CN108794392A - A kind of method of solid-state ball milling synthesis Sorafenib - Google Patents
A kind of method of solid-state ball milling synthesis Sorafenib Download PDFInfo
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- CN108794392A CN108794392A CN201810476691.0A CN201810476691A CN108794392A CN 108794392 A CN108794392 A CN 108794392A CN 201810476691 A CN201810476691 A CN 201810476691A CN 108794392 A CN108794392 A CN 108794392A
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- 238000000498 ball milling Methods 0.000 title claims abstract description 39
- 239000005511 L01XE05 - Sorafenib Substances 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 27
- 229960003787 sorafenib Drugs 0.000 title claims abstract description 27
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 239000007788 liquid Substances 0.000 claims abstract description 13
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 239000012948 isocyanate Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- MCMNRKCIXSYSNV-UHFFFAOYSA-N ZrO2 Inorganic materials O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 5
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 claims description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- YTCGOUNVIAWCMG-UHFFFAOYSA-N 1-chloro-3-(trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC(Cl)=C1 YTCGOUNVIAWCMG-UHFFFAOYSA-N 0.000 claims description 3
- 150000002513 isocyanates Chemical class 0.000 claims description 3
- 239000006166 lysate Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910001220 stainless steel Inorganic materials 0.000 claims description 2
- 239000010935 stainless steel Substances 0.000 claims description 2
- 239000000428 dust Substances 0.000 abstract description 2
- 235000013312 flour Nutrition 0.000 abstract description 2
- 230000004907 flux Effects 0.000 abstract 1
- 230000036632 reaction speed Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 6
- 239000004810 polytetrafluoroethylene Substances 0.000 description 6
- -1 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group Chemical group 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- YVNRUPSDZZZUQJ-UHFFFAOYSA-N [O].NC1=CC=CC=C1 Chemical compound [O].NC1=CC=CC=C1 YVNRUPSDZZZUQJ-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 102000018471 Proto-Oncogene Proteins B-raf Human genes 0.000 description 1
- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to a kind of methods that solid-state ball milling synthesizes Sorafenib.The method is using compound 4- (4- amino-benzene oxygens)-N- picoline -2- formamides and compound 4-chloro -3- trifluoromethyls isocyanates as raw material, or with compound 4-chloro -3- 5-trifluoromethylanilines, compound N, N '-carbonyl dimidazoles and compound 4- (4- amino-benzene oxygens)-N- picoline -2- formamides are raw material, under a small amount of liquid (and alkali) catalysis, solid-state ball milling synthesizes Sorafenib in the ball mill.The main innovation point of the present invention is for the first time solid-state ball milling synthesis Sorafenib in the ball mill, compared with the method for synthesizing Sorafenib in original liquid flux, the method of the present invention has reaction speed fast, non-flour dust overflow, it is good to react controllability, it is easy to operate, reaction yield is high, pollution less, the advantages that feasibility is strong.
Description
Technical field
The present invention relates to the preparing technical fields of Sorafenib, and in particular to a kind of side of solid-state ball milling synthesis Sorafenib
Method.
Background technology
Sorafenib is a kind of novel diaryl contracting urea, the entitled 4- { 4- [({ [4 chloro- 3- (trifluoromethyl) phenyl] of chemistry
Amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides, molecular formula C21H16ClF3N4O3, molecular weight is
464.83 structural formula is Formulas I.
Sorafenib is a kind of target therapeutic agent of multiple target point, has dual antitumor action：Both it can pass through inhibition
The activity of serine/threonine kinases of RAF-1 and B-RAF inhibits tumour to block RAF/MEK/ERK signal transduction pathway
The proliferation of cell, can also by inhibit vascular endothelial growth factor receptor VEGFR and PDGFR tyrosine kinase activity, from
And it blocks the nutrition supply of tumor neovasculature formation and cut-out tumour cell and achievees the purpose that contain tumour growth.
At present there are two types of the primary synthetic methods of Sorafenib, a kind of method is to use the chloro- 3- trifluoromethyls isocyanides of 4-
Sorafenib (US 7235576) is made with the condensation of 4- (4- amino-benzene oxygens)-N- picoline -2- formamides in acid esters.It is another
Method is reacted with the chloro- 3- 5-trifluoromethylanilines of 4- and N, N '-carbonyl dimidazoles (CDI), and generating reactive intermediate N-, (4- is chloro-
3- trifluoromethyls) -1H- imidazoles -1- amides, the intermediate and 4- (4- amino-benzene oxygens)-N- picoline -2- formamides
React to obtain final products Sorafenib (US 7235576).All it is usually organic with dichloromethane etc. in document report building-up process
Solvent reacts in the liquid phase, and the organic reagents such as dichloromethane easily pollute the environment, and reaction also have it is time-consuming, expense solvent,
Industrialized production the shortcomings of there are high risk, high-risks.
Compounds solid state ball-milling reaction is a kind of novel non-liquid reaction in ball mill, has been applied to many organic anti-
Ying Zhong.Due to it is possible to prevente effectively from using dangerous caused by toxic reagent, while reaction mass can be made full and uniform
Mixing, increase the contact surface and frequency of reactant, accelerate reaction rate and receive significant attention.In addition, because hardly making
It with solvent, reacts comparatively safe, clean and is efficient, easy to operate, reaction condition is mild, non-flour dust overflow, solid in ball mill
State ball milling synthetic method can be described as the synthetic method that one kind meeting " Green Chemistry " principle.Solid-state ball milling synthesis side in ball mill
The core technology of method is the application of catalyst, and to control synthetic reaction, catalyst not only has solid catalyst, also useful a small amount of
Liquid accelerates reaction to be catalyzed.The method of the Sorafenib of solid-state ball milling synthesis at present is not reported so far.
Invention content
The object of the present invention is to provide solid-state ball millings in a kind of ball mill to carry out Sorafenib synthetic method.
To achieve the above object, the technical solution that the present invention takes is：
A kind of method of solid-state ball milling synthesis Sorafenib, the method are：(1) different with the chloro- 3- trifluoromethyls of 4-
Cyanate (compound II) and 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (compound III) are raw material, few
Solid-state ball-milling reaction is carried out in the ball mill under quantity of fluid catalysis.It after ball milling, is concentrated after being dissolved with solvent, purifying obtains rope
La Feini (compound I)；(2) with the chloro- 3- 5-trifluoromethylanilines (compound IV) of 4- and N, N '-carbonyl dimidazoles (compound V)
For raw material, ball-milling reaction obtains intermediate N (the chloro- 3- trifluoromethyls of 4-) -1H- imidazoles -1- amides under a small amount of liquid catalyst
(compound VI)；Compound VI and compound III, ball-milling reaction, ball are carried out in the presence of a small amount of liquid and alkali in the ball mill
After mill, Sorafenib (compound I) is obtained with purifying after solvent dissolving concentration.
The present invention synthetic route be：
Route one：
Route two：
Compound II (the chloro- 3- trifluoromethylbenzenes based isocyanates of 4-) and compound III (4- (4- amino-benzene oxygens)-N-
Picoline -2- formamides) molar ratio be 1: 1~1: 1.05；Compound IV (the chloro- 3- 5-trifluoromethylanilines of 4-) and compound
V (N, N '-carbonyl dimidazoles) molar ratio is 1: 1~1: 2；Compound VI (N- (the chloro- 3- trifluoromethyls of 4-) -1H- imidazoles -
1- amides) and compound III molar ratio be 1: 1~1: 1.05.
Accelerate a small amount of liquid reacted in acetonitrile, methanol, dichloromethane, ethyl acetate for being catalyzed in the method
One or more, 0.01~1.00 μ l/mg solid chemical compounds of dosage.
In the method for be catalyzed reaction alkali in potassium carbonate, sodium carbonate, sodium hydroxide, potassium tert-butoxide one kind or
Several mixtures, the molar ratio of compound III (4- (4- amino-benzene oxygens)-N- picoline -2- formamides) and alkali is 1: 1~
1∶2。
It is one or more of in sphere material selection stainless steel, agate or zirconium dioxide used in the ball-milling reaction.Institute
The mill ball co-ground that ball-milling reaction uses the large, medium and small 3 kinds of specifications of diameter is stated, larger diameter accounts for 30%, and intermediate diameter accounts for
50%, small diameter accounts for 20%.A diameter of 3mm~the 40mm of mill ball.
The ball-milling reaction time is 2~8 hours.Rotational speed of ball-mill is 300~500 revs/min.
Midbody compound VI (N- (the chloro- 3- trifluoromethyls of 4-) -1H- that ball-milling reaction obtains in synthetic route two
Imidazoles -1- amides) post-processing approach is including adding water to be vigorously stirred, suction filtration, filtration cakes torrefaction.
After the ball-milling reaction, for lysate organic solvent be selected from methanol, ethyl acetate, dichloromethane,
It is one or more of in acetonitrile, ethyl alcohol, acetone.
Compared with prior art, the beneficial effects of the present invention are：
Solid-state ball milling synthesizes Sorafenib to the present invention in the ball mill, avoids and carries out synthetic reaction in a solvent, reacts
Comparatively safe, cleaning, while reaction rate is accelerated with catalyst (such as a small amount of liquid, alkali), substantially reduce the reaction time.This
Method have many advantages, such as reaction efficiency is high, the reaction time is short, easy to operate, at low cost, pollution less, it is environmentally protective, be suitable for industry
Change and promotes and applies.
Specific implementation mode
With reference to specific example, the invention will be further described.
Embodiment 1：
4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- picoline -2- first
The preparation of amide
In the 100mL polytetrafluoroethylene (PTFE) ball grinders equipped with about 100g zirconium dioxide mill balls, 4- (4- aminobenzene oxygen is added
Base) the chloro- 3- trifluoromethylbenzenes based isocyanate 0.46g of-N- picoline -2- formamides 0.50g (2.06mmol), 4-
240 μ l of (2.06mmol) and acetonitrile (0.25 μ l/mg solid chemical compounds).Drum's speed of rotation is set as 400r/min, closed in tank body
4h is reacted under state to stop.Methanol lysate is added into ball grinder after reaction, rotary evaporated to dryness purifies to obtain brown
Powder 0.92g (yield 96%), purity 99% (HPLC methods).1H NMR (600MHz, DMSO-d6) δ：2.79 (d, J=4.9Hz,
3H), 7.18 (m, 3H), 7.38 (d, J=2.6Hz, 1H), 7.62 (m, 4H), 8.13 (d, J=2.5Hz, 1H), 8.51 (d, J=
5.6Hz, 1H), 8.78 (q, J=4.8Hz, 1H), 9.02 (s, 1H), 9.24 (s, 1H).
Embodiment 2：
The preparation of N- (the chloro- 3- trifluoromethyls of 4-) -1H- imidazoles -1- amides
In the 100mL polytetrafluoroethylene (PTFE) ball grinders equipped with about 100g zirconium dioxide mill balls, the chloro- 3- fluoroforms of 4- are added
Base aniline 1g (5.113mmol), N, N '-carbonyl dimidazoles 0.83g (5.118mmol) and acetonitrile 460 μ l (0.25 μ l/mg solids
Compound).Drum's speed of rotation is set as 400r/min, and TLC methods track to that the reaction was complete, and 5h is reacted under tank body air-tight state and is stopped
Only.After reaction mixture add water to be vigorously stirred, filter, discard filtrate, be dried overnight, obtain white powder 1.18g (yields
80%).
Embodiment 3：
4- { 4- [({ [4- chloro- 3- (trifluoromethyl) phenyl] amino } carbonyl) amino] phenoxy group }-N- picoline -2- first
The preparation of amide
In the 100mL polytetrafluoroethylene (PTFE) ball grinders equipped with about 100g zirconium dioxide mill balls, 4- (4- aminobenzene oxygen is added
Base)-N- picoline -2- formamides 0.12g (0.49mmol), N- (the chloro- 3- trifluoromethyls of 4-) -1H- imidazoles -1- amides
0.14g (0.48mmol), potassium carbonate 0.14g (1.01mmol) and 65 μ l of dichloromethane (0.25 μ l/mg solid chemical compounds).Ball milling
Machine rotating speed is set as 400r/min, and 8h is reacted under tank body air-tight state and is stopped.It is molten that methanol is added into ball grinder after reaction
Product is solved, and liquid is transferred in pear shape bottle, heating makes to be completely dissolved, and rotary evaporated to dryness purifies to obtain brown ceramic powder 0.17g
(yield 72%), purity 99% (HPLC methods).1H NMR (500MHz, DMSO-d6)：δ 2.81 (d, J=4.9Hz, 3H), 7.18
(m, 3H), 7.40 (d, J=2.6Hz, 1H), 7.66 (m, 4H), 8.14 (d, J=2.5Hz, 1H), 8.53 (d, J=5.6Hz,
1H), 8.78 (d, J=4.9Hz, 1H), 9.02 (s, 1H), 9.24 (s, 1H).
Claims (7)
1. a kind of method of solid-state ball milling synthesis Sorafenib, which is characterized in that synthetic route is divided into two kinds：
(1) with the chloro- 3- trifluoromethylbenzenes based isocyanates (compound II) of 4- and 4- (4- amino-benzene oxygens)-N- picolines-
2- formamides (compound III) are raw material, carry out solid-state ball-milling reaction in the ball mill under a small amount of liquid catalyst.Ball milling terminates
Afterwards, it is concentrated after being dissolved with solvent, purifying obtains Sorafenib (compound I)；
(2) with the chloro- 3- 5-trifluoromethylanilines (compound IV) of 4- and N, N '-carbonyl dimidazoles (compound V) for raw material, a small amount of
Ball-milling reaction obtains the (change of intermediate N (the chloro- 3- trifluoromethyls of 4-) -1H- imidazoles -1- amides in the ball mill under liquid catalyst
Close object VI)；Compound VI and compound III, carries out ball-milling reaction, ball milling knot in the ball mill in the presence of a small amount of liquid and alkali
Shu Hou obtains Sorafenib (compound I) with purifying after solvent dissolving concentration；
The structural formula of compound I, II, III, IV, V, VI are as follows：
2. the method for solid-state ball milling synthesis Sorafenib as described in claim 1, it is characterised in that：Compound II and compound
The molar ratio of III is 1: 1~1: 1.05；The molar ratio of compound IV and compound V are 1: 1~1: 2；Compound VI and compound
The molar ratio of III is 1: 1~1: 1.05.
3. the method for solid-state ball milling synthesis Sorafenib as described in claim 1, it is characterised in that：Accelerate reaction for being catalyzed
A small amount of liquid be selected from acetonitrile, methanol, dichloromethane, one or more of ethyl acetate mixture, 0.01~1 μ l/ of dosage
Mg solid chemical compounds；Alkali for being catalyzed reaction is one or more of in potassium carbonate, sodium carbonate, sodium hydroxide, potassium tert-butoxide
The molar ratio of mixture, compound III and alkali is 1: 1~1: 2.
4. the method for solid-state ball milling synthesis Sorafenib as described in claim 1, it is characterised in that：The ball-milling reaction institute
Sphere material is one or more of in stainless steel, agate or zirconium dioxide, the ball-milling reaction is big or middle using diameter,
The mill ball co-ground of small 3 kinds of specifications, larger diameter account for 30%, and intermediate diameter accounts for 50%, and small diameter accounts for 20%, mill ball
A diameter of 3mm~40mm.
5. the method for solid-state ball milling synthesis Sorafenib as described in claim 1, it is characterised in that：The ball-milling reaction time is 2
~8 hours.Rotational speed of ball-mill is 300~500 revs/min.
6. the method for solid-state ball milling synthesis Sorafenib as described in claim 1, it is characterised in that：In synthetic route (2), ball
Midbody compound VI post-processings are obtained by the reaction using adding water to be vigorously stirred in mill, filter, dry.
7. the method for solid-state ball milling synthesis Sorafenib as described in claim 1, it is characterised in that：The ball-milling reaction terminates
Afterwards, the organic solvent for being used for lysate is a kind of or several in methanol, ethyl acetate, dichloromethane, acetonitrile, ethyl alcohol, acetone
Kind.
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