CN104402813B - Novel method for synthesizing sorafenib - Google Patents
Novel method for synthesizing sorafenib Download PDFInfo
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- CN104402813B CN104402813B CN201410777342.4A CN201410777342A CN104402813B CN 104402813 B CN104402813 B CN 104402813B CN 201410777342 A CN201410777342 A CN 201410777342A CN 104402813 B CN104402813 B CN 104402813B
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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
- C07D213/81—Amides; Imides
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Abstract
The invention discloses a novel method for synthesizing sorafenib. The method comprises the following steps: using a (4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide) compound II and a (4-chloro-3-trifluoromethylphenyl-carbamoyl-imidazole) compound III as raw materials, and reacting in an organic solvent inert to the compound III to produce a sorafenib crude product; then, dissolving the sorafenib crude product by the organic solvent and an organic or inorganic acid, and adding a solvent into which sorafenib is difficult to dissolve to enable the sorafenib to be separated out, so as to obtain a sorafenib pure product. The novel method is simple in technical process, ensures high product purity, facilitates operation and is suitable for large-scale industrial production.
Description
Technical field
The present invention relates to medical compounds preparing technical field, more particularly to Sorafenib preparing technical field, more specifically
Ground, is related to the synthetic method and process for purification of a kind of Sorafenib.
Background technology
Compound 4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- methyl pyrroles
Pyridine -2- formamides, also referred to as Sorafenib, molecular formula is C21H16ClF3N4O3, molecular weight is 464.83, and structural formula is formula I.
Sorafenib is a kind of multi-kinase inhibitor, for treating the stomach for not responding to standard treatment or not being resistant to
Enteron aisle stromal tumors and metastatic renal cell cancer.Sorafenib has dual GVT：On the one hand, it can be by suppressing
RAF/MEK/ERK signal transduction pathway, directly suppresses tumour growth；On the other hand, it again can be by suppressing VEGFR and PDGFR
And tumor neovasculature formation is blocked, the growth of tumour cell is suppressed indirectly.
Chinese patent CN101082619 describes a kind of preparation method of Sorafenib.
Its reaction needs to be carried out under conditions of 90 DEG C of high temperature, and the reaction time is up to 5 hours, the chloro- 3- trifluoros of 4- used
The reaction that methylphenyl isocyanate is carried out excessively acutely is difficult to control to.
Chinese patent CN101671299A discloses a kind of preparation method of Sorafenib, and its reaction raw materials has used severe toxicity
Compound phenyl chloroformate, industrial production danger is huge, and unfriendly to environment.
Chinese patent CN102219733A discloses a kind of method for preparing Sorafenib, and its reaction is with one pot of triphosgene
Method prepares Sorafenib.It is well known that triphosgene property is extremely active and has a severe toxicity, it is difficult to control triphosgene and send out with reaction dissolvent
Raw effect generates various impurity, and is difficult to ensure that industrial production safety.
Chinese patent CN102875460A discloses a kind of method for preparing Sorafenib, and its method is equally chloro- using 4-
3- trifluoromethylbenzenes based isocyanate is raw material.
Although prior art can synthesize Sorafenib, generally existing using pyroreaction, using hypertoxic raw material,
The shortcomings of reacting uncontrollable.It is known that the features such as there is excessive risk, high-risk in industrialized production, mild condition, react it is controllable,
Raw material low toxicity substantially reduces undoubtedly can industrial dangerous and production cost.
The content of the invention
In order to solve defect present in prior art, the invention provides a kind of new Sorafenib production technology, institute
Low with material toxicity, reaction condition is gentle, and simple to operate, product purity is up to more than 99.9%.
The present invention relates to a kind of preparation method of Sorafenib, is achieved through the following technical solutions：
A kind of preparation method of Sorafenib, comprises the following steps that：
(1) Sorafenib crude product is prepared
With compound ii (4- (4- amino-benzene oxygens)-N- picoline -2- formamides) and compound III (the chloro- 3- tri- of 4-
Trifluoromethylphenyl carbamyl imidazoles) it is raw material, the reaction in the organic solvent inert to compound III generates Sorafenib
Crude product；
(2) Sorafenib crude product refining
With organic solvent and organic or inorganic acid solution Sorafenib crude product, adding slightly solubility solvent makes Sorafenib
Separate out, obtain Sorafenib sterling.
Prepare the organic solvent that Sorafenib crude product used be the unitary solvents such as ethyl acetate, dichloromethane, acetonitrile or
The binary mixture of the above-mentioned solvent of person；Required reaction temperature is 25 DEG C -65 DEG C；The required reaction time is 1-3h.
The starting compound III (the chloro- 3- trifluoromethyls carbamyl imidazoles of 4-) of Sorafenib crude product is prepared by chemical combination
Thing IV (the chloro- 3- 5-trifluoromethylanilines of 4-) is obtained with compound V (N, N'- carbonyl dimidazoles) synthesis.
The organic solvent that Sorafenib crude product refining is used is the unitary solvents such as ethanol, ethyl acetate, acetonitrile, isopropanol
Or the binary mixture of above-mentioned solvent and water；The acid for being used is concentrated hydrochloric acid, acetic acid, 50% sulfuric acid, methanesulfonic acid, lactic acid etc.；
Refined desired reaction temperature is 60 DEG C -90 DEG C.
The present invention synthetic route be：
Various compound chemical names are as follows：
Chemical compounds I：4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- methyl
Pyridine-2-carboxamide
Compound ii：4- (4- amino-benzene oxygens)-N- picoline -2- formamides
Compound III：The chloro- 3- trifluoromethyls carbamyl imidazoles of 4-
Compounds Ⅳ：The chloro- 3- 5-trifluoromethylanilines of 4-
Compound V：N, N'- carbonyl dimidazoles
Compared with prior art, the present invention has advantages below：
Deadly poisonous compound phenyl chloroformate or deadly poisonous compound triphosgene or 4- chloro- 3- fluoroforms are used existing process more
Base phenyl isocyanate, to industrial production grave danger, the present invention chloro- 3- trifluoromethyls ammonia of low toxicity compounds 4- are brought
Formyl imidazoles instead of above-mentioned deadly poisonous compound, comparatively safe.Additionally, the present invention does not use rotary evaporation, extraction, backflow
Etc. complex operations, technical process is relatively easy.Reaction condition is without the need for nitrogen protection, without high-temperature high-voltage reaction, and product purity can
Up to more than 99.9%.
Specific embodiment
The present invention is further described by following examples, but should be noted that the scope of the present invention is not implemented by these
Any restriction of example.
The prepare compound III (the chloro- 3- trifluoromethyls carbamyl imidazoles of 4-) of embodiment 1
2.0kg compounds Ⅳs (the chloro- 3- 5-trifluoromethylanilines of 4-) are dissolved in into 17.0L 1, in 2- dichloroethanes, stirring,
2.3kg compounds V (N, N'- carbonyl dimidazoles) is added, 50 DEG C are warming up to, 10h is reacted, room temperature reaction 1h is then proceeded to.Cross
Filter, uses 1,2- dichloroethanes to wash 2 times, is filtered dry, and 40 DEG C of vacuum drying obtain 1.6kg compound IIIs (the chloro- 3- trifluoromethylbenzenes of 4-
Base carbamyl imidazoles), purity 99.2%, yield 85%.
Embodiment 2 prepares Sorafenib crude product
Ethyl acetate 200L, compound III 18.7kg, stirring is added to be warming up to 25 DEG C, add compound in retort
II 9.8kg, keeps 25 DEG C of stirring reactions 3h, reaction to be cooled to 20 DEG C of growing the grain 2h after terminating, and filters, and with ethyl acetate two are washed
It is secondary, it is filtered dry, 40 DEG C of vacuum drying obtain Sorafenib crude product 17.2kg, purity 99.18%, yield 91.1%.
Embodiment 3 prepares Sorafenib crude product
Dichloromethane 200L, compound III 18.7kg, stirring is added to be warming up to 35 DEG C, add compound in retort
II 9.8kg, keeps 35 DEG C of stirring reactions 2h, reaction to be cooled to 20 DEG C of growing the grain 2h after terminating, and filters, and with dichloromethane two are washed
It is secondary, it is filtered dry, 40 DEG C of vacuum drying obtain Sorafenib crude product 16.9kg, purity 99.20%, yield 90.22%.
Embodiment 4 prepares Sorafenib crude product
Acetonitrile 200L, compound III 18.7kg, stirring is added to be warming up to 45 DEG C, add compound ii in retort
9.8kg, keeps 45 DEG C of stirring reactions 1.5h, reaction to be cooled to 10 DEG C of growing the grain 2h after terminating, and filters, and is washed twice with acetonitrile, filters
Dry, 40 DEG C of vacuum drying obtain Sorafenib crude product 17.9kg, purity 99.37%, yield 95.5%.
Embodiment 5 prepares Sorafenib crude product
Ethyl acetate 100L, acetonitrile 100L, compound III 18.7kg, stirring is added to be warming up to 65 DEG C in retort, then
Compound ii 9.8kg is added, keeps 65 DEG C of stirring reactions 1h, reaction to be cooled to 15 DEG C of growing the grain 2h after terminating, filtered, use acetic acid second
Ester is washed twice, and is filtered dry, 40 DEG C of vacuum drying, obtains Sorafenib crude product 17.4kg, purity 99.20%, yield 92.9%.
Embodiment 6 prepares Sorafenib crude product
Dichloromethane 100L, ethyl acetate 100L, compound III 18.7kg, stirring is added to be warming up to 50 in retort
DEG C, compound ii 9.8kg is added, keep 50 DEG C of stirring reactions 2h, reaction to be cooled to 15 DEG C of growing the grain 2h after terminating, filter, use
Ethyl acetate is washed twice, and is filtered dry, 40 DEG C of vacuum drying, obtains Sorafenib crude product 17.7kg, purity 99.12%, yield
94.5%.
Embodiment 7 prepares Sorafenib crude product
Dichloromethane 100L, acetonitrile 100L, compound III 18.7kg, stirring is added to be warming up to 50 DEG C in retort, then
Compound ii 9.8kg is added, keeps 50 DEG C of stirring reactions 2h, reaction to be cooled to 15 DEG C of growing the grain 2h after terminating, filtered, use acetic acid second
Ester is washed twice, and is filtered dry, 40 DEG C of vacuum drying, obtains Sorafenib crude product 16.9kg, purity 99.05%, yield 90.22%.
The Sorafenib crude product refining of embodiment 8
Medicinal alcohol 137.0L, purified water 50.0L, Sorafenib crude product 17.2kg (purity are added in retort
98.50%), stirring is warming up to 60 DEG C, adds concentrated hydrochloric acid 5.2kg, stirring solid is all dissolved, and adds activated carbon 0.2kg to take off
Color 30min, filters, and with the mixed liquor of 60 DEG C of ethanol 34.0L and purified water 10.0L carbon-coating is rinsed, and filters, and merging filtrate is to another
In crystallizing tank, it is warming up to 60 DEG C and starts that purified water 342.0L is added dropwise, drop is complete is cooled to 10 DEG C of growing the grain 1h, filters, with purifying washing
Wash twice, be filtered dry, 40 DEG C are vacuum dried to obtain Sorafenib sterling 16.0kg, purity 99.97%, yield 93.0%.
The Sorafenib crude product refining of embodiment 9
Medicinal alcohol 137.0L, purified water 50.0L, Sorafenib crude product 17.2kg (purity are added in retort
98.78%), stirring is warming up to 90 DEG C, adds concentrated hydrochloric acid 5.2kg, stirring solid is all dissolved, and adds activated carbon 0.2kg to take off
Color 30min, filters, and with the mixed liquor of 90 DEG C of ethanol 34.0L and purified water 10.0L carbon-coating is rinsed, and filters, and merging filtrate is to another
In crystallizing tank, it is warming up to 90 DEG C and starts that purified water 342.0L is added dropwise, drop is complete is cooled to 10 DEG C of growing the grain 1h, filters, with purifying washing
Wash twice, be filtered dry, 40 DEG C are vacuum dried to obtain Sorafenib sterling 16.5kg, purity 99.96%, yield 95.9%.
The Sorafenib crude product refining of embodiment 10
Medicinal alcohol 137.0L, purified water 50.0L, Sorafenib crude product 17.2kg (purity are added in retort
98.35%), stirring is warming up to 60 DEG C, adds acetic acid 5.2kg, stirring solid is all dissolved, and adds activated carbon 0.2kg to decolourize
30min, filters, and with the mixed liquor of 60 DEG C of ethanol 34.0L and purified water 10.0L carbon-coating is rinsed, and filters, and merging filtrate is to another knot
In brilliant tank, it is warming up to 60 DEG C and starts that purified water 342.0L is added dropwise, drop is complete is cooled to 10 DEG C of growing the grain 1h, filters, with purifying water washing
Twice, it is filtered dry, 40 DEG C of vacuum drying obtain Sorafenib sterling 16.2kg, purity 99.96%, yield 94.2%.
The Sorafenib crude product refining of embodiment 11
Medicinal alcohol 137.0L, purified water 50.0L, Sorafenib crude product 17.2kg (purity are added in retort
98.67%), stirring is warming up to 60 DEG C, adds 50% sulfuric acid 5.2kg, stirring solid is all dissolved, add activated carbon 0.2kg
Decolouring 30min, filters, and with the mixed liquor of 60 DEG C of ethanol 34.0L and purified water 10.0L carbon-coating is rinsed, and filters, and merging filtrate is to separately
In one crystallizing tank, it is warming up to 60 DEG C and starts that purified water 342.0L is added dropwise, drop is complete is cooled to 10 DEG C of growing the grain 1h, filters, and uses purified water
Wash twice, be filtered dry, 40 DEG C of vacuum drying obtain Sorafenib sterling 15.5kg, purity 99.97%, yield 90.1%.
The Sorafenib crude product refining of embodiment 12
Medicinal alcohol 137.0L, purified water 50.0L, Sorafenib crude product 17.2kg (purity are added in retort
98.34%), stirring is warming up to 60 DEG C, adds methanesulfonic acid 5.2kg, stirring solid is all dissolved, and adds activated carbon 0.2kg to take off
Color 30min, filters, and with the mixed liquor of 60 DEG C of ethanol 34.0L and purified water 10.0L carbon-coating is rinsed, and filters, and merging filtrate is to another
In crystallizing tank, it is warming up to 60 DEG C and starts that purified water 342.0L is added dropwise, drop is complete is cooled to 10 DEG C of growing the grain 1h, filters, with purifying washing
Wash twice, be filtered dry, 40 DEG C of vacuum drying obtain white solid 15.9kg, purity 99.98%, yield 92.4%.
The Sorafenib crude product refining of embodiment 13
Medicinal isopropanol 137.0L, purified water 47.0L, Sorafenib crude product 17.2kg (purity are added in retort
98.52%), stirring is warming up to 70 DEG C, adds concentrated hydrochloric acid 5.2kg, stirring solid is all dissolved, and adds activated carbon 0.2kg to take off
Color 30min, filters, and with the mixed liquor of 60 DEG C of isopropanol 34.0L and purified water 9.0L carbon-coating is rinsed, and filters, and merging filtrate is to separately
In one crystallizing tank, it is warming up to 60 DEG C and starts that purified water 342.0L is added dropwise, drop is complete is cooled to 10 DEG C of growing the grain 1h, filters, and uses purified water
Wash twice, be filtered dry, 40 DEG C are vacuum dried to obtain Sorafenib sterling 15.8kg, purity 99.95%, yield 91.8%.
The actual conditions of the product detection being related in above example is：
The product about 22.0mg of present invention preparation is taken, it is accurately weighed, in putting 100.0ml measuring bottles, plus appropriate diluent, ultrasound
Make to dissolve and be diluted to scale, shake up, as need testing solution；Precision measures need testing solution in right amount, quantitatively dilute with diluent
Release and make the solution containing 2.2 μ g in every 1.0ml, as contrast solution.According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 editions two
Portion annex VD) test, with octadecylsilane chemically bonded silica as filler (Water Symmetry C18,3.5 μm, 4.6 ×
150mm)；With the phosphate buffers of pH 2.4 (take 0.79g anhydrous potassium dihydrogenphosphates, adding water makes to dissolve and be diluted to 1000.0ml,
With phosphorus acid for adjusting pH value to 2.4) as mobile phase A, acetonitrile-ethanol (60:40) it is Mobile phase B, flow velocity is 1.0ml/min, detection
Wavelength is 235nm, 40 DEG C of column temperature.
Although illustrating and describing some exemplary embodiments of the present invention, those skilled in the art should know
Dawn, without departing from the principles and spirit of the present invention, change can be made to these exemplary embodiments, it is of the invention
Scope is limited by claim and its equivalent.
Claims (7)
1. a kind of preparation method of Sorafenib, the method comprising the steps of：
（1）Prepare Sorafenib crude product
With compound ii 4- (4- amino-benzene oxygens)-N- picoline -2- formamides and the chloro- 3- trifluoromethyls of compound III 4-
Phenylcarbamoyl imidazoles is raw material, and the reaction in the organic solvent inert to compound III generates Sorafenib crude product；
（2）Sorafenib crude product refining
With organic solvent and the mixture and organic or inorganic acid solution Sorafenib crude product of water, controlling reaction temperature is 60
DEG C -90 DEG C, purified water is added, be then cooled to 10 DEG C, separate out Sorafenib, obtain Sorafenib sterling；It is wherein described
Organic solvent is ethanol or isopropanol.
2. the preparation method of Sorafenib according to claim 1, it is characterised in that：Prepare Sorafenib crude product to be used
Organic solvent for ethyl acetate, dichloromethane or acetonitrile unitary solvent or above-mentioned solvent binary mixture.
3. the preparation method of Sorafenib according to claim 1, it is characterised in that：Needed for preparing Sorafenib crude product
Reaction temperature is 25 DEG C -65 DEG C.
4. the preparation method of Sorafenib according to claim 1, it is characterised in that：Needed for preparing Sorafenib crude product
Reaction time is 1-3 h.
5. the preparation method of Sorafenib according to claim 1, it is characterised in that：Prepare the raw material of Sorafenib crude product
The chloro- 3- trifluoromethyls carbamyl imidazoles of compound III 4- is by the chloro- 3- 5-trifluoromethylanilines of compounds Ⅳ 4- and chemical combination
The N of thing V, N'- carbonyl dimidazoles synthesis is obtained.
6. the preparation method of Sorafenib according to claim 5, it is characterised in that：The solvent for use of prepare compound III is
1,2- dichloroethanes, dichloromethane, ethyl acetate or acetonitrile.
7. the preparation method of Sorafenib according to claim 1, it is characterised in that：Sorafenib crude product refining is used
Acid be concentrated hydrochloric acid, acetic acid, 50% sulfuric acid, methanesulfonic acid or lactic acid.
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| CN105330600B (en) * | 2015-11-30 | 2018-05-22 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Rui Gefeini |
| CN108794392B (en) * | 2018-05-14 | 2021-08-10 | 中国药科大学 | Method for synthesizing sorafenib by solid-state ball milling |
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| US20030207872A1 (en) * | 2002-01-11 | 2003-11-06 | Bayer Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| CN102219733A (en) * | 2010-04-14 | 2011-10-19 | 上海医药工业研究院 | Method for preparing sorafenib |
| CN102485714B (en) * | 2011-10-09 | 2013-07-24 | 连云港盛和生物科技有限公司 | Method for synthesis of sorafenib through carbonylation |
| US9156789B2 (en) * | 2012-05-21 | 2015-10-13 | Hetero Research Foundation | Process for sorafenib tosylate polymorph III |
| US20150111929A1 (en) * | 2012-05-23 | 2015-04-23 | Shilpa Medicare Limited | Process for preparing crystalline sorafenib tosylate |
| CN103724259A (en) * | 2013-12-12 | 2014-04-16 | 江苏集贤绿色化学科技研究院有限公司 | Synthesis method for sorafenib |
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Effective date of registration: 20221025 Address after: No. 68, Limin West 4th Street, Limin Development Zone, Harbin, Heilongjiang 150500 Patentee after: HARBIN PHARMACEUTICAL GROUP HOLDING Co.,Ltd. Patentee after: MEDSHINE DISCOVERY Inc. Address before: No.109 Xuefu Road, Nangang District, Harbin, Heilongjiang 150046, No.1 Junmin Street, Xiangfang District Patentee before: MEDSHINE DISCOVERY Inc. |