CN104557688A - Synthetic method for Sorafenib intermediate and synthetic method for compound A used for synthesizing Sorafenib intermediate - Google Patents
Synthetic method for Sorafenib intermediate and synthetic method for compound A used for synthesizing Sorafenib intermediate Download PDFInfo
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- CN104557688A CN104557688A CN201410826341.4A CN201410826341A CN104557688A CN 104557688 A CN104557688 A CN 104557688A CN 201410826341 A CN201410826341 A CN 201410826341A CN 104557688 A CN104557688 A CN 104557688A
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- RXZZBPYPZLAEFC-UHFFFAOYSA-N CNC(c1cc(Oc(cc2)ccc2N)ccn1)=O Chemical compound CNC(c1cc(Oc(cc2)ccc2N)ccn1)=O RXZZBPYPZLAEFC-UHFFFAOYSA-N 0.000 description 1
- CVTLBTZPSZDIIS-UHFFFAOYSA-N CNC(c1nccc(Oc(cc2)ccc2N)n1)=O Chemical compound CNC(c1nccc(Oc(cc2)ccc2N)n1)=O CVTLBTZPSZDIIS-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- 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
- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
The invention provides a synthetic method for a Sorafenib intermediate and a synthetic method for a compound A used for synthesizing the sorafenib intermediate. The compound A has a structural formula A described in the specification. The synthetic method for the compound A comprises the following steps: taking a compound B with a structural formula B and a compound C with a structural formula C as substrates, and taking organic alkali as a catalyst for catalyzing the substrates to produce a substitution reaction to obtain a compound A, wherein the structural formula B is described in the specification, the structural formula C is described in the specification, R is linear or branched alkyl of C1-C10, cyclohexyl, methoxy ethyl, alkoxy ethyl, aryl or aryl alkyl; R' is H, mono-substituted halogen, poly-substituted halogen or an electron-donating or electron-withdrawing group. The organic alkali is adopted as the catalyst, so that the reaction efficiency of the compound B and the compound C is improved and the yield of the obtained compound A has a great breakthrough in comparison with the yield in the prior art. The synthetic method provided by the invention is suitable for large-scale industrialized popularization and application.
Description
Technical field
The present invention relates to organic synthesis field, the synthetic method of the synthetic method in particular to a kind of sorafenib intermediate and the compd A for the synthesis of it.
Background technology
Xarelto (structural formula is formula 1) is a kind of oral pharmaceutical for the treatment of tumour of novel many targetings, and its primary development goal is, is used for the treatment of and does not respond the gastrointestinal stromal tumors and metastatic renal cell cancer that maybe can not tolerate to standard treatment.Can the acceptor of optionally some albumen of target, the latter is considered in Tumor Growth, play a part a kind of molecular switch sample.Its above-mentioned indication obtains in the U.S. " the fast passage " that FDA authorizes and examines status.
At present, a lot of patent document discloses the different synthetic methods of Xarelto.Wherein, compound 4-(4-amido phenoxy group)-N-methylnicotinamide (structural formula is the compound 1 of formula 2) is a very important key intermediate, has a lot of patent to make to use it as Material synthesis Xarelto.
And in the document of synthesis 4-(4-amido phenoxy group)-N-methylnicotinamide; generally synthesize according to following synthetic route one; namely be raw material by pyridine-2-carboxylic acids; compound 5 is obtained through acidylate chlorination; obtain compound 6 through amidate action again, make compound 6 be obtained by reacting this 4-(4-amido phenoxy group)-N-methylnicotinamide with p-aminophenol further under the effect of alkali.
Certainly, also the route of other synthesis 4-(4-amido phenoxy group)-N-methylnicotinamides is there is in prior art, such as patent document WO2005082853 discloses following synthetic route two: use p-Nitrophenyl chloride and compound 4-hydroxy base-2-pyridine-N-METHYLFORMAMIDE for raw material under the catalysis of copper powder 180 DEG C of reactions 3 hours with 24% yield obtain compound 4, under the reduction of nickel-hydrogen, obtain compound 1.
Patent document US20030207872 discloses following synthetic route three: using fluoronitrobenzene and 4-hydroxy-2-methyl pyridine is raw material, and by coupling, oxidation and esterification obtain compound 3.
Patent document EP1889836 discloses following synthetic route four: use 4-chloropyridine-2-isopropyl formate and p-NP 120 DEG C of reactions in chlorobenzene within 23 hours, to obtain 4-(4-nitro phenoxyl) pyridine-2-isopropyl formate (compound 3b), but yield is only 45%.
And the coupling step yield of said synthesis route two is too low, and the temperature required for reaction is higher, and comprehensive cost is higher; Yield is all lower in steps in synthetic route three institute, and in second step, used deadly poisonous compound tin anhydride, is difficult to realize suitability for industrialized production; Required for synthetic route four, temperature is higher, and energy consumption is large, and yield is only 45%, is not suitable for suitability for industrialized production.
As can be seen here, in order to meet the Production requirement of BAY 43-9006, a kind of high yield must be provided and the synthetic route of the sorafenib intermediate of applicable suitability for industrialized production.
Summary of the invention
Main purpose of the present invention is the synthetic method providing a kind of synthetic method of sorafenib intermediate and the compd A for the synthesis of it, to solve the problem that in prior art, sorafenib intermediate yield is low.
To achieve these goals, according to an aspect of the present invention, provide a kind of synthetic method with the compd A of structural formula A, structural formula A is
this synthetic method comprises: to have the compd B of structural formula B and to have the Compound C of structural formula C for substrate, take organic bases as catalyst substrate generation substitution reaction, obtain compd A, structural formula B is
structural formula C is
wherein, R is C
1-C
10direct-connected or connect alkyl, cyclohexyl, methoxy ethyl, alkoxyethyl, aryl or arylalkyl; R ' is H, mono-substituted halogen, polysubstituted halogen, supplied for electronic or electron-withdrawing group.
Further, the mol ratio of above-claimed cpd B and Compound C is 1:1.05 ~ 1:2.0.
Further, above-mentioned organic bases is selected from one or more in triethylamine, N, N-diisopropyl ethyl amine, pyridine, N, N-lutidine and DMA.
Further, above-mentioned R is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the tertiary butyl.
Further, above-mentioned synthetic method comprises: compd B, Compound C are mixed with the first organic solvent, form the first reaction system; In the first reaction system, add organic base catalytic compd B and Compound C, at 70 ~ 80 DEG C, substitution reaction occurs, obtain the first product system containing compd A.
Further, above-mentioned first organic solvent is selected from one or more in chlorobenzene, dimethylbenzene, DMF and pyridine.
Further, above-mentioned synthetic method also comprises the sepn process of separating compound A from the first product system, and sepn process comprises: obtain cooling system after the first product system is cooled to 20 ~ 30 DEG C; Adopt methylene dichloride and water to extract cooling system, obtain organic phase and aqueous phase; And organic phase is concentrated, obtain compd A.
According to a further aspect in the invention, provide a kind of synthetic method with the sorafenib intermediate E of structural formula E, structural formula E is
this synthetic method comprises: step S1, adopts above-mentioned synthetic method to obtain compd A; Step S2, carries out methylamine replacement to compd A, obtains the Compound D with structural formula D; And step S3, reduce to Compound D, obtain sorafenib intermediate E, wherein, the R ' in compd A is H, and structural formula D is
Further, above-mentioned steps S2 comprises: mixed with the second organic solvent by compd A, forms the first mixed system; Stir the first mixed system and add methylamine in the first mixed system, obtaining Compound D.
Further, the mol ratio of above-claimed cpd A and methylamine is 1:3 ~ 1:13.8.
Further, above-mentioned second organic solvent is selected from one or more in toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane and the respective aqueous solution.
Further, above-mentioned steps S3 comprises: the HCI solution of Compound D and reduction system are carried out nitro-reduction reaction at the 3rd organic solvent, obtains sorafenib intermediate E.
Further, above-mentioned reduction system is palladium charcoal hydrogen system, iron powder hydrochloric acid system, iron powder acetate system or palladium charcoal formic acid-ammonium formiate system.
Further, above-mentioned reduction system is palladium charcoal hydrogen system, and step S3 comprises: the HCI solution of Compound D and the 3rd organic solvent are mixed in a kettle., form the second mixed system; In the second mixed system, add palladium-carbon catalyst, and pass into hydrogen in reactor, the pressure making hydrogen in reactor is 0.5 ~ 1.5MPa, forms the second reaction system; Time at 45 ~ 55 DEG C, the second reaction system carries out nitro-reduction reaction, obtains sorafenib intermediate E.
Further, above-mentioned reduction system is palladium carbon formic acid-ammonium formiate system, and step S3 comprises: the HCI solution of Compound D and the 3rd organic solvent are mixed in a kettle., form the second mixed system; Palladium-carbon catalyst and ammonium formiate formation the 3rd mixed system is added in the second mixed system; 3rd mixed system be heated to reflux state and add formic acid solution to carry out nitro-reduction reaction in the 3rd mixed system, obtaining sorafenib intermediate E.
Further, the mol ratio of above-claimed cpd D and ammonium formiate is 1:0.2 ~ 1:3; The mol ratio of Compound D and formic acid is 1:1 ~ 1:4.
Further, above-mentioned reduction system is iron powder acetate system, and step S3 comprises: the HCI solution of Compound D, the 3rd organic solvent, acetic acid, iron powder are formed the 4th mixed system; 4th mixed system is heated to reflux state to carry out reduction reaction, obtains sorafenib intermediate E.
Further, the mol ratio of above-claimed cpd D and acetic acid is 1:3 ~ 1:5.
Further, above-mentioned 3rd organic solvent is selected from one or more in methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ethyl acetate, isopropyl acetate and the respective aqueous solution.。
Apply technical scheme of the present invention, employing organic bases is catalyzer, improve the reaction efficiency with compd B and Compound C, and then the yield of the compd A obtained is with great breakthrough relative to prior art, even can reach more than 80%, when being therefore applied in the synthesis of sorafenib intermediate synthesis and BAY 43-9006, applicable large-scale industrialization is applied.
Accompanying drawing explanation
The Figure of description forming a application's part is used to provide a further understanding of the present invention, and schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 shows the nmr spectrum of 4-(4-nitrophenoxy) pyridine-2-methyl-formiate according to embodiments of the invention 3;
Fig. 2 shows the nmr spectrum of 4-(the 4-nitrophenoxy)-N-methylnicotinamide according to embodiments of the invention 3; And
Fig. 3 shows the nmr spectrum of 4-(4-amido the phenoxy group)-N-methylnicotinamide according to embodiments of the invention 3.
Embodiment
It should be noted that, when not conflicting, the embodiment in the application and the feature in embodiment can combine mutually.Below with reference to the accompanying drawings and describe the present invention in detail in conjunction with the embodiments.
In a kind of typical embodiment of the present invention, provide a kind of synthetic method with the compd A of structural formula A, structural formula A is
this synthetic method comprises: to have the compd B of structural formula B and to have the Compound C of structural formula C for substrate, take organic bases as catalyst substrate generation substitution reaction, obtain compd A, structural formula B is
structural formula C is
wherein, R is C
1-C
10direct-connected or connect alkyl, cyclohexyl, methoxy ethyl, alkoxyethyl, aryl or arylalkyl; R ' is H, mono-substituted halogen, polysubstituted halogen electron-donating group or electron-withdrawing group.Above-mentioned mono-substituted halogen just phenyl ring understood by one of ordinary skill in the art 2,3,5, H in 6 on a C position is substituted, and polysubstituted halogen is just on phenyl ring understood by one of ordinary skill in the art 2,3, have the H at least two C positions by one or more halogens in 5,6 replace.Above-mentioned electron-donating group can be methyl, the methoxyl group or benzyloxy etc. of this area routine, and above-mentioned electron-withdrawing group can be the itrile group or carboxylicesters etc. of this area routine.
Above-mentioned synthetic method adopts organic bases to be catalyzer, improve the reaction efficiency with compd B and Compound C, and then the yield of the compd A obtained is with great breakthrough relative to prior art, even can reach more than 80%, when being therefore applied in the synthesis of sorafenib intermediate synthesis and BAY 43-9006, applicable large-scale industrialization is applied.
When with above-mentioned synthetic method synthetic compound A, those skilled in the art can chemically the angle Selection compd B of reaction formula and the mol ratio of Compound C, the present invention gropes through long-term test, the mol ratio of preferred above-claimed cpd B and Compound C is 1:1.05 ~ 1:2.0, to improve the yield of product further.
Select the organic bases that the above-mentioned organic bases for synthetic method of the present invention can be commonly used from prior art, the present invention has considered the cost of organic bases and the catalytic efficiency to substrate, preferred above-mentioned organic bases is selected from triethylamine, N, N-diisopropyl ethyl amine, pyridine, N, one or more in N-lutidine and DMA.The suitability of above-mentioned organic bases and the above-mentioned compd B of the present invention and Compound C is better, and therefore catalytic efficiency is higher.
In a kind of preferred embodiment of the present invention, above-mentioned R is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the tertiary butyl.Adopt above-mentioned C
1to C
4group as R base, easily carry out said process and the cost of raw material is lower, the compd A formed will be more suitable for the synthesis of BAY 43-9006.
In another preferred embodiment of the present invention, above-mentioned synthetic method comprises: compd B, Compound C are mixed with the first organic solvent, form the first reaction system; In the first reaction system, add organic base catalytic compd B and Compound C, at 70 ~ 80 DEG C, substitution reaction occurs, obtain the first product system containing compd A.Above-mentioned reaction is carried out at 70 ~ 80 DEG C, and temperature of reaction is lower, and reaction conditions is gentle, and energy consumption is less, therefore has more important commercial introduction using value.
The first above-mentioned adopted organic solvent be selected from chlorobenzene, dimethylbenzene, DMF and pyridine one or more.First organic solvent with above-mentioned composition has good dispersing property to compd B and Compound C, for both reactions provide good solvent environment, and the separation of easy subsequent compound A.
The compd A obtained to make the present invention can be used widely, above-mentioned synthetic method also comprises the sepn process of separating compound A from the first product system, and sepn process comprises: obtain cooling system after the first product system is cooled to 20 ~ 30 DEG C; Adopt methylene dichloride and water to extract cooling system, obtain organic phase and aqueous phase; And organic phase is concentrated, obtain compd A.
In the another kind of typical embodiment of the present invention, provide a kind of synthetic method with the sorafenib intermediate E of structural formula E, structural formula E is
this synthetic method comprises: step S1, adopts above-mentioned synthetic method to obtain compd A; Step S2, carries out methylamine replacement to compd A, obtains the Compound D with structural formula D; And step S3, reduce to Compound D, obtain sorafenib intermediate E, wherein, the R ' in compd A is H, and described structural formula D is
The ammonia solution of the replacement of step S1, step S2 and the hydrogenation of step S3 combine by such scheme breakthroughly, and the synthesis for sorafenib intermediate E provides new synthetic route; And the yield of the compd A obtained due to above-mentioned steps S1 is higher, therefore by this step and step S3 and step S4 in conjunction with time, the yield of the sorafenib intermediate E of the key intermediate of synthesis BAY 43-9006 can be improved, make it be more suitable for suitability for industrialized production; And due to the reaction process of step S2 and step S3 simple, the subsequent disposal of the product system produced is comparatively simple.
In order to the methylamine improving compd A replaces process, preferred above-mentioned steps S2 comprises: mixed with the second organic solvent by compd A, forms the first mixed system; Stir the first mixed system and add methylamine in the first mixed system, obtaining Compound D.Adding of above-mentioned methylamine can add with the form of the combination of the alcohol solution of methylamine, ethers solution, methylamine hydrochloride, methylamine hydrochloride and organic bases or mineral alkali.
Further, in order to make full use of compd A, the mol ratio of preferred above-claimed cpd A and methylamine is 1:3 ~ 1:13.8.
The second organic solvent adopted in above-mentioned steps S2 process can adopt the Small molecule organic solvents of this area routine, preferably above-mentioned second organic solvent is selected from one or more in toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane and the respective aqueous solution.
Equally, in order to improve the reaction efficiency of step S3, preferred above-mentioned steps S3 comprises: the HCI solution of Compound D and reduction system are carried out nitro-reduction reaction at the 3rd organic solvent, obtains sorafenib intermediate E.Utilize the 3rd organic solvent to increase Compound D and contact effect with the reaction of reduction system, the reaction efficiency of both improvement.
The reduction system that above-mentioned steps S3 adopts is preferably palladium charcoal hydrogen system, iron powder hydrochloric acid system, iron powder acetate system or palladium charcoal formic acid-ammonium formiate system.Above-mentioned reduction system is applied to step S3 reaction conditions and is easy to control and catalytic efficiency is wherein higher.
In a kind of preferred embodiment of the present invention, above-mentioned reduction system is palladium charcoal hydrogen system, and above-mentioned steps S3 comprises: the HCI solution of Compound D and the 3rd organic solvent are mixed in a kettle., form the second mixed system; In the second mixed system, add palladium-carbon catalyst, and pass into hydrogen in reactor, the pressure making hydrogen in reactor is 0.5 ~ 1.5MPa, forms the second reaction system; Time at 45 ~ 55 DEG C, the second reaction system carries out reduction reaction, obtains sorafenib intermediate E.Under palladium-carbon catalyst katalysis, by controlling pressure, the temperature of reaction of hydrogen, hydrogen can fully, fast be carried out to the reduction reaction of Compound D.
In another preferred embodiment of the present invention, above-mentioned reduction system is palladium carbon formic acid-ammonium formiate system, and above-mentioned steps S3 comprises: the HCI solution of Compound D and the 3rd organic solvent are mixed in a kettle., form the second mixed system; Palladium-carbon catalyst and ammonium formiate formation the 3rd mixed system is added in the second mixed system; 3rd mixed system be heated to reflux state and add formic acid solution to carry out nitro-reduction reaction in the 3rd mixed system, obtaining sorafenib intermediate E.
In above-described embodiment implementation process, invention technician is by after carrying out lot of experiments to reaction conditions, reaction raw materials proportioning, the mol ratio of discovery Compound D and ammonium formiate is 1:0.2 ~ 1:3, when the mol ratio of Compound D and formic acid is 1:1 ~ 1:4, nitro in Compound D can thoroughly be reduced, and therefore acquired reaction efficiency is ideal.In addition, the mass ratio of Compound D and palladium-carbon catalyst can set the unified understanding of catalyst action according to according in this area, in general, catalyst levels is more, speed of response gets over block, otherwise speed of response is comparatively slow, in a kind of preferred embodiment of the application, the weight content of preferred above-mentioned Pd in palladium-carbon catalyst is 10%, and the mass ratio of Compound D and this palladium-carbon catalyst is 0.05 ~ 0.2g/g.
In another preferred embodiment of the present invention, above-mentioned reduction system is iron powder acetate system, and above-mentioned steps S3 comprises: the HCI solution of Compound D, the 3rd organic solvent, acetic acid, iron powder are formed the 4th mixed system; 4th mixed system is heated to reflux state to carry out nitro-reduction reaction, obtains sorafenib intermediate E.In above-mentioned steps S3, iron powder coordinates with acetic acid, and the nitro-reduction reaction efficiency that can realize is also ideal.Through lot of experiments research, the mol ratio of preferred above-claimed cpd D and acetic acid is 1:3 ~ 1:5, to obtain good transformation efficiency.In above-mentioned reaction process, consumption is more many within the specific limits is more conducive to fast reaction speed for the usage ratio of iron powder and Compound D, and the mol ratio of preferred compound D and iron powder is 1:3 ~ 1:5.
In addition, above-mentioned reduction system is Raney's nickel-hydrogen system, also can obtain sorafenib intermediate E.
The 3rd organic solvent that the various embodiments described above adopt be preferably selected from methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ethyl acetate, isopropyl acetate and the respective aqueous solution one or more.
Beneficial effect of the present invention is further illustrated below with reference to embodiment and comparative example.
Embodiment 1
Step S1, adds 4-chloropyridine-2-isopropyl formate (compd B in reaction flask; 10.0g; 50.1mmol), p-NP (7.67g; 53.0mmol) and pyridine (5.94g; 75.2mmol); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; After this product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, and aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained, concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitrophenoxy) pyridine-2-isopropyl formate (compd A; 12.9g), the yield 85% of compd A as calculated.
Step S2, adds 4-(4-nitrophenoxy) pyridine-2-isopropyl formate (12.9g that above-mentioned steps obtains in reaction flask; 42.6mmol), with the quality of compd A for benchmark, methyl alcohol (1vol./g), stirs the lower methanol solution (5g/g) dripping the methylamine of 28wt%; TLC follows the tracks of reaction and obtains the second product system to compd A disappearance; Concentrating under reduced pressure removes methyl alcohol in the second product system and unreacted methylamine, obtain oily matter crude product, Virahol (1vol./g) is added in oily matter crude product, then the ethanolic soln (1.2vol./g) of 35wt% hydrogenchloride is under agitation dripped, after insulated and stirred 1h, obtain mixed system; Suction filtration is carried out to mixed system; the filter cake ethanol rinse obtained; the lower 30 DEG C of drying under reduced pressure of nitrogen protection obtain the hydrochloride 11.6g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D), the yield 88% of Compound D as calculated.
Step S3, hydrochloride (the 11.6g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in autoclave, 37.5mmol), with the quality of Compound D for benchmark, then tetrahydrofuran (THF) (8vol./g) is added, finally add the Pd/C (0.05g/g) that Pd content is 10wt%, form the second mixed system; Utilize the first rear substitution autoclave of nitrogen and hydrogen three times, finally control hydrogen pressure 1.0MPa in reactor; Stir at 45 ~ 55 DEG C, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E).By third product system suction filtration, and with the filter cake that tetrahydrofuran (THF) (2vol./g) drip washing obtains, obtain filtrate and washing lotion to merge and obtain tetrahydrofuran (THF) organic phase, successively use saturated sodium bicarbonate (5vol./g), after saturated aqueous common salt (5vol./g) washs tetrahydrofuran (THF) organic phase, organic phase concentrating under reduced pressure is obtained 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 8.7g, the yield 95% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 2
Step S1, adds 4-chloropyridine-2-t-butyl formate (compd B in reaction flask; 10.0g; 46.8mmol), p-NP (7.16g; 51.5mmol) and pyridine (7.40g; 93.6mmol); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; This product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, and aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained; Concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitrophenoxy) pyridine-2-t-butyl formate (compd A; 13.3g), the yield 90% of compd A as calculated.
Step S2,4-(4-nitrophenoxy) pyridine-2-t-butyl formate (13.3g) is added in reaction flask, with the quality of compd A for benchmark, methyl alcohol (1vol./g), stirs the lower methanol solution (5g/g) dripping the methylamine of 28wt%; TLC follows the tracks of reaction and obtains the second product system to compd A disappearance; Concentrating under reduced pressure removes methyl alcohol and unreacted methylamine in the second product system, obtain oily matter crude product, ethanol (1vol./g) is added in oily matter crude product, then the ethanolic soln (1.2vol./g) of 35wt% hydrogenchloride is under agitation dripped, after insulated and stirred 1h, obtain mixed system; Suction filtration is carried out to mixed system; the filter cake ethanol rinse obtained; the lower 30 DEG C of drying under reduced pressure of nitrogen protection obtain the hydrochloride 11.1g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D), the yield 85% of Compound D as calculated.
Step S3, hydrochloride (the 11.1g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in autoclave, 35.8mmol), with the quality of Compound D for benchmark, then methyl alcohol (8vol./g) is added, finally add the Pd/C (0.1g/g) that Pd content is 5wt%, form the second mixed system; Utilize the first rear substitution autoclave of nitrogen and hydrogen three times, finally control hydrogen pressure 0.5MPa in reactor; Stir at 45 ~ 55 DEG C, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E).By third product system suction filtration, and with the filter cake that methyl alcohol (2vol./g) drip washing obtains, obtain filtrate and washing lotion merge concentrating under reduced pressure dry after, add the ethyl acetate solution that ethyl acetate obtains product, after ethyl acetate organic phase successively uses saturated sodium bicarbonate (5vol./g), saturated aqueous common salt (5vol./g) to wash, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 8.1g, the yield 93% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 3
Step S1, adds 4-chloropyridine-2-methyl-formiate (compd B in reaction flask; 10.0g; 58.6mmol), p-NP (8.56g; 61.6mmol) and pyridine (6.95g; 87.9mmol); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; This product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase, merges the organic phase obtained; Concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitrophenoxy) pyridine-2-methyl-formiate (compd A; 12.9g), the yield 91% of compd A as calculated
Step S2, adds 4-(4-nitrophenoxy) pyridine-2-methyl-formiate (12.9g that above-mentioned steps obtains in reaction flask; 42.6mmol), with the quality of compd A for benchmark, methyl alcohol (1vol./g), passes into methylamine gas under stirring; TLC follows the tracks of reaction and obtains the second product system to compd A disappearance, stop passing into methylamine gas, concentrating under reduced pressure removes the second product system methyl alcohol and unreacted methylamine, obtain oily matter crude product, the ethanolic soln (1.2vol./g) that ethanol (1vol./g) then under agitation drips 35wt% hydrogenchloride is added in oily matter crude product, after insulated and stirred 1h, obtain mixed system; Suction filtration is carried out to mixed system; the filter cake ethanol rinse obtained; the lower 30 DEG C of drying under reduced pressure of nitrogen protection obtain the hydrochloride 14.1g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D), the yield 85% of Compound D as calculated.
Step S3, hydrochloride (the 14.1g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in reaction flask, 45.3mmol), with the quality of Compound D for benchmark, then 2-methyltetrahydrofuran (8vol./g) is added, finally add the Pd/C (0.05g/g) that Pd content is 10wt%, form the second mixed system; Ammonium formiate (0.86g is added in the second mixed system, 13.6mmol) post-heating is to backflow, slow dropping formic acid (8.34g, 2-methyltetrahydrofuran solution (2vol./g) system stirred at reflux reaction 181.2mmol), TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E).By third product system suction filtration, and with the filter cake that 2-methyltetrahydrofuran (2vol./g) drip washing obtains, obtain filtrate and washing lotion to merge and obtain 2-methyltetrahydrofuran organic phase, successively use saturated sodium bicarbonate (5vol./g), after saturated aqueous common salt (5vol./g) washs 2-methyltetrahydrofuran organic phase, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 9.9g, the yield 90% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 4
Step S1, adds 4-chloropyridine-2-methyl-formiate (compd B in reaction flask; 10.0g; 58.6mmol), chlorobenzene (5vol./g), p-NP (8.56g; 61.6mmol) and DMA (6.95g; 87.9mmol); Be warming up to 80 ~ 90 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; This product system is cooled to 20 ~ 30 DEG C, and with the quality of compd B for benchmark, directly to add water in this product system (1vol./g), extracting and separating obtains organic phase, and aqueous phase chlorobenzene (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained, concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitrophenoxy) pyridine-2-methyl-formiate (compd A; 11.3g), the yield 80% of compd A as calculated.
Step S2, adds 4-(4-nitrophenoxy) pyridine-2-methyl-formiate (11.3g that above-mentioned steps obtains in reaction flask; 46.9mmol), with the quality of compd A for benchmark, tetrahydrofuran (THF) (10vol./g), triethylamine (19g, 187.5mmol) adds methylamine hydrochloride (12.7g, 187.5mmol) under stirring; Be heated to backflow, TLC follows the tracks of reaction and obtains the second product system to compd A disappearance; Filter after second product system is chilled to 0 ~ 5 DEG C; The filtrate obtained under agitation drips the ethanolic soln (1.2vol./g) of 35wt% hydrogenchloride, after insulated and stirred 1h, obtains mixed system; Suction filtration is carried out to mixed system; the filter cake tetrahydrofuran (THF) drip washing obtained; the lower 30 DEG C of drying under reduced pressure of nitrogen protection obtain the hydrochloride 13.4g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D), the yield 92% of Compound D as calculated.
Step S3, hydrochloride (the 13.4g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in reaction flask, 43.1mmol), with the quality of Compound D for benchmark, then add ethanol (3vol./g), water (3vol./g), acetic acid (12.93g, 215.5mmol), finally adds iron powder (12.1g, 215.5mmol), the second mixed system is formed; Second mixed system is heated to backflow, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E); Suction filtration after third product system is cooled to 20 ~ 30 DEG C, and with the filter cake that ethanol (3vol./g) drip washing obtains, obtains filtrate and washing lotion and merges to be evaporated to and obtain concentrated solution without cut, use pH=7 ~ 8 of sodium bicarbonate adjustment concentrated solution; Use 2-methyltetrahydrofuran (10vol./g) extraction respectively concentrated three times mutually, merge organic phase, after saturated aqueous common salt (5vol./g) washs 2-methyltetrahydrofuran organic phase, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 8.4g, the yield 85% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 5
Step S1, adds 4-chloropyridine-2-methyl-formiate (compd B in reaction flask; 10.0g; 58.6mmol), p-NP (8.56g; 61.6mmol) and N, N-diisopropyl ethyl amine (11.4g; 87.9mmol), DMF (5vol./g); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A, and this product system is cooled to 20 ~ 30 DEG C, and reaction system is directly used in next step;
Step S2, upwards adds salt of wormwood (24.3g, 175.8mmol) in single step reaction system, methylamine hydrochloride (11.9g, 175.8mmol); TLC follows the tracks of reaction and obtains the second product system to compd A disappearance; With the quality of compd B for benchmark, directly to add in the second product system methylene dichloride (10vol./g) and water (5vol./g) afterwards extracting and separating obtain organic phase, aqueous phase methylene dichloride (4vol./g) extracting twice obtains organic phase, merges the organic phase obtained; Concentrated organic phase desolvation, obtains oily matter crude product, adds the ethanolic soln (1.2vol./g) that ethanol (1vol./g) then under agitation drips 35wt% hydrogenchloride, after insulated and stirred 1h, obtains mixed system; Suction filtration is carried out to mixed system; the filter cake ethanol rinse obtained; the lower 30 DEG C of drying under reduced pressure of nitrogen protection obtain the hydrochloride 13.6g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D), as calculated the yield 75% of Compound D after two steps.
Step S3, hydrochloride (the 13.6g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in autoclave, 44.0mmol), with the quality of Compound D for benchmark, then methyl alcohol (4vol./g) and water (4vol./g) is added, finally add Lei Ni-nickel (1g/g), form the second mixed system; Utilize the first rear substitution autoclave of nitrogen and hydrogen three times, finally control hydrogen pressure 0.5MPa in reactor; Stir at 45 ~ 55 DEG C, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E).By third product system suction filtration, and with the filter cake that methyl alcohol (2vol./g) drip washing obtains, the filtrate obtained and washing lotion merge to be evaporated to and obtain concentrated solution without after cut, use sodium bicarbonate adjustment to obtain concentrated solution pH=7 ~ 8; Use isopropyl acetate (10vol./g) aqueous phase extracted three times respectively, merge organic phase, after saturated aqueous common salt (5vol./g) washs isopropyl acetate organic phase, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 9.1g, the yield 90% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 6
Step S1, adds 4-chloropyridine-2-isopropyl formate (compd B in reaction flask; 10.0g; 50.1mmol), the bromo-phenol (11.55g of 4-nitro-3-; 53.0mmol) and pyridine (5.94g; 75.2mmol); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; After this product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, and aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained, concentrated organic phase desolvation, must concentrate and obtain 4-(the bromo-phenoxy group of 4-nitro-3-) pyridine-2-isopropyl formate (compd A; 15.3g), the yield 80% of compd A as calculated.
Step S2, adds 4-(the bromo-phenoxy group of the 4-nitro-3-) pyridine-2-isopropyl formate (15.3g that above-mentioned steps obtains in reaction flask; 40.1mmol), with the quality of compd A for benchmark, methyl alcohol (1vol./g), stirs the lower methanol solution (5g/g) dripping the methylamine of 28wt%; TLC follows the tracks of reaction and obtains the second product system to compd A disappearance; Concentrating under reduced pressure removes methyl alcohol in the second product system and unreacted methylamine, obtain oily matter crude product, Virahol (1vol./g) is added in oily matter crude product, then the ethanolic soln (1.2vol./g) of 35wt% hydrogenchloride is under agitation dripped, after insulated and stirred 1h, obtain mixed system; Suction filtration is carried out to mixed system; the filter cake ethanol rinse obtained; the lower 30 DEG C of drying under reduced pressure of nitrogen protection obtain the hydrochloride 14.0g of 4-(the bromo-phenoxy group of 4-nitro-3-)-N-methylnicotinamide (Compound D), the yield 90% of Compound D as calculated.
Step S3, hydrochloride (the 14.0g of 4-(the bromo-phenoxy group of 4-nitro-3-)-N-methylnicotinamide (Compound D) is added in autoclave, 36.1mmol), with the quality of Compound D for benchmark, then tetrahydrofuran (THF) (8vol./g) is added, finally add the Pd/C (0.2g/g) that Pd content is 10wt%, form the second mixed system; Utilize the first rear substitution autoclave of nitrogen and hydrogen three times, finally control hydrogen pressure 1.5MPa in reactor; Stir at 45 ~ 55 DEG C, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E).By third product system suction filtration, and with the filter cake that tetrahydrofuran (THF) (2vol./g) drip washing obtains, obtain filtrate and washing lotion to merge and obtain tetrahydrofuran (THF) organic phase, successively use saturated sodium bicarbonate (5vol./g), after saturated aqueous common salt (5vol./g) washs tetrahydrofuran (THF) organic phase, organic phase concentrating under reduced pressure is obtained 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 8.34g, the yield 95% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 7
4-chloropyridine-2-isopropyl formate (compd B is added in reaction flask; 10.0g; 50.1mmol), the fluoro-phenol (11.81g of 4-nitro-3-; 75.2mmol) and pyridine (5.94g; 75.2mmol); Be warming up to 90 ~ 100 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; After this product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, and aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained, concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitro-3-fluorophenoxy) pyridine-2-isopropyl formate (compd A; 13.0g), the yield 81% of compd A as calculated.
Embodiment 8
4-chloropyridine-2-isopropyl formate (compd B is added in reaction flask; 10.0g; 50.1mmol), 4-nitro-2-methyl-phenol (8.13g; 53.0mmol) and pyridine (5.94g; 75.2mmol); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing compd A; After this product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, and aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained, concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitro-2-methyl-phenoxv) pyridine-2-isopropyl formate (compd A; 13.5g), the yield 85% of compd A as calculated.
Embodiment 9
4-chloropyridine-2-isopropyl formate (compd B is added in reaction flask; 10.0g; 50.1mmol), 4-nitro-3-itrile group-phenol (8.70g; 53.0mmol) and pyridine (5.94g; 75.2mmol); Be warming up to 70 ~ 80 DEG C, TLC follows the tracks of reaction to compd B and to disappear the first product system obtained containing sorafenib intermediate A; After this product system is cooled to 20 ~ 30 DEG C, with the quality of compd B for benchmark, directly to adding methylene dichloride (2vol./g) and water (1vol./g) in this product system, extracting and separating obtains organic phase, and aqueous phase methylene dichloride (2vol./g) extracting twice obtains organic phase; Merge the organic phase obtained, concentrated organic phase desolvation, must concentrate and obtain 4-(4-nitro-3-itrile group-phenoxy group) pyridine-2-isopropyl formate (compd A; 13.1g), the yield 80% of compd A as calculated.
Embodiment 10
Step S1, S2 are see embodiment 3.
Step S3, hydrochloride (the 14.1g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in reaction flask, 45.3mmol), with the quality of Compound D for benchmark, then 2-methyltetrahydrofuran (8vol./g) is added, finally add the Pd/C (0.2g/g) that Pd content is 10wt%, form the second mixed system; Ammonium formiate (8.6g is added in the second mixed system, 135.9mmol) post-heating is to backflow, slow dropping formic acid (2.09g, 2-methyltetrahydrofuran solution (2vol./g) system stirred at reflux reaction 45.3mmol), TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E).By third product system suction filtration, and with the filter cake that 2-methyltetrahydrofuran (2vol./g) drip washing obtains, obtain filtrate and washing lotion to merge and obtain 2-methyltetrahydrofuran organic phase, successively use saturated sodium bicarbonate (5vol./g), after saturated aqueous common salt (5vol./g) washs 2-methyltetrahydrofuran organic phase, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 10.0g, the yield 91% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 11
Step S1, S2 are see embodiment 4.
Step S3, hydrochloride (the 13.4g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in reaction flask, 43.1mmol), with the quality of Compound D for benchmark, then add ethanol (3vol./g), water (3vol./g), acetic acid (7.76g, 129.3mmol), finally adds iron powder (7.26g, 129.3mmol), the second mixed system is formed; Second mixed system is heated to backflow, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E); Suction filtration after third product system is cooled to 20 ~ 30 DEG C, and with the filter cake that ethanol (3vol./g) drip washing obtains, obtains filtrate and washing lotion and merges to be evaporated to and obtain concentrated solution without cut, use pH=7 ~ 8 of sodium bicarbonate adjustment concentrated solution; Use 2-methyltetrahydrofuran (10vol./g) extraction respectively concentrated three times mutually, merge organic phase, after saturated aqueous common salt (5vol./g) washs 2-methyltetrahydrofuran organic phase, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 8.8g, the yield 80% of sorafenib intermediate E as calculated, purity 99%.
Embodiment 12
Step S1, S2 are see embodiment 4.
Step S3, hydrochloride (the 13.4g of 4-(4-nitrophenoxy)-N-methylnicotinamide (Compound D) is added in reaction flask, 43.1mmol), with the quality of Compound D for benchmark, then add ethanol (3vol./g), water (3vol./g), acetic acid (18.1g, 301.7mmol), finally adds iron powder (16.94g, 301.7mmol), the second mixed system is formed; Second mixed system is heated to backflow, TLC follows the tracks of reaction and reacts completely to Compound D, obtains the third product system containing 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E); Suction filtration after third product system is cooled to 20 ~ 30 DEG C, and with the filter cake that ethanol (6vol./g) drip washing obtains, obtains filtrate and washing lotion and merges to be evaporated to and obtain concentrated solution without cut, use pH=7 ~ 8 of sodium bicarbonate adjustment concentrated solution; Use 2-methyltetrahydrofuran (10vol./g) extraction respectively concentrated three times mutually, merge organic phase, after saturated aqueous common salt (5vol./g) washs 2-methyltetrahydrofuran organic phase, concentrating under reduced pressure obtains 4-(4-amido phenoxy group)-N-methylnicotinamide (sorafenib intermediate E) 8.3g, the yield 75% of sorafenib intermediate E as calculated, purity 99%.
Nmr analysis is carried out to the structure of compd A 4-(4-nitrophenoxy) pyridine-2-methyl-formiate, Compound D 4-(4-nitrophenoxy)-N-methylnicotinamide and sorafenib intermediate E that above-described embodiment 3 obtains, as shown in Figure 1, Figure 2 and Figure 3, corresponding nuclear magnetic data confirms the exactness of each structural formula to corresponding spectrogram.Wherein, showing spectrogram result in Fig. 1 is: 1H (400MHz, DMSO) δ (ppm) 8.70 (d, J=4.0Hz, 1H), 8.35 (d, J=6.0Hz, 2H), 7.64 (s, 1H), 7.46 (d, J=6.4Hz, 2H), 7.40 (d, J=4.0Hz, 1H), 3.87 (s, 3H); Showing spectrogram result in Fig. 2 is:
1h (400MHz, DMSO) δ (ppm) 8.84 (dd, J
1=9.0Hz, J
2=4.2Hz, 1H), 8.63 (d, J=5.6Hz, 1H), 8.36 (d, J=9.2Hz, 2H), 7.57 (d, J=2.8Hz, 1H), 7.46 (d, J=9.2Hz, 2H), 7.34 (dd, J
1=11.2Hz, J
2=2.8Hz, 1H), 2.82 (d, J=4.8Hz, 3H); Showing spectrogram result in Fig. 3 is:
1h (400MHz, DMSO) δ (ppm) 9.04 (d, J=4.8Hz, 1H), 8.59 (d, J=5.6Hz, 1H), 7.58 ~ 7.60 (m, 3H), 7.40 (d, J=2.8Hz, 2H), 7.46 (d, J=9.2Hz, 2H), 7.26 (dd, J
1=11.6Hz, J
2=2.6Hz, 1H), 2.80 (d, J=4.8Hz, 3H).The step S1 of the application obtains the compd A with corresponding chemical structural formula as can be seen here, and rapid S2 obtains the Compound D with corresponding chemical structural formula, and step S3 also obtains the sorafenib intermediate E with corresponding chemical structural formula.And can find through above-described embodiment, the yield of the compd A that the synthetic method of the application obtains is more than 80%, and the yield of the sorafenib intermediate E obtained thus is more than 70%, relative to prior art 45% yield be significantly improved, and building-up process is simple and easy to control, be easy to large-scale industrial production.
As can be seen from the above description, the above embodiments of the present invention achieve following technique effect:
The synthetic method of above-claimed cpd A adopts organic bases to be catalyzer, improve the reaction efficiency with compd B and Compound C, and then the yield of the compd A obtained is with great breakthrough relative to prior art, more than 80%, be therefore applicable to large-scale industrialization and apply.
Further, the ammonia solution of the replacement of step S1, step S2 and the hydrogenation of step S3 are combined, the synthesis for sorafenib intermediate E provides new synthetic route breakthroughly; And the yield of the compound obtained due to above-mentioned steps S1 is higher, therefore by this step and step S3 and step S4 in conjunction with time, the yield of the sorafenib intermediate E of the key intermediate of synthesis BAY 43-9006 can be improved, make it be more suitable for suitability for industrialized production; And due to the reaction process of step S2 and step S3 simple, the subsequent disposal of the product system produced is comparatively simple.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (19)
1. have a synthetic method for the compd A of structural formula A, described structural formula A is
it is characterized in that, described synthetic method comprises:
There is the compd B of structural formula B and there is the Compound C of structural formula C for substrate, be substrate generation substitution reaction described in catalyst with organic bases, obtain described compd A,
Described structural formula B is
Described structural formula C is
Wherein, described R is C
1-C
10direct-connected or connect alkyl, cyclohexyl, methoxy ethyl, alkoxyethyl, aryl or arylalkyl;
Described R ' is H, mono-substituted halogen, polysubstituted halogen, supplied for electronic or electron-withdrawing group.
2. synthetic method according to claim 1, is characterized in that, the mol ratio of described compd B and described Compound C is 1:1.05 ~ 1:2.0.
3. synthetic method according to claim 1, is characterized in that, described organic bases be selected from triethylamine, N, N-diisopropyl ethyl amine, pyridine, N, N-lutidine and DMA one or more.
4. synthetic method according to claim 1, is characterized in that, described R is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the tertiary butyl.
5. synthetic method according to any one of claim 1 to 4, is characterized in that, described synthetic method comprises:
Described compd B, described Compound C are mixed with the first organic solvent, forms the first reaction system;
In described first reaction system, add compd B described in described organic base catalytic and described Compound C, at 70 ~ 80 DEG C, substitution reaction occurs, obtain the first product system containing described compd A.
6. synthetic method according to claim 5, is characterized in that, described first organic solvent be selected from chlorobenzene, dimethylbenzene, DMF and pyridine one or more.
7. synthetic method according to claim 5, is characterized in that, described synthetic method also comprises the sepn process being separated described compd A from described first product system, and described sepn process comprises:
Cooling system is obtained after described first product system is cooled to 20 ~ 30 DEG C;
Adopt methylene dichloride and water to extract described cooling system, obtain organic phase and aqueous phase; And
Described organic phase is concentrated, obtains described compd A.
8. have a synthetic method of the sorafenib intermediate E of structural formula E, described structural formula E is
it is characterized in that, described synthetic method comprises:
Step S1, adopts the synthetic method according to any one of claim 1 to 7 to obtain described compd A;
Step S2, carries out methylamine replacement to described compd A, obtains the Compound D with structural formula D; And
Step S3, reduces to described Compound D, obtains described sorafenib intermediate E,
Wherein, the R ' in described compd A is H, and described structural formula D is
9. synthetic method according to claim 8, is characterized in that, described step S2 comprises:
Described compd A is mixed with the second organic solvent, forms the first mixed system;
Stir described first mixed system and add methylamine in described first mixed system, obtaining described Compound D.
10. synthetic method according to claim 9, is characterized in that, the mol ratio of described compd A and described methylamine is 1:3 ~ 1:13.8.
11. synthetic methods according to claim 9, it is characterized in that, described second organic solvent be selected from toluene, dimethylbenzene, methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane and the respective aqueous solution one or more.
12. synthetic methods according to claim 8, is characterized in that, described step S3 comprises:
The HCI solution of described Compound D and reduction system are carried out nitro-reduction reaction at the 3rd organic solvent, obtains described sorafenib intermediate E.
13. synthetic methods according to claim 12, is characterized in that, described reduction system is palladium charcoal hydrogen system, iron powder hydrochloric acid system, iron powder acetate system or palladium charcoal formic acid-ammonium formiate system.
14. synthetic methods according to claim 13, is characterized in that, described reduction system is palladium charcoal hydrogen system, and described step S3 comprises:
The HCI solution of described Compound D and the 3rd organic solvent are mixed in a kettle., forms the second mixed system;
In described second mixed system, add palladium-carbon catalyst, and pass into hydrogen in described reactor, the pressure making hydrogen in described reactor is 0.5 ~ 1.5MPa, forms the second reaction system;
Time at 45 ~ 55 DEG C, described second reaction system carries out described nitro-reduction reaction, obtains described sorafenib intermediate E.
15. synthetic methods according to claim 13, is characterized in that, described reduction system is palladium carbon formic acid-ammonium formiate system, and described step S3 comprises:
The HCI solution of described Compound D and the 3rd organic solvent are mixed in a kettle., forms the second mixed system;
Palladium-carbon catalyst and ammonium formiate formation the 3rd mixed system is added in described second mixed system;
Described 3rd mixed system be heated to reflux state and add formic acid solution to carry out described nitro-reduction reaction in described 3rd mixed system, obtaining described sorafenib intermediate E.
16. synthetic methods according to claim 15, is characterized in that, the mol ratio of described Compound D and described ammonium formiate is 1:0.2 ~ 1:3; The mol ratio of described Compound D and described formic acid is 1:1 ~ 1:4.
17. synthetic methods according to claim 13, is characterized in that, described reduction system is iron powder acetate system, and described step S3 comprises:
The HCI solution of described Compound D, the 3rd organic solvent, acetic acid, iron powder are formed the 4th mixed system;
Described 4th mixed system is heated to reflux state to carry out described reduction reaction, obtains described sorafenib intermediate E.
18. synthetic methods according to claim 17, is characterized in that, the mol ratio of described Compound D and described acetic acid is 1:3 ~ 1:5.
19. synthetic methods according to claim 12, it is characterized in that, described 3rd organic solvent be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ethyl acetate, isopropyl acetate and the respective aqueous solution one or more.
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