Summary of the invention
The purpose of the present invention is: it solves the problems, such as Ceritinib intermediate synthesis in the prior art, provides a kind of more suitableIndustrialized production is closed, cost is lower, is more easier the preparation method of the Ceritinib intermediate of operation.
Realizing the technical solution of the object of the invention is:
A kind of preparation method of Ceritinib intermediate includes the following steps: the bromo- 2- isopropoxy -5- methylbenzene of (1) 4-Amine is reacted with aceticanhydride generates N- (the bromo- 2- isopropoxy -5- tolyl of 4-) acetamide；It is preferred that the step (1) is in reaction flaskGlacial acetic acid is added in the middle bromo- 2- isopropoxy -5- methylaniline of loading 4- at room temperature, opens stirring, and aceticanhydride is added dropwise, then heatsReflux, is cooled to room temperature, is poured into ice water, stirs, and filters, washing, dry N- (the bromo- 2- isopropoxy -5- toluene of 4-Base) acetamide.
(2) N- benzyl -4- piperidones is generated by 4- piperidines reactive ketone；Preferred steps (2) are to sequentially add in reaction flask4- piperidones, potassium carbonate, DMF open stirring, stir at room temperature, and chlorobenzene is added dropwise, drips, is heated to 80 DEG C and keeps the temperature, thenIt is cooled to room temperature, water is added, stirring is extracted with ethyl acetate, and ethyl acetate layer is washed with salt, and it is dry with anhydrous sodium sulfate, subtractPressure concentration, obtains crude product, and methanol is added: chloroform=2:98 purification obtains this step product.
(3) N- (the bromo- 2- isopropoxy -5- tolyl of 4-) acetamide carries out docking with N- benzyl -4- piperidones and reacts；It is excellentStep (3) is selected to be packed into magnesium chips, anhydrous THF and compound N-(the bromo- 2- isopropoxy -5- tolyl of 4-) in dry reaction flask1,2- Bromofume is added under nitrogen protection for acetamide, heats initiation reaction, dropwise additionization compound N-(the bromo- 2- isopropyl oxygen of 4-Base -5- tolyl) acetamide, it is dissolved in the solution of anhydrous THF, keeps slightly boiled reflux, TLC detection compound N- (the bromo- 2- isopropyl of 4-Oxygroup -5- tolyl) acetamide fully reacting, it is spare to be cooled to room temperature；Above-mentioned reaction solution is cooled to 0-5 DEG C, chemical combination is added dropwiseObject N- benzyl -4- piperidones is dissolved in the solution of THF, keeps interior temperature to be no more than 10 DEG C, is stirred at room temperature after adding, TLC detection reactionCompletely, saturation NH is added4THF is concentrated under reduced pressure in Cl aqueous solution quenching reaction, and residue is extracted with toluene, and organic phase merges, washingIt is spare.
(4) preceding step reaction product is subjected to decarboxylation reaction and generates N- (4- (1- benzyl -1,2,3,6- tetrahydropyridine -4-Base) -2- isopropoxy -5- tolyl) acetamide；Preferred steps (4) are that TSOHH is added into above-mentioned toluene solution2O, nitrogenTemperature rising reflux under gas shielded is generated with fraction water device water-dividing to no water, TLC detect fully reacting, cool to 40 DEG C hereinafter,Na2CO3Aqueous solution washing, salt washing, Na2SO4Dry, concentration and recovery toluene, residue recrystallizes to produce with toluene/petroleum etherProduct.
(5) N- (4- (1- benzyl -1,2,3,6- tetrahydropyridine -4- base) -2- isopropoxy -5- tolyl) acetamide is existedFinal product 2- isopropoxy -5- methyl -4- piperidines-aniline, i.e. Ceritinib intermediate is generated in the presence of catalyst；It is preferred that walkingSuddenly (5) are that N- (4- (1- benzyl -1,2,3,6- tetrahydropyridine -4- base) -2- isopropoxy -5- tolyl) is added in autoclaveAcetamide, 5%pd/c, methanol, in certain temperature and pressure 3Kg pressure, 50 DEG C of reactions, middle control raw material fully reacting, suction filtration is goneExcept pd/c, methanol is concentrated under reduced pressure to there is solid precipitation, cooling filters to obtain product 2- isopropoxy -5- methyl -4- (piperidin-4-yl)Aniline.
The present invention has the effect of positive: the present invention develops the new preparation method of Ceritinib intermediate, the synthesisRoute cost is lower, and raw material is easy to get at low cost, and each portion's reaction condition is easily controllable as mild as a dove, is more suitable large-scaleIndustrial production.
Specific embodiment
(embodiment 1)
Step 1: the bromo- 2- isopropoxy -5- methylaniline (56G, 231.1mmol) of 4- is packed into 1000ml reaction flask,At room temperature plus in 200ml glacial acetic acid, stirring is opened, is added dropwise aceticanhydride (26.2ml, 277mmol), reflux 30min is then heated to,It is cooled to room temperature, is poured into 500ml ice water, stir 10min, filter, washing, dry N- (the bromo- 2- isopropoxy -5- of 4-Tolyl) acetamide 62.7g (95% yield).
Step 2: 4- piperidones (99.13g, 1mol) is sequentially added in 2000ml reaction flask, potassium carbonate (138g,1mol), DMF 500ml opens stirring, stirs 30min at room temperature, is added dropwise chlorobenzene (112g, 1mol), drips, be heated to 80 °And 5H is kept the temperature, it is then cooled to room temperature, adds 1000ml water, stirs 30min, is extracted with ethyl acetate 800ml*3, ethyl acetate layerIt is washed 2 times with 300ml salt, has anhydrous sodium sulfate dry, be concentrated under reduced pressure, obtain crude product, methanol is added: chloroform=2:98 is exquisite, obtainsProduct 175g. (yield=92.6%).
Step 3: it is packed into magnesium chips (2.88G, 0.12mol) in 500ml dry there-necked flask, anhydrous THF (10ML) and changeObject N- (the bromo- 2- isopropoxy -5- tolyl of 4-) acetamide (2.86g, 0.01mol) is closed, 1,2- dibromo is added under nitrogen protectionEthane (0.5g) heats initiation reaction, dropwise additionization compound N-(the bromo- 2- isopropoxy -5- tolyl of 4-) acetamide(25.74g, 0.09mol) is dissolved in the solution of the anhydrous THF of 90ML, keeps slightly boiled reflux 3H, TLC detection compound N- (the bromo- 2- of 4-Isopropoxy -5- tolyl) acetamide fully reacting, it is spare to be cooled to room temperature.
Above-mentioned reaction solution is cooled to 0-5 DEG C, compound N-benzyl -4- piperidones (19g, 0.1mol) is added dropwise and is dissolved inThe solution of 50MLTHF keeps interior temperature to be no more than 10 DEG C, is stirred at room temperature after adding 1 hour, and TLC detects fully reacting.It is added100ML is saturated NH4THF is concentrated under reduced pressure in Cl aqueous solution quenching reaction, and residue extracts (100Ml*3) with toluene, organic to be harmoniousAnd it washes spare.
Step 4: TSOHH is added into above-mentioned toluene solution2O (855mg, 4.5mmol) heats up back under nitrogen protectionStream, is generated with fraction water device water-dividing to no water, and TLC detects fully reacting, cools to 40 DEG C hereinafter, Na2CO3Aqueous solution washing, saltWashing, Na2SO4 is dry, concentration and recovery toluene, and residue recrystallizes to obtain product the 29g, (reason of total recovery 85% with toluene/petroleum etherBy 34G).
Step 5: N- (4- (1- phenyl -1,2,3,6- tetrahydropyridine -4- base) -2- isopropyl is added in 1000L autoclaveOxygroup -5- tolyl) acetamide (37.8g, 0.1mol), 5%pd/c 1g, 300ml methanol, 3kg pressure, 50 degree of reaction 2Hr,Middle control raw material fully reacting filters removal Pd/C, methanol is concentrated under reduced pressure to there is solid wash-off, cooling filters to obtain product 2- isopropyl oxygenBase -5- methyl -4- piperidines-aniline 235g (yield 95%).
(embodiment 2)
Step 1: the bromo- 2- isopropoxy -5- methylaniline (56G, 231.1mmol) of 4- is packed into 1000ml reaction flask,At room temperature plus in 200ml glacial acetic acid, stirring is opened, is added dropwise aceticanhydride (26.2ml, 277mmol), reflux 45min is then heated to,It is cooled to room temperature, is poured into 500ml ice water, stir 10min, filter, washing, dry N- (the bromo- 2- isopropoxy -5- of 4-Tolyl) acetamide 62.7g (95% yield).
Step 2: 4- piperidones (99.13g, 1mol) is sequentially added in 2000ml reaction flask, potassium carbonate (138g,1mol), DMF 500ml opens stirring, stirs 30min at room temperature, is added dropwise chlorobenzene (112g, 1mol), drips, be heated to 80 °And 6H is kept the temperature, it is then cooled to room temperature, adds 1000ml water, stirs 60min, is extracted with ethyl acetate 800ml*3, ethyl acetate layerIt is washed 2 times with 300ml salt, has anhydrous sodium sulfate dry, be concentrated under reduced pressure, obtain crude product, methanol is added: chloroform=2:98 is exquisite, obtainsProduct 175g. (yield=92.6%).
Step 3: it is packed into magnesium chips (2.88G, 0.12mol) in 500ml dry there-necked flask, anhydrous THF (10ML) and changeObject N- (the bromo- 2- isopropoxy -5- tolyl of 4-) acetamide (2.86g, 0.01mol) is closed, 1,2- dibromo is added under nitrogen protectionEthane (0.5g) heats initiation reaction, dropwise additionization compound N-(the bromo- 2- isopropoxy -5- tolyl of 4-) acetamide(25.74g, 0.09mol) is dissolved in the solution of the anhydrous THF of 90ML, keeps slightly boiled reflux 3.5H, (4- is bromo- by TLC detection compound N-2- isopropoxy -5- tolyl) acetamide fully reacting, it is spare to be cooled to room temperature.
Above-mentioned reaction solution is cooled to 0-5 DEG C, compound N-benzyl -4- piperidones (19g, 0.1mol) is added dropwise and is dissolved inThe solution of 50MLTHF keeps interior temperature to be no more than 10 DEG C, is stirred at room temperature after adding 1 hour, and TLC detects fully reacting.It is added100ML is saturated NH4THF is concentrated under reduced pressure in Cl aqueous solution quenching reaction, and residue extracts (100Ml*3) with toluene, organic to be harmoniousAnd it washes spare.
Step 4: TSOHH is added into above-mentioned toluene solution2O (855mg, 4.5mmol) heats up back under nitrogen protectionStream, is generated with fraction water device water-dividing to no water, and TLC detects fully reacting, cools to 40 DEG C hereinafter, Na2CO3Aqueous solution washing, saltWashing, Na2SO4 is dry, concentration and recovery toluene, and residue recrystallizes to obtain product the 29g, (reason of total recovery 85% with toluene/petroleum etherBy 34G).
Step 5: N- (4- (1- phenyl -1,2,3,6- tetrahydropyridine -4- base) -2- isopropyl is added in 1000L autoclaveOxygroup -5- tolyl) acetamide (37.8g, 0.1mol), 5%pd/c 1g, 300ml methanol, 3kg pressure, 50 degree of reaction 2H, inRaw material fully reacting is controlled, removal Pd/C is filtered, methanol is concentrated under reduced pressure to there is solid wash-off, cooling filters to obtain product 2- isopropyl oxygenBase -5- methyl -4- piperidines-aniline 235g (yield 95%).
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical scheme and beneficial effectsIt describes in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is allWithin the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in guarantor of the inventionWithin the scope of shield.