CN106632263B - A kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine - Google Patents
A kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine Download PDFInfo
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Abstract
The present invention relates to technical field of organic synthesis, especially disclose a kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.The step of highway route design of the synthetic method is as follows, and synthesis needs is few, and the side reaction that the reaction of every step generates is few, and purification is simple, does not need to carry out column chromatography for separation, and experimental implementation is simple, and required equipment is simple, is suitable for industrialized production.
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly to a kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine.
Background technique
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (Crizotinib) is that the ATP of inhibition Met, ALK, ROS for being developed by Pfizer are emulative
Multiple target point kinases inhibitor confirms that it has human body in the tumor patient of ALK, ROS and Met abnormal kinase respectively
Significant clinical efficacy.From 2011 since the U.S. is through FDA approval listing, the synthetic method in relation to (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine just constantly has
Report occurs.
The applicant has carried out comparative study to the existing synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine at work, it is believed that is primarily present
Following problem: one, synthetic route is longer, causes yield low, processing trouble；Two, method of purification mostly uses column to chromatograph, cost
Height, operation difficulty are big；Three, synthetic route design is not reasonable, and side reaction is more, and product purity is not high, and it is low to also result in yield,
Processing trouble.Such as provided in the patent application of Publication No. CN105272966A one kind " ALK inhibitor gram azoles for Buddhist nun and its
The preparation method of analog or salt ", the step 1 and step 2 of embodiment 1 all use the process for separation and purification of column chromatography, behaviour
Make complexity, is unsuitable for industrialized production.One kind " the compound gram azoles provided in the patent application of Publication No. CN105924431A
For the synthesis technology of Buddhist nun ", the synthetic route of embodiment 1 includes eight synthesis steps, and synthetic route is longer, also results in processing
It is comparatively laborious, equally it is unfavorable for industrialized production.
In order to be more suitable for industrialized amplification production, it is necessary to carry out research to the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and change
Into.
Summary of the invention
The invention mainly solves the technical problem of providing a kind of synthetic methods of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, synthesize the step of needing
It is few, and the side reaction of every step reaction is few, purification is simple, does not need to carry out column chromatography for separation, is suitable for industrialized production.
In order to solve the above technical problems, the technical solution adopted by the present invention is that: a kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is led to
Cross following steps realization:
S1: compound shown in preparation formula 3
10L glycol dimethyl ether is measured, is added in reaction kettle, is then added 5L water, be stirred, later in nitrogen atmosphere
Under enclosing, bis- (diphenylphosphine) ferrocene of 1,1'- of 10g palladium acetate and 50g are added into the reaction kettle, then again by 1kg's
Compound shown in formula 1 is added in reaction kettle, sequentially adds compound shown in the formula 2 of 1.9kg and the potassium carbonate of 1.9kg later,
It stirs and evenly mixs, the heating equipment of the reaction kettle is opened, the material in reaction kettle is heated to 90~95 DEG C, is then existed
Sustained response 12~16 hours at this temperature, end of reaction；It is post-processed later, reaction solution after completion of the reaction is subtracted
2L water is added to being evaporated off in the residue after glycol dimethyl ether in pressure distillation, the glycol dimethyl ether recycling and reusing distilled out,
Then it filters, obtained filtrate is extracted with 1.5L ethyl acetate, and water phase extracted adjusts pH value with the dilute hydrochloric acid of 1Mol/L and arrives
5.5~6.5, solid is largely precipitated, and filters later, collects filter cake, obtained filter cake is dried and removed water in a vacuum drying oven
Point, then compound shown in formula 3, yellow solid are obtained with re-crystallizing in ethyl acetate；
S2: compound shown in preparation formula 5
Compound shown in the formula 3 of 1.5kg is taken, is added in the n,N-Dimethylformamide solvent of 5L, mechanical stirring is opened,
Under nitrogen atmosphere, the potassium carbonate of 800g is added portionwise again into n,N-Dimethylformamide solvent, in addition potassium carbonate process
Middle control temperature of reaction system adds compound shown in the formula 4 of 1.25kg at 10 ± 2 DEG C later, the reaction that then will be obtained
Mixed liquor is heated to 95~100 DEG C, reacts 8~12 hours, end of reaction；It is post-processed later, by the reaction of end of reaction
Liquid is down to 35 DEG C hereinafter, then filtering, and obtained filtrate is poured into 25L water, stirred 3~5 minutes by collection filtrate, has a large amount of
Solid be precipitated, be cooled to later 5 DEG C hereinafter, stand 2~8 hours, then filter, collect filter cake, filter cake is in vacuum oven
Middle drying obtains compound shown in formula 5, yellow solid；
S3: compound shown in preparation formula 6
Dehydrated alcohol 10L is taken, is mixed with the saturated aqueous ammonium chloride of 5L, mixed liquor is formed, then into the mixed liquor
Compound shown in the formula 5 of 2.0kg is added, opens mechanical stirring, the reduced iron powder of 390g is added portionwise into reaction system, adds
Temperature of reaction system is controlled during reduced iron powder and is no more than 50 DEG C, and reduced iron powder continues stirring 1 hour after adding, then with 10
DEG C/heating rate of 30min, and the temperature of reaction system is warming up to 85~90 DEG C, back flow reaction 2~4 hours, end of reaction；
It is post-processed later, reacted reaction solution is cooled to 35 DEG C hereinafter, being subsequently poured into the suction filtration leakage for being equipped with diatomite layer
In bucket, filtering, filter cake is washed with the dehydrated alcohol of 2L, collects filtrate, and filtrate is concentrated into 1L, is placed in 0 DEG C of environment later,
6~12 hours are stood, compound shown in formula 6, faint yellow solid are obtained；
S4: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is prepared, the structural formula of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is as shown in formula 7
Compound shown in formula 6 by 1.0kg is added in the dehydrated alcohol of 5L, is opened mechanical stirring, is placed in 0 DEG C of ring
In border, under nitrogen atmosphere, then into dehydrated alcohol be added 6mol/L aqueous hydrochloric acid solution 1L, rise to 15~30 after addition
DEG C, it reacts 8~12 hours, end of reaction；It is post-processed later, the reaction solution of end of reaction is concentrated under reduced pressure at 35 DEG C or less
To 1L, sodium hydrate aqueous solution tune pH value is then added into the raffinate after concentration to 12~14, has solid precipitation, filters,
Filter cake is collected, and the filter cake is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product, and filtrate is extracted with ethyl acetate 2~5 times, combined ethyl acetate extraction
Liquid, the acetic acid ethyl acetate extract with anhydrous sodium sulfate it is dry after ethyl acetate be evaporated off again obtain solid, the solid be gram in azoles
For Buddhist nun's crude product, obtained (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product is merged, is recrystallized with dehydrated alcohol, obtains (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine product, white
Solid.
Preferably, in step S1, the material in the reaction kettle is heated to 90 DEG C, is then continued at such a temperature
Reaction 16 hours.Under the reaction conditions, the more thoroughly complete of progress is reacted, side reaction is few, obtained reactant system impurity
It is few, it is easy to purify.
In step S2, after compound shown in formula 4 is added, obtained reaction mixture is heated to 100 DEG C, reaction 12 is small
When.Equally, under the reaction conditions, the more thoroughly complete of progress is reacted, side reaction is few, and obtained reactant system impurity is few,
It is easy to purify.
In step S3, laying depth of the diatomite layer in suction funnel is 5~8cm.It can make reactant under the thickness
In sticky mass it is clean by filtering, convenient for post-processing when solid precipitation.
In step S4, when sodium hydrate aqueous solution tune pH value being added into the raffinate after concentration, pH value is adjusted to 13.?
Under the pH value condition, the precipitation in solid form that the (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine product after concentration in raffinate can be more, post-processing letter
It is single.
The beneficial effects of the present invention are: the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine provided by the invention, the step of synthesis needs, is few,
And the side reaction that every step reaction generates is few, purification is simple, does not need to carry out column chromatography for separation, experimental implementation is simple, required equipment
Simply, it is suitable for industrialized production.
Specific embodiment
Technical solution of the present invention is described in detail below.
A kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, is realized by following steps:
S1: compound shown in preparation formula 3
Measuring 10L glycol dimethyl ether, (glycol dimethyl ether can also use toluene, DMF, DMSO, 1,4- dioxane etc.
Solvent replacement), it is added in reaction kettle, then adds 5L water, be stirred, later under nitrogen atmosphere, to the reaction kettle
Middle bis- (diphenylphosphine) ferrocene (dppf) of 1,1'- that 10g palladium acetate and 50g is added, then again by chemical combination shown in the formula of 1kg 1
Object is added in reaction kettle, sequentially adds compound shown in the formula 2 of 1.9kg and the potassium carbonate of 1.9kg later, stirs and evenly mixs, will
The heating equipment of the reaction kettle is opened, and the material slow heating in reaction kettle is warming up to 90~95 DEG C, then in the temperature
Lower sustained response 12~16 hours monitors reaction process with HPLC in reaction process, is post-processed, will be reacted after completion of the reaction
After reaction solution be evaporated under reduced pressure, the glycol dimethyl ether recycling and reusing distilled out, to glycol dimethyl ether is evaporated off
2L water is added in residue afterwards, then filters, obtained filtrate is extracted with 1.5L ethyl acetate, and water phase extracted is used
The dilute hydrochloric acid of 1Mol/L adjusts pH value to 5.5~6.5, and solid is largely precipitated, and filters later, collects filter cake, the filter cake that will be obtained
Moisture is dried and removed in a vacuum drying oven, then obtains compound shown in formula 3, yellow solid with re-crystallizing in ethyl acetate；
S2: compound shown in preparation formula 5
Compound shown in the formula 3 of 1.5kg is taken, n,N-Dimethylformamide solvent (N, N- the dimethyl formyl of 5L is added to
Amine can also be replaced with n,N-dimethylacetamide or DMSO) in, mechanical stirring is opened, under nitrogen atmosphere, to N, N- diformazan
The potassium carbonate (potassium carbonate can also change sodium carbonate or triethylamine into) of 800g is added portionwise in base formamide solvent again, in addition carbon
Temperature of reaction system is controlled during sour potassium at 10 ± 2 DEG C, is added compound shown in the formula 4 of 1.25kg later, is then incited somebody to action
To reaction mixture be heated to 95~100 DEG C, react 8~12 hours, monitor reaction process, reaction with HPLC in reaction process
It is post-processed after finishing, the reaction solution of end of reaction is down to 35 DEG C hereinafter, then filtering, collection filtrate, by what is obtained
Filtrate is poured into 25L water, is stirred 3~5 minutes, has a large amount of solids to be precipitated, and is cooled to 5 DEG C later hereinafter, stand 2~8 hours,
Then it filters, collects filter cake, filter cake is dried in a vacuum drying oven, obtains compound shown in formula 5, yellow solid；
S3: compound shown in preparation formula 6
Dehydrated alcohol 10L is taken, is mixed with the saturated aqueous ammonium chloride of 5L, mixed liquor is formed, then into the mixed liquor
Compound shown in the formula 5 of 2.0kg is added, opens mechanical stirring, the reduced iron powder of 390g is added portionwise into reaction system, adds
Temperature of reaction system is controlled during reduced iron powder and is no more than 50 DEG C, and reduced iron powder continues stirring 1 hour after adding, then with 10
DEG C/heating rate of 30min, and the temperature of reaction system is warming up to 85~90 DEG C, back flow reaction 2~4 hours, in reaction process
Reaction process is monitored with HPLC, is post-processed after end of reaction, reacted reaction solution is cooled to 35 DEG C hereinafter, then
It pours into and is equipped in the suction funnel of diatomite layer, filter, filter cake is washed with the dehydrated alcohol of 2L, collects filtrate, filtrate concentration
It to 1L, is placed in 0 DEG C of environment later, stands 6~12 hours, obtain compound shown in formula 6, faint yellow solid；
S4: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is prepared, (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine structural formula is as shown in formula 7
Compound shown in formula 6 by 1.0kg is added in the dehydrated alcohol of 5L, is opened mechanical stirring, is placed in 0 DEG C of ring
In border, under nitrogen atmosphere, then into dehydrated alcohol be added 6mol/L aqueous hydrochloric acid solution 1L, rise to 15~30 after addition
DEG C, it reacts 8~12 hours, end of reaction；It is post-processed later, the reaction solution of end of reaction is concentrated under reduced pressure at 35 DEG C or less
To 1L, sodium hydrate aqueous solution tune pH value is then added into the raffinate after concentration to 12~14, has solid precipitation, filters,
Filter cake is collected, and the filter cake is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product, and filtrate is extracted with ethyl acetate 2~5 times, combined ethyl acetate extraction
Liquid, the acetic acid ethyl acetate extract with anhydrous sodium sulfate it is dry after ethyl acetate be evaporated off again obtain solid, the solid be gram in azoles
For Buddhist nun's crude product, obtained (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product is merged, is recrystallized with dehydrated alcohol, obtains (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine product, white
Solid.
Technical solution for a better understanding of the invention, is set forth below specific embodiment, but be not restricted to that this specification
Described embodiment, on the contrary, purpose of providing these embodiments is make to present disclosure understand it is more thorough
Comprehensively.
Embodiment 1
A kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, is realized by following steps:
S1: compound shown in preparation formula 3
10L glycol dimethyl ether is measured, is added in reaction kettle, is then added 5L water, be stirred, later in nitrogen atmosphere
Under enclosing, bis- (diphenylphosphine) ferrocene of 1,1'- of 10g palladium acetate and 50g are added into reaction kettle, then again by 1 institute of the formula of 1kg
Show that compound is added in reaction kettle, sequentially add compound shown in the formula 2 of 1.9kg and the potassium carbonate of 1.9kg later, stirring is mixed
It is even, the material slow heating in reaction kettle is warming up to 90 DEG C, then sustained response 16 hours, HPLC monitoring are anti-at such a temperature
It should finish；It is post-processed later, reaction solution after completion of the reaction is evaporated under reduced pressure, the glycol dimethyl ether distilled out returns
It receives and recycles, 2L water is added to being evaporated off in the residue after glycol dimethyl ether, then filters, obtained filtrate 1.5L acetic acid
Ethyl ester extraction, water phase extracted adjust pH value to 6 or so with the dilute hydrochloric acid of 1Mol/L, and solid is largely precipitated, and filters later, receive
Collect filter cake, obtained filter cake is dried and removed into moisture in a vacuum drying oven, then obtains 3 institute of formula with re-crystallizing in ethyl acetate
Show compound, yellow solid, 1.6kg, purity 98%, yield 90%；
The nuclear magnetic data and LC-MS testing result of compound shown in formula 3 are as follows:
HNMR(CDCl3, 400MHz) and δ=8.51 (s, 1H), 8.26 (s, 1H), 8.18-8.10 (m, 2H), 6.02 (s,
1H),3.59-3.51(m,1H),3.21-3.19(m,4H),2.15-2.10(m,2H),1.96-1.89(m,2H),1.31(s,
9H)；LC-MS(M+1):390.2.
S2: compound shown in preparation formula 5
Compound shown in the formula 3 of 1.5kg is taken, is added in the n,N-Dimethylformamide solvent of 5L, mechanical stirring is opened,
Under nitrogen atmosphere, the potassium carbonate of 800g is added portionwise again into n,N-Dimethylformamide solvent, in addition potassium carbonate process
Middle control temperature of reaction system adds compound shown in the formula 4 of 1.25kg at 10 ± 2 DEG C later, the reaction that then will be obtained
Mixed liquor is heated to 100 DEG C, reacts 12 hours, and HPLC monitors end of reaction；It is post-processed later, by the reaction of end of reaction
Liquid is down to 35 DEG C hereinafter, then filtering, and obtained filtrate is poured into 25L water, stirs 3 minutes, there is a large amount of solids by collection filtrate
It being precipitated, is cooled to 5 DEG C later hereinafter, stand 5 hours, then filters, collect filter cake, filter cake dries in a vacuum drying oven,
Obtain compound shown in formula 5, yellow solid, 1.93kg, purity 97%, yield 88%；
The nuclear magnetic data and LC-MS testing result of compound shown in formula 5 are as follows:
HNMR(CDCl3, 400MHz) and δ=8.79 (s, 1H), 8.29 (s, 1H), 8.09-8.02 (m, 2H), 7.22-7.16
(m,2H),5.20(m,1H),3.70-3.67(m,1H),3.41-3.22(m,4H),2.09-2.01(m,2H),1.91-1.89
(m, 2H), 1.81 (d, J=6.4Hz, 3H), 1.30 (s, 9H)；LC-MS(M+1):580.1,582.1.
S3: compound shown in preparation formula 6
Dehydrated alcohol 10L is taken, is mixed with the saturated aqueous ammonium chloride of 5L, mixed liquor is formed, then into the mixed liquor
Compound shown in the formula 5 of 2.0kg is added, opens mechanical stirring, the reduced iron powder of 390g is added portionwise into reaction system, adds
Temperature of reaction system is controlled during reduced iron powder and is no more than 50 DEG C, and reduced iron powder continues stirring 1 hour after adding, then with 10
DEG C/heating rate of 30min, the temperature heating of reaction system is heated in reflux state, about 85~90 DEG C of temperature, reflux is anti-
It answers 2 hours, HPLC monitors end of reaction；It is post-processed later, reacted reaction solution is cooled to 35 DEG C hereinafter, then falling
Enter to be equipped in the suction funnel of diatomite layer, laying depth of the diatomite layer in suction funnel is 7cm, filtering, filter cake use
The dehydrated alcohol of 2L washs, and collects filtrate, and filtrate is concentrated into 1L, is placed in 0 DEG C of environment later, stands 6 hours, obtains formula
Compound shown in 6, faint yellow solid, 1.8kg, purity 95%, yield 95%；
S4: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is prepared, (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine structural formula is as shown in formula 7
Compound shown in formula 6 by 1.0kg is added in the dehydrated alcohol of 5L, is opened mechanical stirring, is placed in 0 DEG C of ring
In border, under nitrogen atmosphere, then into dehydrated alcohol be added 6mol/L aqueous hydrochloric acid solution 1L, 20 DEG C are risen to after addition,
Reaction 8 hours, HPLC monitor end of reaction；It is post-processed, the reaction solution of end of reaction is depressurized at 35 DEG C or less dense later
It is reduced to 1L, sodium hydrate aqueous solution tune pH value is then added into the raffinate after concentration to 13, has solid precipitation, filters, filter
Cake is collected, and filter cake is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product, and filtrate is extracted with ethyl acetate 3 times, combined ethyl acetate extract liquor, ethyl acetate
Ethyl acetate is evaporated off again after extract liquor anhydrous sodium sulfate drying and obtains solid, which is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product, will be obtained
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product merge, recrystallized with dehydrated alcohol, obtain (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine product, white solid, 780g, purity
98%, yield 95%.
The nuclear magnetic data and LC-MS testing result of compound shown in formula 5 are as follows:
HNMR(400MHZ,DMSO-d6):7.84(s,1H),7.68(m,1H),7.50(m,1H),7.46(s,1H),7.37
(m,1H),6.83(m,1H),6.02(m,1H),5.57(s,2H),4.09(m,1H),2.98(m,2H),2.53(m,2H),1.88
(m,2H),1.82(s,3H),1.73(m,3H),1.70(m,2H)；LC-MS(M+1):450.1,452.1.
It should also be specified that the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine provided by the invention, wherein each raw material is all to use
The representation method of specific value, it will be understood by a person skilled in the art that carrying out expansion in proportion based on these specific numerical value
Or reduce, all within the scope of the present invention.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalents made by bright specification, be applied directly or indirectly in other relevant technical fields, be included in it is of the invention
In scope of patent protection.
Claims (5)
1. a kind of synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine, which is characterized in that realized by following steps:
S1: compound shown in preparation formula 3
10L glycol dimethyl ether is measured, is added in reaction kettle, is then added 5L water, be stirred, later in nitrogen atmosphere
Under, bis- (diphenylphosphine) ferrocene of 1,1'- of 10g palladium acetate and 50g are added into the reaction kettle, then again by the formula of 1kg 1
Shown compound is added in reaction kettle, sequentially adds compound shown in the formula 2 of 1.9kg and the potassium carbonate of 1.9kg later, stirs
It mixes, the material in the reaction kettle is heated to 90~95 DEG C, then sustained response 12~16 hours at such a temperature,
End of reaction；It is post-processed later, reaction solution after completion of the reaction is evaporated under reduced pressure, the glycol dimethyl ether distilled out
Recycling and reusing is added 2L water to being evaporated off in the residue after glycol dimethyl ether, then filters, obtained filtrate 1.5L second
Acetoacetic ester extraction, water phase extracted adjust pH value to 5.5~6.5 with the dilute hydrochloric acid of 1Mol/L, and solid is largely precipitated, and takes out later
Filter collects filter cake, obtained filter cake is dried and removed moisture in a vacuum drying oven, is then obtained with re-crystallizing in ethyl acetate
Compound shown in formula 3, yellow solid；
S2: compound shown in preparation formula 5
Compound shown in the formula 3 of 1.5kg is taken, is added in the n,N-Dimethylformamide solvent of 5L, mechanical stirring is opened, in nitrogen
Under atmosphere is enclosed, the potassium carbonate of 800g is added portionwise again into n,N-Dimethylformamide solvent, is controlled during adding potassium carbonate
Temperature of reaction system processed adds compound shown in the formula 4 of 1.25kg at 10 ± 2 DEG C later, then mixes obtained reaction
Liquid is heated to 95~100 DEG C, reacts 8~12 hours, end of reaction；It is post-processed later, the reaction solution of end of reaction is dropped
To 35 DEG C hereinafter, then filtering, filtrate is collected, obtained filtrate is poured into 25L water, stirred 3~5 minutes, there are a large amount of solids
It is precipitated, is cooled to 5 DEG C later hereinafter, stand 2~8 hours, then filters, collect filter cake, filter cake does in a vacuum drying oven
It is dry, obtain compound shown in formula 5, yellow solid；
S3: compound shown in preparation formula 6
Dehydrated alcohol 10L is taken, is mixed with the saturated aqueous ammonium chloride of 5L, mixed liquor is formed, is then added into the mixed liquor
Compound shown in the formula 5 of 2.0kg opens mechanical stirring, and the reduced iron powder of 390g, addition reduction are added portionwise into reaction system
Control temperature of reaction system during iron powder and be no more than 50 DEG C, reduced iron powder continues stirring 1 hour after adding, then with 10 DEG C/
The temperature of reaction system is warming up to 85~90 DEG C by the heating rate of 30min, and back flow reaction 2~4 hours, end of reaction；Later
It is post-processed, reacted reaction solution is cooled to 35 DEG C hereinafter, be subsequently poured into the suction funnel for being equipped with diatomite layer,
Filtering, filter cake are washed with the dehydrated alcohol of 2L, collect filtrate, and filtrate is concentrated into 1L, is placed in 0 DEG C of environment later, stand 6
~12 hours, obtain compound shown in formula 6, faint yellow solid；
S4: (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is prepared
Compound shown in formula 6 by 1.0kg is added in the dehydrated alcohol of 5L, is opened mechanical stirring, is placed in 0 DEG C of environment
In, under nitrogen atmosphere, then into dehydrated alcohol be added 6mol/L aqueous hydrochloric acid solution 1L, rise to 15~30 after addition
DEG C, it reacts 8~12 hours, end of reaction；It is post-processed later, the reaction solution of end of reaction is concentrated under reduced pressure at 35 DEG C or less
To 1L, sodium hydrate aqueous solution tune pH value is then added into the raffinate after concentration to 12~14, has solid precipitation, filters,
Filter cake is collected, and the filter cake is (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product, and filtrate is extracted with ethyl acetate 2~5 times, combined ethyl acetate extraction
Liquid, the acetic acid ethyl acetate extract with anhydrous sodium sulfate it is dry after ethyl acetate be evaporated off again obtain solid, the solid be gram in azoles
For Buddhist nun's crude product, obtained (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine crude product is merged, is recrystallized with dehydrated alcohol, obtains (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine product, white
Solid.
2. the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 1, which is characterized in that in step S1, by the reaction
Material in kettle is heated to 90 DEG C, then sustained response 16 hours at such a temperature.
3. the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 2, which is characterized in that in step S2, be added shown in formula 4
After compound, obtained reaction mixture is heated to 100 DEG C, is reacted 12 hours.
4. the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 3, which is characterized in that in step S3, diatomite layer exists
Laying depth in suction funnel is 5~8cm.
5. the synthetic method of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine according to claim 4, which is characterized in that in step S4, to after concentration
When sodium hydrate aqueous solution tune pH value being added in raffinate, pH value is adjusted to 13.
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| CN102532106A (en) * | 2012-02-20 | 2012-07-04 | 济南纽华医药科技有限公司 | Synthesis method of crizotinib serving as antitumor molecular targeting medicament |
| WO2014020467A2 (en) * | 2012-07-30 | 2014-02-06 | Fresenius Kabi Oncology Ltd | Process for the preparation of pyrazole substituted aminoheteroaryl compounds |
| CN103664896A (en) * | 2013-11-25 | 2014-03-26 | 济南精合医药科技有限公司 | Synthetic process method for novel antineoplastic molecular targeted drug of crizotinib |
| CN105272966A (en) * | 2014-06-25 | 2016-01-27 | 南京雷科星生物技术有限公司 | Preparation method of ALK inhibitor crizotinib and analogue or salt thereof |
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| WO2014020467A2 (en) * | 2012-07-30 | 2014-02-06 | Fresenius Kabi Oncology Ltd | Process for the preparation of pyrazole substituted aminoheteroaryl compounds |
| CN103664896A (en) * | 2013-11-25 | 2014-03-26 | 济南精合医药科技有限公司 | Synthetic process method for novel antineoplastic molecular targeted drug of crizotinib |
| CN105272966A (en) * | 2014-06-25 | 2016-01-27 | 南京雷科星生物技术有限公司 | Preparation method of ALK inhibitor crizotinib and analogue or salt thereof |
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