CN102675198B - One kind prepares and purifies the method for the formamide of 4 (4 amino-benzene oxygen) N picolines 2 - Google Patents
One kind prepares and purifies the method for the formamide of 4 (4 amino-benzene oxygen) N picolines 2 Download PDFInfo
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- CN102675198B CN102675198B CN201210152043.2A CN201210152043A CN102675198B CN 102675198 B CN102675198 B CN 102675198B CN 201210152043 A CN201210152043 A CN 201210152043A CN 102675198 B CN102675198 B CN 102675198B
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- formamides
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- benzene oxygens
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Abstract
The invention discloses a kind of method for preparing and purifying the formamide (I) of 4 (4 amino-benzene oxygen) N picolines of Sorafenib key intermediate 2.
Description
Technical field
The present invention relates to one kind to prepare and purify Sorafenib key intermediate 4- (4- amino-benzene oxygens)-N- methyl pyrroles
The method of pyridine -2- formamides (I).
Background technology
Sorafenib (II) is a kind of multi-kinase inhibitor, and by Bayer Bitterfeld GmbH, drugmaker succeeds in developing.Sorafenib is
A kind of new Mutiple Targets antineoplastic, there is dual GVT, both can be by blocking by the thin of RAF/MEK/ERK mediations
Born of the same parents' signal transduction pathway and directly suppress the propagation of tumour cell, can also be by suppressing VEGF and platelet derived growth factor
(PDGF) acceptor and block tumor neovasculature formation, indirectly suppress tumour cell growth.
There are many documents to describe the synthesis of Sorafenib with patent at present, in these synthetic routes, mostly by 4- (4-
Amino-benzene oxygen) the important intermediate of-N- picoline -2- formamides (I) as synthesis Sorafenib.
Such as CN 1721397A, US 2002165394, US 2003105091, US 2003144278, US
2009068146th, OPRD 2,002 777 etc. describes compound (II) preparation method, and this method can use following scheme table
Show：
But under study for action it was found that the Sorafenib (II) obtained according to prior art not only yield is not high, and
Purity is bad, it is necessary to which fine purification can be only achieved requirement.Its reason is analyzed, problem mainly appears on intermediate (I) preparation.
According to prior art, in the presence of potassium tert-butoxide/potassium carbonate, the conversion ratio of compound (III) prepare compound (I) is not high, leads
Cause a large amount of starting material lefts, strong influence prepares intermediate (I) yield.In order to improve conversion, it is necessary to extend the reaction time,
Industry's enlarging production is caused to take.
Secondly according to prior art, obtained intermediate (I) purity is all undesirable, and directly compound (I) is carried out
Purification has higher difficulty, and these largely have impact on the yield and purity of Sorafenib (II).
The content of the invention
The first aspect of the present invention provides one kind and prepares Sorafenib key intermediate 4- (4- aminobenzene oxygen in high yield
Base)-N- picoline -2- formamides (I) method, comprise the following steps：
(a) PAP (IV) and potassium tert-butoxide are reacted to obtain mixture in organic solvent, and organic solvent is selected from
DMA、DMF、THF；
(b) N- methyl -4- Chloro-2-Pyridyles formamides (III) and highly basic are added in said mixture, reaction obtains 4- (4-
Amino-benzene oxygen)-N- picoline -2- formamides (I), wherein highly basic is selected from potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, hydrogen
Sodium oxide molybdena,
Reaction equation is as follows：
It is of the present invention to prepare corresponding 4- with PAP (IV) from N- methyl -4- Chloro-2-Pyridyles formamides (III)
The reaction of (4- amino-benzene oxygens)-N- picoline -2- formamides (I) needs to use potassium tert-butoxide and highly basic, and needs to divide
Two stages add.The potassium tert-butoxide and the mol ratio of compound (IV) that first stage adds are between 3: 1~1: 2；Second-order
The highly basic and the mol ratio of compound (IV) that section adds are between 1: 1~3: 1.Alkali adds at twice, and existing with highly basic replacement
The potassium carbonate used in technology, substantially increases reaction speed.
According to one embodiment of present invention, from N- methyl -4- Chloro-2-Pyridyles formamides (III) and PAP
(IV) operating process of the reaction of corresponding 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I) is prepared substantially such as
Under：
PAP (IV), potassium tert-butoxide and solvent are added in reaction bulb, at room temperature, is stirred 2 hours；Then according to
Secondary addition N- methyl -4- Chloro-2-Pyridyles formamides (III), second part of highly basic, temperature reaction 1-24 hours；Add water and acetic acid
Ethyl ester is extracted, and liquid separation obtains organic phase；Viscous brown thing 4- (4- amino-benzene oxygens)-N- first is obtained after removal of solvent under reduced pressure
Yl pyridines -2- formamides (I).
The second aspect of the invention provides a kind of purifying 4- (4- amino-benzene oxygens)-N- picoline -2- formamides
(I) method, is comprised the steps of：
(a) 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I) are reacted with oxalic acid in organic solvent
To 4- (4- amino-benzene oxygens)-N- picoline -2- formamides oxalates (V),
(b) it is selective, oxalates (V) is further purified with suitable organic solvent,
(c) gained oxalates (V) is neutralized with alkali in a solvent, and isolated 4- (4- amino-benzene oxygens)-N- picolines-
2- formamides (I).
In above-mentioned purge process, preferable scheme：
In step (a), the organic solvent is selected from ethyl acetate, dichloromethane, chloroform, dioxane, ether, different
The tertiary ether of propyl ether, first, toluene, tetrahydrofuran, methanol, ethanol, ethyl acetate.
In step (b), purifying solvent for use is selected from methanol, ethanol, isopropanol.
In step (c), neutralization is that the in the mixed solvent that water and suitable organic solvent are formed is carried out, and selected has
Solvent is：Ethyl acetate, dichloromethane, chloroform, ether, isopropyl ether, methyl tertiary butyl ether(MTBE).What neutralization reaction used
Alkali, it is selected from：Potassium carbonate, sodium carbonate, sodium acid carbonate, sodium hydroxide, potassium hydroxide.
According to one embodiment of present invention, the operating process of above-mentioned purge process approximately as：
In reaction bulb add 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I) crude product, organic acid and
Organic solvent, stirring make it fully dissolve, and stir at a suitable temperature 1-24 hours, and solid separates out；Filtering, obtains solid；
White solid 4- (4- amino-benzene oxygens)-N- methyl is obtained after obtained solid is recrystallized in suitable organic solvent
Pyridine-2-carboxamide acid salt (V)；By 4- (4- amino-benzene oxygens)-N- picoline -2- formamides acid salt (V), alkali, water
And organic solvent mixing, at a suitable temperature, stir 1-24 hours；Organic phase is separated, organic phase depressurizes remove after drying
Organic solvent is removed, obtains 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I) sterling.
New intermediate 4- (4- amino-benzene oxygens)-N- picoline -2- formamide oxalates that the present invention also provides
(V)。
Prior art is disclosed with hydrochloric acid and crude product (I) into salt refining, but practical operation is not easy into salt, and due to system
In it is aqueous so that yield is relatively low.The present invention is using oxalic acid in organic solvent into salt, it was surprisingly found that is very easy into salt
And Precipitation in organic solvent, therefore easily separated, high income.
As a preferable scheme, the invention provides a kind of preparing in Sorafenib key with high-purity high-yield
The method of mesosome 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I), comprises the following steps：
(a) in DMF, PAP (IV) reacts to obtain mixture with potassium tert-butoxide,
(b) N- methyl -4- Chloro-2-Pyridyles formamides (III) and highly basic are added into said mixture, reaction obtains 4-
(4- amino-benzene oxygens)-N- picoline -2- formamides (I),
(c) (I) obtains 4- (4- amino-benzene oxygens)-N- picoline -2- formamides in ethyl acetate with oxalic acid into salt
Oxalates (V),
(d) it is selective, further recrystallized with ethanol (V),
(e) gained oxalates (V) in the in the mixed solvent alkali of water and ethyl acetate and, the 4- of isolated high-purity
(4- amino-benzene oxygens)-N- picoline -2- formamides (I).
Embodiment
Technical scheme is further illustrated with specific embodiment below, but protection scope of the present invention is not limited to
This：
Comparative example：The synthesis of 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I)
At room temperature, 800g para-aminophenol and 830g potassium tert-butoxides are added into 8L DMF, stirs 2h.Add
1250gN- methyl -4- Chloro-2-Pyridyles formamides (III) and 1012g potassium carbonate, after be warming up to 80 DEG C of reaction 12h, HPLC shows
Show that also 65% raw material is not converted.Continue reaction to 24h, HPLC shows raw material still residue 50%, abandons reacting.
Embodiment one：The synthesis of 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I)
At room temperature, 800g para-aminophenol and 830g potassium tert-butoxides are added into 8L DMF, stirs 2h.Add
1250g N- methyl -4- Chloro-2-Pyridyles formamides (III) and 830g potassium tert-butoxides, after be warming up to 80 DEG C of reaction 8h, HPLC shows
Show that material content is less than 1%.Room temperature is cooled to, adds 8L water, and 10L ethyl acetate, liquid separation obtain organic phase.Aqueous phase uses 10L again
Ethyl acetate extracts, and merges organic phase after liquid separation.After organic phase is dried with anhydrous magnesium sulfate, removal of solvent under reduced pressure obtains 1550g palm fibres
Brown viscous thing 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I).
Embodiment two：The synthesis of 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I)
At room temperature, 800g para-aminophenol and 830g potassium tert-butoxides are added into 8L DMF, stirs 2h.Add
1250gN- methyl -4- Chloro-2-Pyridyles formamides (III) and 411g potassium hydroxide, after be warming up to 80 DEG C of reaction 8h, HPLC shows
Show that material content is less than 1%.Room temperature is cooled to, adds 8L water, and 10L ethyl acetate, liquid separation obtain organic phase.Aqueous phase uses 10L again
Ethyl acetate extracts, and merges organic phase after liquid separation.After organic phase is dried with anhydrous magnesium sulfate, removal of solvent under reduced pressure obtains 1700g palm fibres
Color dope 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I).
The synthesis of the 4- of embodiment three (4- amino-benzene oxygens)-N- picoline -2- formamides acid salt (V)
Viscous brown thing in embodiment two is dissolved in 8L ethyl acetate.880g oxalic acid is added, is analysed after 24h is stirred at room temperature
Go out a large amount of solids.Solid is filtered to obtain, 2300g solids are obtained after drying.This solid is recrystallized in ethanol, 2150g is obtained after drying
White solid 4- (4- amino-benzene oxygens)-N- picoline -2- formamides acid salt (V), two-step reaction yield 88%, purity
99.9%.
The preparation of example IV 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I) sterling
2000g 4- (4- amino-benzene oxygens)-N- picoline -2- formamides acid salt (V) is added to 15L acetic acid second
The in the mixed solvent of ester and 15L water composition.500g sodium acid carbonates are added, 1h is stirred at room temperature.Liquid separation, obtain organic phase.Organic phase passes through
After drying, organic solvent is removed under reduced pressure and produces 1385g 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I) sterling,
Yield 95%, purity 99.9%.
Claims (5)
1. the method that one kind prepares 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (I), comprises the following steps：
(a) PAP (IV) and potassium tert-butoxide react to obtain mixture in organic solvent, and the organic solvent is DMF,
Wherein the mol ratio of potassium tert-butoxide and compound (IV) is 3:1~1:2；
(b) N- methyl -4- Chloro-2-Pyridyles formamides (III) and highly basic are added into said mixture, reaction obtains 4- (4- ammonia
Phenoxyl)-N- picoline -2- formamides (I), the highly basic is selected from potassium hydroxide, the highly basic and compound (IV) of addition
Mol ratio 1:1~3:1；
(c) 4- (4- the amino-benzene oxygens)-N- picoline -2- formamides (I) obtained the method for step (b) are in organic solvent
In react to obtain 4- (4- amino-benzene oxygens)-N- picoline -2- formamides oxalates (V) with oxalic acid,
(d) it is selective, oxalates (V) is further purified with suitable organic solvent,
(e) gained oxalates (V) is neutralized with alkali in a solvent, isolated 4- (4- amino-benzene oxygens)-N- picoline -2- first
Acid amides (I).
2. according to the method for claim 1, wherein step (c) organic solvent is selected from ethyl acetate, dichloromethane, three
The tertiary ether of chloromethanes, dioxane, ether, isopropyl ether, first, toluene, tetrahydrofuran, methanol, ethanol.
3. according to the method for claim 1, wherein organic solvent used in step (d) is selected from methanol, ethanol, isopropanol.
4. according to the method for claim 1, wherein step (e) solvent for use is that the mixing that water and organic solvent form is molten
Agent, organic solvent are selected from ethyl acetate, dichloromethane, chloroform, ether, isopropyl ether, methyl tertiary butyl ether(MTBE).
5. according to the method for claim 1, wherein alkali used in step (e) is selected from sodium acid carbonate, potassium carbonate, sodium carbonate, hydrogen
Sodium oxide molybdena, potassium hydroxide.
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| CN201210152043.2A CN102675198B (en) | 2012-05-10 | 2012-05-10 | One kind prepares and purifies the method for the formamide of 4 (4 amino-benzene oxygen) N picolines 2 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101220024A (en) * | 2007-12-11 | 2008-07-16 | 杜晓敏 | A set of anti-cancer compound restraining kinase |
| CN101260106A (en) * | 2007-03-06 | 2008-09-10 | 中国药科大学 | Raf kinase inhibitor, preparing method and use thereof |
| CN101674833A (en) * | 2007-03-20 | 2010-03-17 | 柯瑞斯公司 | Raf kinase inhibitors containing a zinc binding moiety |
-
2012
- 2012-05-10 CN CN201210152043.2A patent/CN102675198B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101260106A (en) * | 2007-03-06 | 2008-09-10 | 中国药科大学 | Raf kinase inhibitor, preparing method and use thereof |
| CN101674833A (en) * | 2007-03-20 | 2010-03-17 | 柯瑞斯公司 | Raf kinase inhibitors containing a zinc binding moiety |
| CN101220024A (en) * | 2007-12-11 | 2008-07-16 | 杜晓敏 | A set of anti-cancer compound restraining kinase |
Non-Patent Citations (2)
| Title |
|---|
| 42(42氨基苯氧基) 222(烷基氨甲酰基)吡啶的合成;闫凤美等;《化学研究与应用》;20101231;第22卷(第12期);1601-1604 * |
| Sorafenib硫脲衍生物的合成及活性研究;杨照等;《药学学报》;20111231;第46卷(第9期);1093-1097 * |
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Address after: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee after: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Patentee after: Shanghai Aobo biomedical Co.,Ltd. Address before: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee before: ZHEJIANG HUAHAI PHARMACEUTICAL Co.,Ltd. Patentee before: Shanghai Aobo Biomedical Technology Co.,Ltd. |
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