CN110317168A - A kind of purification process of bosutinib - Google Patents
A kind of purification process of bosutinib Download PDFInfo
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- CN110317168A CN110317168A CN201810294560.0A CN201810294560A CN110317168A CN 110317168 A CN110317168 A CN 110317168A CN 201810294560 A CN201810294560 A CN 201810294560A CN 110317168 A CN110317168 A CN 110317168A
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- bosutinib
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- crude product
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- Plural Heterocyclic Compounds (AREA)
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Abstract
The present invention provides a kind of purification process of bosutinib, comprising: 1) bosutinib crude product is dissolved in acetonitrile-water mixed solvent；(2) optionally, active carbon decoloring, filtering obtain filtrate；(3) cooling down, crystallization filters, and it is dry, it obtains bosutinib and purifies product.Purification process provided by the invention can replace column chromatographic purification methods or prepare chromatographic purification method, it directlys adopt usual method for crystallising in removal bosutinib crude product and is difficult to the impurity purified, the quantity of solvent needed is small, and operating procedure is easy, it purifies yield and product purity is higher, be conducive to industrialized production.
Description
Technical field
The application belongs to field of medicine and chemical technology, is related to a kind of purification process of bosutinib.
Background technique
Bosutinib is a kind of kinases inhibitor with Src/Abl dual restraining activities, and chemical structural formula is such as
Shown in Formulas I.The inhibitor was developed by Hui Shi (Wyeth) drugmaker under Pfizer (Pfizer), in September 4 in 2012
Day successfully obtain FDA approval listing, trade name Bosulif, for treat to previously treat drug resistance or do not tolerate chronic phase,
Accelerated period or rapid change period Philadelphia chromosome are positive chronic granulocytic leukemia (CML) adult patients and new diagnosis of (Ph+)
For chronic phase Ph+CML patient.In Europe, bosutinib is approved for treatment chronic phase, accelerated period, rapid change period Ph+CML
Adult patient, previously oneself used one or more for the treatment of with tyrosine kinase inhibitors to these patients, and these patients are not
It is applicable in Imatinib, nilotinib and Dasatinib.
In production process, bosutinib crude product is often contained a large amount of impurities, and needs to be further purified.WO2007005462 is disclosed
Bosutinib anhydride, hydrate and a variety of crystallizations of other solvates and preparation method thereof.CN101792416A is disclosed
The method of bosutinib crude product is recrystallized after a kind of column chromatography (ethanol/methylene system) in ether；
CN105384686A discloses a kind of purification process of aprotic polar solvent/aqueous systems recrystallization.
In the prior art, the purification effect of column chromatography is good, can remove most of impurity in bosutinib crude product, but its
Operate loaded down with trivial details, solvent usage amount is big, and treatment cost of waste liquor is high, is not suitable for industrial mass production；And if chromatographed without column,
The direct recrystallization purifying bosutinib crude product product obtained of the prior art is difficult to reach medicinal standard.Therefore, bosutinib
Purifying process need further to study.
Summary of the invention
The present invention provides a kind of purification process of bosutinib, characterized by comprising: 1) bosutinib crude product is molten
In acetonitrile-water mixed solvent；(2) optionally, active carbon decoloring, filtering obtain filtrate；(3) cooling down, crystallization filters, and it is dry,
It obtains bosutinib and purifies product.
In some embodiments of the present invention, the mass volume ratio of the bosutinib crude product and acetonitrile be 1g:5mL~
1g:25mL；In some typical embodiments, the mass volume ratio of the bosutinib crude product and acetonitrile be 1g:9mL~
1g:20mL；In some more typical embodiments, the mass volume ratio of the bosutinib crude product and acetonitrile is 1g:
10mL；In some more typical embodiments, the mass volume ratio of the bosutinib crude product and acetonitrile is 1g:
11.25mL；In some more typical embodiments, the mass volume ratio of the bosutinib crude product and acetonitrile is 1g:
15mL；In some more typical embodiments, the mass volume ratio of the bosutinib crude product and acetonitrile is 1g:20mL.
In some embodiments of the present invention, the volume ratio of the water and acetonitrile is 10:1~1:10；Of the invention
In some typical embodiments, the volume ratio of the water and acetonitrile is 1:1~1:3；In some more typical embodiments
In, the volume ratio of the water and acetonitrile is 1:1；In some more typical embodiments, the volume ratio of the water and acetonitrile
For 1:2；In some more typical embodiments, the volume ratio of the water and acetonitrile is 1:3.
In some embodiments of the present invention, the temperature that the bosutinib crude product is dissolved in acetonitrile-water mixed solvent can
To be 20 DEG C~100 DEG C, preferably 50 DEG C~90 DEG C, more preferably 60 DEG C~85 DEG C.
In some embodiments of the present invention, it is 5%~15% that dosage, which is added, in the single of active carbon in the step (2)
(w/w)；In some embodiments, the once used amount of active carbon is 5%~10% (w/w) in the step (2)；It is some more
For in typical embodiment, the once used amount of active carbon is 5% (w/w) in the step (2)；In some more typical realities
It applies in scheme, the once used amount of active carbon is 10% (w/w) in the step (2).The w/w refers to the quality and step of active carbon
Suddenly in (1) quality of bosutinib crude product ratio.
In some embodiments of the present invention, the number of active carbon decoloring can be 0~5 time, preferably 1 in step (2)
It is secondary, 2 times or 3 times.
In some typical embodiments of the invention, after active carbon is added every time in step (2), holding system temperature is
20 DEG C~100 DEG C, preferably 50 DEG C~100 DEG C, more preferably 60 DEG C~85 DEG C；Stir 15 minutes to 1 hours, preferably 20 to
40 minutes, more preferable 30 minutes.
In some typical embodiments of the invention, step (1), (2) and (3) carries out under nitrogen protection.
In specific embodiment of the invention, the volume ratio of the water and acetonitrile is 1:3；It is living in the step (2)
Property charcoal once used amount be 10% (w/w)；The number of active carbon decoloring is 1 time in step (2).
In some embodiments of the present invention, the purification process of aforementioned bosutinib crude product can further include step
Suddenly (4): the bosutinib purifying product that step (3) obtains being dissolved in ethanol-water mixed solvent, are stirred, cooling, crystallization filters, and does
It is dry, obtain bosutinib highly finished product.
In some embodiments of the present invention, the quality of the step (3) obtains bosutinib purifying product and ethyl alcohol
Volume ratio is 1g:5mL~1g:25mL；In some implementation cases of the invention, the bosutinib that the step (3) obtains is purified
The mass volume ratio of product and ethyl alcohol is 1g:10mL~1g:20mL；In some implementation cases of the invention, the step (3) is obtained
Bosutinib purifying product and ethyl alcohol mass volume ratio be 1g:10mL.
In some embodiments of the present invention, the volume ratio of water and ethyl alcohol be 10:1~1:10, preferably 2:1~1:2,
More preferably 1:2.
In some embodiments of the present invention, it is mixed that the bosutinib purifying product that the step (3) obtains are dissolved in alcohol-water
The temperature of bonding solvent can be 20 DEG C~100 DEG C, preferably 50 DEG C~100 DEG C, more preferably 60 DEG C~85 DEG C.
In some embodiments of the present invention, the step (4) carries out under nitrogen protection.
In some embodiments of the present invention, cooling, which can be, cools to -5 DEG C~60 DEG C, preferably 0 DEG C~30 DEG C.Drop
Temperature includes but is not limited to natural cooling cooling.
In some embodiments of the present invention, drying is preferably dried under reduced pressure, and is dried in vacuo at further preferred 45 DEG C.
In the present invention, unless specifically stated any use, in step (1), bosutinib crude product is dissolved in the mode of acetonitrile-water mixed solvent
Including but not limited to: bosutinib crude product is added to acetonitrile-water in the mixed solvent in a., reheats；B. by bosutinib crude product and
Acetonitrile first mixes, and adds water, then heats；Or c. first mixes bosutinib crude product and water, adds acetonitrile, then plus
Heat.
In the present invention, unless specifically stated any use, in step (4), the bosutinib purifying product that the step (3) obtains are dissolved in
The mode of ethanol-water mixed solvent includes but is not limited to: bosutinib purifying product are added into ethanol-water mixed solvent by a., then
Heating；B. bosutinib is purified into product and ethyl alcohol first mixes, added water, then heat；Or c. by bosutinib purifying product and
Water first mixes, and adds ethyl alcohol, then heats.
The bosutinib purifying product I type crystallization that a specific embodiment of the invention is prepared into has X- as shown in Figure 1
Ray Powder Diffraction pattern.
The bosutinib highly finished product crystallization that a specific embodiment of the invention is prepared into is that I type crystallizes.
In the present invention, unless specifically stated any use, in bosutinib crude product, bosutinib purifying product or bosutinib highly finished product
The content of bosutinib and impurity is measured by high performance liquid chromatography (HPLC), is filling with octadecylsilane chemically bonded silica
Agent (chromatographic column be Waters Sunfire C18,4.6mm × 250mm, 5 μm or efficiency it is suitable)；Mobile phase A is 10mmol/L first
Acid ammonium solution (takes ammonium formate about 0.63g, adds water 1000ml to dissolve, add triethylamine 1ml, with first acid for adjusting pH value to 3.0), flow
Phase B is acetonitrile, carries out linear gradient elution by table 1, flow velocity is 1.0ml per minute, and column temperature is 30 DEG C, Detection wavelength 256nm.
Table 1
Take bosutinib crude product appropriate, it is accurately weighed, add 60% acetonitrile solution to dissolve and quantify dilution and is made in every 1ml about
Solution containing 40 μ g, precision measure 10 μ l and inject liquid chromatograph, measure by preceding method, record chromatogram.The result shows that rich
Relaxing for the chromatographic peak retention time of Buddhist nun is 15.6min, the chromatographic peak of multiple impurity additionally occurs, when including but not limited to retaining
Between be 11.5min chromatographic peak (i.e. impurity m), (i.e. impurity n), retention time are the chromatographic peak that retention time is 12.4min
Chromatographic peak (i.e. the impurity o), chromatographic peak (i.e. the impurity k), retention time 40.3min that retention time is 28.8min of 17.2min
Chromatographic peak (i.e. impurity q) or their mixture.
In foregoing impurities, impurity o and impurity q concrete structure formula are as shown in table 2,
Table 2
Wherein, inferred according to LC-MS, the structure of impurity k is selected from
In the present invention, unless specifically stated any use, the impurity content is calculated by HPLC areas of peak normalization method.
In some embodiments of the present invention, in the bosutinib purifying product that step (3) obtains, total miscellaneous content≤
1.0%.Total miscellaneous all impurity referred in bosutinib purifying product.
In some embodiments of the present invention, in the bosutinib purifying product that step (3) obtains, the list of impurity X is miscellaneous to be contained
Amount≤0.1%.The impurity X includes but is not limited to impurity m, impurity n, impurity o, impurity k and impurity q.
In embodiments of the invention, bosutinib crude product can be prepared by the following method to obtain in step (1), tool
Body the following steps are included:
(A) in the presence of dibenzo-18 crown-6-ether and potassium carbonate, the chloro- 6- methoxyl group-7- hydroxyl-3- quinolinecarbonitriles of 4-
Alkylated reaction occurs in aprotic polar solvent for (starting material 1) and the bromo- 3- chloropropane of 1-, obtains the chloro- 6- methoxyl group-of 4-
7- (3- chloropropanol oxygen radical) -3- quinolinecarbonitriles (Formula II), the chloro- 6- methoxyl group -7- hydroxyl -3- quinolinecarbonitriles of 4- and the bromo- 3- chlorine third of 1-
The molar ratio of alkane is 1:10 to 1:1, and reaction temperature is 20 DEG C -60 DEG C, and the aprotic polar solvent is selected from 1- methyl -2-
Pyrrolidones, dimethyl acetamide and dimethylformamide；
(B) in the presence of pyridine hydrochloride, the chloro- 6- methoxyl group -7- of the 4- of Formula II (3- chloropropanol oxygen radical) -3- quinolinecarbonitriles with
Condensation reaction occurs in aprotic polar solvent for 2,4- bis- chloro- 5- aminoanisoles, and ethyl acetate, water and salt is then added
Acid obtains 4- [(2,4- bis- chloro- 5- methoxyphenyl) amino] -6- methoxyl group -7- (3- chloropropanol oxygen radical) -3- of formula III at salt
Quinolinecarbonitriles hydrochloride, Formula II compound and 2, the molar ratio of the chloro- 5- aminoanisole of 4- bis- are 1:1 to 1:4, reaction temperature
Degree is 60 DEG C -120 DEG C, and the aprotic polar solvent is selected from 1-Methyl-2-Pyrrolidone, dimethyl acetamide and dimethyl methyl
Amide；
(C) in the presence of iodide, 4- [(2,4- bis- chloro- 5- methoxyphenyl) amino] -6- methoxyl group -7- of formula III
(3- chloropropanol oxygen radical) -3- quinolinecarbonitriles hydrochloride reacts in aprotic polar solvent with N methyl piperazine, obtains the Bo Shu of Formulas I
For Buddhist nun, the iodide are selected from potassium iodide, sodium iodide, magnesium iodide and lithium iodide, and the aprotic polar solvent is selected from 1- methyl-
2-Pyrrolidone, dimethyl acetamide and dimethylformamide,
In certain embodiments, step (A), (B), the aprotic polar solvent in (C) are all made of 1- methyl-
2-Pyrrolidone.
In the present invention, unless specified, chronomere h refers to hour；Min refers to minute.
In the present invention, unless specified, MTBE refers to methyl tertiary butyl ether(MTBE)；NMP refers to N-Methyl pyrrolidone；DMSO
Refer to dimethyl sulfoxide；THF refers to tetrahydrofuran.
In the present invention, unless specified, " active carbon decoloring " is directed to that certain carbon content active is added in solution, stirring,
It filters while hot, obtains filtrate.
In the present invention, unless specifically stated any use, the mixed solution (water: acetonitrile (V:V=1:1~1:3)) of water and acetonitrile is returned
Flowing temperature is 50 DEG C~90 DEG C.
In the present invention, unless specifically stated any use, the mixed solution (water: ethyl alcohol (V:V=2:1~1:2)) of water and ethyl alcohol is returned
Flowing temperature is 50 DEG C~90 DEG C.
The purification process of bosutinib provided by the invention can replace column chromatographic purification methods or prepare chromatogram purification side
Method, the quantity of solvent needed is small, can be to avoid generating a large amount of waste liquids, and operating procedure is easy, purify yield and product purity compared with
Height is conducive to industrialized production.In addition, bosutinib crude product often contains plurality of impurities, including but not limited to impurity m, impurity n,
Impurity o, impurity k, impurity q or their mixture, wherein impurity q have latent gene toxicity, and if do not use column chromatograph or
Chromatogram purification bosutinib crude product is prepared, and directlys adopt usual method for crystallising, it is difficult to while reducing these impurity in crude product
Content, and bosutinib purification process provided by the invention the miscellaneous content of the list of foregoing impurities can be controlled 0.1% with
Under.
Detailed description of the invention
The X-ray powder diffraction spectrum (wavelength 1.54060) of the bosutinib purifying product I type crystallization of Fig. 1 embodiment 6.
Specific embodiment
Following embodiment is further non-limitingly described in detail technical solution of the present invention.They should not be considered as
It limits the scope of the present invention, and only exemplary illustration and Typical Representative of the invention.Solvent used in the present invention, examination
Agent and raw material etc. be commercially available chemistry it is pure or analysis net product.
Embodiment 1: the preparation of bosutinib purifying product
0.86g bosutinib crude product is added in 50ml there-necked flask, is stirred at room temperature and 17ml acetonitrile, white opacity is added；Nitrogen
It is heated to flowing back under gas shielded, yellow clarification；17ml purified water is added dropwise, flow back dissolved clarification；Flow back 5min, yellow clarification；Slowly stir
It mixes and is cooled to room temperature, be stirred overnight；Filtering, washing, 45~50 DEG C are dried under reduced pressure；Obtain bosutinib purifying product white solid
0.75g, yield 87.2%, purity 99.46%.
Embodiment 2: the preparation of bosutinib purifying product
5.00g bosutinib crude product is added in 100ml there-necked flask, acetonitrile-water (V:V=3:1) mixed solvent is added
White opacity is stirred at room temperature in 65ml；Stirred under nitrogen atmosphere is heated to flowing back, dissolution；Active carbon 0.25g, reflux is added
30min, heat filter；It is transferred in 100ml there-necked flask, a little muddy appearance, the complete dissolved clarification of agitating and heating reflux；Active carbon is added
0.25g；Stirred under nitrogen atmosphere is heated to reflux 30min, heat filter, the clarification of filtrate yellow；Filtrate is transferred in 100ml there-necked flask,
Stirred under nitrogen atmosphere is heated to reflux；It is naturally cooling to room temperature, is stirred overnight, is filtered, 40~50 DEG C are dried under reduced pressure, and obtain Bo Shu
Product white solid 3.62g, yield 72.4%, purity 99.39% are purified for Buddhist nun.
Embodiment 3: the preparation of bosutinib purifying product
5.00g bosutinib crude product is added in 100ml there-necked flask, acetonitrile-water (V:V=3:1) mixed solvent is added
White opacity is stirred at room temperature in 75ml；Stirred under nitrogen atmosphere is heated to flowing back, and yellow clarification, reflux is completely dissolved；It is added and lives
Property charcoal 0.50g, continuing stirred under nitrogen atmosphere is heated to reflux 30min, heat filter；Filtrate is transferred in 100ml there-necked flask, is added and lives
Property charcoal 0.50g, stirred under nitrogen atmosphere is heated to reflux 30min, heat filter；Filtrate is transferred in 100ml there-necked flask, and active carbon is added
0.50g, stirred under nitrogen atmosphere are heated to reflux 30min, heat filter, and filtrate is transferred in 100ml there-necked flask, are naturally cooling to room
Temperature is stirred overnight；Filtering, 40~50 DEG C are dried under reduced pressure, obtain bosutinib purifying product white solid 2.15g, yield 43.0%,
Purity 99.31%.
Embodiment 4: the preparation of bosutinib purifying product
5.00g bosutinib crude product is added in 250ml there-necked flask, acetonitrile-water (V:V=2:1) mixed solvent is added
White opacity is stirred at room temperature in 75ml；Stirred under nitrogen atmosphere is heated to flowing back, yellow clarification, temperature control reflux 5min；It is slowly stirred
It is cooled to room temperature, is then transferred in low temperature, stirring is cooled to 0~10 DEG C；0~10 DEG C of stirring 2h of temperature control, filtering, purified water
20ml washing, 40~50 DEG C are dried under reduced pressure, and obtain bosutinib purifying product white solid 3.76g, yield 75.2%, purity
99.26%.
Embodiment 5: the preparation of bosutinib purifying product
5.00g white solid is added in 250ml there-necked flask, it is molten that 100ml acetonitrile-water (V:V=3:1) mixing is added in stirring
White opacity is stirred at room temperature in agent；Stirred under nitrogen atmosphere is heated to flowing back, yellow clarification, temperature control reflux 5min；It is slowly stirred drop
It warms to room temperature, is then transferred in low temperature, stirring is cooled to 0~10 DEG C；0~10 DEG C of stirring 2h of temperature control, filtering, purified water 20ml
Washing, 40~50 DEG C are dried under reduced pressure, and obtain bosutinib purifying product white solid 3.48g, yield 69.6%, purity 99.39%.
Embodiment 6: the preparation of bosutinib purifying product
Mixed liquor (the V:V=of acetonitrile (164.42kg) and purified water (69.38kg) are added in 500L glass-lined reactor
3:1), it is added with stirring 18.50kg bosutinib crude product；It is heated with stirring to dissolved clarification under the conditions of nitrogen protection, active carbon is added
925g continues to be heated with stirring to reflux；Temperature control reflux 30min, nitrogen filters pressing, by reaction solution filters pressing to crystallization kettle, filtrate yellow
Clarification；It is slowly stirred and is cooled to room temperature, stirring and crystallizing 12h；Rejection filter, solid are washed and are got rid of using purified water (37.00kg × 3)
Filter, 40 DEG C of -50 DEG C of vacuum drying 12h of gained wet product obtain bosutinib purifying category white solid 11.00kg, yield
59.5%, purity 99.47%.
Embodiment 7: the preparation of bosutinib highly finished product
The bosutinib purifying product obtained in addition 10.00g embodiment 6 in 250ml there-necked flask, addition alcohol-water (V:
V=2:1 white opacity is stirred at room temperature in) mixed solvent 150ml；Stirred under nitrogen atmosphere is heated to flowing back, and flow back 15min, yellow
Clarification；Stirred under nitrogen atmosphere is naturally cooling to 20~30 DEG C, temperature control stirring 3h；Filtering purifies water washing, 40-50 DEG C of decompression
It is dry, obtain bosutinib highly finished product white solid 9.10g, yield 91.0%.
Embodiment 8: dissolvent residual measurement
The measurement of 1-Methyl-2-Pyrrolidone
Bosutinib about 0.15g is taken, it is accurately weighed, it sets in 10ml measuring bottle, adds isopropanol to dissolve and be diluted to scale, shake
It is even, as test solution；Separately take 1-Methyl-2-Pyrrolidone appropriate, it is accurately weighed, add isopropanol to dissolve and quantifies dilution system
At, containing about the mixed solution of 7.95 μ g of 1-Methyl-2-Pyrrolidone, being shaken up, as reference substance solution in every 1ml.According to residual solvent
Measuring method (four general rules of Chinese Pharmacopoeia version in 2015,0861 third method) measurement, with -95% dimethyl polysiloxane of 5% diphenyl
Capillary column for fixer and by alkali deactivation processing is chromatographic column [DM-5Amine (30m × 0.32mm × 1.0 μm) or property
It can comparable chromatographic column therewith]；Initial temperature is 50 DEG C, is maintained 5 minutes, is warming up to 200 DEG C with 20 DEG C of rate per minute, dimension
It holds 5 minutes；Nitrogen buffer gas, split sampling；Injector temperature is 180 DEG C；Detector (FID) temperature is 250 DEG C；Precision amount
Test solution and each 1 μ l of reference substance solution are taken, gas chromatograph is injected separately into, records chromatogram.By external standard method with peak area
It calculates.
The measurement of acetonitrile and ethyl alcohol
Bosutinib about 0.1g is taken, accurately weighed, in top set empty bottle, 2ml dimethyl sulfoxide is added in precision, and shaking makes molten
Solution, sealing, as test solution；Separately take acetonitrile and ethyl alcohol each appropriate, it is accurately weighed, add dmso solution and quantifies dilute
It releases and is made in every 1ml containing about the mixed solution of 70 μ g of 20.5 μ g of acetonitrile and ethyl alcohol, precision measures 2ml, in top set empty bottle, sealing,
As reference substance solution.It is measured according to residual solvent measuring method (four general rules of Chinese Pharmacopoeia version in 2015,0,861 second method), with 6%
- 94% dimethyl polysiloxane of cyanogen propyl phenyl be fixer capillary column be chromatographic column [DB-624 (30m × 0.53mm ×
3.0 μm) or performance comparable chromatographic column therewith]；Initial temperature is 40 DEG C, is maintained 8 minutes, with 20 DEG C of rate per minute heating
To 200 DEG C, maintain 5 minutes；Nitrogen buffer gas, split sampling；Injector temperature is 180 DEG C；Detector (FID) temperature is
250℃；Ml headspace bottle equilibrium temperature is 85 DEG C, and equilibration time is 30 minutes.Test solution and reference substance solution is taken to distinguish head space
Sample introduction 1ml records chromatogram.By external standard method with calculated by peak area.
The measurement result of embodiment 7 is as shown in table 3,
Table 3
| Sample | Dissolvent residual |
| Bosutinib purifies product | NMP is not detected, acetonitrile 0.0802% |
| Highly finished product | Acetonitrile is not detected, ethyl alcohol 0.04% |
Embodiment 9: influence of the dicyandiamide solution to bosutinib purifying crude effect
The access same batch bosutinib crude product of part, referring to the Examination on experimental operation of embodiment 1, using suitable different
Solvent system purifies bosutinib crude product.
Referring to the impurity content in aforementioned high performance liquid chromatography (HPLC) measuring method measurement product；Calculation method uses
Areas of peak normalization method, the results are shown in Table 4,
Table 4
Wherein, " --- " indicates not measuring the substance.
Embodiment 10: influence of the active carbon decoloring to bosutinib purifying crude effect
3.00g bosutinib crude product is added in 100ml there-necked flask, acetonitrile-water (V:V=3:1) mixed solvent is added
45ml is stirred at room temperature, white opacity；Stirred under nitrogen atmosphere is heated to flowing back, and yellow clarification, reflux is completely dissolved；It is added and lives
Property charcoal 0.30g, continue stirred under nitrogen atmosphere be heated to reflux 30min；Heat filter, filtrate are transferred in 100ml there-necked flask, slowly stir
It mixes, is naturally cooling to room temperature；Nitrogen protection is stirred overnight, and filtering purifies water washing, and 40~50 DEG C are dried under reduced pressure, and obtain Bo Shu
Product 1.64g, yield 54.7%, purity 99.39% are purified for Buddhist nun.
Referring to impurity content in aforementioned high performance liquid chromatography (HPLC) measurement product, calculation method uses peak area normalizing
Change method, the results are shown in Table 5,
Table 5
Wherein, " --- " indicates not measuring the substance.
Claims (10)
1. a kind of purification process of bosutinib, characterized by comprising: (1) bosutinib crude product is dissolved in acetonitrile-water and mixed
Solvent；(2) optionally, active carbon decoloring, filtering obtain filtrate；(3) cooling down, crystallization filters, and it is dry, it is pure to obtain bosutinib
Change product.
2. the method according to claim 1, wherein the mass volume ratio of bosutinib crude product and acetonitrile is 1g:5mL~1g:
25mL, preferably 1g:9mL~1g:20mL, more preferably 1g:10mL, 1g:11.25mL, 1g:15mL or 1g:20mL；Water and second
The volume ratio of nitrile is 10:1~1:10, preferably 1:1~1:3, more preferably 1:1,1:2 or 1:3.
3. method according to claim 1 or 2, it is 20 DEG C that wherein bosutinib crude product, which is dissolved in the temperature of acetonitrile-water mixed solvent,
~100 DEG C, preferably 50 DEG C~90 DEG C, more preferably 60 DEG C~85 DEG C.
4. any one of -3 method according to claim 1, it is w/w=5% that wherein dosage, which is added, in the single of active carbon in step (2)
~15%, preferably w/w=5%~10%, more preferably w/w=5% or w/w=10%, the w/w refer to the matter of active carbon
The ratio of amount and the quality of bosutinib crude product in step (1).
5. any one of -4 method according to claim 1, wherein the number of active carbon decoloring is 0~5 time in step (2), preferably 1
It is secondary, 2 times or 3 times.
6. any one of -5 method according to claim 1, after wherein active carbon is added every time in step (2), holding system temperature is
20 DEG C~100 DEG C, preferably 50 DEG C~100 DEG C, more preferably 60 DEG C~85 DEG C；Mixing time is 15 minutes to 1 hours, excellent
It selects 20 to 40 minutes, more preferable 30 minutes.
7. any one of -6 method according to claim 1, in the bosutinib purifying product that wherein step (3) obtains, total miscellaneous content
≤ 1.0%.
8. -7 method according to claim 1, it is characterised in that further include: (4) bosutinib that obtains step (3) purify product
It is dissolved in ethanol-water mixed solvent, is stirred, cooling, crystallization filters, and it is dry, obtain bosutinib highly finished product.
9. the mass volume ratio of method according to claim 8, bosutinib purifying product and ethyl alcohol that wherein step (3) obtains is
1g:5mL~1g:25mL, preferably 1g:10mL~1g:20mL, more preferably 1g:10mL；The volume ratio of water and ethyl alcohol is 10:1
~1:10, preferably 2:1~1:2, more preferably 1:2.
10. any one of -9 method according to claim 1, wherein each step carries out under nitrogen protection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810294560.0A CN110317168A (en) | 2018-03-30 | 2018-03-30 | A kind of purification process of bosutinib |
Applications Claiming Priority (1)
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