CN100371327C - One-step synthesis of 2-amino-6-alkoxy-3-nitropyridine - Google Patents
One-step synthesis of 2-amino-6-alkoxy-3-nitropyridine Download PDFInfo
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- CN100371327C CN100371327C CNB2005100954716A CN200510095471A CN100371327C CN 100371327 C CN100371327 C CN 100371327C CN B2005100954716 A CNB2005100954716 A CN B2005100954716A CN 200510095471 A CN200510095471 A CN 200510095471A CN 100371327 C CN100371327 C CN 100371327C
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Abstract
本发明涉及一种药物中间体的制备方法，特指以2，6-二氯-3-硝基吡啶为起始原料，氨水、烷醇、无机碱作为催化反应原料一步合成2-氨基-6-烷氧基-3-硝基吡啶的方法。其采取2，6-二氯-3-硝基吡啶为起始原料，同时加入一定量的氨基化原料氨水和过量的烷氧基化原料即相应的烷醇于低压反应釜中，并加入适量的无机碱作为催化反应原料，于90～150℃条件下，反应8～12小时后，冷却至常温，静置过夜，第二天抽滤，干燥后用乙醇重结晶，并用活性炭脱色，抽滤，干燥，即得成目的产物。该法具有简单、高效和安全的特点，目的产品有40%～70%收率，产品纯度＞98%。The present invention relates to a preparation method of a pharmaceutical intermediate, specifically referring to the one-step synthesis of 2-amino-6 by using 2,6-dichloro-3-nitropyridine as the starting material, ammonia water, alkanol and inorganic base as the catalytic reaction raw materials. - the method of alkoxy-3-nitropyridine. It takes 2,6-dichloro-3-nitropyridine as the starting material, and at the same time adds a certain amount of amination raw material ammonia water and excess alkoxylation raw material, that is, the corresponding alkanol, into a low-pressure reactor, and adds an appropriate amount of The inorganic base is used as the raw material for the catalytic reaction. After reacting for 8-12 hours under the condition of 90-150°C, cool to room temperature, let it stand overnight, filter it with suction the next day, recrystallize it with ethanol after drying, decolorize it with activated carbon, and filter it with suction , dried to obtain the desired product. The method is simple, efficient and safe. The target product has a yield of 40% to 70%, and the product purity is >98%.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, refer in particular to 2,6-two chloro-3-nitropyridines are starting raw material, and ammoniacal liquor, alkanol, mineral alkali are as the method for catalyzed reaction raw material-step Synthetic 2-amino-6-alkoxyl group-3-nitropyridine.
Background technology
2-amino-6-alkoxyl group-3-nitropyridine is the important pharmaceutical intermediate of a class, particularly has a wide range of applications in the synthetic and research of anti-ulcerative drug.2-amino-6-alkoxyl group-3-nitropyridine synthetic method is general as applying for a patent described in WO2004092166 and the US2004229861, the ammoxidation of the first step is made solvent with ethanol, raw material 2,6-two chloro-3-nitropyridines and ammoniacal liquor carry out under backflow and non-pressurized condition, get intermediates 2-amino-6-chloro-3-nitropyridine, yield low (30%), purity also not high (92%).The alkoxylation in second step is under the condition of corresponding sodium alkyl alcohol, and is that product 2-amino-6-chloro-3-nitropyridine of solvent and the first step reacts with corresponding alkanol, obtains the purpose product.
The first step reaction:
The reaction of second step:
The yield also not high (70%) of this step reaction, the total recovery of two-step reaction also has only 20%, in the reaction owing to will use sodium alkoxide to make raw material, therefore to severe reaction conditions, raw material, solvent and equipment all need do not have water treatment, have brought inconvenience to suitability for industrialized production, have also increased production cost.
Summary of the invention
The present invention is directed to the problem that above 2-amino-6-alkoxyl group-3-nitropyridine synthetic method exists, propose a kind of with 2,6-two chloro-3-nitropyridines are starting raw material, and ammoniacal liquor, alkanol, mineral alkali are as the method for catalyzed reaction raw material-step Synthetic 2-amino-6-alkoxyl group-3-nitropyridine.The one-step synthesis technology of its 2-that adopts amino-6-alkoxyl group-3-nitropyridine, in the low pressure reaction still, carry out, ammoniacal liquor that disposable input ammoxidation and alkoxylation are required and corresponding alkanol and a certain amount of mineral alkali are made the catalyzed reaction raw material, under 90～150 ℃ of conditions, reacted 8～12 hours, can high yield and highly selective obtain purpose product 2-amino-6-alkoxyl group-3-nitropyridine.This method has simple, efficient and safe characteristics, has overcome the deficiency and the shortcoming of original method, satisfies the purpose and the demand of suitability for industrialized production fully.
The technical scheme that realizes the object of the invention is:
Synthetic compound involved in the present invention is:
R=CH wherein
3-, CH
3CH
2-, CH
3CH
2CH
2-, CH
3CH
2CH
2CH
2-, (CH
3)
2CH-, (CH
3)
3CCH
2-etc.Synthetic method is with 2, and 6-two chloro-3-nitropyridines are starting raw material, and adding a certain amount of amination raw material ammonia water and excessive alkoxylate raw material simultaneously is that corresponding alkanol is in the low pressure reaction still, and add an amount of mineral alkali as the catalyzed reaction raw material, under 90～150 ℃ of conditions, react after 8～12 hours, be cooled to normal temperature, standing over night, second day suction filtration, dry back ethyl alcohol recrystallization, and use activated carbon decolorizing, suction filtration, drying promptly gets product.Single step reaction synthesizes purpose product 2-amino-6-alkoxyl group-3-nitropyridine.That is:
The charging capacity of ammoniacal liquor is a starting raw material 2,1.5～3.0 times of 6-two chloro-3-nitropyridine mole numbers, and preferred range is 2.0～2.5 times.
The charging capacity of alkanol is a starting raw material 2,50～200 times of 6-two chloro-3-nitropyridine mole numbers, and preferred range is 100～150 times.
The charging capacity of mineral alkali is a starting raw material 2,1.5～2.5 times of 6-two chloro-3-nitropyridine mole numbers, and preferred range is 1.8～2.5 times.
The kind of alkanol includes: methyl alcohol, ethanol, propyl alcohol, Virahol and propyl carbinol etc.
Aforesaid method recrystallization method purifying purpose product, reaction yield 40%～70%, product purity＞98%.
Wherein said mineral alkali is sodium hydroxide, potassium hydroxide.
The invention has the beneficial effects as follows:
Applying for a patent WO2004092166 with document compares with method described in the US2004229861, the inventive method is by 2 equally, 6-two chloro-3-nitropyridines are that starting raw material sets out, main technique such as temperature of reaction, reaction pressure and reactant ratio by control-Ding influence parameter, employing-step synthesis method and avoid having used sodium alkoxide, make ammoxidation and alkoxylation occur in specified location simultaneously, high yield and the 2-amino that obtains comprising 2-amino-6-methoxyl group-3-nitropyridine-6-alkoxyl group-3-nitropyridine series product highly selective.Therefore this method has simple, efficient and safe characteristics, and the purpose product has 40%～70% yield, product purity＞98%.And only have about 20% by the yield of the synthetic purpose product of aforementioned documents method.
Embodiment
Embodiment 1
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (18.75 moles) methyl alcohol, 12.0 gram (0.3 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 18.1 restrains yield 65.1%, purity＞98%, fusing point: 166～168 ℃.
Embodiment 2
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (18.75 moles) methyl alcohol, 12.0 gram (0.3 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 15.0 grams (0.29 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 13.3 restrains yield 47.8%, purity＞98%, fusing point: 166～168 ℃.
Embodiment 3
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (18.75 moles) methyl alcohol, 18.0 gram (0.45 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, suction filtration, dry yellow powdery solid 13.3g, yield 47.9%, purity＞95%, the fusing point: 163～168 ℃ of getting.
Embodiment 4
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (18.75 moles) methyl alcohol, 17 gram (0.3 mole) potassium hydroxide are dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 8 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 18.3 restrains yield 65.3%, purity＞98%, fusing point: 166～168 ℃.
Embodiment 5
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (13.0 moles) ethanol, 12.0 gram (0.3 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 19.6 restrains yield 69.3%, purity＞98%, fusing point: 129～130 ℃.
Embodiment 6
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (10.0 moles) propyl alcohol, 12.0 gram (0.3 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 19.3 restrains yield 65.0%, purity＞98%, fusing point: 116～118 ℃.
Embodiment 7
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (10.0 moles) Virahols, 12.0 gram (0.3 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 11.0 restrains yield 36.7%, purity＞98%, fusing point: 123～125 ℃.
Embodiment 8
With 30.0 gram (0.155 moles) 2,6-two chloro-3-nitropyridines are dissolved in 600.0 gram (8.1 moles) propyl carbinols, 12.0 gram (0.3 mole) sodium hydroxide is dissolved in 112.5 gram water, and weighing 33% ammoniacal liquor 20.0 grams (0.39 mole), add in the lump in the low pressure reaction still, stirring is opened in sealing, be warming up to about 110 ℃ 10 hours reaction times.Be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, and suction filtration is dry that yellow powder needle-like solid 13.7 restrains yield 43.2%, purity＞98%, fusing point: 108～110 ℃.
Claims (4)
1.2-the one-step synthesis of amino-6-alkoxyl group-3-nitropyridine, it is characterized in that with 2,6-two chloro-3-nitropyridines are starting raw material, adding a certain amount of amination raw material ammonia water and excessive alkoxylate raw material simultaneously is that corresponding alkanol is in the low pressure reaction still, and add an amount of mineral alkali as the catalyzed reaction raw material, under 90～150 ℃ of conditions, react after 8～12 hours, be cooled to normal temperature, standing over night, second day suction filtration, ethyl alcohol recrystallization is used in dry back, and uses activated carbon decolorizing, suction filtration, drying promptly gets product; Wherein the charging capacity of ammoniacal liquor is a starting raw material 2,1.5～3.0 times of 6-two chloro-3-nitropyridine mole numbers, the charging capacity of alkanol is 50～200 times of above-mentioned starting raw material mole number, the charging capacity of mineral alkali is 1.5～2.5 times of above-mentioned starting raw material mole number, and the kind of alkanol is: methyl alcohol, ethanol, propyl alcohol, Virahol and propyl carbinol.
2. the one-step synthesis of 2-amino according to claim 1-6-alkoxyl group-3-nitropyridine, the charging capacity that it is characterized in that ammoniacal liquor is a starting raw material 2,2.0～2.5 times of 6-two chloro-3-nitropyridine mole numbers.
3. the one-step synthesis of 2-amino according to claim 1-6-alkoxyl group-3-nitropyridine, the charging capacity that it is characterized in that alkanol is a starting raw material 2,100～150 times of 6-two chloro-3-nitropyridine mole numbers.
4. the one-step synthesis of 2-amino according to claim 1-6-alkoxyl group-3-nitropyridine, the charging capacity that it is characterized in that mineral alkali is a starting raw material 2,1.8～2.5 times of 6-two chloro-3-nitropyridine mole numbers.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2005100954716A CN100371327C (en) | 2005-11-17 | 2005-11-17 | One-step synthesis of 2-amino-6-alkoxy-3-nitropyridine |
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| CNB2005100954716A CN100371327C (en) | 2005-11-17 | 2005-11-17 | One-step synthesis of 2-amino-6-alkoxy-3-nitropyridine |
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| CN100371327C true CN100371327C (en) | 2008-02-27 |
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| CN103060918B (en) * | 2011-10-21 | 2016-03-23 | 中国科学院福建物质结构研究所 | 2-amino-3-nitropyridine Bromide nonlinear optical crystal |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1453278A (en) * | 2002-04-23 | 2003-11-05 | 中国人民解放军军事医学科学院放射医学研究所 | Omprazole compound and its prepn and application |
| WO2004092166A2 (en) * | 2003-04-15 | 2004-10-28 | Merck & Co., Inc. | Cgrp receptor antagonists |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1453278A (en) * | 2002-04-23 | 2003-11-05 | 中国人民解放军军事医学科学院放射医学研究所 | Omprazole compound and its prepn and application |
| WO2004092166A2 (en) * | 2003-04-15 | 2004-10-28 | Merck & Co., Inc. | Cgrp receptor antagonists |
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Assignee: Changzhou Qiangli Chemical Co., Ltd. Assignor: Jiangsu Polytechnic University Contract fulfillment period: 2008.2.28 to 2015.2.27 contract change Contract record no.: 2008320000635 Denomination of invention: One-step synthesis method of 2-amido-6-alkoxy-3-nitropyridine Granted publication date: 20080227 License type: Exclusive license Record date: 2008.10.8 |
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Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.2.28 TO 2015.2.27; CHANGE OF CONTRACT Name of requester: CHANGZHOU CITY QIANGLI CHEMICAL ENGINEERING CO., L Effective date: 20081008 |
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