method operation steps is comparatively loaded down with trivial details, and while separation for the large product of amount, difficulty and cost all increase accordingly, therefore it is very important selecting suitable recrystallization reagent that both are carried out effectively separating, therefore carried out selecting screening for recrystallization reagent, detailed process is as follows:
1) selection of the recrystallization solvent of the chloro-3-nitropyridine of 4-amino-2-
First carried out single recrystallization reagent the chloro-3-nitropyridine of 4-amino-2-is purified, but effect is bad, the rear method of having selected multiple recrystallization combination is purified, and concrete outcome phenomenon is as shown in the table:
Select separately as can be seen from the above table ethyl acetate or dehydrated alcohol crystallization that polarity is larger all undesirable, select sherwood oil or methylene dichloride equal solvent that polarity is less, can not dissolve the solid of wanting crystallization, so consider to select the mixing of two or more solvents to reach the polarity that we want, but in conjunction with toxicity and the operability of solvent, show that by experiment the recrystallization ethyl acetate of the chloro-3-nitropyridine of 4-amino-2-and sherwood oil are preferred plan as reagent.
2) selection of the recrystallization solvent of 4-amino-2-chloro-5-nitropyridine
Select separately as can be seen from the above table ethyl acetate or dehydrated alcohol crystallization that polarity is larger all undesirable, select sherwood oil or methylene dichloride equal solvent that polarity is less, can not dissolve the solid of wanting crystallization, so in conjunction with toxicity and the operability of solvent, recrystallization 95% the ethanol that draws by experiment 4-amino-2-chloro-5-nitropyridine is best.
the selection of embodiment 15 recrystallization reagent dosages
The pure and mild rate of recovery of product that recrystallization is obtained is high, the consumption of solvent is a key, add solvent very few, dissolution of solid is incomplete, and impurity is more, the product obtaining is impure, just dissolved solids of the amount of the solvent adding, if the solvent adding is volatile, possibility make solution become supersaturation because reduce temperature and separate out precipitation like this, but can not add excessive a lot of solvent, avoid waste.Thereby to select suitable solvent load be the committed step separating, the consumption of the recrystallization solvent of the chloro-3-nitropyridine of 4-amino-2-is selected, as shown in the table:
As can be seen from the above table total consumption of the recrystallization solvent of the chloro-3-nitropyridine of 4-amino-2-be 0.5～5 times of yellow powder shape solid II volume for best, select ethyl acetate: sherwood oil is that 1:3～10 are for best.
The above, be only preferred embodiment of the present invention, is not the restriction of other form made for the present invention.Any those skilled in the art, may utilize above-mentioned technology contents as enlightenment, are changed or be modified as the equivalent embodiment of equivalent variations.But every technical solution of the present invention content that do not depart from, the simple modification of above embodiment having been done according to technical spirit of the present invention, equivalent variations and remodeling, still belong to the protection domain of the claims in the present invention.
Claims (5)
1. a synthetic method for the chloro-3-nitropyridine of 4-amino-2-,
it is characterized in that:adopting the chloro-4-aminopyridine of 2-is raw material, 65% nitric acid and the vitriol oil carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-chloro-5-nitropyridine simultaneously, obtain corresponding sterling after recrystallization purifying, process is as follows:
2. the synthetic method of the chloro-3-nitropyridine of 4-amino-2-according to claim 1,
it is characterized in thatit carries out according to following steps order:
1) at 0 ℃, chloro-the 2-of 200 weight parts 4-aminopyridine is dissolved in the vitriol oil of 1200～2000 parts by volume, drips 65% nitric acid of 600～1400 parts by volume, after dropwising, at 15～20 ℃, react 2h, then pour in frozen water, at 0 ℃, stir, pass into NH
3regulating pH is 3, separates out white powder solid I, filters;
White powder solid I is dissolved in the vitriol oil of 2000～2600 parts by volume, is heated to 80～100 ℃ of reaction 3h, under room temperature, stir and spend the night, then pour in frozen water, pass into NH at 0 ℃
3regulating pH value is finally 3, obtains yellow powder shape solid II, is the mixture of the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine;
3) yellow powder shape solid II is carried out to recrystallization, recrystallization reagent adopts ethyl acetate and sherwood oil, be heated to reflux, after be down to 30～40 ℃, separate out yellow powder shape solid III, filter, wherein:
Filter solid be the chloro-3-nitropyridine of sterling 4-amino-2-; Yield is 75～85%, and purity is 95～99%;
Filtrate decompression desolvation, it is sterling 4-amino-2-chloro-5-nitropyridine that residuum obtains pale yellow powder shape solid IV with 95% ethyl alcohol recrystallization; Yield is 15～25%, and purity is 95～99%;
In said process, the proportionlity of weight and volume is gram: milliliter.
3. the synthetic method of the chloro-3-nitropyridine of 4-amino-2-according to claim 2,
it is characterized in thatdescribed step 2) in use NH
3regulating pH value is finally 3 to be to the method that obtains yellow powder shape solid II:
First use NH
3regulate pH to 1.5～2, generate safran precipitation, filter, reject precipitation, filtrate is continued logical NH again
3to pH be 3, filter, obtain the mixture that yellow powder shape solid II is the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, the yield of isomer is 95～98%, purity is that the yield of the chloro-3-nitropyridine of 95～99.5%, 4-amino-2-is 75～85%.
4. the synthetic method of the chloro-3-nitropyridine of 4-amino-2-according to claim 2,
it is characterized in thatdescribed step 2) in use NH
3regulating pH value is finally 3 to be to the method that obtains yellow powder shape solid II:
Use NH
3directly adjusting pH is 3, make solvent refluxing 10min with sherwood oil or toluene afterwards, be cooled to room temperature, filter, obtain the mixture that yellow powder shape solid II is the chloro-3-nitropyridine of isomer 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, the yield of isomer is 95～98%, and purity is that the yield of the chloro-3-nitropyridine of 95～99.5%, 4-amino-2-is 75～85%.
5. the synthetic method of the chloro-3-nitropyridine of 4-amino-2-according to claim 2,
it is characterized in thatin described step 3), the total consumption of recrystallization reagent is 0.5～5 times of yellow powder shape solid II volume, and wherein the volume ratio of ethyl acetate and sherwood oil is 1:3～10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410034222.5A CN103819398B (en) | 2014-01-24 | 2014-01-24 | The synthetic method of the chloro-3-nitropyridine of 4-amino-2- |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410034222.5A CN103819398B (en) | 2014-01-24 | 2014-01-24 | The synthetic method of the chloro-3-nitropyridine of 4-amino-2- |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103819398A true CN103819398A (en) | 2014-05-28 |
| CN103819398B CN103819398B (en) | 2016-05-04 |
Family
ID=50754734
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410034222.5A Expired - Fee Related CN103819398B (en) | 2014-01-24 | 2014-01-24 | The synthetic method of the chloro-3-nitropyridine of 4-amino-2- |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103819398B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218179A (en) * | 2018-03-02 | 2019-09-10 | 新发药业有限公司 | A kind of environment-friendly preparation method of the chloro- 3- nitropyridine of 4- amino -2- |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004023897A1 (en) * | 2002-09-12 | 2004-03-25 | Marc Schwaller | Composition containing in combination at least one gourd oil and at least one borage oil, use thereof as medicine, as dermatological or dermato-cosmetic agent |
| CN1694889A (en) * | 2002-09-12 | 2005-11-09 | 阿文尼尔药品公司 | Phenyl-aza-benzimidazole compounds for modulating ige and inhibiting cellular proliferation |
| CN102898361A (en) * | 2012-10-08 | 2013-01-30 | 鲁东大学 | Method for preparing 2-chlorine-3-amino-4-picoline |
-
2014
- 2014-01-24 CN CN201410034222.5A patent/CN103819398B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004023897A1 (en) * | 2002-09-12 | 2004-03-25 | Marc Schwaller | Composition containing in combination at least one gourd oil and at least one borage oil, use thereof as medicine, as dermatological or dermato-cosmetic agent |
| CN1694889A (en) * | 2002-09-12 | 2005-11-09 | 阿文尼尔药品公司 | Phenyl-aza-benzimidazole compounds for modulating ige and inhibiting cellular proliferation |
| CN102898361A (en) * | 2012-10-08 | 2013-01-30 | 鲁东大学 | Method for preparing 2-chlorine-3-amino-4-picoline |
Non-Patent Citations (2)
| Title |
|---|
| EUNA YOO等: "Structure–activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines", 《ORGANIC & BIOMOLECULAR CHEMISTRY》, vol. 11, 15 August 2013 (2013-08-15), XP055165875, DOI: 10.1039/c3ob40816g * |
| 邵玉娴: "2-氯-5-硝基吡啶和4-氨基-2-氯吡啶的合成研究", 《南京理工大学硕士学位论文》, 31 December 2009 (2009-12-31), pages 16 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218179A (en) * | 2018-03-02 | 2019-09-10 | 新发药业有限公司 | A kind of environment-friendly preparation method of the chloro- 3- nitropyridine of 4- amino -2- |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103819398B (en) | 2016-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2006219727B2 (en) | Crystallisation and purification of glycopyrronium bromide | |
| CN101973981B (en) | Refining method of 1-(5-isoquinoline sulfonyl) homopiperazine hydrochloride | |
| CN103755628B (en) | The synthetic method of the iodo-5-bromopyridine of 2-amino-3- | |
| CN106146560A (en) | A kind of process for purification of high-purity phosphoric acid specially azoles amine | |
| CN102351847A (en) | Industrial method for refining esomeprazole sodium salt | |
| CN108358929A (en) | Refining method of tofacitinib citrate | |
| CN103819398A (en) | Method for synthesizing 4-amino-2-chlorine-3-nitro pyridine | |
| CN103319422B (en) | A kind of Gefitinib crystal formation and preparation method thereof | |
| CN103360326A (en) | Method for refining Gefinitib crystal form I | |
| CN103420979A (en) | Esomeprazole sodium refining method | |
| CN110128293B (en) | Medical intermediate impurity and preparation method and application thereof | |
| CN102557980B (en) | Method for preparing high-purity capsaicine monomer by crystallization | |
| CN102146044B (en) | Preparation method of propranolol hydrochloride single enantiomers | |
| CN104558104B (en) | A kind of process for purification of argatroban refinement mother liquor recovery article | |
| CN106146403B (en) | A kind of purification process of the miscellaneous Shandong amine of grace | |
| CN110922360B (en) | Method for continuously preparing edaravone | |
| CN114163411A (en) | Preparation method of enantiomer pure dihydromyricetin | |
| CN103304464A (en) | Preparation method of levetiracetam | |
| CN101514163A (en) | Optically pure Sibutramine and process for preparing salt derivative thereof | |
| CN104098547A (en) | Refining method for hydroxyfasudil | |
| CN105777714B (en) | The process for purification of fluorine imatinib | |
| CN105218515B (en) | A kind of preparation method of medicinal lenalidomide hemi-hydrate crystalline | |
| CN114957130B (en) | Purification method and application of high-purity 5-benzylidene hydantoin | |
| CN109096136B (en) | Erlotinib intermediate compound and refining method thereof | |
| CN115124506B (en) | Preparation method of digestive system medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160504 |