CN103694145B - The synthetic method of (2-methyl-5-nitrophenyl) guanidine sulfate - Google Patents
The synthetic method of (2-methyl-5-nitrophenyl) guanidine sulfate Download PDFInfo
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Abstract
The invention belongs to medicine intermediate technical field, particularly the synthetic method of a kind of imatinib mesylate intermediate (2-methyl-5-nitrophenyl) guanidine sulfate.With 2-amino-4-nitrotoluene and oxygen Methyl Isourea Sulfate for raw material, in ethanol and DMF, react under alkaline condition, then through acid adjustment, suction filtration, (2-methyl-5-nitrophenyl) guanidine sulfate.Adopt oxygen Methyl Isourea Sulfate to replace cyanamide to react, raw material is easy to get, and reaction conditions is simple, and be not difficult to the by product processed, product purity is high, and high purity more than 99.7%, yield is high.
Description
Technical field
The invention belongs to medicine intermediate technical field, particularly the synthetic method of a kind of imatinib mesylate intermediate (2-methyl-5-nitrophenyl) guanidine sulfate.
Background technology
(2-methyl-5-nitrophenyl) guanidine sulfate is the important intermediate of synthesizing methanesulfonic acid imatinib, the chemical name of imatinib mesylate is 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl benzenamine mesylate, it is a kind of kinases inhibitor, be first binding mode (MOA) suppressed with protein kinase, play the marketed drug that sensing inhibitor (STI) acts on.
The structural formula of (2-methyl-5-nitrophenyl) guanidine is as follows:
The synthesizing with amino-4 nitrotoluenes of 2-for raw material of (2-methyl-5-nitrophenyl) guanidine in prior art, react with cyanamide and generate, operational path is as follows:
The shortcoming of this technology is: cyanamide method often needs special condition, long reaction time, and cyanamide has severe toxicity, and unstable, be easily condensed into Dyhard RU 100, cause product purity low, yield is low.
Summary of the invention
The object of this invention is to provide the synthetic method of one (2-methyl-5-nitrophenyl) guanidine sulfate, adopt oxygen Methyl Isourea Sulfate to replace cyanamide to react, raw material is easy to get, reaction conditions is simple, be not difficult to the by product processed, product purity is high, and yield is high.
The synthetic method of (2-methyl-5-nitrophenyl) of the present invention guanidine sulfate, with 2-amino-4-nitrotoluene and oxygen Methyl Isourea Sulfate for raw material, in ethanol and DMF, react under alkaline condition, then through acid adjustment, suction filtration, (2-methyl-5-nitrophenyl) guanidine sulfate is obtained.
The mol ratio of 2-amino-4-nitrotoluene and oxygen Methyl Isourea Sulfate is 1.0:1.0 ~ 1.1.
The feed ratio of ethanol and 2-amino-4-nitrotoluene is 30 ~ 40:20, wherein ethanol in mL, 2-amino-4-nitrotoluene in g.The feed ratio of DMF and 2-amino-4-nitrotoluene is 5 ~ 10:20, wherein DMF in mL, 2-amino-4-nitrotoluene in g.Be used alone solute effect when ethanol makees solvent poor, if only make solvent with DMF, its cost is higher and be also unfavorable for the recycling in later stage, so the present invention adopts ethanol and DMF to make mixed solvent, the carrying out that solute effect impels reaction can either be reached, again save cost.
Alkaline condition is pH is 9 ~ 13, and when the less reaction of pH value is slower, when pH value is less than 9, sluggish, reaction required time is long, if when pH is greater than 13, affects the stability of product.
Alkaline condition alkali used is the one in sodium hydroxide, sodium carbonate or ammoniacal liquor.
Reaction times is 3 ~ 8h.Reacted rear acid adjustment, acid adjustment is for be adjusted to 6 ~ 7 by pH, and pH value, in the scope of this partial neutral, is conducive to the purity improving product.
Compared with prior art, the present invention has the following advantages:
Adopt oxygen Methyl Isourea Sulfate to replace cyanamide to react, raw material is easy to get, and reaction conditions is simple, and be not difficult to the by product processed, product purity is high, and high purity more than 99.7%, yield is high.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
By 20g(0.131mol) amino-4 nitrotoluenes of 2-add there-necked flask, add 30ml ethanol, 8mlDMF, by 10%NaOH alkali tune to pH=12, stir 20min, add 33g(0.134mol) oxygen Methyl Isourea Sulfate, be heated to backflow, reaction 5h; After reaction terminates, use 8%H
2sO
4acid adjustment, to pH=6.5, is then incubated 40min; Insulation terminates, and is cooled to 0 DEG C, suction filtration, and by 120ml washing with alcohol twice, dry, obtain solid product 31.16g, purity is 99.7%, yield 83.0%.
Embodiment 2
By 20g(0.131mol) amino-4 nitrotoluenes of 2-add there-necked flask, add 35ml ethanol, 6mlDMF, with 25% ammoniacal liquor alkali tune to pH=11, stir 30min, add 32g(0.131mol) oxygen Methyl Isourea Sulfate, be heated to backflow, react 6h; After reaction terminates, use 10%H
2sO
4acid adjustment, to pH=7.0, is then incubated 30min; Insulation terminates, and is cooled to 0 DEG C, suction filtration, and by 100ml washing with alcohol twice, dry, obtain solid product 31.85g, purity is 99.8%, yield 81.2%.
Embodiment 3
By 20g(0.131mol) amino-4 nitrotoluenes of 2-add there-necked flask, add 38ml ethanol, 5mlDMF, with 25% ammoniacal liquor alkali tune to pH=13, stir 30min, add 35g(0.144mol) oxygen Methyl Isourea Sulfate, be heated to backflow, react 8h; After reaction terminates, use 10%H
2sO
4acid adjustment, to pH=6.0, is then incubated 30min; Insulation terminates, and is cooled to 0 DEG C, suction filtration, and by 100ml washing with alcohol twice, dry, obtain solid product 32.62g, purity is 99.9%, yield 85.0%.
Embodiment 4
By 20g(0.131mol) amino-4 nitrotoluenes of 2-add there-necked flask, add 40ml ethanol, 10mlDMF, with 25% ammoniacal liquor alkali tune to pH=9, stir 30min, add 35g(0.144mol) oxygen Methyl Isourea Sulfate, be heated to backflow, react 3h; After reaction terminates, use 10%H
2sO
4acid adjustment, to pH=7.0, is then incubated 30min; Insulation terminates, and is cooled to 0 DEG C, suction filtration, and by 100ml washing with alcohol twice, dry, obtain solid product 33.58g, purity is 99.8%, yield 87.5%.
Claims (1)
1. the synthetic method of one kind (2-methyl-5-nitrophenyl) guanidine sulfate, it is characterized in that: amino for 20g2--4 nitrotoluenes are added there-necked flask, add 38ml ethanol, 5mlDMF, by 25% ammoniacal liquor alkali tune to pH=13, stir 30min, add 35g oxygen Methyl Isourea Sulfate, be heated to backflow, reaction 8h; After reaction terminates, use 10%H
2sO
4acid adjustment, to pH=6.0, is then incubated 30min; Insulation terminates, and is cooled to 0 DEG C, suction filtration, by 100ml washing with alcohol twice, dries, obtains solid product.
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| JP2020002108A (en) * | 2018-06-29 | 2020-01-09 | 住友化学株式会社 | Manufacturing method of benzoic acid compound |
| CN113636958A (en) * | 2021-08-09 | 2021-11-12 | 江苏八巨药业有限公司 | Preparation method of 2-methyl-5-nitrophenylguanidine |
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| WO2008070350A2 (en) * | 2006-10-27 | 2008-06-12 | The Board Of Regents Of The University Of Texas System | Methods and compositions related to wrapping of dehydrons |
| CN101528700A (en) * | 2006-11-16 | 2009-09-09 | 意大利合成制造有限公司 | Process for the preparation of Imatinib and intermediates thereof |
| CN101717352A (en) * | 2009-11-30 | 2010-06-02 | 浙江工业大学 | Method for synthesizing agmatine sulfate |
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| CN102015678A (en) * | 2008-01-25 | 2011-04-13 | 霍夫曼-拉罗奇有限公司 | Fused pyridines active as inhibitors of c-Met |
| CN102796110A (en) * | 2011-05-23 | 2012-11-28 | 复旦大学 | Aniline pyrimidine compound and preparation method and application thereof |
| CN102911157A (en) * | 2011-08-02 | 2013-02-06 | 沈阳药科大学 | (E)-3-[2-bromo-5-(3-substituted propoxy)]phenyl-N-{4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl acrylamide compound |
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Patent Citations (7)
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|---|---|---|---|---|
| WO2008070350A2 (en) * | 2006-10-27 | 2008-06-12 | The Board Of Regents Of The University Of Texas System | Methods and compositions related to wrapping of dehydrons |
| CN101528700A (en) * | 2006-11-16 | 2009-09-09 | 意大利合成制造有限公司 | Process for the preparation of Imatinib and intermediates thereof |
| CN102015678A (en) * | 2008-01-25 | 2011-04-13 | 霍夫曼-拉罗奇有限公司 | Fused pyridines active as inhibitors of c-Met |
| WO2011039782A1 (en) * | 2009-09-29 | 2011-04-07 | Ind-Swift Laboratories Limited | Processes for preparing imatinib and pharmaceutically acceptable salts thereof |
| CN101717352A (en) * | 2009-11-30 | 2010-06-02 | 浙江工业大学 | Method for synthesizing agmatine sulfate |
| CN102796110A (en) * | 2011-05-23 | 2012-11-28 | 复旦大学 | Aniline pyrimidine compound and preparation method and application thereof |
| CN102911157A (en) * | 2011-08-02 | 2013-02-06 | 沈阳药科大学 | (E)-3-[2-bromo-5-(3-substituted propoxy)]phenyl-N-{4-methyl-3-[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl acrylamide compound |
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Denomination of invention: Synthesis of (2-methyl-5-nitrophenyl) guanidine sulfate Effective date of registration: 20211216 Granted publication date: 20160210 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |
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Date of cancellation: 20220721 Granted publication date: 20160210 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |