CN106496192B - A kind of preparation method of Crizotinib or deuterated Crizotinib - Google Patents
A kind of preparation method of Crizotinib or deuterated Crizotinib Download PDFInfo
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Abstract
The present invention relates to the preparation methods of a kind of Crizotinib or deuterated Crizotinib, belong to pharmaceutical compound field.The preparation method of Crizotinib or deuterated Crizotinib of the invention includes: 1) III compound of preparation formula；2) IV compound of preparation formula；3) V compound of preparation formula.The present invention uses the type I compound with nitro to do substrate and carries out palladium catalysed cross coupling reaction, do not have lone pair electrons in nitro, the complexing of nitro and palladium catalyst is weaker, to reduce the dosage of palladium catalyst and remove the difficulty of palladium catalyst in product, in addition with isopropanol and the water mixed solvent recrystallization of low toxicity in the present invention, reduce the residual of solvent in bulk pharmaceutical chemicals, and significantly improves the yield of purifying.
Description
Technical field
The present invention relates to the preparation methods of a kind of Crizotinib or deuterated Crizotinib, belong to pharmaceutical compound technology
Field.
Background technique
Crizotinib (Crizotinib), the entitled 3- [(1R) -1- (2,6- bis- chloro- 3- fluorophenyl) ethyoxyl]-of chemistry
5- [1- (4- piperidyl) -1H- pyrazoles -4- base] -2-aminopyridine is by Pfizer's research and development for being denaturalized lymph between treating
The Locally Advanced of tumor kinases (ALK) positive or the small molecule kinase inhibitors of metastatic non-small cell lung cancer (NSCLC), are mesh
Preceding only one treats the drug of such disease, and in August, 2011 obtains FDA approval and lists in the U.S., then in South Korea, Japan, Europe
Alliance's listing obtains SFDA approval in January, 2013 in Discussion on Chinese Listed, trade name(Chinese trade name Sai Ruike).This
Product for target spot, pass through inhibition with ALK, hepatocyte growth factor receptor (c-met, H GFR) and tyrosine kinase receptor (RON)
ALK and c-met phosphorylation blocks growth of tumour cell and survival.
Currently, synthesis Crizotinib or deuterated Crizotinib generally use following route: VII compound of formula and formula 1
Mitsunobu occurs and reacts production 2, nitro is in acid condition that amino obtains formula 3 by iron powder reducing in formula 2, and formula 3 is in NBS
Effect obtains the formula 4 of bromo, and Suzuki coupling reaction production IV occurs for formula 4 and formula II, after the protection purification of IV deamination of formula
Crizotinib or deuterated Crizotinib.
It is above it is various in, R1For hydrogen or deuterium, work as R1When for hydrogen, formula V is Crizotinib, works as R1When for deuterium, formula V is deuterium
For Crizotinib.
Aryl bromide (formula 4) and borate (formula II) carry out palladium catalysed cross coupling reaction and construct formula IV, product formula IV in this method
In contain amino, product is closely complexed with palladium after fully reacting, increase the difficulty that palladium catalyst is removed during separation product,
To keep the content of metallic catalyst palladium in bulk pharmaceutical chemicals higher.
Recrystallization is the customary means in chemical purification, can substantially reduce the impurity content in product.Patent (CN
Disclose deuterated Crizotinib crystalline form and preparation method thereof in 104402868A), but the organic solvent used in it be toxicity compared with
Big acetonitrile, and consumption of organic solvent and the dosage of water are larger, make Determination of Residual Organic Solvents in the deuterated Crizotinib of preparation
It is larger.
Summary of the invention
The object of the present invention is to provide the preparation methods of a kind of Crizotinib or deuterated Crizotinib.
To achieve the goals above, The technical solution adopted by the invention is as follows:
The preparation method of a kind of Crizotinib or deuterated Crizotinib includes the following steps:
1) III compound of preparation formula
Type I compound and II compound of formula are acted in palladium catalyst occurs III compound of coupling reaction preparation formula,
2) IV compound of preparation formula
III compound nitro of formula restores IV compound of preparation formula,
3) V compound of preparation formula
IV compound deamination of formula protects V compound of preparation formula；
R in the type I compound, V compound of III compound of formula, IV compound of formula and formula1For hydrogen or deuterium, work as R1For hydrogen
When, V compound of formula is Crizotinib, works as R1When for deuterium, V compound of formula is deuterated Crizotinib.
The preparation method of the Crizotinib or deuterated Crizotinib compared with prior art, makes in the prior art
It is there is the formula 4 of amino to carry out palladium catalysed cross coupling reaction, and there are lone pair electrons in amino, the complexing power of amino and palladium
It is relatively strong, to reduce the activity of catalyst, increase the dosage of catalyst, amino and palladium catalyst in IV compound of product formula
Close complexing, increases the difficulty for removing palladium catalyst in product.And bottom is done using the type I compound with nitro in the application
Object carries out palladium catalysed cross coupling reaction, does not contain lone pair electrons in nitro, and the complexing of nitro and palladium catalyst is weaker, to subtract
Lack the dosage of palladium catalyst and reduces the difficulty for removing palladium catalyst in product.
In the preparation method of the Crizotinib of aforementioned present invention or deuterated Crizotinib, I chemical combination of step 1) Chinese style
Object can be prepared using a variety of methods, such as carry out bromine substitution reaction preparation to 2 compound of formula.In the present invention with the following method
It prepares type I compound: under nitrogen protection, VII compound of formula being added in the first organic solvent, -15 DEG C -5 DEG C is cooled to, adds
Enter triphenylphosphine, VI compound of formula is added, diisopropyl azodiformate or diethyl azodiformate is added, control temperature is small
In 0 DEG C, be added dropwise and be warming up to room temperature, react 2-24h, isolate and purify to get.
VII compound R of formula1For hydrogen or deuterium.
VII compound synthesis of formula is referring to (publication number: CN104327053A), and VI compound synthesis of formula is referring to patent
(WO2012116050A2)。
First organic solvent can be in toluene, methylene chloride, dichloroethanes, chloroform or tetrahydrofuran
It is a kind of.
A kind of method of preferred preparation type I compound is as follows: under nitrogen protection, VII compound of 1.0equiv formula being added
Enter in toluene, be cooled to -5 DEG C, 1.1equiv triphenylphosphine is added, it is molten that the toluene containing VI compound of 1.1equiv formula is added
Liquid, be added dropwise 1.1equiv diisopropyl azodiformate, temperature less than 0 DEG C, after be warmed to room temperature reaction for 24 hours, purification & isolation to obtain the final product.
The purification & isolation is conventional separation methods, can specifically use following scheme: reaction solution is concentrated after reaction, in -20
Cooling 30min-2h, filters, cold toluene filter wash cake, concentrated solvent at DEG C -78 DEG C, and 95% ethyl alcohol is added, is down to room temperature, disperses
After filter, respectively with 95% ethyl alcohol and petroleum ether filter wash cake.
The meaning of " equiv " is equivalent in the 1.0equiv, i.e. molar ratio, in the present invention all equiv meanings with
This is identical, and the present invention is hereinafter no longer explained.
In the preparation method of the Crizotinib of aforementioned present invention or deuterated Crizotinib, the step 1) preparation formula III
The coupling reaction that compound uses is protected in inert gas for Suzuki coupling reaction (Suzuki Coupling Reaction)
It is heated under the conditions of shield, palladium catalyst, phosphorus ligand, alkali and the second organic solvent, type I compound and II compound of formula pass through palladium chtalyst
III compound of coupling reaction preparation formula of agent.
The palladium catalyst can be palladium acetate, tris(dibenzylideneacetone) dipalladium, palladium trifluoroacetate, dibenzyl benzylacetone
Any one in palladium, two (acetylacetone,2,4-pentanedione) palladiums, bis- (cyanophenyl) palladium chlorides, tetra-triphenylphosphine palladium or palladium chloride etc..
The phosphorus ligand can for bis- (diphenylphosphine) ferrocene of 1,1'-, triphenylphosphine, 2- dicyclohexylphosphontetrafluoroborate biphenyl,
2- dicyclohexylphosphontetrafluoroborate -3,6- dimethoxy -1,2- (di-t-butyl phosphine) biphenyl, 2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxys, three
Butyl phosphine or 2, any one in bis- (diphenylphosphine) diphenyl ether of 2- etc..
The alkali is the substance with alkalinity, including organic base or inorganic base, wherein organic base can for triethylamine and
N,N-diisopropylethylamine etc., inorganic base can be sodium carbonate, potassium carbonate and potassium acetate etc., and alkali used is appointing in above-mentioned alkali
It anticipates one kind.
It is inert protective gas that the inert gas, which can be specifically chosen nitrogen using nitrogen, argon gas etc., the present invention,.
Second organic solvent is Isosorbide-5-Nitrae-dioxane, any one in n,N-dimethylacetamide (DMA).
II compound synthesis of formula is referring to publication (publication number: CN104327053A).
The specific method is as follows for III compound of preparation formula: under inert gas protection, by 1.0equiv type I compound and 1
II compound of~3equiv formula is dissolved in organic solvent, and 1~5equiv alkali is added, sequentially adds 0.005~0.1equiv palladium
0.01~0.2equiv phosphorus ligand is added in catalyst, reacts 12-24h, and concentration removes solvent, and water is added, is extracted with methylene chloride
It takes, merges organic phase, anhydrous sodium sulfate is dry, and concentration is added the L-cysteine of 300-400 mesh silica gel absorption, uses 300-400
Mesh silica gel mixed sample recrystallizes to obtain III compound of formula with ethyl acetate and petroleum ether after the concentration of column chromatographic purifying.
The preparation of the L-cysteine of the silica gel absorption is referring to publication (US20060091067).
The method of preferred III compound of preparation formula is as follows: under nitrogen protection, by 1equiv type I compound with
II compound of 1.3equiv formula is dissolved in Isosorbide-5-Nitrae-dioxane, and 4.0equiv potassium carbonate is added, sequentially adds 0.05equiv vinegar
0.1equiv 1 is added in sour palladium, and bis- (diphenylphosphine) ferrocene of 1'- react 20 hours, and concentration removes solvent, and water, dichloro is added
Methane extraction merges organic phase, and anhydrous sodium sulfate is dry, and the L-cysteine of 300-400 mesh silica gel absorption is added in concentration, uses
300-400 mesh silica gel mixed sample recrystallizes to obtain III compound of formula with ethyl acetate and petroleum ether after the concentration of column chromatographic purifying.
In the preparation method of the Crizotinib of aforementioned present invention or deuterated Crizotinib, preparation formula IV is changed in step 2)
Closing object is to act on III compound nitro of following formula in reducing agent to restore IV compound of preparation formula.
The reducing agent is that can restore any substance of nitro, golden using reproducibility is added under acid condition in the present invention
Belong to powder collectively as reducing agent, the reducing metal powder includes iron powder, zinc powder etc..Preferred embodiment of the invention is in acetic acid
Effect is lower to be added reproducibility iron powder.
IV compound of preparation formula method particularly includes: under the conditions of 40 DEG C, V compound of 1.0equiv formula is added to nothing
In water acetic acid, anhydrous acetic acid and dehydrated alcohol are added after dissolution, 1-5equiv iron powder is added, is warming up to 80 DEG C, react 1-2h,
Organic solvent is evaporated off in concentration, and ethyl acetate and ethyl alcohol is added, and ice water is added；With 4N NaOH aqueous solution tune pH > 9, divide after filtering
Liquid collects organic phase, and water phase is extracted with ethyl acetate, and merges organic phase, anhydrous sodium sulfate is dry, petroleum ether/acetic acid after concentration
Ethyl ester (volume ratio 1:1-1:10) recrystallizes to obtain VI compound of formula.
The method of IV compound of preferred preparation formula is that 3equiv iron powder, the body of preferred petrol ether/ethyl acetate is added
Product is than being 1:5.
In the preparation method of the Crizotinib of aforementioned present invention or deuterated Crizotinib, preparation formula V is changed in step 3)
Closing object is that IV compound of formula deamination under Bronsted acid effect protects V compound of preparation formula.
The Bronsted acid is hydrochloric acid, and trifluoroacetic acid etc. can ionize out hydrionic acid.
The specific method is as follows for V compound of preparation formula: IV compound of formula is dissolved into organic solvent, is cooled to 0 DEG C,
Concentrated hydrochloric acid is slowly added dropwise, temperature is controlled between 0-15 DEG C, finished, and is warming up to room temperature, is reacted 0.5-4h, is added into reaction solution
Water, liquid separation, phase of fetching water；Organic phase is extracted with water again, merges water phase, and 40%NaOH aqueous solution tune pH > 13 control temperature in 5-25
℃；V (methylene chloride): V (isopropanol)=1:1 extraction merges organic phase, and dry, concentration is concentrated again after isopropanol dissolution
(repeating the operation within methylene chloride reaches the limitation) obtains solid.
The preparation method of the Crizotinib of aforementioned present invention or deuterated Crizotinib can continue to obtained product
It is purified, specific purification process is attached most importance to crystallization treatment, and the recrystallization processing method is as follows: V compound of formula is added to body
For product than the in the mixed solvent for 3:1 isopropyl alcohol and water, the volume of mixed solvent and the mass ratio of V compound of formula are 6.5mL/g,
75 DEG C are heated to, all dissolves, cools to 40 DEG C with the speed of 0.1 DEG C/min, 8~12h of stirring at a temperature of this, fraction solids analysis
Out, pure water is added dropwise, the volume and Crizotinib of water be added or the mass ratio of deuterated Crizotinib are 11mL/g, are added
Finish, 10~12h is stirred at 40 DEG C, is cooled to 5 DEG C with 0.2 DEG C/min；1~3h is stirred at 5 DEG C；Filtering, pure water washing, vacuum
It is drying to obtain.
In the prior art, Formula V compound recrystallization acetonitrile and water mixed solvent recrystallize, and acetonitrile is organic to be more toxic
Solvent, and the dosage of acetonitrile and water is larger, and the recrystallization process of Formula V compound is optimized in the application, uses low toxicity instead
Isopropanol and water mixed solvent recrystallization, the dosage of consumption of organic solvent or water is less, and it is residual to reduce organic solvent in product
Allowance improves the yield of recrystallization, more environmentally-friendly.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, embodiment of the present invention will be made into one below
Step ground detailed description.
Embodiment 1
The synthetic route of Crizotinib is as follows in the present embodiment:
VII compound of the present embodiment Chinese style and II compound synthesis of formula referring to publication (publication number:
CN104327053A), VI compound synthesis of formula is referring to patent (WO2012116050A2).
The synthesis step of Crizotinib is as follows in the present embodiment:
It prepares type I compound: compound VII (50g, 238mmol) is added containing 1800mL toluene (dry through molecular sieve)
5L there-necked flask in, N2Protection, is cooled to -5 DEG C；PPh is added3(1.1equiv, 262mmol, 68.6g)；Compound VI is added
The toluene solution 400mL (molecular sieve is dry) of (1.1equiv, 262mmol, 57g)；Diisopropyl azodiformate is added dropwise
(DIAD) (1.1equiv, 262mmol, 52mL) is kept for 0 DEG C of temperature < during being added dropwise, finished, 30 DEG C, and reaction is for 24 hours.Reaction
Liquid is concentrated into 1000mL, and cooling 30min, filters (solid impurity is mainly triphenylphosphinc oxide), cold toluene filter wash at -20 DEG C
Cake；Concentrated solvent is added 95% ethyl alcohol (500mL × 2), and concentration removes solvent；200mL95% ethyl alcohol is added again, heats,
It vibrates (crushing solid as far as possible), is down to room temperature, filter, respectively with 95% ethyl alcohol and petroleum ether filter wash cake, obtain type I compound
(73.4g, 179mmol), white solid, yield 75%, the hydrogen spectrum of type I compound are as follows:1HNMR (400MHz, CDCl3): 8.09-
8.08 (d, J=1.8Hz, 1H), 7.41-7.40 (d, J=1.7Hz, 1H), 7.36-7.32 (dd, J=4.8Hz, 8.9Hz, 1H),
7.14-7.10 (dd, J=7.8Hz, 8.9Hz, 1H) 6.11-6.06 (q, J=7.0Hz, 13.4Hz, 1H), 1.86 (d, J=
6.7Hz, 3H).
III compound of preparation formula: by II compound of type I compound (40g, 98mmol) and formula (1.3equiv, 48g,
It 127.4mmol) is added in the 2L bottle of the 800mL containing dioxane, K is added2CO3(4equiv, 54g, 390mmol) and water 80mL, N2
Ventilation 5 times；It is added Pd (OAc)2(0.05equiv, 1.1g, 4.9mmol) and 1, bis- (diphenylphosphine) ferrocene of 1'-
(0.1equiv, 5.4g, 9.8mmol), uses N again2Ventilation 5 times；90 DEG C are warming up to, 20h is reacted.Reaction terminates, and is down to room temperature,
Concentration removes solvent；Water is added, methylene chloride extraction merges organic phase, and anhydrous sodium sulfate is dry, and half Guang of 7.5g is added in concentration
The silica gel of propylhomoserin absorption mixes sample rear pillar chromatographic purifying, after mobile phase concentration, is heated to 70 DEG C of dissolutions with ethyl acetate 100mL, delays
It is slow that petroleum ether 500mL is added dropwise, it is down to room temperature after stirring 2h, dry yellow solid (48g, 83mmol) after filtering, yield 85%,
The hydrogen of III compound of formula is composed are as follows:1HNMR (400MHz, CDCl3): 8.12-8.13 (d, J=1.7Hz, 1H), 7.70-7.69 (d, J
=4.0Hz, 1H), 7.34-7.31 (dd, J=4.8Hz, 8.9Hz, 1H), 7.30-7.29 (d, J=1.7Hz, 1H), 7.10-
7.06 (dd, J=7.9Hz, 8.9Hz, 1H) 6.19-6.14 (q, J=6.6Hz, 13.3Hz, 1H), 4.32-4.26 (m, 3H),
2.91-2.88 (m, 2H), 2.17-2.17 (m, 2H), 1.98-1.92 (m, 2H), 1.89 (d, J=6.7Hz, 3H), 1.49 (s,
9H)。
IV compound of preparation formula: at 40 DEG C, 500mL anhydrous acetic acid is added in 2L reaction flask, III compound of formula is added
(100g, 172mmol) adds 400mL anhydrous acetic acid and dehydrated alcohol 600mL, then be added Fe powder (3equiv, 28.9g,
516mmol), 80 DEG C are warming up to, 1h is reacted at a temperature of this, concentration removes organic solvent, and 2500mL ethyl acetate and 300mL is added
Ice is added in ethyl alcohol, and with 4N NaOH aqueous solution tune pH > 9, sand core funnel filtering, liquid separation takes organic phase, and water phase is extracted with ethyl acetate
It taking, merges organic phase, anhydrous sodium sulfate is dry, and concentration removes organic solvent, and crude product is added 300~500mL of ethyl acetate, and 80 DEG C
Petroleum ether 1500mL is added dropwise until crude product is entirely molten in reflux, and flow back 2h, is cooled to room temperature, and filters, petroleum ether filter wash cake, obtains the change of formula IV
It closes object (92.8g, 168mmol), off-white powder, yield 98%, the hydrogen spectrum of IV compound of formula are as follows:1H NMR (400MHz,
CDCl3): δ=7.73 (d, J=1.68Hz, 1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.30 (dd, J=4.8Hz, 8.8Hz,
1H), 7.05 (dd, J=8.0Hz, 8.8Hz, 1H), 6.87 (d, J=1.8Hz, 1H), 5.02-4.82 (br, 2H), 4.35-4.15
(m, 3H), 3.02-2.82 (m, 2H), 2.18-2.13 (m, 2H), 1.92-1.86 (m, 2H), 1.85 (d, J=6.7Hz, 3H),
1.48 (s, 9H).
V compound of preparation formula: formula IV (390g, 708mmol) is added in methylene chloride (1600mL), is cooled to 0 DEG C；
It is added dropwise concentrated hydrochloric acid (500mL), 0-15 DEG C of temperature；It finishes, reacts at room temperature 3h.500mL water, liquid separation, water intaking are added into reaction solution
Phase；Organic phase is extracted with water again, merges water phase.40%NaOH aqueous solution tune pH > 13,5-25 DEG C of temperature；V (methylene chloride): V
(ethyl alcohol)=1:1 extracts (400mL × 5), merges organic phase, and anhydrous sodium sulfate is dry, and concentration, isopropanol (1000mL × 3) is again
It is secondary concentration (by product ethyl alcohol and methylene chloride eliminate), quantitatively obtain V compound of formula.
V compound of formula recrystallization: isopropanol is added in V compound of formula (450g, 998mmol contain a small amount of isopropanol)
In the mixed solution of (2250mL) and pure water (675mL), 75 DEG C are warming up to, the dissolution of V compound of formula；Slow cooling is to 40 DEG C
(0.1 DEG C/min), stirs 12h at a temperature of this, at 40 DEG C, pure water 4950mL (6.9mL/min) is slowly added dropwise, finishes, and 40 DEG C
Lower stirring 12h；5 DEG C are slowly dropped to, stirs 1.5h at 5 DEG C；Filtering, pure water washing (1500mL × 2)), 55 DEG C of vacuum drying
Obtain white solid 425g, yield 94%, the hydrogen spectrum of V compound of formula are as follows:1H-NMR (400MHz, CDCl3): 7.76 (d, J=
1.7Hz, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 7.30 (dd, J=4.8Hz, 8.9Hz, 1H), 7.05 (dd, J=8.0Hz,
8.8Hz, 1H), 6.87 (d, J=1.64Hz, 1H), 6.07 (q, J=6.7Hz, 13.3Hz, 1H), 4.76 (br, 2H), 4.25-
4.16 (m, 1H), 3.29-3.21 (m, 2H), 2.83-2.73 (m, 2H), 2.20-2.13 (m, 2H), 1.97-1.88 (m, 2H),
(1.86-1.84 d, J=6.7Hz, 3H).
Embodiment 2
The synthetic route of deuterated Crizotinib is as follows in the present embodiment:
VII compound of the present embodiment Chinese style and II compound synthesis of formula referring to publication (publication number:
CN104327053A), VI compound synthesis of formula is referring to patent (WO2012116050A2).
The synthesis step of deuterated Crizotinib is as follows in the present embodiment:
Specific method is identical as the synthesis step of Crizotinib in embodiment:
The preparation of type I compound: the synthesis step Chinese style I of Crizotinib is changed in the preparation and embodiment of type I compound
The preparation method for closing object is identical.Yield 75%, hydrogen spectrum are as follows:1HNMR (400MHz, CDCl3): 8.09-8.08 (d, J=1.8Hz,
1H), 7.41-7.40 (d, J=1.7Hz, 1H), 7.36-7.32 (dd, J=4.8Hz, 8.9Hz, 1H), 7.14-7.10 (dd, J=
7.8Hz, 8.9Hz, 1H), 1.86 (s, 3H).
The preparation of III compound of formula: the synthesis step Chinese style III of Crizotinib in the preparation and embodiment of III compound of formula
The preparation method of compound is identical.Yield 85%, hydrogen spectrum are as follows:1HNMR (400MHz, CDCl3): 8.12-8.13 (d, J=1.7Hz,
1H), 7.70-7.69 (d, J=4.0Hz, 1H), 7.34-7.31 (dd, J=4.8Hz, 8.9Hz, 1H), 7.30-7.29 (d, J=
1.7Hz, 1H), 7.10-7.06 (dd, J=7.9Hz, 8.9Hz, 1H), 4.32-4.26 (m, 3H), 2.91-2.88 (m, 2H),
2.17-2.17 (m, 2H), 1.98-1.92 (m, 2H), 1.89 (s, 3H), 1.49 (s, 9H).
The preparation of IV compound of formula: the synthesis step Chinese style IV of Crizotinib in the preparation and embodiment of IV compound of formula
The preparation method of compound is identical.Yield 98%, hydrogen spectrum are as follows:1H NMR (400MHz, CDCl3): δ=7.73 (d, J=1.68Hz,
1H), 7.56 (s, 1H), 7.48 (s, 1H), 7.30 (dd, J=4.8Hz, 8.8Hz, 1H), 7.05 (dd, J=8.0Hz, 8.8Hz,
1H), 6.87 (d, J=1.8Hz, 1H), 6.09-6.04 (q, J=6.8Hz, 13.3Hz, 1H), 5.02-4.82 (br, 2H),
4.35-4.15 (m, 3H), 3.02-2.82 (m, 2H), 2.18-2.13 (m, 2H), 1.92-1.86 (m, 2H), 1.85 (s, 3H),
1.48 (s, 9H).
The preparation of V compound of formula: the synthesis step Chinese style V of Crizotinib in the preparation and embodiment of V compound of formula
The preparation method of compound is identical.Yield 94%, hydrogen spectrum are as follows:1H-NMR (400MHz, CDCl3): 7.76 (d, J=1.7Hz, 1H),
7.57 (s, 1H), 7.50 (s, 1H), 7.30 (dd, J=4.8Hz, 8.9Hz, 1H), 7.05 (dd, J1=8.0Hz, 8.8Hz, 1H),
6.87 (d, J=1.64Hz, 1H), 4.76 (br, 2H), 4.25-4.16 (m, 1H), 3.29-3.21 (m, 2H), 2.83-2.73 (m,
2H), 2.20-2.13 (m, 2H), 1.97-1.88 (m, 2H), 1.85 (s, 3H).
Claims (8)
1. the preparation method of a kind of Crizotinib or deuterated Crizotinib, which comprises the steps of:
1) III compound of preparation formula
Type I compound and II compound of formula pass through III compound of coupling reaction preparation formula of palladium chtalyst,
2) IV compound of preparation formula
III compound nitro of formula restores IV compound of preparation formula,
3) V compound of preparation formula
IV compound deamination of formula protects V compound of preparation formula,
R in the type I compound, V compound of III compound of formula, IV compound of formula and formula1For hydrogen or deuterium, work as R1When for hydrogen, formula
V compound is Crizotinib, works as R1When for deuterium, V compound of formula is deuterated Crizotinib.
2. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, which is characterized in that the step
It is rapid 1) in type I compound prepared by following methods: under nitrogen protection, will VII compound of formula be added organic solvent in, be cooled to-
15 DEG C -- 5 DEG C, triphenylphosphine is added, VI compound of formula is added, diisopropyl azodiformate or azoformic acid diethyl is added
Ester, control temperature less than 0 DEG C, be added dropwise and be warming up to room temperature, react 2-24h, isolate and purify to get,
3. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, which is characterized in that the step
It is rapid 1) in III compound of preparation formula be heated under the conditions of inert gas shielding, palladium catalyst, phosphorus ligand, alkali and organic solvent,
Type I compound and II compound of formula pass through III compound of coupling reaction preparation formula of palladium catalyst.
4. the preparation method of Crizotinib or deuterated Crizotinib according to claim 3, which is characterized in that described
Palladium catalyst is palladium acetate, tris(dibenzylideneacetone) dipalladium, palladium trifluoroacetate, dibenzyl benzylacetone palladium, two (acetylacetone,2,4-pentanediones)
It is a kind of in palladium, bis- (cyanophenyl) palladium chlorides, tetra-triphenylphosphine palladium or palladium chloride.
5. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, which is characterized in that the step
It is rapid 2) in IV compound of preparation formula be reducing agent act on III compound nitro of following formula restore IV compound of preparation formula.
6. the preparation method of Crizotinib or deuterated Crizotinib according to claim 5, which is characterized in that described
Reducing agent is to use iron powder as reducing agent in acid condition.
7. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, which is characterized in that the step
It is rapid 3) in V compound of preparation formula be IV compound of formula Bronsted acid effect under deamination protect V compound of preparation formula.
8. the preparation method of Crizotinib according to claim 1 or deuterated Crizotinib, which is characterized in that described
V compound of formula prepared in step 3) is also recrystallized to obtain higher purity, and the recrystallization is to change formula V
It closes object and is added to the in the mixed solvent that volume ratio is 5:1~1:1 isopropyl alcohol and water, volume and V compound of formula of mixed solvent
Mass ratio is 5~10mL/g, is heated to 70-75 DEG C, all dissolves, cool to 40 DEG C with the speed of 0.1-0.5 DEG C/min, this temperature
8~12h of lower stirring is spent, fraction solids are precipitated, and pure water, volume and the azoles in Crizotinib or deuterated gram of water be added is added dropwise
The mass ratio of base of a fruit Buddhist nun is 10~15mL/g, and keeping temperature is 40 DEG C, continues to stir 2-12h, after it is slow with 0.1-0.5 DEG C/min speed
Slowly 5 DEG C are cooled to, 1-3h, filtering are stirred, the pure water washing of filter cake is dried in vacuo.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101967140A (en) * | 2010-09-14 | 2011-02-09 | 郑州泰基鸿诺药物科技有限公司 | Deuterated crizotinib as well as derivant, preparation method and application thereof |
| WO2012116050A2 (en) * | 2011-02-24 | 2012-08-30 | Eternity Bioscience Inc. | Phosphorus containing compounds as protein kinase inhibitors |
| CN104327053A (en) * | 2014-08-06 | 2015-02-04 | 北京凯悦宁医药科技有限公司 | Deuterated crizotinib and derivative thereof, preparation method and application |
| 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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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101967140A (en) * | 2010-09-14 | 2011-02-09 | 郑州泰基鸿诺药物科技有限公司 | Deuterated crizotinib as well as derivant, preparation method and application thereof |
| WO2012116050A2 (en) * | 2011-02-24 | 2012-08-30 | Eternity Bioscience Inc. | Phosphorus containing compounds as protein kinase inhibitors |
| 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 |
| CN104327053A (en) * | 2014-08-06 | 2015-02-04 | 北京凯悦宁医药科技有限公司 | Deuterated crizotinib and derivative thereof, preparation method and application |
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