CN107915676A - The preparation method of Sorafenib - Google Patents
The preparation method of Sorafenib Download PDFInfo
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- CN107915676A CN107915676A CN201711014693.XA CN201711014693A CN107915676A CN 107915676 A CN107915676 A CN 107915676A CN 201711014693 A CN201711014693 A CN 201711014693A CN 107915676 A CN107915676 A CN 107915676A
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- 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 30
- 239000005511 L01XE05 - Sorafenib Substances 0.000 title claims abstract description 30
- 229960003787 sorafenib Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- -1 2- carbonyl methylamino -4- chloropyridines Chemical class 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 14
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 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 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- NNMYRMGMVLMQAY-UHFFFAOYSA-N 4-chloropyridine-2-carboxylic acid Chemical class OC(=O)C1=CC(Cl)=CC=N1 NNMYRMGMVLMQAY-UHFFFAOYSA-N 0.000 claims description 4
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical class CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 abstract 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- DGRVQOKCSKDWIH-UHFFFAOYSA-N 1-chloro-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1Cl DGRVQOKCSKDWIH-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001629 suppression Effects 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 invention discloses the preparation method of Sorafenib, the Sorafenib chemical name { 4 [({ 4 chlorine 3 (trifluoromethyl) phenyl] amino } carbonyl for 4) amino] phenoxy group } 2 formamide of N picolines；Preparation process of the present invention is succinct, and raw material is easy to get, economic and environment-friendly, is advantageously implemented industrialization, and the economic technology of Sorafenib bulk pharmaceutical chemicals can be promoted to develop, and reduces manufacturing cost, and yield is high, and environmental pollution is small, suitable for producing in enormous quantities.
Description
Technical field
The present invention relates to the preparation method of pharmaceutical technology field, more particularly to Sorafenib.
Background technology
Sorafenib is a kind of multi-kinase inhibitor, for treating the stomach for not responding to or not being resistant to standard treatment
Enteron aisle stromal tumors and metastatic renal cell cancer.Sorafenib has dual anti-tumor effect：On the one hand, it can pass through suppression
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, suppress the growth of tumour cell indirectly.
The content of the invention
The present invention provides the preparation method of Sorafenib；Preparation process of the present invention is succinct, and raw material is easy to get, economic ring
To protect, be advantageously implemented industrialization, the economic technology of Sorafenib bulk pharmaceutical chemicals can be promoted to develop, reduce manufacturing cost, yield is high,
Environmental pollution is small, suitable for producing in enormous quantities.
To achieve the above object, technical scheme is implemented as follows：
A kind of preparation method of Sorafenib, the Sorafenib chemical name are 4- { 4- [({ 4- chloro- 3- (trifluoromethyl) benzene
Base] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides, the preparation method of the Sorafenib, which is made, to be included
Following processing step：
（1）In 2- carboxyl -4- chloropyridines 1. middle addition methylamine and organic solvent, in 50% hydrochloric acid, 120 DEG C are heated to, instead
Answer 4 it is small when, cooling, generation 2- carbonyl methylamino -4- chloropyridines are 2.；
（2）In step（1）3. the 2- carbonyl methylamino -4- chloropyridines of generation are 2. middle to add p-nitrophenol, in solvent acetic acid second
Condensation reaction, generation compound 4- occur in ester（4- nitros）Benzyloxy -2- carbonyls methylamino pyridine is 4.；
（3）In step（2）Generation compound 4- [（4- nitros）Benzyloxy] -2- carbonyls methylamino pyridine 4. in be passed through ammonia,
Catalyst is added, reduction reaction, generation compound 4- occurs（4- amino）Benzyloxy -2- carbonyls methylamino pyridine is 5.；
（4）Take the chloro- 3- trifluoromethylbenzenes of 2,5- bis- to be 6. placed in autoclave, and add hydrazine hydrate and pyridine and organic solvent,
180 DEG C, when reaction 6 is small are heated to, cooling, removes excessive hydrazine, is evaporated in vacuo, and residue adds solvent and recrystallized, and obtains
To the chloro- 3- trifluoromethyls hydrazines of 2- 7.；
（5）In step（4）The obtained chloro- 3- trifluoromethyls hydrazines of 2- are 7. middle to add methanol and catalyst, heating reflux reaction 1
Hour, 8. cold filtration, obtains the chloro- 3- 5-trifluoromethylanilines of 2-；
（6）In step（5）The chloro- 3- 5-trifluoromethylanilines of 2- of generation are 8. middle to add formic acid and certain organic solvent, at 50 DEG C
Under, react 2 it is small when, after cooling, generation compound 2- chloro- 3- trifluoromethylbenzenes amido aldehydes are 9.；
（7）By step（5）Generate compound 4-（4- amino）5. and step benzyloxy -2- carbonyls methylamino pyridine（3）Generation
9. the chloro- 3- trifluoromethylbenzenes amido aldehydes of compound 2- mix, add 80% hydrochloric acid solution and organic solvent, it is small to be heated to reflux 5
When, generation condensation reaction, generation 4- 4- [(4- chloro- 3- (trifluoromethyl) phenyl] and amino } carbonyl) amino] phenoxy group }-N- first
10. yl pyridines -2- formamides, are Sorafenib.
Prepare organic solvent used in Sorafenib for ethyl acetate, dichloromethane, acetonitrile, absolute ethyl alcohol, isopropanol,
The binary mixture of the unitary such as methanol solvent or above-mentioned solvent.
The step（1）Middle recrystallization solvent for use is petroleum ether.
The step（2）The catalyst of middle addition is solid-state different-phase catalyst Raney's nickel.
The step（6）The catalyst of middle addition is quaternary ammonium salt 4-butyl ammonium hydrogen sulfate and iron.
Its chemical equation is：
。
Compared with prior art, the present invention have the advantages that：
Preparation process of the present invention is succinct, and raw material is easy to get, economic and environment-friendly, is advantageously implemented industrialization, can promote Sorafenib
The economic technology development of bulk pharmaceutical chemicals, reduces manufacturing cost, and yield is high, and environmental pollution is small, suitable for producing in enormous quantities.
Embodiment
The present invention is further elaborated with reference to specific embodiment.
Embodiment 1
The preparation method of Sorafenib, comprises the following steps that：
（1）In 2- carboxyl -4- chloropyridines 1.（21.1g）Middle addition methylamine（4.6g）And organic solvent absolute ethyl alcohol（100ml）,
In 50% hydrochloric acid（200ml）In, 120 DEG C, when reaction 4 is small are heated to, cooling, generation 2- carbonyl methylamino -4- chloropyridines are 2.
（15.2g）；
（2）In step（1）The 2- carbonyl methylamino -4- chloropyridines of generation are 2.（11.4g）Middle addition p-nitrophenol is 3.
（12.6g）, in solvent ethyl acetate（50ml）Middle generation condensation reaction, generation compound 4-（4- nitros）Benzyloxy -2- carbonyls
Methylamino pyridine is 4.（21.3g）；
（3）In step（2）Generation compound 4- [（4- nitros）Benzyloxy] -2- carbonyls methylamino pyridine is 4.（21.0g）In lead to
Enter ammonia（1000ml）, catalyst quaternary ammonium salt 4-butyl ammonium hydrogen sulfate and iron are added, reduction reaction, generation compound 4- occurs
（4- amino）Benzyloxy -2- carbonyls methylamino pyridine is 5.（20.1g）；
（4）Take the chloro- 3- trifluoromethylbenzenes of 2,5- bis- 6.（10.8g）It is placed in autoclave, and adds hydrazine hydrate（18g）And pyridine
（50ml）And organic solvent ethyl acetate and dichloromethane（200ml）, 180 DEG C, when reaction 6 is small are heated to, cooling, removed
The hydrazine of amount, vacuum distillation, residue add solvent petroleum ether and are recrystallized, and obtain the chloro- 3- trifluoromethyls hydrazines of 2- 7.
（11.2g）；
（5）In step（4）The obtained chloro- 3- trifluoromethyls hydrazines of 2- are 7.（10g）Middle addition methanol（60ml）With solid-state out-phase
Catalyst Raney's nickel（20g）, when heating reflux reaction 1 is small, 8. cold filtration, obtains the chloro- 3- 5-trifluoromethylanilines of 2-（8.6g）；
（6）In step（5）The chloro- 3- 5-trifluoromethylanilines of 2- of generation are 8.（7.9g）Middle addition formic acid（120ml）Have with certain
Solvent acetonitrile and absolute ethyl alcohol（200ml）, at 50 DEG C, react 2 it is small when, after cooling, generation compound in the chloro- 3- of 2-
Trifluoromethylbenzene amido aldehyde is 9.（12.1g）；
（7）Step（5）Generate compound 4-（4- amino）Benzyloxy -2- carbonyls methylamino pyridine is 5.（18.4g）And step（3）It is raw
Into the chloro- 3- trifluoromethylbenzenes amido aldehydes of compound 2- 9.（9.1g）Mixing, adds 80% hydrochloric acid solution（160ml）With it is organic
Solvent isopropanol and methanol（300ml）, be heated to reflux 5 it is small when, occur condensation reaction, generate the 4- { 4- [({ chloro- 3- (fluoroforms of 4-
Base) phenyl] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides are 10.（24.1g）, it is Sorafenib.
Its chemical equation is：
。
Embodiment 2
The preparation method of Sorafenib, comprises the following steps that：
（1）Take the chloro- 3- trifluoromethylbenzenes of 2,5- bis- 6.（15.4g）It is placed in autoclave, and adds hydrazine hydrate（26g）And pyridine
（150ml）And organic solvent ethyl acetate and dichloromethane（250ml）, 130 DEG C, when reaction 4 is small are heated to, is cooled down, is removed
Excessive hydrazine, vacuum distillation, residue add solvent petroleum ether and are recrystallized, and obtain the chloro- 3- trifluoromethyls hydrazines of 2- 7.
（12.1g）；
（2）In step（1）The obtained chloro- 3- trifluoromethyls hydrazines of 2- are 7.（10g）Methanol will be added（100ml）With solid-state out-phase
Catalyst Raney's nickel（10g）, when heating reflux reaction 2 is small, 8. cold filtration, obtains the chloro- 3- 5-trifluoromethylanilines of 2-（6.1g）；
（3）In step（2）The chloro- 3- 5-trifluoromethylanilines of 2- of generation are 8.（5.8g）Middle addition formic acid（200ml）Have with certain
Solvent absolute ethyl alcohol（500ml）, at 80 DEG C, react 4 it is small when, after cooling, generate the chloro- 3- trifluoromethyls of organic matter 2-
Phenylamino aldehyde is 9.（5.2g）；
（4）In 2- carboxyl -4- chloropyridines 1.（18.6g）Middle addition methylamine（6.8g）And organic solvent isopropanol and absolute ethyl alcohol
（600ml）, in 80% hydrochloric acid（160ml）In, 200 DEG C, when reaction 3 is small are heated to, cooling, generates 2- carbonyl methylamino -4- chlorine
Pyridine is 2.（9.3g）；
（5）In step（4）The 2- carbonyl methylamino -4- chloropyridines of generation are 2.（7.5g）Middle addition p-nitrophenol is 3.（21.3g）,
In solvent ethyl acetate（250ml）Middle generation condensation reaction, generation compound 4-（4- nitros）Benzyloxy -2- carbonyl methylamino pyrroles
Pyridine is 4.（11.3g）；
（6）In step（5）Generation compound 4- [（4- nitros）Benzyloxy] -2- carbonyls methylamino pyridine is 4.（10.2g）In lead to
Enter ammonia（2000ml）, catalyst quaternary ammonium salt 4-butyl ammonium hydrogen sulfate and iron are added, reduction reaction, generation compound 4- occurs
（4- amino）Benzyloxy -2- carbonyls methylamino pyridine is 5.（8.7g）；
（7）Step（5）Generate compound 4-（4- amino）Benzyloxy -2- carbonyls methylamino pyridine is 5.（8.5g）And step（3）It is raw
Into the chloro- 3- trifluoromethylbenzenes amido aldehydes of compound 2- 9.（4.6g）Mixing, adds 80% hydrochloric acid solution（320ml）With it is organic
Solvent isopropanol（250ml）, be heated to reflux 10 it is small when, occur condensation reaction, generate 4- { 4- [({ 4- chloro- 3- (trifluoromethyl) benzene
Base] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides are 10.（7.2g）, it is Sorafenib.
Prepare organic solvent used in Sorafenib for ethyl acetate, dichloromethane, acetonitrile, absolute ethyl alcohol, isopropanol,
The binary mixture of the unitary such as methanol solvent or above-mentioned solvent.
Its chemical equation is as described in Example 1.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended right
It is required that rather than described above limit, it is intended that all changes in the implication and scope of the equivalency of claim will be fallen
Change is included in the present invention.Any mark in claim should not be considered as to the involved claim of limitation.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, belongs to the scope of protection of the invention.
Claims (5)
1. a kind of preparation method of Sorafenib, the Sorafenib chemical name is 4- { 4- [({ the chloro- 3- of 4- (trifluoromethyl)
Phenyl] amino } carbonyl) amino] phenoxy group }-N- picoline -2- formamides, it is characterised in that：The Sorafenib is made
Preparation method comprises the following steps that：
（1）In 2- carboxyl -4- chloropyridines 1. middle addition methylamine and organic solvent, in 50% hydrochloric acid, 120 DEG C are heated to, instead
Answer 4 it is small when, cooling, generation 2- carbonyl methylamino -4- chloropyridines are 2.；
（2）In step（1）3. the 2- carbonyl methylamino -4- chloropyridines of generation are 2. middle to add p-nitrophenol, in solvent acetic acid second
Condensation reaction, generation compound 4- occur in ester（4- nitros）Benzyloxy -2- carbonyls methylamino pyridine is 4.；
（3）In step（2）Generation compound 4- [（4- nitros）Benzyloxy] -2- carbonyls methylamino pyridine 4. in be passed through ammonia,
Catalyst is added, reduction reaction, generation compound 4- occurs（4- amino）Benzyloxy -2- carbonyls methylamino pyridine is 5.；
（4）Take the chloro- 3- trifluoromethylbenzenes of 2,5- bis- to be 6. placed in autoclave, and add hydrazine hydrate and pyridine and organic solvent,
180 DEG C, when reaction 6 is small are heated to, cooling, removes excessive hydrazine, is evaporated in vacuo, and residue adds solvent and recrystallized, and obtains
To the chloro- 3- trifluoromethyls hydrazines of 2- 7.；
（5）In step（4）The obtained chloro- 3- trifluoromethyls hydrazines of 2- are 7. middle to add methanol and catalyst, heating reflux reaction 1
Hour, 8. cold filtration, obtains the chloro- 3- 5-trifluoromethylanilines of 2-；
（6）In step（5）The chloro- 3- 5-trifluoromethylanilines of 2- of generation are 8. middle to add formic acid and certain organic solvent, at 50 DEG C
Under, react 2 it is small when, after cooling, generation compound 2- chloro- 3- trifluoromethylbenzenes amido aldehydes are 9.；
（7）By step（5）Generate compound 4-（4- amino）5. and step benzyloxy -2- carbonyls methylamino pyridine（3）Generation
9. the chloro- 3- trifluoromethylbenzenes amido aldehydes of compound 2- mix, add 80% hydrochloric acid solution and organic solvent, it is small to be heated to reflux 5
When, generation condensation reaction, generation 4- 4- [(4- chloro- 3- (trifluoromethyl) phenyl] and amino } carbonyl) amino] phenoxy group }-N- first
10. yl pyridines -2- formamides, are Sorafenib.
2. the preparation method of Sorafenib according to claim 1, it is characterised in that：Preparing used in Sorafenib has
Solvent is ethyl acetate, dichloromethane, acetonitrile, absolute ethyl alcohol, isopropanol, methanol etc.
The binary mixture of unitary solvent or above-mentioned solvent.
3. the preparation method of Sorafenib according to claim 1, it is characterised in that：The step（1）Middle recrystallization institute
It is petroleum ether with solvent.
4. the preparation method of Sorafenib according to claim 1, it is characterised in that：The step（2）Middle addition is urged
Agent is solid-state different-phase catalyst Raney's nickel.
5. the preparation method of Sorafenib according to claim 1, it is characterised in that：The step（6）Middle addition is urged
Agent is quaternary ammonium salt 4-butyl ammonium hydrogen sulfate and iron.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711014693.XA CN107915676A (en) | 2017-10-26 | 2017-10-26 | The preparation method of Sorafenib |
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| CN101052619A (en) * | 2004-09-29 | 2007-10-10 | 拜耳医药保健股份公司 | Method for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide |
| WO2016005874A1 (en) * | 2014-07-09 | 2016-01-14 | Shilpa Medicare Limited | Process for the preparation of regorafenib and its crystalline forms |
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| CN101052619A (en) * | 2004-09-29 | 2007-10-10 | 拜耳医药保健股份公司 | Method for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide |
| WO2016005874A1 (en) * | 2014-07-09 | 2016-01-14 | Shilpa Medicare Limited | Process for the preparation of regorafenib and its crystalline forms |
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| SHINJI KOTACHI 等: "Ruthenium catalysed N,N"-Diarylurea Synthesis from N-Aryl substituted Formamides and Aminoarenes", 《J. CHEM. SOC.，CHEM. COMMUN.》 * |
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