CN103819398B - The synthetic method of the chloro-3-nitropyridine of 4-amino-2- - Google Patents
The synthetic method of the chloro-3-nitropyridine of 4-amino-2- Download PDFInfo
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- CN103819398B CN103819398B CN201410034222.5A CN201410034222A CN103819398B CN 103819398 B CN103819398 B CN 103819398B CN 201410034222 A CN201410034222 A CN 201410034222A CN 103819398 B CN103819398 B CN 103819398B
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- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000010189 synthetic method Methods 0.000 title claims abstract description 21
- 238000001953 recrystallisation Methods 0.000 claims abstract description 26
- 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 abstract description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 238000006396 nitration reaction Methods 0.000 claims abstract description 17
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 8
- ZPFUWAVLEWIOEJ-UHFFFAOYSA-N 2-nitropyridin-4-amine Chemical compound NC1=CC=NC([N+]([O-])=O)=C1 ZPFUWAVLEWIOEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- -1 chloro-3-nitropyridine of isomers Chemical class 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000000843 powder Substances 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-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 11
- 238000003756 stirring Methods 0.000 claims description 11
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- BLBDTBCGPHPIJK-UHFFFAOYSA-N 4-Amino-2-chloropyridine Chemical compound NC1=CC=NC(Cl)=C1 BLBDTBCGPHPIJK-UHFFFAOYSA-N 0.000 claims description 5
- 235000004237 Crocus Nutrition 0.000 claims description 5
- 241000596148 Crocus Species 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
- 229960004979 fampridine Drugs 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000004807 desolvation Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 239000000463 material Substances 0.000 claims 1
- 239000003208 petroleum Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 238000000926 separation 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
- 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
- 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 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000002253 acid Substances 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
- 150000003222 pyridines Chemical class 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 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 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- PNKKEBHEJYPJBR-UHFFFAOYSA-N 2-chloro-5-nitropyridin-3-amine Chemical compound NC1=CC([N+]([O-])=O)=CN=C1Cl PNKKEBHEJYPJBR-UHFFFAOYSA-N 0.000 description 1
- BAZVFQBTJPBRTJ-UHFFFAOYSA-N 2-chloro-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Cl)N=C1 BAZVFQBTJPBRTJ-UHFFFAOYSA-N 0.000 description 1
- HLTDBMHJSBSAOM-UHFFFAOYSA-N 2-nitropyridine Chemical compound [O-][N+](=O)C1=CC=CC=N1 HLTDBMHJSBSAOM-UHFFFAOYSA-N 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 125000005605 benzo group Chemical group 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
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 238000012805 post-processing Methods 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
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, nitric acid and the concentrated sulfuric acid of employing 65% carry out nitration reaction as nitration mixture, the chloro-3-nitropyridine of isomers 4-amino-2-making and the yield of 4-amino-2-chloro-5-nitropyridine are 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, further can prepare the medicines such as E1 organized enzyme inhibitor, adenosyl homocysteine hydrolase inhibitor, PLK1 recombinant protein inhibitor, benzimidazole.
Description
Technical field
The invention belongs to pharmaceutical 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 resist vaccinaPoison, variola virus, human cytomegalovirus, banded virus, HIV are viral, H1N1And H3N2Virus etc.; Or a kind of nucleosides is derivativeThe intermediate of thing (E1 organized enzyme inhibitor), is used for treating cell proliferation obstacle, comprises 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 dysostosisSick; 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 made productThe yield of thing is lower, as world patent WO2007047793 is the synthetic of a kind of cyclopentenol nucleoside compound intermediate and controlsTreat the method for virus infections, adopting the chloro-4-aminopyridine of 2-is raw material, and 70% fuming nitric aicd and the concentrated sulfuric acid, as nitration mixture, carry outNitration reaction, adopt silica gel column chromatography to carry out products of separated, obtains 70% the chloro-3-nitropyridine of 4-amino-2-and 25%4-amino-2-chloro-5-nitropyridine, and 5% impurity.
World patent WO200684281 is a kind of preparation of E1 organized enzyme inhibitor nucleoside derivates, adopts the chloro-4-of 2-Aminopyridine is raw material, and 90% fuming nitric aicd and the concentrated sulfuric acid, as nitration mixture, carry out nitration reaction, the product obtaining be 4-amino-The mixture of the chloro-3-nitropyridine of 2-and 4-amino-2-chloro-5-nitropyridine, adopts rapid column chromatography method to separate, and adoptsMobile phase be carrene: ethyl acetate is 1:4, obtains 44% the chloro-3-nitropyridine of 4-amino-2-, but obtains productYield lower. And the highly volatile in air of the carrene in mobile phase, may cause the proportioning of mobile phase to changeBecome, separating effect is bad, and column chromatography chromatogram method can not be carried out the separation of large-tonnage product, and the activity of fuming nitric aicd is higher simultaneously, butIts price is more expensive, and 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 in the middle of very important medicineBody, market demand is huge, has good market prospects, so how to synthesize the chloro-3-nitropyridine of 4-amino-2-and 4-ammoniaBase-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, is to provide the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, adoptsNitric acid with 65% and the concentrated sulfuric acid carry out nitration reaction as nitration mixture, and the isomers making is the chloro-3-nitropyridine of 4-amino-2-With the mixture of 4-amino-2-chloro-5-nitropyridine, yield is 95～98%, and purity is 95～99.5%; After right through being recrystallizedIt carries out purifying, and chloro-4-amino-2-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine have been carried out effectively dividingFrom, the chloro-3-nitropyridine of 4-amino-2-making, yield is 75～85%, purity is 95～99%; The chloro-5-nitre of 4-amino-2-The yield of yl pyridines 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:
A synthetic method for the chloro-3-nitropyridine of 4-amino-2-, adopting the chloro-4-aminopyridine of 2-is raw material, 65%Nitric acid and the concentrated sulfuric acid carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-simultaneouslyChloro-5-nitropyridine, obtains corresponding sterling after recrystallization purifying, 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 suitable according to following stepsOrder is carried out:
1), at 0 DEG C, chloro-the 2-of 200 weight portions 4-aminopyridine is dissolved in the concentrated sulfuric acid of 1200～2000 parts by volume,65% the nitric acid that drips 600～1400 parts by volume after dropwising, reacts 2h at 15～20 DEG C, then pours in frozen water 0At DEG C, stir, pass into NH3Regulating pH is 3, separates out white powder solid I, filters; Then,
2) white powder solid I is dissolved in the concentrated sulfuric acid of 2000～2600 parts by volume, is heated to 80～100 DEG C insteadAnswer 3h, under room temperature, stir and spend the night, then pour in frozen water, pass into NH at 0 DEG C3Regulating pH value is finally 3, obtains yellow powder shapeSolid II, is the mixture of the chloro-3-nitropyridine of isomers 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 concentrated sulfuric acid is very high in reaction system, short time interior possibility internal temperature cooling is insufficient, and itself is added to the concentrated sulfuric acidWill heat release in water, if be not exclusively added in frozen water can very exothermic in cooling, easily cause danger, fill so will stir to spend the nightDivide cooling.
3) yellow powder shape solid II is recrystallized, adopts ethyl acetate and benzinum to make recrystallization reagent, heatingTo reflux, after be down to 30～40 DEG C, 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, residue 95% ethyl alcohol recrystallization, obtaining pale yellow powder shape solid IV is 4-ammoniaBase-2-chloro-5-nitropyridine, yield is 15～25%, purity is 95～99%;
In said process, the proportionate relationship of weight and volume is gram: milliliter.
As further restriction:
A, use NH in described3Regulate 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 crocus precipitation, filter, reject precipitation, filtrate is continued logical NH again3To pHBe 3, filter, obtaining yellow powder shape solid II is the chloro-3-nitropyridine of isomers 4-amino-2-and the chloro-5-nitre of 4-amino-2-The mixture of yl pyridines, the yield of isomers is 95～98%, purity is 95～99.5%, 4-amino-2-chloro-3-nitropyridineYield is 75～85%.
2. use NH3Directly being adjusted to pH is 3, makes solvent refluxing 10min with benzinum or toluene afterwards, is cooled to room temperature, filter,Obtain yellow powder shape solid II and be the chloro-3-nitropyridine of isomers 4-amino-2-and 4-amino-2-chloro-5-nitropyridineMixture, the yield of isomers is 95～98%, 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, itsThe volume ratio of middle ethyl acetate and benzinum is 1:3～10.
Owing to having adopted above-mentioned technical scheme, compared with prior art, obtained technological progress is in the present invention:
The present invention adopts 65% nitric acid and the concentrated sulfuric acid to carry out nitration reaction as nitration mixture, makes isomers 4-amino-2-Chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine, the yield of isomers is 95～98%, purity is 95～99.5%;After through recrystallization, it is carried out to purifying, and chloro-4-amino-2-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine are enteredGo effective separation, the chloro-3-nitropyridine of 4-amino-2-making, yield is 75～85%, purity is 95～99%; 4-ammoniaThe yield of base-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, enters oneStep is for the preparation of E1 organized enzyme inhibitor, adenosyl homocysteine hydrolase inhibitor, PLK1 recombinant protein inhibitor, benzo miaowThe medicines such as azoles.
The present invention is described in further detail below in conjunction with Figure of description and specific embodiment.
Brief description of the drawings
Fig. 1 is 4-amino-2-chloro-3-nitropyridine in the embodiment of the present invention 11HHMR figure;
Fig. 2 is 4-amino-2-chloro-5-nitropyridine in the embodiment of the present invention 11HHMR figure.
Detailed description of the invention
The synthetic method of 1 one kinds of chloro-3-nitropyridines of 4-amino-2-of embodiment
A synthetic method for the chloro-3-nitropyridine of 4-amino-2-, adopting the chloro-4-aminopyridine of 2-is raw material, 65%Nitric acid and the concentrated sulfuric acid carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-simultaneouslyChloro-5-nitropyridine, obtains corresponding sterling after recrystallization purifying, process is as follows:
。
Its synthetic method is carried out according to following steps order:
1) at 0 DEG C, chloro-the 2-of 200g 4-aminopyridine is dissolved in the concentrated sulfuric acid of 1200mL, drips 65% of 1000mLNitric acid, after dropwising, at 15 DEG C, react 2h, then pour in frozen water, stir at 0 DEG C, pass into NH3Regulating pH is 3, analysesGo out white powder solid I, filter;
2) white powder solid I is dissolved in the concentrated sulfuric acid of 2000mL, is heated to 80 DEG C of reaction 3h, under room temperature, stirSpend the night, then pour in frozen water, pass into NH at 0 DEG C3First pH is adjusted to 1.5, generates crocus precipitation, filter, reject precipitation,Filtrate is continued logical NH again3To pH be 3, filter, obtaining yellow powder shape solid II is the chloro-3-nitro of isomers 4-amino-2-pyrroleThe mixture of pyridine and 4-amino-2-chloro-5-nitropyridine, the yield of isomers is 98%, purity is 98%, wherein, 4-amino-2-The yield of chloro-3-nitropyridine 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 concentrated sulfuric acid is very high in reaction system, short time interior possibility internal temperature cooling is insufficient, and itself is added to the concentrated sulfuric acidWill heat release in water, if be not exclusively added in frozen water can very exothermic in cooling, easily cause danger, fill so will stir to spend the nightDivide cooling.
3) yellow powder shape solid II is recrystallized (wherein: recrystallization reagent is ethyl acetate and benzinum, always usesAmount is 3 times of yellow powder shape solid II volume, and the volume ratio of ethyl acetate and benzinum is 1:5), be heated to backflow, after fallTo 30 DEG C, 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 is de-Desolventize, it is the chloro-5-nitro of sterling 4-amino-2-pyrrole that residue obtains pale yellow powder shape solid IV with 95% ethyl alcohol recrystallizationPyridine, yield is 22%, purity is 98%.
The synthetic method of 2 one kinds of chloro-3-nitropyridines of 4-amino-2-of embodiment
A synthetic method for the chloro-3-nitropyridine of 4-amino-2-, adopting the chloro-4-aminopyridine of 2-is raw material, 65%Nitric acid and the concentrated sulfuric acid carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate 4-amino-2-simultaneouslyChloro-5-nitropyridine, obtains corresponding sterling after recrystallization purifying, process is as follows:
。
Its synthetic method is carried out according to following steps order:
1) at 0 DEG C, chloro-the 2-of 200g 4-aminopyridine is dissolved in the concentrated sulfuric acid of 1800mL, drips 65% of 1000mLRed fuming nitric acid (RFNA), after dropwising, at 20 DEG C, react 2h, then pour in frozen water, stir at 0 DEG C, pass into NH3Regulating pH is 3,Separate out white powder solid I, filter; Then,
2) white powder solid I is dissolved in the concentrated sulfuric acid of 2500mL, is heated to 90 DEG C of reaction 3h, under room temperature, stirSpend the night, then pour in frozen water, pass into NH at 0 DEG C3Be 3 with being directly adjusted to pH, make solvent refluxing with benzinum or toluene afterwards10min, is cooled to room temperature, filters, and obtaining yellow powder shape solid II is the chloro-3-nitropyridine of isomers 4-amino-2-and 4-The mixture of amino-2-chloro-5-nitropyridine, the yield of isomers is 98%, purity is 99%; Wherein, the chloro-3-of 4-amino-2-The yield of nitropyridine 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 concentrated sulfuric acid is very high in reaction system, short time interior possibility internal temperature cooling is insufficient, and itself is added to the concentrated sulfuric acidWill heat release in water, if be not exclusively added in frozen water can very exothermic in cooling, easily cause danger, fill so will stir to spend the nightDivide cooling.
3) yellow powder shape solid II is recrystallized (recrystallization reagent the adopts volume ratio ethyl acetate that is 1:8 andBenzinum, total consumption is 2 times of yellow powder shape solid II volume), be heated to reflux, after be down to 35 DEG C, separate out yellow powderShape solid III;
Filter to obtain the chloro-3-nitropyridine of sterling 4-amino-2-; Yield is 85%, and purity is 97%; Filtrate decompression removes moltenAgent, it is sterling 4-amino-2-chloro-5-nitropyridine that residue obtains pale yellow powder shape solid IV with 95% ethyl alcohol recrystallization; ReceiveRate is 15%, and purity is 96%.
The synthetic method of the chloro-3-nitropyridine of embodiment 3-124-amino-2-
Embodiment 3-7 is respectively the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, and they and embodiment 1 are notOnly be technical parameter difference related in synthetic method with part, specific as follows shown in:
Note: isomers purity and yield refer to the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridineTotal purity and yield.
Embodiment 8-12 is respectively the synthetic method of the chloro-3-nitropyridine of a kind of 4-amino-2-, they and embodiment's 2Difference is only technical parameter difference related in synthetic method, specific as follows shown in:
Note: isomers purity and yield refer to the chloro-3-nitropyridine of 4-amino-2-and 4-amino-2-chloro-5-nitropyridineTotal purity and yield.
Embodiment 13NH3Regulate the method for pH value to select
The present invention adopts NH3Regulate pH value, replaced and in prior art, used ammoniacal liquor to regulate the method that pH value is 3, ammoniaNH3Concentration is far away higher than ammoniacal liquor NH3Concentration, in the middle of the process of reacting with acid, so both can reduce the use of ammoniacal liquorAmount, can save again the time of reaction, has reduced production cost, is conducive to carry out industrialized production, has removed preparation processIn crocus solid impurity, thereby by the purity of chloro-4-amino-2-3-nitropyridine and 4-amino-2-chloro-5-nitropyridineImprove, therefore its method is screened, process is as follows:
As can be seen from the above table, adopt NH3Regulate stage by stage the method for pH value or the method that regulates pH value to be recrystallized again, energyEnough remove crocus solid impurity. Logical NH3Adjust pH value of solution=1.5～2, filter, more logical NH3Adjust pH value of solution=3, or logical NH3Adjust moltenLiquid pH=3, then add benzinum or refluxing toluene 10min, the method for these two kinds of post processings all can obtain the chloro-3-nitre of 4-amino-2-The mixture of yl pyridines and 4-amino-2-chloro-5-nitropyridine, has alleviated separating difficulty like this, is conducive to further divideFrom.
The be recrystallized selection of reagent of embodiment 14
Because the chloro-3-nitropyridine of 4-amino-2-and two kinds of compounds of 4-amino-2-chloro-5-nitropyridine are same differentiationStructure body, both shapes are more similar, and the method using in prior art is column chromatography, the method operating procedure is comparatively loaded down with trivial details,And while separation for the large product of amount, difficulty and cost all increase accordingly, therefore select suitable recrystallization reagentBoth are carried out effectively separating is very important, has therefore carried out selecting screening for recrystallization reagent, detailed process asShown in lower:
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 notGood, 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 absolute ethyl alcohol crystallization that polarity is larger all undesirable, select the utmost pointBenzinum or carrene equal solvent that property is less, can not dissolve the solid of wanting crystallization, so will consider to select two kinds or manyThe mixing of planting solvent reaches the polarity that we want, and still, in conjunction with toxicity and the operability of solvent, draws by experiment 4-The recrystallization of the chloro-3-nitropyridine of amino-2-is preferred plan with ethyl acetate and benzinum 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 absolute ethyl alcohol crystallization that polarity is larger all undesirable, select the utmost pointProperty less benzinum or carrene equal solvent, can not dissolve the solid of wanting crystallization, so in conjunction with the toxicity of solvent and canOperability, recrystallization 95% the ethanol that draws by experiment 4-amino-2-chloro-5-nitropyridine is best.
The be recrystallized selection of reagent dosage of embodiment 15
The pure and mild rate of recovery of product that recrystallization is obtained is high, and the consumption of solvent is a key, adds solvent very few, solidDissolve not exclusively, impurity is more, and the product obtaining is impure, and just dissolved solid of the amount of the solvent adding, if the solvent addingVolatile, possibility make solution become supersaturation because reduce temperature and separate out precipitation like this, and it is very excessive still can not to addMany solvents, avoid waste. Thereby select suitable solvent load be separate committed step, the chloro-3-nitro of 4-amino-2-pyrroleThe consumption of the recrystallization solvent of pyridine is selected, as shown in the table:
Total consumption of the recrystallization solvent of the chloro-3-nitropyridine of 4-amino-2-is yellow powder shape as can be seen from the above table0.5～5 times of solid II volume is best, selects ethyl acetate: benzinum is that 1:3～10 are for best.
The above, be only preferred embodiment of the present invention, is not the limit of other form made for the present inventionSystem. Any those skilled in the art, may utilize above-mentioned technology contents as enlightenment, are changed or be modified as to be equal toThe equivalent embodiment changing. But every technical solution of the present invention content that do not depart from, according to technical spirit of the present invention to more thanThe simple modification that embodiment has done, equivalent variations and remodeling, still belong to the protection domain of the claims in the present invention.
Claims (3)
1. a synthetic method for the chloro-3-nitropyridine of 4-amino-2-, is characterized in that: adopt the chloro-4-aminopyridine of 2-to beRaw material, 65% nitric acid and the concentrated sulfuric acid carry out nitration reaction as nitration mixture and prepare the chloro-3-nitropyridine of 4-amino-2-, generate simultaneously4-amino-2-chloro-5-nitropyridine obtains the chloro-3-nitro of 4-amino-2-pyrrole after recrystallization from ethyl acetate/petroleum ether purifyingPyridine sterling and filtrate, concentrating filter liquor obtains solid, and solid finally makes the chloro-5-nitro of 4-amino-2-through 95% ethyl alcohol recrystallizationPyridine, process is as follows:
；
It carries out according to following steps order:
1) at 0 DEG C, chloro-the 2-of 200 weight portions 4-aminopyridine is dissolved in the concentrated sulfuric acid of 1200～2000 parts by volume, drips65% nitric acid of 600～1400 parts by volume after dropwising, reacts 2h at 15～20 DEG C, then pours in frozen water, at 0 DEG CStir, pass into NH3Regulating pH is 3, separates out white powder solid I, filters;
2) white powder solid I is dissolved in the concentrated sulfuric acid of 2000～2600 parts by volume, is heated to 80～100 DEG C of reactions3h, stirs and spends the night under room temperature, then pours in frozen water, passes into NH at 0 DEG C3Regulating pH value is finally 3, obtains yellow powder shape solidBody II, is the mixture of the chloro-3-nitropyridine of isomers 4-amino-2-and 4-amino-2-chloro-5-nitropyridine;
3) yellow powder shape solid II is recrystallized, recrystallization reagent adopts ethyl acetate and benzinum, be heated to reflux,After be down to 30～40 DEG C, 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, residue with 95% ethyl alcohol recrystallization obtain pale yellow powder shape solid IV be sterling 4-amino-2-chloro-5-nitropyridine; Yield is 15～25%, and purity is 95～99%; Wherein, the total consumption of recrystallization reagent is yellow powder shape0.5～5 times of solid II volume, wherein the volume ratio of ethyl acetate and benzinum is 1:3～10;
In said process, the proportionate relationship of weight and volume is gram: milliliter.
2. the synthetic method of the chloro-3-nitropyridine of 4-amino-2-according to claim 1, is characterized in that described step2) in, use NH3Regulating pH value is finally 3 to be to the method that obtains yellow powder shape solid II:
First use NH3Regulate pH to 1.5～2, generate crocus precipitation, filter, reject precipitation, filtrate is continued logical NH again3To pH be3, filter, obtaining yellow powder shape solid II is the chloro-3-nitropyridine of isomers 4-amino-2-and the chloro-5-nitro of 4-amino-2-The mixture of pyridine, the yield of isomers is 95～98%, purity is the receipts of the chloro-3-nitropyridine of 95～99.5%, 4-amino-2-Rate is 75～85%.
3. the synthetic method of the chloro-3-nitropyridine of 4-amino-2-according to claim 1, is characterized in that described step2) in, use NH3Regulating pH value is finally 3 to be to the method that obtains yellow powder shape solid II:
Use NH3Directly adjusting pH is 3, makes solvent refluxing 10min with benzinum or toluene afterwards, is cooled to room temperature, filters, and obtains yellowPulverulent solids II is the mixture of the chloro-3-nitropyridine of isomers 4-amino-2-and 4-amino-2-chloro-5-nitropyridine, differentThe yield of structure body is 95～98%, and purity is that the yield of the chloro-3-nitropyridine of 95～99.5%, 4-amino-2-is 75～85%.
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| 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 |
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