CN106496192A - A kind of Crizotinib or the preparation method of deuterated Crizotinib - Google Patents
A kind of Crizotinib or the preparation method of deuterated Crizotinib Download PDFInfo
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Abstract
The present invention relates to the preparation method of a kind of Crizotinib or deuterated Crizotinib, belongs to pharmaceutical compound field.The preparation method of the Crizotinib or deuterated Crizotinib of the present invention includes：1) formula III compound is prepared；2) formula IV compound is prepared；3) V compound of formula.The present invention does substrate using the type I compound with nitro and carries out palladium catalysed cross coupling reaction, there are no in nitro lone pair electrons, nitro is weaker with the complexing of palladium catalyst, so as to reducing the consumption of palladium catalyst and removing the difficulty of palladium catalyst in product, in addition the isopropanol and water mixed solvent recrystallization of low toxicity are used in the present invention, the residual of solvent in crude drug is reduced, and significantly improves the yield of purification.
Description
Technical field
The present invention relates to the preparation method of a kind of Crizotinib or deuterated Crizotinib, belongs to pharmaceutical compound technology
Field.
Background technology
Crizotinib (Crizotinib), chemical entitled 3- [(1R) -1- (2,6- bis- chloro- 3- fluorophenyls) ethyoxyl] -
5- [1- (4- piperidyls) -1H- pyrazoles -4- bases]-PA, be by Pfizer research and develop for degeneration lymph between treatment
The positive Locally Advanced of tumor kinases (ALK) or the small molecule kinase inhibitors of metastatic nonsmall-cell lung cancer (NSCLC), are mesh
Front only one treats the medicine of such disease, and in August, 2011 obtains FDA approvals and lists in the U.S., subsequently in Korea, Japan, Europe
Alliance lists, and in January, 2013 is obtained SFDA and ratifies in Discussion on Chinese Listed, trade name(Chinese trade name Sai Ruike).This
Product with ALK, C-MET HGFr (c-met, H GFR) and tyrosine kinase receptor (RON) be target spot, by suppress
ALK and c-met phosphorylations blocking growth of tumour cell and survival.
At present, synthesis Crizotinib or deuterated Crizotinib typically adopt following route：VII compound of formula and formula 1
Generation Mitsunobu reacts production 2, and in formula 2, nitro is obtained formula 3 by iron powder reducing for amino in acid condition, and formula 3 is in NBS
Effect obtains the formula 4 of bromo, and formula 4 occurs Suzuki coupling reactions with formula II and generates formula IV, after the protection purification of formula IV deaminizating
Crizotinib or deuterated Crizotinib.
In various above, R1For hydrogen or deuterium, work as R1For hydrogen when, formula V be Crizotinib, work as R1For deuterium when, formula V be deuterium
For Crizotinib.
In the method, aryl bromide (formula 4) and borate (formula II) carry out palladium catalysed cross coupling reaction and build formula IV, product formula IV
In contain amino, product and the tight complexation of palladium after reaction completely remove the difficulty of palladium catalyst during increased separation product,
So that the content of metallic catalyst palladium is higher in crude drug.
Recrystallization is the customary means in chemical purification, can substantially reduce the impurity content in product.Patent (CN
Disclose deuterated Crizotinib crystal form and preparation method thereof in 104402868A), but the organic solvent used by which be toxicity compared with
Big acetonitrile, and the large usage quantity of consumption of organic solvent and water, make Determination of Residual Organic Solvents in the deuterated Crizotinib of preparation
Larger.
Content of the invention
It is an object of the invention to provide the preparation method of a kind of Crizotinib or deuterated Crizotinib.
To achieve these goals, the technical solution used in the present invention is as follows：
The preparation method of a kind of Crizotinib or deuterated Crizotinib comprises the steps：
1) formula III compound is prepared
Formula III compound prepared and coupling reaction with formula II compound in palladium catalyst effect in type I compound there is,
2) formula IV compound is prepared
Formula III compound nitro reduction prepares formula IV compound,
3) V compound of formula
Formula IV compound deaminizating protects V compound of formula；
R in the type I compound, formula III compound, V compound of formula IV compound and formula1For hydrogen or deuterium, work as R1For hydrogen
When, V compound of formula is Crizotinib, works as R1For deuterium when, V compound of formula be deuterated Crizotinib.
The preparation method of described Crizotinib or deuterated Crizotinib compared with prior art, is made in prior art
Be that formula 4 with amino carries out palladium catalysed cross coupling reaction, and there are in amino lone pair electrons, the complexing power of amino and palladium
Relatively strong, so as to reduce the activity of catalyst, increased the consumption of catalyst, amino and palladium catalyst in product formula IV compound
Closely complexation, increased the difficulty for removing palladium catalyst in product.And bottom is done using the type I compound with nitro in the application
Thing carries out palladium catalysed cross coupling reaction, does not contain lone pair electrons in nitro, and nitro is weaker with the complexing of palladium catalyst, so as to subtract
Lack the consumption of palladium catalyst and reduce the difficulty for removing palladium catalyst in product.
In the preparation method of the Crizotinib of the invention described above or deuterated Crizotinib, step 1) in formula I chemical combination
Thing can be prepared using multiple methods, for example, carry out bromine substitution reaction preparation to 2 compound of formula.Adopt with the following method in the present invention
Prepare type I compound：Under nitrogen protection, VII compound of formula is added in the first organic solvent, is cooled to -15 DEG C -5 DEG C, plus
Enter triphenylphosphine, add VI compound of formula, add diisopropyl azodiformate or diethyl azodiformate, control temperature is little
In 0 DEG C, completion of dropping is warming up to room temperature, reacts 2-24h, isolates and purifies, obtain final product.
VII compound R of formula1For hydrogen or deuterium.
Described VII compound synthesis of formula are referring to (publication number：CN104327053A), VI compound synthesis of formula are referring to patent
(WO2012116050A2).
The first described organic solvent can be in toluene, dichloromethane, dichloroethanes, chloroform or tetrahydrofuran
A kind of.
A kind of preferred method for preparing type I compound is as follows：Under nitrogen protection, VII compound of 1.0equiv formulas is added
Enter in toluene, be cooled to -5 DEG C, add 1.1equiv triphenylphosphines, add the toluene containing VI compound of 1.1equiv formulas molten
Liquid, Deca 1.1equiv diisopropyl azodiformate, temperature are less than 0 DEG C, after be warmed to room temperature reaction 24h, purification ＆ isolation obtains final product.
Described purification ＆ isolation is conventional separation methods, can specifically adopt following scheme：Reaction terminates rear reactant liquor concentration, in -20
30min-2h is cooled down at DEG C -78 DEG C, and sucking filtration, cold toluene filter wash cake, concentrated solvent add 95% ethanol, are down to room temperature, disperse
After filter, respectively with 95% ethanol and petroleum ether filter wash cake.
In the 1.0equiv implication of " equiv " be equivalent, i.e. mol ratio, the present invention in all equiv implications with
This is identical, and the present invention is hereinafter no longer explained.
In the preparation method of the Crizotinib of the invention described above or deuterated Crizotinib, step 1) described prepare formula III
The coupling reaction that compound is adopted is Suzuki coupling reaction (Suzuki Coupling Reaction), i.e., protect in noble gases
Heat under the conditions of shield, palladium catalyst, phosphorus part, alkali and the second organic solvent, type I compound passes through palladium chtalyst with formula II compound
The coupling reaction of agent prepares formula III compound.
Described palladium catalyst can be palladium, three (dibenzalacetone) two palladium, palladium trifluoroacetate, dibenzyl benzylacetone
Any one in palladium, two (acetylacetone,2,4-pentanedione) palladium, double (cyanophenyl) Palladous chloride .s, tetra-triphenylphosphine palladium or Palladous chloride. etc..
Described phosphorus part can be double (diphenylphosphine) ferrocene of 1,1'-, triphenylphosphine, 2- dicyclohexylphosphontetrafluoroborate biphenyl,
2- dicyclohexylphosphontetrafluoroborate -3,6- dimethoxys -1,2- (di-t-butyl phosphine) biphenyl, 2- dicyclohexylphosphontetrafluoroborates -2 ', 6 '-dimethoxy, three
Any one in butyl phosphine or double (diphenylphosphine) diphenyl ether of 2,2- etc..
Described alkali is the material with alkalescence, including organic base or inorganic base, wherein organic base can be triethylamine and
DIPEA etc., inorganic base can be sodium carbonate, potassium carbonate and potassium acetate etc., and alkali used is appointing in above-mentioned alkali
Meaning is a kind of.
The noble gases can adopt nitrogen, argon etc., and specifically chosen nitrogen of the invention is inert protective gas.
The second described organic solvent be Isosorbide-5-Nitrae-dioxane, any one in N,N-dimethylacetamide (DMA).
The formula II compound synthesis are referring to publication (publication number：CN104327053A).
The concrete grammar for preparing formula III compound is as follows：Under inert gas shielding, by 1.0equiv type I compounds and 1
～3equiv formula II compounds are dissolved in organic solvent, are added 1～5equiv alkali, are sequentially added 0.005～0.1equiv palladiums
Catalyst, adds 0.01～0.2equiv phosphorus parts, reacts 12-24h, and concentration removes solvent, adds water, is extracted with dichloromethane
Take, merge organic faciess, anhydrous sodium sulfate drying, concentration add the L-Cysteine of 300-400 mesh silica gel adsorptions, use 300-400
Mesh silica gel mixed sample, after column chromatography purified concentration, obtains formula III compound with ethyl acetate and petroleum ether recrystallization.
The preparation of the L-Cysteine of described silica gel adsorption is referring to disclosed patent (US20060091067).
The method for preferably preparing formula III compound is as follows：Under nitrogen protection, by 1equiv type I compounds with
1.3equiv formula II compounds are dissolved in Isosorbide-5-Nitrae-dioxane, are added 4.0equiv potassium carbonate, are sequentially added 0.05equiv vinegar
Sour palladium, adds 0.1equiv 1, double (diphenylphosphine) ferrocene of 1'- to react 20 hours, and concentration removes solvent, adds water, dichloro
Methane is extracted, and merges organic faciess, and anhydrous sodium sulfate drying, concentration add the L-Cysteine of 300-400 mesh silica gel adsorptions, use
300-400 mesh silica gel mixed samples, after column chromatography purified concentration, obtain formula III compound with ethyl acetate and petroleum ether recrystallization.
In the preparation method of the Crizotinib of the invention described above or deuterated Crizotinib, step 2) in prepare formula IV
Compound is that formula III compound nitro reduction prepares formula IV compound under reducing agent effect.
Described reducing agent is for reducing any material of nitro, golden using addition reproducibility under acid condition in the present invention
Collectively as reducing agent, described reducing metal powder includes iron powder, zinc powder etc. to category powder.The preferred version of the present invention is in acetic acid
Effect is lower to add reproducibility iron powder.
The concrete grammar for preparing formula IV compound is：Under the conditions of 40 DEG C, V compound of 1.0equiv formulas is added to nothing
In water acetic acid, anhydrous acetic acid and dehydrated alcohol after dissolving, is added, adds 1-5equiv iron powders, be warming up to 80 DEG C, react 1-2h,
Concentration is evaporated off organic solvent, adds ethyl acetate and ethanol, adds frozen water；PH is adjusted with 4N NaOH aqueous solutions>9, divide after filtration
Liquid, collects organic faciess, and water is mutually extracted with ethyl acetate, and merges organic faciess, anhydrous sodium sulfate drying, petroleum ether/acetic acid after concentration
(volume ratio is 1 to ethyl ester:1-1:10) recrystallization obtains VI compound of formula.
The method for preferably preparing formula IV compound is addition 3equiv iron powders, the body of preferred petrol ether/ethyl acetate
Product is than being 1：5.
In the preparation method of the Crizotinib of the invention described above or deuterated Crizotinib, step 3) in formula V change
Compound is formula IV compound deaminizating protection V compound of formula under Bronsted acid effect.
Described Bronsted acid is hydrochloric acid, and trifluoroacetic acid etc. can ionize out hydrionic acid.
The concrete grammar of V compound of formula is as follows：By formula IV compound dissolution in organic solvent, 0 DEG C is cooled to,
It is slowly added dropwise concentrated hydrochloric acid, temperature control is finished, is warming up to room temperature, react 0.5-4h, add in reactant liquor between 0-15 DEG C
Water, point liquid, phase of fetching water；Organic faciess are extracted with water again, merge water phase, and 40%NaOH aqueous solutions adjust pH>13, control temperature is in 5-25
℃；V (dichloromethane):V (isopropanol)=1:1 extraction, merges organic faciess, dries, concentration, is concentrated after isopropanol dissolving again
(repeating the operation within dichloromethane reaches the limitation) obtains solid.
The Crizotinib of the invention described above or the preparation method of deuterated Crizotinib, can continue the product to obtaining
Carry out purification, specific purification process is attached most importance to crystallization treatment, the recrystallization processing method is as follows：V compound of formula is added to body
Product is than being 3:In the mixed solvent of 1 isopropyl alcohol and water, the volume of mixed solvent is 6.5mL/g with the mass ratio of V compound of formula,
75 DEG C being heated to, all being dissolved, 40 DEG C is cooled to the speed of 0.1 DEG C/min, stir 8～12h at a temperature of this, fraction solids are analysed
Go out, Deca pure water, the mass ratio of the volume of added water and Crizotinib or deuterated Crizotinib is 11mL/g, plus
Finish, 10～12h is stirred at 40 DEG C, be cooled to 5 DEG C with 0.2 DEG C/min；1～3h is stirred at 5 DEG C；Filter, pure water washing, vacuum
It is drying to obtain.
In prior art, Formula V compound recrystallization acetonitrile and water mixed solvent recrystallization, acetonitrile are that toxicity is larger organic
Solvent, and the large usage quantity of acetonitrile and water, and the application is optimized to the recrystallization process of Formula V compound, uses low toxicity instead
Isopropanol and water mixed solvent recrystallization, consumption of organic solvent or water consumption less, reduce organic solvent in product residual
Allowance, improves the yield of recrystallization, more environmentally-friendly.
Specific embodiment
For making the object, technical solutions and advantages of the present invention clearer, embodiment of the present invention will be made into one below
Step ground is described in detail.
Embodiment 1
In the present embodiment, the synthetic route of Crizotinib is as follows：
VII compound of the present embodiment Chinese style and formula II compound synthesis are referring to publication (publication number：
CN104327053A), VI compound synthesis of formula are referring to patent (WO2012116050A2).
In the present embodiment, the synthesis step of Crizotinib is as follows：
Prepare type I compound：Compound VII (50g, 238mmol) is added and contains 1800mL toluene (through molecular sieve drying)
5L there-necked flasks in, N2Protection, is cooled to -5 DEG C；Add PPh3(1.1equiv, 262mmol, 68.6g)；Add compound VI
The toluene solution 400mL (molecular sieve drying) of (1.1equiv, 262mmol, 57g)；Deca diisopropyl azodiformate
(DIAD) (1.1equiv, 262mmol, 52mL), during Deca, 0 DEG C of keeping temperature ＜, finishes, 30 DEG C, reacts 24h.Reaction
Liquid is concentrated into 1000mL, cools down 30min, sucking filtration (solid impurity is mainly triphenylphosphinc oxide), cold toluene filter wash at -20 DEG C
Cake；Concentrated solvent, adds 95% ethanol (500mL × 2), concentration to remove solvent；Add 200mL95% ethanol again, heat,
Vibration (crushes solid) as far as possible, is down to room temperature, filters, respectively with 95% ethanol and petroleum ether filter wash cake, obtain type I compound
(73.4g, 179mmol), white solid, yield 75%, the hydrogen of type I compound are composed and are：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).
Prepare formula III compound：By type I compound (40g, 98mmol) and formula II compound (1.3equiv, 48g,
127.4mmol) add in the 2L bottles containing dioxane 800mL, add K2CO3(4equiv, 54g, 390mmol) and water 80mL, N2
Ventilation 5 times；Add Pd (OAc)2Double (diphenylphosphine) ferrocene of (0.05equiv, 1.1g, 4.9mmol) and 1,1'-
(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；Add water, dichloromethane to extract, merge organic faciess, anhydrous sodium sulfate drying, concentration add half Guangs of 7.5g
The silica gel of propylhomoserin absorption, mixes sample rear pillar chromatography purification, after mobile phase concentration, is heated to 70 DEG C of dissolvings with ethyl acetate 100mL, delays
Slow Deca petroleum ether 500mL, is down to room temperature after stirring 2h, dry yellow solid (48g, 83mmol) after filtration, yield 85%,
The hydrogen of formula III compound is composed：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).
Prepare formula IV compound：At 40 DEG C, 500mL anhydrous acetic acids are added in 2L reaction bulbs, formula III compound is added
(100g, 172mmol), adds 400mL anhydrous acetic acids and dehydrated alcohol 600mL, be subsequently added Fe powder (3equiv, 28.9g,
516mmol), 80 DEG C are warming up to, 1h at a temperature of this, is reacted, concentration removes organic solvent, adds 2500mL ethyl acetate and 300mL
Ethanol, adds ice, adjusts pH with 4N NaOH aqueous solutions>9, sand core funnel is filtered, and point liquid takes organic faciess, and water is extracted with ethyl acetate
Take, merge organic faciess, anhydrous sodium sulfate drying is concentrated and removes organic solvent, crude product addition 300～500mL of ethyl acetate, 80 DEG C
Backflow, Deca petroleum ether 1500mL entirely molten to crude product, flow back 2h, is cooled to room temperature, filters, and petroleum ether filter wash cake obtains formula IV
Compound (92.8g, 168mmol), off-white powder, yield 98%, the hydrogen of formula IV compound are composed and are：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 formula：Formula IV (390g, 708mmol) is added in dichloromethane (1600mL), 0 DEG C is cooled to；
Deca concentrated hydrochloric acid (500mL), temperature 0-15 DEG C；Finish, room temperature reaction 3h.500mL water is added in reactant liquor, point liquid, water intaking
Phase；Organic faciess are extracted with water again, merge water phase.40%NaOH aqueous solutions adjust pH>13, temperature 5-25 DEG C；V (dichloromethane):V
(ethanol)=1:1 extraction (400mL × 5), merges organic faciess, and anhydrous sodium sulfate drying is concentrated, and isopropanol (1000mL × 3) is again
Secondary concentration (eliminating the ethanol and dichloromethane in product), quantitatively obtains V compound of formula.
V compound recrystallization of formula：V compound of formula (450g, 998mmol, containing a small amount of isopropanol) is added isopropanol
(2250mL), and in the mixed solution of pure water (675mL), 75 DEG C are warming up to, V compound dissolution 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, is slowly added dropwise pure water 4950mL (6.9mL/min), finishes, 40 DEG C
Lower stirring 12h；5 DEG C are slowly dropped to, 1.5h at 5 DEG C, is stirred；Filter, pure water washing (1500mL × 2)), 55 DEG C of vacuum drying
White solid 425g, yield 94% is obtained, the hydrogen spectrum of V compound of formula is：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
In the present embodiment, the synthetic route of deuterated Crizotinib is as follows：
VII compound of the present embodiment Chinese style and formula II compound synthesis are referring to publication (publication number：
CN104327053A), VI compound synthesis of formula are referring to patent (WO2012116050A2).
In the present embodiment, the synthesis step of deuterated Crizotinib is as follows：
Concrete grammar is identical with the synthesis step of Crizotinib in embodiment:
The preparation of type I compound:The preparation of type I compound and formula I in the synthesis step of Crizotinib in embodiment
The preparation method of compound is identical.Yield 75%, hydrogen are composed and are：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 formula III compound:The preparation of formula III compound and formula III in the synthesis step of Crizotinib in embodiment
The preparation method of compound is identical.Yield 85%, hydrogen are composed and are：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 formula IV compound:The preparation of formula IV compound and formula IV in the synthesis step of Crizotinib in embodiment
The preparation method of compound is identical.Yield 98%, hydrogen are composed and are：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 of V compound of formula and embodiment
The preparation method of compound is identical.Yield 94%, hydrogen are composed and are：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, it is characterised in that comprise the steps：
1) formula III compound is prepared
Type I compound prepares formula III compound with formula II compound by the coupling reaction of palladium chtalyst,
2) formula IV compound is prepared
Formula III compound nitro reduction prepares formula IV compound,
3) V compound of formula
Formula IV compound deaminizating protects V compound of formula,
R in the type I compound, formula III compound, V compound of formula IV compound and formula1For hydrogen or deuterium, work as R1For hydrogen when, formula
V compound is Crizotinib, works as R1For deuterium when, V compound of formula be deuterated Crizotinib.
2. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, it is characterised in that the step
Rapid 1) in type I compound prepared by following methods：Under nitrogen protection, VII compound of formula is added in organic solvent, be cooled to-
15 DEG C -- 5 DEG C, triphenylphosphine is added, add VI compound of formula, add diisopropyl azodiformate or azoformic acid diethyl
Ester, control temperature are less than 0 DEG C, and completion of dropping is warming up to room temperature, react 2-24h, isolate and purify, obtain final product.
3. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, it is characterised in that the step
Rapid 1) in prepare formula III compound be under the conditions of inert gas shielding, palladium catalyst, phosphorus part, alkali and organic solvent heat,
Type I compound prepares formula III compound with formula II compound by the coupling reaction of palladium catalyst.
4. the preparation method of Crizotinib or deuterated Crizotinib according to claim 3, it is characterised in that described
Palladium chtalyst is palladium, three (dibenzalacetone) two palladium, palladium trifluoroacetate, dibenzyl benzylacetone palladium, two (acetylacetone,2,4-pentanedione) palladium,
A kind of in double (cyanophenyl) Palladous chloride .s, tetra-triphenylphosphine palladium or Palladous chloride..
5. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, it is characterised in that the step
Rapid 2) in prepare formula IV compound be reducing agent effect under formula III compound nitro reduction prepare formula IV compound.
6. the preparation method of Crizotinib or deuterated Crizotinib according to claim 5, it is characterised in that described
Reducing agent is in acid condition with iron powder as reducing agent.
7. the preparation method of Crizotinib or deuterated Crizotinib according to claim 1, it is characterised in that the step
Rapid 3) in V compound of formula be formula IV compound Bronsted acid effect under deaminizating protection V compound of formula.
8. the preparation method of Crizotinib according to claim 1 or deuterated Crizotinib, it is characterised in that described
Step 3) in prepare V compound of formula also need to carry out recrystallization to obtain higher purity, the recrystallization is by V change of formula
Compound is added to volume ratio for 5:1～1:In the mixed solvent of 1 isopropyl alcohol and water, the volume of mixed solvent and V compound of formula
Mass ratio is 5～10mL/g, is heated to 70-75 DEG C, all dissolves, cools to 40 DEG C with the speed of 0.1-0.5 DEG C/min, this temperature
Degree 8～12h of lower stirring, fraction solids are separated out, Deca pure water, azoles in the volume of added water and Crizotinib or deuterated gram
The mass ratio of base of a fruit Buddhist nun is 10～15mL/g, and keeping temperature is 40 DEG C, continues stirring 2-12h, after slow with 0.1-0.5 DEG C/min speed
Slowly 5 DEG C are cooled to, 1-3h is stirred, is filtered, the pure water washing of filter cake is vacuum dried.
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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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