CN105924390B - A kind of synthetic method of Mei Tafeini - Google Patents
A kind of synthetic method of Mei Tafeini Download PDFInfo
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- CN105924390B CN105924390B CN201610332374.2A CN201610332374A CN105924390B CN 105924390 B CN105924390 B CN 105924390B CN 201610332374 A CN201610332374 A CN 201610332374A CN 105924390 B CN105924390 B CN 105924390B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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Abstract
The present invention relates to the synthetic methods of anti-cancer active compound Mei Tafeini.Mei Tafeini, entitled 4 { 4 [3 (4 chlorine, 3 trifluoromethyl) urea] 3 fluorophenoxies } pyridine, 2 formamide of chemistry（Compound 1）.We are with 4 chloropyridine of raw material, 2 formamide（Commercially available）For raw material, Mei Tafeini is prepared by 2 metal catalyzed coupling reaction, isocyanates addition reaction synthesis steps.Compared to the method for existing literature report, the method that the present invention describes is effective, practical, and can be amplified to large-scale production, and product gross production rate is significantly improved.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to the conjunction of the β-elemene Mei Tafeini of VEGFR, RAF targeting
Into method.
Background technology
Vascular endothelial growth factor (VEGF) is one of most important Porcine HGF during Tumor Angiongesis,
Tumor vessel is extremely sensitive to VEGF, and VEGF mRNA concentration is significantly higher than normal cell in many tumour cells, these
Tumour includes lung cancer.Mei Tafeini, chemical name are 4- { 4- [3- (the chloro- 3- trifluoromethyls of 4-) urea] -3- fluorophenoxies }
Pyridine-2-carboxamide, structure such as following formula（Compound 1）It is shown, it is a kind of effective VEGF and RAF kinase inhibitors, thus be
Potential effective β-elemene（See CDE evaluation weekly 2015.7.19-2015.7.25）.Meanwhile according to Japanese Miyagi cancers
Research center report, in preclinical Anticancer Activities, Mei Tafei you have with having listed anticancer drug Rui Gefeini
（Regorafenib）Similar active anticancer.Domestic Preclinical Drug research also demonstrates it in people's liver tumour nude mice model reality
There is apparent antitumous effect in testing（Patent application CN102885814A）.
Domestic Hunan Nan Xin pharmaceutical Co. Ltds independent development Mei Tafeini has made at present as anti-lung cancer drug candidate
Clinical official written reply is obtained for a kind new medicine.Therefore, the bulk pharmaceutical chemicals life after the production of pilot scale research sample or listing either from now on
Production technically has and is further improved technique, reduces production cost, increase the requirement that process environments are friendly spent.
In terms of the synthesis technology described in existing and document, rarely fully synthetic reports of Mei Tafeini.Patent
The method of CN102885814A reports, is related to 4- chloropyridine -2- formamides and with the fluoro- 4-aminophenol of 3- in DMF, in t-
In the presence of BuOK, 1650C reacts, yield about 45%.It is apparent that this severe reaction conditions, is related to high temperature, highly basic reaction,
Especially reaction dissolvent DMF Partial digestions on this condition, it is difficult to which recovery causes environmental protection pressure.Meanwhile yield is also relatively low,
When being not suitable for large-scale production.Foreign patent US 20050245530, it was recently reported that 4- chloropyridine -2- formamides and with the fluoro- 4- of 3-
Amino-phenol is in NMP（N- methylpiperidones）In, 250 0C reaction synthesis compounds 3, yield 50%, reaction condition is equally very severe
It carves, yield is not also high.
Metallic catalyst can have as having the title of organic synthesis " soldering apparatus " containing Ni metal, Pd compounds or complex compound
Effect promotes the formation of C-C, C-N, C-O key in drug synthetic reaction, and some catalyst can also be some organic solvent reaction conversions
For aqueous solvent phase reaction, become the important member in green chemistry（See document " copper catalysis water phase Ullmann type couples
Repercussion study is in progress ", organic chemistry, 2013,33,760-770）, have in modern medicines and intermediate synthesis and extensively should
With.In our inventions, in Mei Tafeini synthesis steps 1, to the coupling reaction of aryl alkyl halide and phenol, Buchwald is employed
As a result types of metals catalyst effectively increases reaction yield, and catalyst cost itself is not also high.In the reaction of the 2nd step,
It is heated and reacted in ethyl acetate with the chloro- 3- trifluoromethylbenzenes based isocyanates of 4- by compound 3, obtained by silica gel column purification
Product, the yield moon 18%, hence it is evident that it is relatively low, be not suitable for industrialized production.The method that we use, uses instead in dichloromethane solvent, adds
Hunig base catalysis, room temperature reaction extend the reaction time, yield are made to be increased to 60%.2 step overall yield of reaction are compared
CN102885814A（2 step total recoverys 8%）, 40% is increased to, is good for the environment.
Invention content
In view of situation described above, asked present in existing Mei Tafeini synthetic methods the purpose of the present invention is overcoming
Topic provides the Mei Tafeini synthetic methods that a kind of reaction is more effective, cost is less expensive, more environmentally friendly.In order to realize this purpose, I
With 4- chloropyridine -2- formamides（Compound 2, commercially available）For raw material, Mei Tafeini is made by metal catalysed reaction.Work
CuI, Cs in skill step2CO3, Phen or Me4Phen（Structure sees below formula）It is commercially available raw material.The synthesis road that we use
Line such as following formula：
Wherein, organic ligand Phen, Me4Phen has following chemical structural formula：
It is as follows：
With raw material 4- chloropyridine -2- formamides（Commercially available）For raw material, 4- { 4- [3- are made by following process steps
(the chloro- 3- trifluoromethyls of 4-) urea] -3- fluorophenoxies } pyridine-2-carboxamide（Mei Tafeini, compound 1）：
Step 1：In dry reaction bulb, it is put into CuI, Cs2CO3, organic ligand Me4Phen, compound 2, toluene.
Mixture under an argon atmosphere, heats lower reaction generation target product.Product crude product is recrystallized to give purity in ethyl acetate
Qualified intermediate.
Step 2：The chloro- 3- trifluoromethylbenzenes based isocyanates of 4-, DMF are put into reaction bulb.2- ammonia is added dropwise to reaction bulb
Base formoxyl -4-（（The fluoro- 4- amino of 3-）Phenoxy group）The dichloromethane solution of pyridine.Reaction is stirred at room temperature in reaction solution.Reaction
Solvent is boiled off after the completion.It remains in re-crystallizing in ethyl acetate and obtains 1 finished product of compound.
In a preferred embodiment of the present invention, the solvent described in step 1 is toluene, DMF.It is preferred that toluene.Used urges
Agent is that mol ratio is 5%-10%CuI, 5-10% ligands Phen, Me4Phen, preferably 5%CuI, 10%Me4Phen.Reaction temperature
For 70-1200C, preferably 80-850C.Step 2 reaction dissolvent be dichloromethane, DMF, dichloromethane and DMF mixed solvents, it is excellent
Dichloromethane-DMF mixed solvents are selected, catalysts are triethylamine, N, N- diisopropyl ethyl amines, preferably N, N- diisopropyls
Ethylamine, the preferred 25-30 of reaction temperature0C。
Compared with prior art, advantageous effects of the invention are embodied in:
The synthesis of compound 1 is significantly improved by metal catalysed reaction step, mild condition, yield, improves yield, subtract
Solvent usage amount is lacked, has made technical process more " green " environmental protection.Moreover, these Optimal improvements so that from compound I to finished product
Total recovery, compared to the method for patent CN103058922 B descriptions, total recovery is synthesized from compound 2 to Mei Tafeini up to 40% or so
Only 8% or so, yield is significantly improved.
Specific embodiment
1 2- carbamoyls -4- of embodiment（（The fluoro- 4- amino of 3-）Phenoxy group）Pyridine（Compound 4）Synthesis
In dry reaction bulb, it is put into CuI（9.5g, 49.9mmoL）、Cs2CO3（490.0g, 1504.0mmoL）、
Me4Phen（24.0g 101.6mmoL）, compound 2（247.2 g, 1000mmoL）, toluene（500mL）.Mixture is in argon gas gas
Under atmosphere, 80-850It is reacted for 24 hours under C oil baths.It is cooled to room temperature, adds in ethyl acetate（1500mL）, reaction solution is by one section
Silicagel column filters, and washs filter cake, merging filtrate with ethyl acetate 500mL, and decompression boils off filtrate solvent.Concentrated residues object is suitable
Crystallization obtains 173.1 g of white solid in amount ethyl acetate-light petrol.Yield 70%.1H NMR(400MHz, DMSO-d 6 )： δ
5.21 (s, 2 H), 6.77 (dd, 1 H), 6.85 (t, 1 H), 7.01 (dd, 1 H), 7.10 (dd, 1 H),
7.34 (d, 1 H), 7.68 (br s, 1 H), 8.10 (br s, 1 H), 8.45 (d, 1 H); MS (ESI) m/
z: 248.1 (M + H+)。
2 4- of embodiment { 4- [3- (the chloro- 3- trifluoromethyls of 4-) urea] -3- fluorophenoxies } pyridine-2-carboxamide（Change
Close object 1）Synthesis
The chloro- 3- trifluoromethylbenzenes based isocyanates of 4- are put into reaction bulb（26.6g 120mmoL）、DMF（50mL）、N,
N- diisopropyl ethyl amines（2.6g, 20mmoL）.2- carbamoyls -4- is slowly added dropwise to reaction bulb（（The fluoro- 4- amino of 3-）Benzene
Oxygroup）Pyridine（24.7g 100mmoL）Dichloromethane（350mL）Solution.Reaction solution is stirred at room temperature for 24 hours to the reaction was complete.
Boil off solvent.It remains in re-crystallizing in ethyl acetate and obtains 28.1 g white solids（Compound 1）, yield 60%.1H NMR (400
MHz, DMSO-d 6 )：δ 7.18 (d, 1H), 7.20 (m, 1H), 7.32 (m, 1H), 7.40 (d, 1H), 7.61 (d,
2H), 7.72(s, 1H), 8.18(m, 3H), 8.52(d, 1H), 8.73(s, 1H),9.51(s, 1H); MS(ESI)
m/z: 469.1(M+H)+。
Claims (4)
1. a kind of synthetic method of Mei Tafeini, it is characterised in that include the following steps:
Step 1, compound 3 is synthesized by Buchwald catalytic coupling methods：Using compound 2 and the fluoro- 4-aminophenol of 3- as raw material,
Using toluene or DMF as reaction dissolvent, in CuI, Cs2CO3, organic ligand 3,4,7,8- tetramethyl -1,10- phenanthrolines effect
Under, 700C – 120 0C reaction generation compounds 3；Structural formula of compound sees below equation, wherein Me4Phen is 3,4,
7,8- tetramethyl -1,10- phenanthrolines；
Step 2, compound 3 and the chloro- 3- trifluoromethylbenzenes based isocyanates of 4- be in DMF or dichloromethane, in triethylamine or N,
Under the catalysis of N- diisopropyl ethyl amines, crude product is obtained under room temperature reaction, compound 1 is made after refinement treatment.
2. synthetic method as described in claim 1, reaction dissolvent described in step 1 is toluene.
3. synthetic method as described in claim 1, CuI, 3 in step 1,4,7,8- tetramethyl -1,10- phenanthrolines, Cs2CO3It rubs
You are than being 5%：10%：150%.
4. synthetic method as described in claim 1, step 1 reaction temperature is 80-850C。
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| CZ299125B6 (en) * | 1999-01-13 | 2008-04-30 | Bayer Corporation | Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors, their use and pharmaceutical compositions containing thereof |
| US7547779B2 (en) * | 2003-10-06 | 2009-06-16 | Glaxo Group Limited | Preparation of 1,6-disubstituted azabenzimidazoles as kinase inhibitors |
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