CN108997208A - A kind of preparation method of Sorafenib - Google Patents
A kind of preparation method of Sorafenib Download PDFInfo
- Publication number
- CN108997208A CN108997208A CN201810595812.3A CN201810595812A CN108997208A CN 108997208 A CN108997208 A CN 108997208A CN 201810595812 A CN201810595812 A CN 201810595812A CN 108997208 A CN108997208 A CN 108997208A
- Authority
- CN
- China
- Prior art keywords
- sorafenib
- added
- reaction
- crude product
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Abstract
The present invention relates to a kind of preparation methods of Sorafenib, and this method comprises the following steps: by para-aminophenol heating melting, ether condensation reaction occur with 4- chloro-n-methyl pyridine-2-carboxamide under the action of KOH and generates intermediate I；Intermediate I, 3- trifluoromethyl -4- chlorobenzene methanol are subjected to " one pot " reaction under the effect of the catalyst afterwards, it is post-treated to obtain Sorafenib crude product, Sorafenib sterling is further purified to obtain.Method high conversion rate of the invention, safety are non-hazardous, pollution-free, reaction condition is mild, high income, product purity are high and is suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of preparation method of Sorafenib.
Background technique
Sorafenib (sorafenib, trade name Nexavar), chemical name: 4- { 4- [3- (the chloro- 3- trifluoromethyl-benzene of 4-
Base)-uride]-phenoxy group }-pyridine-2-carboxylic acids methylamine, it is a kind of Orally active multi-kinase inhibitor, has and inhibit tumour cell
Duplication and the effect of Tumor Angiongesis, Onyx company have been originally found this noval chemical compound, and then, Beyer Co., Ltd takes part in this
The later development (code name BAY-43-9006) of medicine.Original research personnel have found that Sorafenib has the work for inhibiting Raf kinases
With, then again find that the medicine is also able to suppress vascular endothelial growth factor (VEGFR), platelet derived growth factor BB, class
FMS tyrosine kinase (Flt-3), c-Kit albumen and RET receptor tyrosine kinase.Its chemical structural formula is as follows:
It is as follows at present about the reported several preparation methods of the synthesis of Sorafenib:
Technical solution 1: patent WO2006034796, WO2009054004, WO0042010, WO0041698, WO2007/
059154A2、WO2007/053574A2、WO2009/034308A2、US7235576、US20010016659、
US2003144278、CN102219733、CN 103724258、CN102875460、CN 104710354、CN10105269A、
CN105859612, CN105801475, CN101082619, Zhao, which multiply, (Chinese Journal of Pharmaceuticals, 2007,38 (9) 614- such as
616), grandson superfine (Chemical Engineer's the 1st phase in 2011,63-65) etc. reports a kind of method for preparing Sorafenib, reaction
It needs to need using the synthesis of phosgene or isocyanates using phosgene, surpalite or triphosgene.Phosgene is a kind of hypertoxic gas,
By-product causes serious pollution to the environment to production equipment seriously corroded, all brings immense pressure to environmental protection and labour protection, can only be specific
Plant produced and use.Later period research and development surpalite (trichloromethyl chloroformate), [carbonic acid is bis- (trichloromethyl) for triphosgene
Ester] substitution phosgene, but both raw materials are all to be decomposed into monochromatic light gas during the reaction to participate in reaction, are not solved inherently
Phosgene severe toxicity, the intrinsic problem such as pollution environment, there are serious security risks.A kind of severe toxicity of surpalite conduct simultaneously itself has
The liquid of penetrating odor still has biggish risk；Triphosgene property is extremely active and has severe toxicity, it is difficult to control triphosgene
It has an effect with reaction dissolvent and generates various impurity, and be difficult to ensure industrial production safety.
Technical solution 2:WO2004113274, WO2009111061, US20090253913, CN103724259,
The document reports such as CN104402813 are by 4- (4- amino-benzene oxygen) -2- (methylcarbamoyl) pyridine, the chloro- 3- (fluoroform of 4-
Base) aniline occur in the presence of 1,1 '-carbonyl dimidazoles (CDI) three intermolecular condensations generate Sorafenib.
Method synthesis Sorafenib Tosylate yield is general, and time-consuming for entire technique, cumbersome；And N, N'-
Carbonyl dimidazoles price is higher, to moist lability, meets water and is hydrolyzed in a few seconds and releases carbon dioxide, cause charging not
Accurately, it is easy to generate more difficult isolated dimer, while its synthesis is also required to be unfavorable for industrialized production using phosgene.
Technical solution 3: Chinese patent CN101671299, CN103408488 disclose a kind of preparation side of Sorafenib
Method, this method is by the chloro- 3- 5-trifluoromethylaniline of 4- and chloro-carbonic acid -2- nitro phenyl ester or phenyl chloroformate through addition-elimination reaction
(the chloro- 3- trifluoromethyl of 4-) carbamic acid -2- nitro phenyl ester and (the chloro- 3- trifluoromethyl of 4-) amino first are generated respectively
Acid phenenyl ester, it is then post-treated to obtain Sorafenib.The method overall yield is lower, and chloro-carbonic acid -2- nitro phenyl ester or chloro-carbonic acid
The synthetic yield of phenyl ester is lower, while the purifying of product also needs column chromatography separation method, and economy is too poor；Though the synthesis process
It so avoids using triphosgene, but raw material chloro-carbonic acid -2- nitro phenyl ester and phenyl chloroformate are unstable and have corrosivity, to equipment
With certain damage, industrial production danger is huge, and unfriendly to environment.
And in the document of synthetic intermediate (4- (4- amido phenoxy group)-N- methylnicotinamide), usually according to
Synthetic route disclosed in CN201210154022.4 is synthesized, i.e., using 2- pyridine carboxylic acid as raw material, by acylation, chlorination
Compound 2 is obtained, obtains compound 3 using amidation process, further makes compound 3 in the presence of alkali and p-aminophenyl
Phenol reacts to obtain 4- (4- the amino-benzene oxygen)-N- methyl -2- pyridine carboxamide.But the route uses the N for being difficult to recycle, N- bis-
Methylformamide or n,N-dimethylacetamide, synthesis cost is higher, pollutes larger.
Certainly, there is also the routes of other synthesis 4- (4- amido phenoxy group)-N- methylnicotinamides in the prior art, such as
Patent document WO2005082853 discloses following synthetic route: using paranitrochlorobenzene and compound 4-hydroxy base -2- pyridine-N-
Methylformamide is that 180 DEG C of reactions obtain compound 4 with 24% yield in 3 hours to raw material under the catalysis of copper powder, in nickel-hydrogen gas
Reduction under obtain compound 1.The synthetic route coupling step yield is too low, and reaction temperature is higher, and energy consumption is high, overall cost compared with
It is high.
Patent document US20030207872 discloses following synthetic route: use is to fluoronitrobenzene and 4- hydroxy-2-methyl
Pyridine is raw material, and by coupling, oxidation and esterification obtain compound 3.All step yields of the synthetic route are all relatively low, and
And highly toxic compound selenium dioxide is used in second step, it is difficult to realize industrialized production.
Patent document EP1889836 discloses following synthetic route: using 4- chloropyridine -2- isopropyl formate and to nitro
Phenol 120 DEG C of reactions in chlorobenzene obtain 4- (4- nitro phenoxyl) pyridine -2- isopropyl formate (compound 3b) in 23 hours,
But yield is only 45%.Temperature required for the synthetic route is higher, and energy consumption is big, and yield is only 45%, is not suitable for
Industrialized production.
Patent document CN201410826341.4 discloses following synthetic route, with 4- chloropyridine -2- isopropyl formate and
P-nitrophenol is raw material, is reacted in pyridine, and 4- (4-nitrophenoxy) pyridine -2- methyl formate (compound 6) is obtained, then
It restores to obtain compound 1 through amino and Pd/C-H2.The synthetic route has used pyridine, and genotoxicity is larger, and the smell is awful, ring
Border pollution.
It can be seen that although the prior art can synthesize Sorafenib, it is generally existing to use complex process, use play
The disadvantages of toxogen material, operating difficulties, yield are low, purity is low, reaction is uncontrollable.It, must in order to meet the production requirement of Sorafenib
It must provide that a kind of high yield, high-purity, safety is non-hazardous, pollution-free and the synthesis road of the Sorafenib of suitable industrialized production
Line.
Summary of the invention
Technical problem to be solved by the present invention lies in existing prepare in Sorafenib technology that there are technique is multiple to overcome
Miscellaneous, operating difficulties, yield are low, purity is low, expensive catalyst and the defect for not being suitable for industrialized production, and provide one kind
The preparation method of Sorafenib.Method high conversion rate of the invention, safety are non-hazardous, pollution-free, reaction condition is mild, yield
Height, product purity are high and are suitable for industrialized production.Technical scheme is as follows:
A kind of preparation method of Sorafenib, it is characterised in that including following operating procedure:
1) ether contracting occurs under the action of KOH with 4- chloro-n-methyl pyridine-2-carboxamide for para-aminophenol heating melting
Reaction is closed, intermediate I is generated；
2) 3- trifluoromethyl -4- chlorobenzene methanol, intermediate I, NaN3、PhICl2And " one pot " occurs for phase transfer catalyst
Reaction, it is post-treated to obtain Sorafenib crude product；
3) sterling is further purified to obtain in Sorafenib crude product；
In step 1), para-aminophenol, KOH, 4- chloro-n-methyl pyridine-2-carboxamide the mass ratio of the material be 0.90~
1.2:1:0.8~1.0.Wherein, in step 1), the substance of para-aminophenol, KOH, 4- chloro-n-methyl pyridine-2-carboxamide
Amount is than being 1.05:1:0.9.
In step 2), the phase transfer catalyst is tetrabutylammonium bromide, and reaction dissolvent is tetrahydrofuran, 3- fluoroform
Base -4- chlorobenzene methanol, intermediate I, NaN3、PhICl2The mass ratio of the material be 1:2~3:3~4:1.5~2.5；3- fluoroform
The mass ratio of the material of base -4- chlorobenzene methanol and phase transfer catalyst is 1:0.011~0.015；The post-processing step are as follows: will
Reaction solution is cooled to room temperature, and is added to the in the mixed solvent of water and ethyl acetate, is stirred, and is layered, and washing is drained, dry, is obtained
Sorafenib crude product.Wherein, the phase transfer catalyst is tetrabutylammonium bromide, and reaction dissolvent is tetrahydrofuran, 3- trifluoro
Methyl -4- chlorobenzene methanol, intermediate I, NaN3、PhICl2The mass ratio of the material be 1:2.5:3.5:2；3- trifluoromethyl -4- chlorobenzene
The mass ratio of the material of methanol and phase transfer catalyst is 1:0.013, the volume ratio of the in the mixed solvent water and ethyl acetate
For 3:2.
In step 3), the purification step are as follows: crude product is added to the water, diluted hydrochloric acid aqueous solution adjusts pH, and crude product is molten
Solution is added dropwise sodium bicarbonate aqueous solution and adjusts pH, and solid is precipitated；Solid is dissolved in organic solvent, active carbon is added, heating is stirred
It mixes, filters, it is cooling, it is added in purified water, precipitates crystal, control temperature and mixing speed growing the grain, filtering, cold purifying washing
It washs, drains, obtain white solid, it is dry, obtain sterling.Wherein, the mass volume ratio of crude product and water is 1g:12~18mL, dilute salt
The pH that aqueous acid is adjusted is 2.5~3.0；The pH that sodium bicarbonate aqueous solution is adjusted is 6.5~7.0；The organic solvent is
Acetone；Heating temperature is 40~45 DEG C；Cooling temperature is 0~5 DEG C, and mixing speed is 60 revs/min, mixing time 30min；
The mass fraction of diluted hydrochloric acid aqueous solution solute is 10%；The mass fraction of the sodium bicarbonate aqueous solution solute is 6%.
Compared with the prior art, the preparation method of Sorafenib provided by the present invention has high conversion rate, safety without danger
Harmful, pollution-free, reaction condition is mild, high income, product purity are high and the features such as being suitable for industrialized production, Core Superiority
It is to react para-aminophenol heating melting, in generation with 4- chloro-n-methyl pyridine-2-carboxamide temperature control under the action of KOH
Mesosome I, reaction yield are high, and purity is high, post-processing is simple, and yield is up to 97%, meets the requirement of Green Chemistry, avoid using
Organic solvent causes damages to environment, also saves a large amount of solvent consumption expense, while avoiding using highly basic such as potassium tert-butoxides,
Cause amido bond to be broken, also avoids greatly reducing production cost using expensive catalyst；Afterwards by 3- trifluoromethyl-
4- chlorobenzene methanol, intermediate I, NaN3、PhICl2And " one pot " reaction, post-treated get Suo Lafei occur for phase transfer catalyst
Buddhist nun, the reaction is non-hazardous safely, pollution-free, reaction condition is mild, avoids making using the synthesis needs of phosgene or isocyanates
With toxic gases such as phosgene, surpalite or triphosgenes；Acid-base accommodation is utilized in present invention purification, removes partial impurities；After utilize
Solvent carries out crystallization, removes impurity, is finally purified impurity substantially, purified product purity reaches 99.9%.The preparation side
Method is suitble to industrialization amplification to require, and for the preparations of Sorafenib or other compounds, to provide another important and practical novel
Compound.
Specific embodiment
Technical solution of the present invention is further non-limitingly described below in conjunction with several preferred embodiments.
The synthesis of embodiment 1-1 intermediate I
In a 100mL there-necked flask with magnetic stirring apparatus, thermometer and reflux condensing tube, it is added 105mmol's
The KOH of 100mmol is added after heating melting for para-aminophenol, stir it is lower react 10min, then be added into reaction system
The 4- chloro-n-methyl pyridine-2-carboxamide of 90mmol, temperature control reaction；Terminal is detected with TLC, 1.5h reaction terminates；To reactant
The 5%NaOH solution of heat is added in system, heat preservation is washed 3 times in 80 DEG C~85 DEG C, will after 3 times are washed with water at the same temperature
Reaction mixture is poured into cold water while hot, cooling, filtering, dry 21.30g intermediate I, yield 97.3%, purity
99.91%.
The synthesis of embodiment 1-2 intermediate I
In a 100mL there-necked flask with magnetic stirring apparatus, thermometer and reflux condensing tube, pair of 90mmol is added
The KOH of 100mmol is added after heating melting for amino-phenol, stir it is lower react 10min, then 100mmol is added into reaction system
4- chloro-n-methyl pyridine-2-carboxamide, temperature control reaction；Terminal is detected with TLC, 1.5h reaction terminates；Add into reaction system
Enter the 5%NaOH solution of heat, heat preservation is washed 3 times in 80 DEG C~85 DEG C, after 3 times are washed with water at the same temperature, reaction is mixed
It closes object to be poured into cold water while hot, cooling, filtering, dry 20.11g intermediate I, yield 91.7%, purity 99.75%.
The synthesis of embodiment 1-3 intermediate I
In a 100mL there-necked flask with magnetic stirring apparatus, thermometer and reflux condensing tube, it is added 120mmol's
The KOH of 100mmol is added after heating melting for para-aminophenol, stir it is lower react 10min, then be added into reaction system
The 4- chloro-n-methyl pyridine-2-carboxamide of 80mmol, temperature control reaction；Terminal is detected with TLC, 1.5h reaction terminates；To reactant
The 5%NaOH solution of heat is added in system, heat preservation is washed 3 times in 80 DEG C~85 DEG C, will after 3 times are washed with water at the same temperature
Reaction mixture is poured into cold water while hot, cooling, filtering, dry 17.95g intermediate I, yield 92.2%, purity
99.83%.
The synthesis of embodiment 1-4 intermediate I
In a 100mL there-necked flask with magnetic stirring apparatus, thermometer and reflux condensing tube, pair of 90mmol is added
The KOH of 100mmol is added after heating melting for amino-phenol, stir it is lower react 10min, then 80mmol is added into reaction system
4- chloro-n-methyl pyridine-2-carboxamide, temperature control reaction；Terminal is detected with TLC, 1.5h reaction terminates；Add into reaction system
Enter the 5%NaOH solution of heat, heat preservation is washed 3 times in 80 DEG C~85 DEG C, after 3 times are washed with water at the same temperature, reaction is mixed
It closes object to be poured into cold water while hot, cooling, filtering, dry 18.09g intermediate I, yield 92.9%, purity 99.85%.
The synthesis of embodiment 1-5 intermediate I
In a 100mL there-necked flask with magnetic stirring apparatus, thermometer and reflux condensing tube, it is added 120mmol's
The KOH of 100mmol is added after heating melting for para-aminophenol, stir it is lower react 10min, then be added into reaction system
The 4- chloro-n-methyl pyridine-2-carboxamide of 100mmol, temperature control reaction；Terminal is detected with TLC, 1.5h reaction terminates；To reaction
The 5%NaOH solution of heat is added in system, heat preservation is washed 3 times in 80 DEG C~85 DEG C, after 3 times are washed with water at the same temperature,
Reaction mixture is poured into cold water while hot, cooling, filtering, dry 22.73g intermediate I, yield 93.4%, purity
99.87%
The synthesis of embodiment 2-1 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 50mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 9.0g, yield 96.8%.
The synthesis of embodiment 2-2 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
30mmol PhICl2、80mmol NaN3, 0.22mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 40mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.60g, yield 92.5%.
The synthesis of embodiment 2-3 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
50mmol PhICl2、60mmol NaN3, 0.3mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, under the conditions of 0 DEG C
2h is stirred, is then placed into 80 DEG C of oil bath and reacts 4h, TLC monitors end of reaction, is added among 60mmol into two-mouth bottle
Body I, continue under the conditions of 80 DEG C stir 2h reaction system is down to room temperature after reaction, by reaction solution be added 60mL water and
The in the mixed solvent of 40mL ethyl acetate stirs, and layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, and 50mL is full
And NaCl, it drains, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.58g, yield 92.3%.
The synthesis of embodiment 2-4 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
30mmol PhICl2、60mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 40mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.43g, yield 90.7%.
The synthesis of embodiment 2-5 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
30mmol PhICl2、80mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 60mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.38g, yield 90.1%.
The synthesis of embodiment 2-6 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.22mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 50mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.77g, yield 94.3%.
The synthesis of embodiment 2-7 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.1mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, under the conditions of 0 DEG C
2h is stirred, is then placed into 80 DEG C of oil bath and reacts 4h, TLC monitors end of reaction, is added among 50mmol into two-mouth bottle
Body I, continue under the conditions of 80 DEG C stir 2h reaction system is down to room temperature after reaction, by reaction solution be added 60mL water and
The in the mixed solvent of 40mL ethyl acetate stirs, and layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, and 50mL is full
And NaCl, it drains, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.26g, yield 80.9%.
The synthesis of embodiment 2-8 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL acetonitrile, stirred under the conditions of 0 DEG C
2h is mixed, is then placed into 80 DEG C of oil bath and reacts 4h, TLC monitors end of reaction, and 50mmol intermediate is added into two-mouth bottle
I, continue under the conditions of 80 DEG C stir 2h reaction system is down to room temperature after reaction, by reaction solution be added 60mL water and
The in the mixed solvent of 40mL ethyl acetate stirs, and layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, and 50mL is full
And NaCl, it drains, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 7.44g, yield 80.0%.
The synthesis of embodiment 2-9 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL ethyl acetate, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 50mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.21g, yield 88.3%.
The synthesis of embodiment 2-10 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL carbon tetrachloride, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 50mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water is added in reaction solution
It with the in the mixed solvent of 40mL ethyl acetate, stirs, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, 50mL
Saturated sodium-chloride washing, is drained, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 4.68g, yield 50.3%.
The synthesis of embodiment 2-11 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.26mmol 4 bromide and 100mL tetrahydrofuran, stirred under the conditions of 0 DEG C
2h is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, and 50mmol intermediate compound I is added into two-mouth bottle,
Continue stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 60mL water and 40mL is added in reaction solution
The in the mixed solvent of ethyl acetate stirs, and layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, and 50mL is saturated chlorine
Change sodium washing, drains, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.23g, yield 88.5%.
The synthesis of embodiment 2-12 Sorafenib crude product
Under conditions of nitrogen protection, successively into reaction flask be added 3- trifluoromethyl -4- chlorophenethylol 20mmol,
40mmol PhICl2、70mmol NaN3, 0.26mmol tetrabutylammonium bromide (TBAB) and 100mL tetrahydrofuran, in 0 DEG C of condition
Lower stirring 2h, is then placed into 80 DEG C of oil bath and reacts 4h, and TLC monitors end of reaction, is added in 50mmol into two-mouth bottle
Mesosome I continues stirring 2h under the conditions of 80 DEG C and reaction system is down to room temperature after reaction, 100mL is added in reaction solution
In ethyl acetate, stirring, layering, water phase is extracted with ethyl acetate once, combined ethyl acetate, the washing of 50mL saturated sodium-chloride,
It drains, 40 DEG C of dryings of vacuum obtain Sorafenib crude product 8.11g, yield 87.2%.
Embodiment 3-1 Sorafenib sterling
Crude product 10g is added in 150mL water, is stirred, pH to 2.5~3.0 is adjusted with 10% diluted hydrochloric acid aqueous solution, in room
Temperature stirring, crude product dissolution, filtering obtain crude product solution；6% sodium bicarbonate solution is added dropwise into above-mentioned solution, adjusts pH to 6.5
~7.0,5 DEG C are cooled to, insulated and stirred filters, and water washing filter cake is drained, obtains solid；Obtained solid is dissolved in acetone,
Active carbon is added, is heated to 40~45 DEG C, is sufficiently stirred, filtrate is obtained after filtering, filtrate is cooled to 0~5 DEG C, is added to purifying
It in water, precipitates crystal, controls temperature and 60 revs/min of mixing speed, mixing time 30min, growing the grain 1.5h, filtering, crystal
It with cold purifying water washing, drains, obtains white solid, 40 DEG C of dryings of vacuum obtain Sorafenib sterling 9.64g, yield
96.4%, purity 99.96%.
Embodiment 3-2 Sorafenib sterling
Crude product 10g is added in 120mL water, is stirred, pH to 2.5~3.0 is adjusted with 10% diluted hydrochloric acid aqueous solution, in room
Temperature stirring, crude product dissolution, filtering obtain crude product solution；6% sodium bicarbonate solution is added dropwise into above-mentioned solution, adjusts pH to 6.5
~7.0,5 DEG C are cooled to, insulated and stirred filters, and water washing filter cake is drained, obtains solid；Obtained solid is dissolved in acetone,
Active carbon is added, is heated to 40~45 DEG C, is sufficiently stirred, filtrate is obtained after filtering, filtrate is cooled to 0~5 DEG C, is added to purifying
It in water, precipitates crystal, controls temperature and 60 revs/min of mixing speed, mixing time 30min, growing the grain 1.5h, filtering, crystal
It with cold purifying water washing, drains, obtains white solid, 40 DEG C of dryings of vacuum obtain Sorafenib sterling 9.56g, yield
95.6%, purity 99.94%.
Embodiment 3-3 Sorafenib sterling
Crude product 10g is added in 180mL water, is stirred, pH to 2.5~3.0 is adjusted with 10% diluted hydrochloric acid aqueous solution, in room
Temperature stirring, crude product dissolution, filtering obtain crude product solution；6% sodium bicarbonate solution is added dropwise into above-mentioned solution, adjusts pH to 6.5
~7.0,5 DEG C are cooled to, insulated and stirred filters, and water washing filter cake is drained, obtains solid；Obtained solid is dissolved in acetone,
Active carbon is added, is heated to 40~45 DEG C, is sufficiently stirred, filtrate is obtained after filtering, filtrate is cooled to 0~5 DEG C, is added to purifying
It in water, precipitates crystal, controls temperature and 60 revs/min of mixing speed, mixing time 30min, growing the grain 1.5h, filtering, crystal
It with cold purifying water washing, drains, obtains white solid, 40 DEG C of dryings of vacuum obtain Sorafenib sterling 9.52g, yield
95.2%, purity 99.96%.
Embodiment 3-4 Sorafenib sterling
Crude product 10g is added in 150mL water, is stirred, pH to 1.5~2.0 is adjusted with 10% diluted hydrochloric acid aqueous solution, in room
Temperature stirring, crude product dissolution, filtering obtain crude product solution；6% sodium bicarbonate solution is added dropwise into above-mentioned solution, adjusts pH to 7.0
~7.5,5 DEG C are cooled to, insulated and stirred filters, and water washing filter cake is drained, obtains solid；Obtained solid is dissolved in acetone,
Active carbon is added, is heated to 50~55 DEG C, is sufficiently stirred, filtrate is obtained after filtering, filtrate is cooled to 0~5 DEG C, is added to purifying
It in water, precipitates crystal, controls temperature and 60 revs/min of mixing speed, mixing time 30min, growing the grain 1.5h, filtering, crystal
It with cold purifying water washing, drains, obtains white solid, 40 DEG C of dryings of vacuum obtain Sorafenib sterling 9.03g, yield
90.3%, purity 99.94%.
Embodiment 3-5 Sorafenib sterling
Crude product 10g is added in 150mL water, is stirred, pH to 2.5~3.0 is adjusted with 10% diluted hydrochloric acid aqueous solution, in room
Temperature stirring, crude product dissolution, filtering obtain crude product solution；6% sodium bicarbonate solution is added dropwise into above-mentioned solution, adjusts pH to 7.0
~7.5,5 DEG C are cooled to, insulated and stirred filters, and water washing filter cake is drained, obtains solid；Obtained solid is dissolved in acetone,
Active carbon is added, is heated to 50~55 DEG C, is sufficiently stirred, filtrate is obtained after filtering, filtrate is cooled to 0~5 DEG C, is added to purifying
It in water, precipitates crystal, controls temperature and 60 revs/min of mixing speed, mixing time 30min, growing the grain 1.5h, filtering, crystal
It with cold purifying water washing, drains, obtains white solid, 40 DEG C of dryings of vacuum obtain Sorafenib sterling 9.09g, yield
90.9%, purity 99.95%.
Embodiment 3-6 Sorafenib sterling
Crude product 10g is added in 150mL water, is stirred, pH to 2.5~3.0 is adjusted with 10% diluted hydrochloric acid aqueous solution, in room
Temperature stirring, crude product dissolution, filtering obtain crude product solution；6% sodium bicarbonate solution is added dropwise into above-mentioned solution, adjusts pH to 6.5
~7.0,5 DEG C are cooled to, insulated and stirred filters, and water washing filter cake is drained, obtains solid；Obtained solid is dissolved in acetone,
Active carbon is added, stir thoroughly at room temperature obtains filtrate, filtrate is cooled to 0~5 DEG C, is added in purified water after filtering, be precipitated brilliant
Body controls temperature and 60 revs/min of mixing speed, mixing time 30min, growing the grain 1.5h, filtering, the cold purified water of crystal
Washing, drains, obtains white solid, 40 DEG C of dryings of vacuum obtain Sorafenib sterling 9.15g, yield 91.5%, purity
99.95%.
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow
The personage for knowing technique cans understand the content of the present invention and implement it accordingly, and protection model of the invention can not be limited with this
It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Sorafenib, it is characterised in that including following operating procedure:
1) ether condensation occurs for para-aminophenol heating melting instead with 4- chloro-n-methyl pyridine-2-carboxamide under the action of KOH
It answers, generates intermediate I；
2) 3- trifluoromethyl -4- chlorobenzene methanol, intermediate I, NaN3、PhICl2And " one pot " reaction occurs for phase transfer catalyst,
It is post-treated to obtain Sorafenib crude product；
3) sterling is further purified to obtain in Sorafenib crude product；
2. a kind of preparation method of Sorafenib according to claim 1, which is characterized in that in step 1), p-aminophenyl
Phenol, KOH, 4- chloro-n-methyl pyridine-2-carboxamide the mass ratio of the material be 0.90~1.2:1:0.8~1.0.
3. a kind of preparation method of Sorafenib according to claim 1, which is characterized in that in step 2), the phase
Transfer catalyst is tetrabutylammonium bromide, and reaction dissolvent is tetrahydrofuran, 3- trifluoromethyl -4- chlorobenzene methanol, intermediate I,
NaN3、PhICl2The mass ratio of the material be 1:2~3:3~4:1.5~2.5；3- trifluoromethyl -4- chlorobenzene methanol is urged with phase transfer
The mass ratio of the material of agent is 1:0.011~0.015.
4. a kind of preparation method of Sorafenib according to claim 1, which is characterized in that in step 2), after described
Processing step are as follows: reaction solution is cooled to room temperature, the in the mixed solvent of water and ethyl acetate is added to, is stirred, layering is washed
It washs, drains, it is dry, obtain Sorafenib crude product.
5. a kind of preparation method of Sorafenib according to claim 1, which is characterized in that in step 3), described is pure
Change step are as follows: crude product is added to the water, diluted hydrochloric acid aqueous solution adjusts pH, and crude product dissolution is added dropwise sodium bicarbonate aqueous solution and adjusts
PH, solid are precipitated；Solid is dissolved in organic solvent, active carbon is added, is heated, is stirred, is filtered, it is cooling, it is added to purified water
In, it precipitates crystal, controls temperature and mixing speed growing the grain, filtering, cold purifying water washing is drained, obtains white solid, does
It is dry, obtain sterling.
6. a kind of preparation method of Sorafenib according to claim 2, which is characterized in that in step 1), p-aminophenyl
Phenol, KOH, 4- chloro-n-methyl pyridine-2-carboxamide the mass ratio of the material be 1.05:1:0.9.
7. a kind of preparation method of Sorafenib according to claim 3, which is characterized in that in step 2), the phase
Transfer catalyst is tetrabutylammonium bromide, and reaction dissolvent is tetrahydrofuran, 3- trifluoromethyl -4- chlorobenzene methanol, intermediate I,
NaN3、PhICl2The mass ratio of the material be 1:2.5:3.5:2；The substance of 3- trifluoromethyl -4- chlorobenzene methanol and phase transfer catalyst
Amount ratio be 1:0.013.
8. a kind of preparation method of Sorafenib according to claim 4, which is characterized in that in step 2), described is mixed
The volume ratio of water and ethyl acetate is 3:2 in bonding solvent.
9. a kind of preparation method of Sorafenib according to claim 5, which is characterized in that in step 3), crude product and water
Mass volume ratio be 1g:12~18mL, diluted hydrochloric acid aqueous solution adjust pH be 2.5~3.0；What sodium bicarbonate aqueous solution was adjusted
PH is 6.5~7.0；The organic solvent is acetone；Heating temperature is 40~45 DEG C；Cooling temperature is 0~5 DEG C, stirring speed
Degree is 60 revs/min, mixing time 30min.
10. a kind of preparation method of Sorafenib according to claim 5, which is characterized in that in step 3), dilute hydrochloric acid water
The mass fraction of solution's solute is 10%；The mass fraction of the sodium bicarbonate aqueous solution solute is 6%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810595812.3A CN108997208A (en) | 2018-06-11 | 2018-06-11 | A kind of preparation method of Sorafenib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810595812.3A CN108997208A (en) | 2018-06-11 | 2018-06-11 | A kind of preparation method of Sorafenib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108997208A true CN108997208A (en) | 2018-12-14 |
Family
ID=64600657
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810595812.3A Pending CN108997208A (en) | 2018-06-11 | 2018-06-11 | A kind of preparation method of Sorafenib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108997208A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104672129A (en) * | 2013-11-26 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of urea compound |
-
2018
- 2018-06-11 CN CN201810595812.3A patent/CN108997208A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104672129A (en) * | 2013-11-26 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of urea compound |
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| 刘友平等: "《理化基本技能训练》", 31 August 2014, 中国医药科技出版社 * |
| 李敬芬等: "《药物合成反应》", 31 August 2010, 浙江大学出版社 * |
| 李晓强: "二氯碘苯及其类似物在醇或醛氧化转化中的应用", 《中国博士学位论文全文数据库 工程科技I辑》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100503601C (en) | Process of preparing troipisetron | |
| CN108558747A (en) | A kind of preparation method of Rui Gefeini | |
| CN104478769B (en) | His synthetic method of a kind of Baily department of applicable suitability for industrialized production | |
| CN105566215B (en) | A kind of Rui Gefeini preparation method | |
| CN108383749A (en) | The synthetic method and its intermediate of A Palu amine | |
| CN108440403A (en) | A kind of preparation method of Rui Gefeini | |
| CN109320413A (en) | A kind of preparation method of phenylacetic acid class compound | |
| CN109988077A (en) | A kind of synthetic method and intermediate of A Palu amine | |
| CN104311485B (en) | A kind of preparation method treating leukemic medicine bosutinib | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN108997208A (en) | A kind of preparation method of Sorafenib | |
| CN103626697B (en) | A kind of preparation method of the cyanopyridine of 2 chlorine, 4 trifluoromethyl 3 | |
| CN108276327A (en) | A kind of preparation method of Sorafenib | |
| WO2023174449A1 (en) | Method for preparing n-(3-chloro-4-(2-pyridylmethoxy)phenyl)-2-cyanoacetamide | |
| CN101973955B (en) | Method for synthesizing isatoic anhydride | |
| CN102432509B (en) | Method for preparing 4-methylsulfonyltoluene | |
| CN108276328A (en) | A kind of preparation method of Sorafenib | |
| CN107698651B (en) | A kind of production technology of high-purity dutasteride | |
| CN102093292B (en) | Method for synthesizing DL-alpha-amino caprolactam | |
| CN104592122A (en) | Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline | |
| CN103965104B (en) | A kind of preparation method of tyrosine kinase inhibitor and its intermediate | |
| CN102675148A (en) | Preparation method of hydroxybenzyl cyanide | |
| CN103664766B (en) | Preparation method of 2-aminopyridine-4-methyl alcohol | |
| CN103172564B (en) | The preparation method of Aripiprazole | |
| CN113999127A (en) | Synthesis method and reaction system of arylamine compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181214 |