CN106699650A - Preparation method of high-purity 5-methyl-nicotinic acid - Google Patents
Preparation method of high-purity 5-methyl-nicotinic acid Download PDFInfo
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- CN106699650A CN106699650A CN201611075131.1A CN201611075131A CN106699650A CN 106699650 A CN106699650 A CN 106699650A CN 201611075131 A CN201611075131 A CN 201611075131A CN 106699650 A CN106699650 A CN 106699650A
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a preparation method of high-purity 5-methyl-nicotinic acid. The preparation method comprises the steps of adopting pollution-free water as a solvent, adopting 3,5-dimethyl pyridine as a starting material, adopting potassium permanganate as an oxidizing agent, reacting under mild conditions, and preparing a target product through one-step reaction, wherein the potassium permanganate as a strong oxidant, so that a by-product 3,5-dipicolinic acid is generated inevitably. A unique post-processing method is adopted in the process, and the target product and the by-product are effectively separated by adopting the solubility difference of the target product and the by-product under different pH (Potential Of Hydrogen) value conditions, so that the purity of a crude product can reach not less than 98.5 percent, the purity after refining can reach less than 99 percent, and the quality of similar products at home and abroad is at the leading level.
Description
Technical field
The present invention relates to a kind of chemical field, more particularly to a kind of preparation method of high-purity 5- methylnicotinic acids.
Background technology
5- methylnicotinic acids are important pharmaceutical intermediates, for preparing the medicines such as Claritin Rupatadine fumarate in
Mesosome.5- methylnicotinic acids are generally obtained by 3,5- lutidines through potassium permanganate oxidation.Such as J.Org.Chem.1988,53,
3513-3521 and J.Med.Chem.1994,37,2697-2703.Pharmacy is in progress, and 2005,29 (1)：31-33 passes through orthogonal test
The technique is improved, yield is brought up to 51%.But the method has the following disadvantages：(1) selectivity of oxidation is not high,
5- methylnicotinic acids and pyridine -3,5- dicarboxylic acids can be generated simultaneously to separate both, it is necessary to pass through to adjust pH；And reaction yield is usual
Below 50%；(2) because the water solubility of potassium permanganate is general, reaction needs to use substantial amounts of water, causes single batch of yield very low；
(3) manganese dioxide for being produced in course of reaction is more difficult to filter, is difficult to amplify；(4) for production scale, potassium permanganate is used as oxidation
Agent it is relatively costly.In view of disadvantages described above, it is necessary to which the preparation method is further studied.
The content of the invention
Based on the technical problem that background technology is present, the present invention proposes a kind of preparation side of high-purity 5- methylnicotinic acids
Method.
Technical scheme is as follows：
A kind of preparation method of high-purity 5- methylnicotinic acids, comprises the following steps：
A, to adding running water in reactor, then squeeze into 3,5- lutidines, stir, between 25-35 DEG C of temperature control, and
4-5h adds potassium permanganate, is then incubated 30 DEG C of reaction 15-18h；
B, filter core filter by-product manganese dioxide, and filtrate concentrated hydrochloric acid regulation pH is 0.3-0.6；
C, centrifugation filter by-product 3,5- pyridinedicarboxylic acids, and filtrate continuation concentrated hydrochloric acid regulation PH is 2.5-3.2, is collected by centrifugation
Crude product；
D, drying, crude product ethanol are heated to 75-85 DEG C of dissolving, heat filtering, and filtrate is cooled to 0-5 DEG C of stirring 1.5-
2.5h, centrifugation, in drying 8-10h at 60-70 DEG C, you can.
Preferably, in described step B, described concentrated hydrochloric acid regulation pH is 0.5.
Preferably, in described step C, described concentrated hydrochloric acid regulation pH is 3.0.
Chemical equation of the invention is as follows：
The present invention is advantageous in that：It is solvent, 3,5- dimethyl that preparation method of the invention uses free of contamination water
Pyridine is initiation material, and potassium permanganate is oxidant, is reacted in a mild condition, and single step reaction prepares target product, due to height
Potassium manganate is strong oxidizer, inevitably generates accessory substance 3, and 5- pyridinedicarboxylic acids employ the rear place of uniqueness in this technique
Reason method, employs target product and the accessory substance difference of solubility under different pH condition and it is effectively separated, slightly
Up to more than 98.5%, purity is at home and abroad in a leading position product purity more up to more than 99% in like product quality after refining
Level.
Specific embodiment
Embodiment 1：
A kind of preparation method of high-purity 5- methylnicotinic acids, comprises the following steps：
A, to 1200L running water is added in 2000L enamel reaction stills, then squeeze into 3,5- lutidines 120kg, stir,
Between 25-35 DEG C of temperature control, and 300kg potassium permanganate is added with 4.5h, be then incubated 30 DEG C of reaction 16h；
B, filter core filter by-product manganese dioxide, and filtrate adjusts pH0.5 with concentrated hydrochloric acid；
C, centrifugation filter by-product 3, and 5- pyridinedicarboxylic acids, filtrate continuation adjusts PH3.0, crude product is collected by centrifugation with concentrated hydrochloric acid；
D, drying, crude product 1200L ethanol are heated to 80 DEG C of dissolvings, heat filtering, and filtrate is cooled to 0-5 DEG C of stirring 2h, from
The heart, in drying 8.5h at 65 DEG C, you can.The purity of final product is 99.5%.
Embodiment 2：
A kind of preparation method of high-purity 5- methylnicotinic acids, comprises the following steps：
A, to 1200L running water is added in 2000L enamel reaction stills, then squeeze into 3,5- lutidines 120kg, stir,
Between 25-35 DEG C of temperature control, and 300kg potassium permanganate is added with 5h, be then incubated 30 DEG C of reaction 15-18h；
B, filter core filter by-product manganese dioxide, and filtrate adjusts pH0.3 with concentrated hydrochloric acid；
C, centrifugation filter by-product 3, and 5- pyridinedicarboxylic acids, filtrate continuation adjusts PH3.2, crude product is collected by centrifugation with concentrated hydrochloric acid；
D, drying, crude product 1200L ethanol are heated to 75 DEG C of dissolvings, heat filtering, and filtrate is cooled to 5 DEG C of stirring 1.5h, from
The heart, in drying 8h at 70 DEG C, you can.The purity of final product is 99.3%.
Embodiment 3：
A kind of preparation method of high-purity 5- methylnicotinic acids, comprises the following steps：
A, to 1200L running water is added in 2000L enamel reaction stills, then squeeze into 3,5- lutidines 120kg, stir,
Between 25-35 DEG C of temperature control, and 300kg potassium permanganate is added with 4h, be then incubated 30 DEG C of reaction 15-18h；
B, filter core filter by-product manganese dioxide, and filtrate adjusts pH0.6 with concentrated hydrochloric acid；
C, centrifugation filter by-product 3, and 5- pyridinedicarboxylic acids, filtrate continuation adjusts PH2.5, crude product is collected by centrifugation with concentrated hydrochloric acid；
D, drying, crude product 1200L ethanol are heated to 85 DEG C of dissolvings, heat filtering, and filtrate is cooled to 0 DEG C of stirring 2.5h, from
The heart, in drying 10h at 60 DEG C, you can.The purity of final product is 99.3%.
Comparative example 1
PH in step B in embodiment 1 is adjusted, its influence to final product purity is studied.
| pH | 0.2 | 0.3 | 0.4 | 0.5 | 0.6 | 0.7 |
| Purity % | 99.5 | 99.5 | 99.5 | 99.5 | 99.4 | 99.0 |
By above detection data it is recognised that pH is adjusted to after 0.5, then pH is reduced, the purity to final product does not have
Directly affect, therefore consider cost, the pH of optimization is 0.5.
Comparative example 2
PH in step C in embodiment 1 is adjusted, its influence to final product purity is studied.
| pH | 2.2 | 2.5 | 2.7 | 3.0 | 3.2 | 3.4 |
| Purity % | 99.5 | 99.5 | 99.5 | 99.5 | 99.3 | 99.1 |
By above detection data it is recognised that pH is adjusted to after 3.0, then pH is reduced, the purity to final product does not have
Directly affect, therefore consider cost, the pH of optimization is 3.0.
This detection data is just for above-mentioned detection sample.
The above, the only present invention preferably specific embodiment, but protection scope of the present invention is not limited thereto,
Any one skilled in the art the invention discloses technical scope in, technology according to the present invention scheme and its
Inventive concept is subject to equivalent or change, should all be included within the scope of the present invention.
Claims (3)
1. a kind of preparation method of high-purity 5- methylnicotinic acids, it is characterised in that comprise the following steps：
A, to adding running water in reactor, then squeeze into 3,5- lutidines, stir, between 25-35 DEG C of temperature control, and in 4-5h
Potassium permanganate is added, 30 DEG C of reaction 15-18h are then incubated；
B, filter core filter by-product manganese dioxide, and filtrate concentrated hydrochloric acid regulation pH is 0.3-0.6；
C, centrifugation filter by-product 3,5- pyridinedicarboxylic acids, and filtrate continuation concentrated hydrochloric acid regulation PH is 2.5-3.2, is collected by centrifugation thick
Product；
D, drying, crude product ethanol are heated to 75-85 DEG C of dissolving, heat filtering, and filtrate is cooled to 0-5 DEG C of stirring 1.5-2.5h, from
The heart, in drying 8-10h at 60-70 DEG C, you can.
2. the preparation method of high-purity 5- methylnicotinic acids as claimed in claim 1, it is characterised in that in described step B, institute
The concentrated hydrochloric acid regulation pH for stating is 0.5.
3. the preparation method of high-purity 5- methylnicotinic acids as claimed in claim 1, it is characterised in that in described step C, institute
The concentrated hydrochloric acid regulation pH for stating is 3.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611075131.1A CN106699650A (en) | 2016-11-30 | 2016-11-30 | Preparation method of high-purity 5-methyl-nicotinic acid |
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| CN201611075131.1A CN106699650A (en) | 2016-11-30 | 2016-11-30 | Preparation method of high-purity 5-methyl-nicotinic acid |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558043A (en) * | 2012-01-13 | 2012-07-11 | 江苏中邦制药有限公司 | Combining method of 5-methyl-niacin |
| CN102584695A (en) * | 2012-01-13 | 2012-07-18 | 江苏中邦制药有限公司 | Preparing method of 5-methylnicotinicacid |
-
2016
- 2016-11-30 CN CN201611075131.1A patent/CN106699650A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558043A (en) * | 2012-01-13 | 2012-07-11 | 江苏中邦制药有限公司 | Combining method of 5-methyl-niacin |
| CN102584695A (en) * | 2012-01-13 | 2012-07-18 | 江苏中邦制药有限公司 | Preparing method of 5-methylnicotinicacid |
Non-Patent Citations (6)
| Title |
|---|
| ELENA CARCELLER,等: "[(3-Pyridylalkyl)piperidylidene]benzocycloheptapyridine Derivatives as Dual Antagonists of PAF and Histamine", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| EVAN P. KYBA,等: "A General Synthesis of Substituted Fluorenones and Azafluorenones", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 倪生良: "卢帕他定中间体5-甲基烟酸的合成", 《内蒙古石油化工》 * |
| 张楠,等: "附载型高锰酸钾/三氧化二铝对2,6-二甲基吡啶选择氧化的研究", 《广东化工》 * |
| 王震宇,等: "卢帕他定中间体5-甲基吡啶-3-羧酸的合成工艺改进", 《药学进展》 * |
| 陈建华,等: "富马酸卢帕他定的合成", 《中国医药工业杂志》 * |
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Application publication date: 20170524 |
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| RJ01 | Rejection of invention patent application after publication |